ES2361949T3 - CRYSTALLINE FORMS OF 4- [2- (4-METHYLPHENYL SULFANIL) -PHENYL] PIPERIDINE WITH INHIBITION OF THE COMBINED SEROTONIN AND NOREPINEFRINE REABSORTION FOR THE TREATMENT OF NEUROPATHIC PAIN. - Google Patents

Abstract

Compound which is the HBr addition salt of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine in a crystalline form.

Description

The perception of pain is more complicated than a direct transmission of signals from an injured part of the body to specific receptors in the brain, and in which the perceived pain is proportional to the injury. Rather, damage to the peripheral tissue and nerve damage can cause alterations in the central nervous structures involved in the perception of pain affecting sensitivity to subsequent pain. This neuroplasticity can cause a central sensitization in response to noxious stimuli that last much longer, which can manifest as, e.g. eg, chronic pain, that is, the perception of pain remains even after the harmful stimulus has been interrupted, or as hyperalgesia, that is, an increase in the response to a stimulus, which is usually painful. One of the most mysterious and dramatic examples of this is the "phantom limb syndrome", that is, the persistence of pain that existed in a limb before its amputation. For a recent study of neuroplasticity and pain see Melzack et al., In Ann. N.Y. Acad. Sci., 933, 157174, 2001.

Chronic pain, such as neuropathic pain manifests itself differently than other types of pain, e.g. eg, somatic or visceral pain. Pain is often described as stabbing, burning, pins and needles, numb or hurtful. Common causes of neuropathic pain include alcoholism, amputation, back, leg and hip problems, chemotherapy, diabetes, HIV, multiple sclerosis, vertebral surgery and herpes zoster virus infection.

The main component for chronic pain can explain why chronic pain such as p. For example, neuropathic pain hardly responds to classical analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDS) and opioid analgesics. Tricyclic antidepressants (ATC), typified by amitriline, have become patterns for the treatment of neuropathic pain, and the effect is believed to be mediated by the combined inhibitory effect on the serotonin transporter and the norepinephrine transporter [Clin. Ther., 26, 951-979, 2004]. More recently, so-called double-acting antidepressants with an inhibitory effect on the reabsorption of both serotonin and norepinephrine have been used clinically for the treatment of neuropathic pain [Human Psychopharm., 19, S21-S25, 2004]. Examples of double acting antidepressants are venlafaxine and duloxetine, and this class of antidepressants is often referred to as SNRI.

Data on the use of selective serotonin reuptake inhibitors (SSRIs) for neuropathic pain are scarce, but generally suggest a limited effect [Bas. Clin. Pharmacol., 96, 399-409, 2005]. In fact, it has been assumed that SSRIs are only weak antinocirreceptives in and of themselves but this inhibition of the serotonin transporter increases the antinocirreceptive effect of the norepinephrine resorption inhibitor. This notion is supported by a study of 22 animals and five humans, a study that demonstrates that ISRNs have a superior antinocirreceptive effect compared to norepinephrine reabsorption inhibitors, which are again superior to SSRIs [Pain. Med., 4, 310-316, 2000].

Recent data on the 5’-HT3 antagonist ondansetron implies that 5’-HT3 antagonists may have an analgesic effect and thus be useful in the treatment of neuropathic pain [Anesth. Analg., 97, 1474-1478, 2003].

The use of tricyclic antidepressants is associated with known anticholinergic side effects, such as drowsiness, anxiety, insomnia and cognitive and memory difficulties. Therefore, there is a need in the art to find alternative routes of treatment of neuropathic pain.

The international patent application published as WO 2003/029232 discloses p. eg, the compound 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine as the free base and the corresponding HCl salt. It has been published that the compound is an inhibitor of serotonin transporter and serotonin 2C receptor (5-HT2C) and is said to be useful for the treatment of affective disorders, e.g. eg, depression and anxiety.

Compendium of the invention

The present inventors have surprisingly discovered that in addition to the already known pharmacological profile, 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine is a potent inhibitor of serotonin reabsorption and norepinephrine reabsorption, a receptor antagonist 3 (5 -HT3) serotonin, a serotonin 2A receptor antagonist (5- HT2A) and an adrenergic inhibitor or α1 receptor, and the compound may as such be useful in the treatment p. eg, of chronic pain. Accordingly, the invention relates to compound I, which is 4- [2- (4-methylphenyl-sulfanyl) phenyl] piperidine and the pharmaceutically acceptable salts selected therefrom in a crystalline form.

In one embodiment, the invention relates to compound I for use in therapy.

image 1

In one embodiment, the invention relates to a method of treatment comprising the administration of a therapeutically effective amount of compound I to a patient in need thereof.

In one embodiment, the invention relates to a pharmaceutical composition comprising compound I.

In one embodiment, the invention relates to the use of compound I for the preparation of a medicament.

Figures

Figure 1: X-ray diffraction model of the HBr addition salt of compound I Figure 2: X-ray diffraction model of the solvate of the HBr addition salt of compound I Figure 3: X-ray diffraction model of the palmitic acid addition salt of compound I Figure 4: X-ray diffraction model of the DL-lactic acid addition salt of compound I Figure 5: X-ray diffraction model of the adipic acid addition salt ( 1: 1) of compound I

(form α + β)

Figure 6: X-ray diffraction model of the adipic acid addition salt (2: 1) of compound I Figure 7: X-ray diffraction model of the fumaric acid addition salt (1: 1) of compound I Figure 8: X-ray diffraction model of the glutaric acid addition salt (1: 1) of compound I

Figure 9: X-ray diffraction model of the malonic acid addition salt (1: 1) of compound I, form α Figure 10: X-ray diffraction model of the malonic acid addition salt of compound I, form

β

Figure 11: X-ray diffraction model of the oxalic acid addition salt (1: 1) of compound I

Figure 12: X-ray diffraction model of the sebacoinic acid addition salt (2: 1) of the compound I Figure 13: X-ray diffraction model of the succinic acid addition salt (2: 1) of compound I Figure 14: X-ray diffraction model of the L-malic acid addition salt (1: 1) of compound I,

α form

Figure 15: X-ray diffraction model of the L-malic acid addition salt (1: 1) of compound I, β form Figure 16: X-ray diffraction model of the D-tartaric acid addition salt (1: 1) of compound I Figure 17: X-ray diffraction model of the L-aspartic acid addition salt (1: 1) of compound I

in the mixture with L-aspartic acid

Figure 18: X-ray diffraction model of the hydrated addition salt of L-aspartic acid (1: 1) of compound I in the mixture with L-aspartic acid Figure 19: X-ray diffraction model of the glutamic acid addition salt (1: 1) of compound I

in the mixture with glutamic acid monohydrate Figure 20: X-ray diffraction model of the citric acid addition salt (2: 1) of compound I Figure 21: X-ray diffraction model of the HCl acid addition salt of compound I Figure 22: X-ray diffraction model of the phosphoric acid addition salt (1: 1) of compound I Figure 23: Dopamine concentrations in the prefrontal cortex at the time of administration of

compounds of the present invention. Figure 24: Acetylcholine concentrations in the prefrontal cortex at the time of administration of compounds of the present invention.

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Figure 25a + b: Acetylcholine concentrations in the prefrontal cortex and ventral hippocampus at the time of administration of compounds of the present invention.

Detailed description of the invention

The present invention relates to compound I, which is 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine and

to its selected pharmaceutically acceptable salts in crystalline form. The structure of 4- [2- (4

methylphenylsulfanyl) -phenyl] piperidine is as follows

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The pharmacological profile of the compounds of the present invention is represented in the examples, but can be summarized as follows. The compounds are reabsorption inhibitors of serotonin and norepinephrine; inhibit serotonin 2A, 2C and 3 receptors; and inhibit the α-1 receptor

adrenergic

The pharmaceutically acceptable salts selected are acid acid addition salts

They are harmless. Such salts include salts prepared from organic acids, such as

lactic, malonic, aspartic and glutamic acids. Said salts can also be prepared from the acid.

15 hydrobromic. Additional useful salts are listed in the table in Example 1D (Table 1).

In one embodiment, the compound of the present invention, ie the compound of formula I, is the HBr addition salt.

In one embodiment, the compound of the present invention is the addition salt of DL-lactic acid, and in particular the 1: 1 salt.

In one embodiment, the compound of the present invention is the addition salt of L-aspartic acid, and in particular the 1: 1 salt.

In one embodiment, the compound of the present invention is the addition salt of glutamic acid, and in particular the 1: 1 salt.

In one embodiment, the compound of the present invention is the addition salt of glutaric acid, and in particular the 1: 1 salt.

In one embodiment, the compound of the present invention is the acid addition salt.

malonic, and in particular the 1: 1 salt that has been found to exist in two α polymorphic modifications

and β of which the β form is believed to be the most stable based on a lower solubility.

In one embodiment, the compounds of the present invention are in purified form. The term "purified form" is intended to indicate that the compounds are essentially free of other compounds or of other forms, ie polymorphs of said compound, as may be the case.

Oral dosage forms, and in particular tablets and capsules, frequently

they are preferred by the patients and by the doctor because of the ease of administration and therefore

Better observance For tablets and capsules, it is preferable that the active ingredients be

35 crystals.

The crystals of the present invention may exist in the form of solvates, that is crystals in which the solvent molecules are part of the crystalline structure. The solvate can be formed in water, in which case the solvates are called hydrates. Alternatively, solvates may be formed in other solvents, such as e.g. eg, ethanol, acetone or ethyl acetate. The exact amount of solvate with

40 frequency depends on the conditions. For example, hydrates will usually lose water as the temperature rises or as the relative humidity decreases. Compounds that do not change or change only little when conditions, such as p. eg, humidity changes are generally considered more appropriate for pharmaceutical formulations. It is noteworthy that the HBr addition salt does not form hydrates when it precipitates in water while such compounds

45 as the addition salts of succinate acid, malate and tartrate itself.

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Some compounds are hygroscopic, that is, they absorb water when they are exposed to moisture. Hygroscopy is generally considered an undesirable property for compounds that must be presented in a pharmaceutical formulation, in particular in an anhydrous formation such as tablets or capsules. In one embodiment, the invention provides crystals with low hygroscopy.

For oral pharmaceutical forms, which use crystalline active ingredients is also useful if such crystals are well defined. In the present context, the expression "well defined" in particular means that stoichiometry is well defined, that is, the ratio between the ions that form the salt is the ratio between small whole numbers, such as 1: 1, 1: 2 , 2: 1, 1: 1: 1, etc. In one embodiment, the compounds of the present invention are well defined crystals.

The solubility of an active ingredient is also of importance for the choice of the pharmaceutical form since it can have a direct impact on bioavailability. For oral pharmaceutical forms, a higher solubility of the active ingredient is generally believed to be beneficial since it increases bioavailability. Some patients, p. For example, older patients may have difficulty swallowing the tablets and oral drop solutions may be a suitable alternative that avoids the need to swallow the tablets. To limit the volume of a solution in buccal drops, it is necessary to have a high concentration of the active ingredient in the solution, which again requires a high solubility of the compound. As shown in Table 3, the addition salts of DL-lactic acid, L-aspartic acid, glutamic acid, glutaric acid and malonic acid have an exceptionally high solubility.

The crystalline forms impact the filtration and treatment properties of a compound. Needle-shaped crystals tend to be more difficult to handle in a production medium since filtration becomes more difficult and takes more time. The exact crystallized form of a given salt may depend p. eg, of the conditions under which the salt precipitated. The rate of addition of the HBr acid of the present invention grows in the form of needles, the crystals are solvated when they precipitate in ethanol, acetic acid and propanol, but the crystals in a non-hydrated form, which are not needle-shaped, when the HBr addition salt precipitates in water, provide superior filtration properties.

Table 3 further describes the resulting pH, ie the pH in the saturated salt solution. This property is of importance because moisture can never be completely avoided during storage and the accumulation of moisture will result in a decrease in pH in or on a tablet comprising a salt at the resulting low pH, which may decrease the shelf life. In addition, a salt with a resulting low pH can lead to corrosion of the process equipment if the tablets are prepared by wet granulation. The data in Table 3 suggest that the addition salts of HBr, HCl and adipic acid may be higher in this regard.

In one embodiment, the compound of the present invention is the addition salt of HBr in a crystalline form, in particular in a purified form. In a further embodiment, said HBr salt has peaks in an X-ray powder diffractogram (DPRX) at about 6.08 °, 14.81 °, 19.26 ° and 25.38 ° 2θ, and in particular said HBr salt has a DPRX as depicted in Figure 1.

In one embodiment, the compound of the present invention is the addition salt of DL-lactic acid (1: 1) in a crystalline form, in particular in a purified form. In a further embodiment, said salt of DL-lactic acid has peaks in a DPRX at about 5.30 °, 8.81 °, 9.44 ° and 17.24 ° 2θ, and in particular said addition salt of DL-lactic acid has a DPRX as depicted in Figure 4.

In one embodiment, the compound of the present invention is the addition salt of Laspartic acid (1: 1) in a crystalline form, in particular in a purified form. In a further embodiment, said L-aspartic acid addition salt is not solvated and has peaks in a DPRX at approximately 11.05 °, 20.16 °, 20.60 ° and 25.00 ° 2θ, and in particular said L-acid salt Aspartic, when mixed with L-aspartic acid, it presents a DPRX as shown in Figure 17.

In one embodiment, said L-aspartic acid addition salt is a hydrate, in particular in a purified form. In a further embodiment, said hydrate of the L-aspartic acid addition salt has peaks in a DPRX at approximately 7.80 °, 13.80 °, 14.10 ° and 19.63 ° 2θ, and in particular said addition salt hydrate of L-aspartic acid, when mixed with L-aspartic acid presents a DPRX as shown in Figure 18.

In one embodiment, the compound of the present invention is the addition salt of glutamic acid (1: 1) in a crystalline form, in particular in a purified form. In a further embodiment, said glutamic acid addition salt has peaks in a DPRX at approximately 7.71 °, 14.01 °, 19.26 ° and 22.57 ° 2θ, and in particular said glutamic acid salt, when mixed with the acid Glutamic monohydrate presents a DPRX as depicted in Figure 19.

In one embodiment, the compound of the present invention is the addition salt of malonic acid.

(1: 1) in a crystalline form, in particular in a purified form. In a further embodiment, said malonic acid addition salt is the α form and has peaks in a DPRX at approximately 10.77 °, 16.70 °, 19.93 ° and 24.01 ° 2θ, or said malonic acid addition salt is the β form and has peaks in a DPRX at about 6.08 °, 10.11, 18.25 °, 20.26 ° 2 and in particular said salt of the malonic acid has a DPRX as shown in Figure 9 or 10.

image5

In one embodiment, the compound of the present invention is the addition salt of glutaric acid.

(1: 1) in a crystalline form, in particular in a purified form. In a further embodiment, said glutaric acid addition salt has peaks in a DPRX at approximately 9.39 °, 11.70 °, 14.05 ° and 14.58 ° 2θ, and in particular said glutaric acid salt has a DPRX as depicted in the figure

8.

As mentioned above, the compounds of the present invention are particularly very suitable for the treatment of chronic pain. Chronic pain includes indications such as phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (NPH), carpal tunnel syndrome (STC), HIV neuropathy, complex regional pain syndrome (CPRS ), trigeminal trigeminal neuralgia / painful trigeminal / tic neuralgia, surgical intervention (e.g., postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina pectoris, pain associated with menstruation, cancer-associated pain, dental pain, migraine, migraine, tension-type migraine, trigemic neuralgia, temporomandibular joint syndrome, muscle injury with myofascial pain, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema associated with trauma associated with burns, sprains or bone fracture pain due to osteoartri Tis, osteoporosis, bone metastasis or for unknown reasons, gout, fibrositis, myofascial pain, external thoracic syndromes, upper back pain or lower back pain (in which the back pain comes from general spine disease , regional or primary (radiculopathy), pelvic pain, heart chest pain, non-cardiac chest pain, pain associated with spinal cord injury (SCI), central pain after stroke, cancer neuropathy, AIDS pain, pain Depranocytic or geriatric pain.

In particular, the compounds of the present invention are useful for the treatment of mood disorders, such as depression associated with the chronic pain indications listed above.

Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensation and an emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP Classification of chronic paine, 2nd edition , IASP Press (2002), 210). Even when pain is always subjective, its causes or syndromes can be classified. "Neuropathic pain" as a subtype is defined by the IASP as "pain initiated or produced by a lesion or primary dysfunction in the nervous system."

Different subtypes of neuropathic pain are recognized by the IASP, and are examples:

 Allodynia that is defined as “a pain due to a stimulus that normally does not cause pain”

 Causalgia that is defined as a syndrome of sustained burn pain, allodynia and hyperpathy after a traumatic nerve injury, often combined with vasomotor and sudomotor dysfunction and subsequent trophic changes. ”

 Hyperesthesia, which is defined as "increased sensitivity to stimulation excluding sensations."

 Neuralgia, which is defined as “pain in the distribution of a nerve or nerves”.

 Neuritis, which is defined as "inflammation of a nerve or nerves."

 Neuropathy, which is defined as "a functional disorder or pathological change in a nerve: in a nerve mononeuropathy, in several multiple nerve mononeuropathy, if diffuse and bilateral, polyneuropathy." Neuropathy may be associated with, for example, diabetes in which case it is called diabetic neuropathy.

 Hyperalgesia, which is defined as "an increased response to a stimulus that is normally painful."

 Hyperpathy, which is defined as “a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially to a repetitive stimulus as well as an increased threshold”.

The stimuli that cause neuropathic pain can be mechanical or thermal.

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The unique pharmacological profile of the compounds of the present invention makes them suitable for the treatment of other diseases, which are not directly related to chronic pain. The 5-HT2C receptors are located p. For example, in dopaminergic neurons where activation exerts a tonic inhibitory influence on dopamine release, and 5-HT2C antagonists will effect an increase in dopamine concentration. The data presented in Example 23 demonstrate that the compounds of the present invention certainly give rise to a dose-dependent increase in extracellular concentrations of dopamine in the brain. In this context it can be assumed that 5-HT2C antagonists are very suitable in particular for the treatment of depression that is refractory to treatment with selective serotonin reuptake inhibitors [PsychoPharmacol. Bull., 39, 147-166, 2006]. This hypothesis is supported by several clinical studies that present a combination of mirtazipine and SSRI that is superior to that of SSRIs only for the treatment of depressed patients with an inadequate clinical response (treatment-resistant depression, DRT or refractory depression) [Psychother. Psychosom. 75, 139-153,2006]. Mirtazapine is also a 5HT2 and 5-HT3 antagonist, indicating that the compounds that exert serotonin reuptake inhibition in combination with the 5-HT2 and 5-HT3 antagonism, such as the compounds of the present invention They are useful for the treatment of DRT, that is, they will increase the remission rate for patients suffering from treatment-resistant depression.

The data presented in Examples 2F and 2G demonstrate that the compounds of the present invention result in an increase in the extracellular concentration of acetylcholine in the prefrontal cortex and in the ventral hippocampus. There is no old clinical evidence that increasing acetylcholine concentrations in the brain is a way to treat Alzheimer's disease and cognitive impairment in general, that is, the use of acetylcholine esterase inhibitors in the treatment of Alzheimer's disease. In this context, the compounds of the present invention are believed to be useful in the treatment of Alzheimer's disease and cognitive insufficiency, and also in mood disorders, such as depression associated with Alzheimer's disease and insufficiency. cognitive

A segment of depressive patients will respond to treatment with eg SSRIs in the sense that they will improve in clinically relevant depression scales, such as MADRD and HAMD, but where other symptoms such as sleep disorders and cognitive impairment remain . In the present context, patients are said to respond partially to treatment. Due to the effects set forth above on acetylcholine concentrations, the compounds of the present invention can be expected to be useful in the treatment of cognitive insufficiency in addition to depression. Clinical studies have shown that the compound prazosin, which is an α-1 adrenergic receptor antagonist reduces sleep disorders [Biol. Psychiatry., 61, 928-934, 2007]. In addition, the antagonism of 5-HT2A and 5-HT2C of the compounds of the present invention is also believed to have a sedative, sleep-enhancing effect [Neuropharmacol., 33, 467-471, 1994] for this reason the compounds of the The present invention are useful for the treatment of patients who respond partially or in other words patients with the compounds of the present invention will reduce the fraction of patients who respond partially.

Inattentive hyperactivity disorder (THFA) is one of the most common neurobehavioral disorders. THFA is characterized by the presence of a triad of social and communicative alterations with restricted, repetitive or stereotyped behaviors. THFA normally begins norepinephrine in childhood or adolescence, but symptoms may continue into adulthood. Atomoxetine is currently the only non-stimulant substance approved by the FDA for the treatment of THFA [Drugs, 64, 205-222, 2004]. Atomoxetine is a norepinephrine reabsorption inhibitor, and this suggests which compounds of the present invention can be used in the treatment of THFA. In addition, the compounds of the present invention may have a sedative effect due to the α-1 adrenergic receptor and 5-HT2 antagonism set forth above, which is beneficial in the treatment of THFA.

Melancholy is a specific subtype of depression often related to severe depression; This type of depression is also called melancholy depression. Melancholy is associated with anxiety, fear of the future, insomnia and loss of appetite. Compounds that inhibit the reabsorption of both serotonin and norepinephrine, such as eg, venlafaxine, have been shown to be specific effective in the treatment of patients with severe depression and melancholy [Depres. Anxiety., 12, 50-54, 2000]. As stated above, the compounds that exert 5-HT2C antagonism increase the concentration of dopamine, hence it is expected that these compounds will be effective in the treatment of melancholy [Psychpharm., 39, 147-166, 2006]. In addition, the α-1 adrenergic receptor and 5-HT2 antagonism of the compounds of the present invention can be expected to help normalize sleep, hence such compounds are useful in the treatment of melancholy.

The FDA has recently approved sertraline and paroxetine, two SSRIs, for the treatment of posttraumatic stress disorder (PTSD). In addition, compounds with 5HT2A antagonistic activity are useful since they can be expected to contain agitation, insomnia and explosive character in patients with PTSD [Curr. Opinion Invest., Drug, 4, 37-41, 2003]. Accordingly, the compounds of the present invention can be expected to be useful in the treatment of PTSD.

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Flushes is a symptom associated with the menopausal transition. Some women may have it to a degree that interferes with sleep or activities in general, and in which treatment is necessary. Estrogen replacement hormone therapy has been proven practical for decades, however, recently concern has been expressed in side effects, such as breast cancer and cardiac episodes. Clinical tests with SSRI and SNRI have shown that these compounds have an effect on flushes, although less than for estrogens [J. Am. Med. Ass., 295, 2057-2071, 2006]. Treatment of flushes with compounds that inhibit the reabsorption of serotonin and / or norepinephrine, e.g. For example, the compounds of the present invention could, however, be an alternative treatment for women who cannot or will not accept estrogens.

Sleep apnea or obstructive sleep apnea-hyponea syndrome or disorderly obstructive sleep breathing is a disorder for which effective pharmacotherapy remains to be identified. Several animal studies, however, suggest that 5-HT3 antagonists, p. eg, the compounds of the present invention can be effective in a therapeutic intervention [Sleep, 21, 131-136, 1998; Sleep, 8, 871, 878, 2001].

The 5-HT3 ondansetron antagonist has recently proved effective in the treatment of bulimia, such as alcohol, nicotine or carbohydrate bulimia; and alcoholism and drug dependence.

Other suggested uses of 5-HT3 antagonists include vomiting, in particular vomiting caused by chemotherapy, eating disorders, such as bulimia and irritable bowel syndrome (IBS) [Exp. Opin. Ther. Targets., 11, 527-540, 2007].

The compounds of the present invention that are endowed with a single pharmacological profile can also be expected to be useful in the treatment of affective disorders, depression, major depression disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis or disease. of Parkinson's, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobias, social phobia, agoraphobia and stress urinary incontinence.

In one embodiment, the invention relates to a method of treating chronic pain, depression in patients who respond in part, treatment-resistant depression, Alzheimer's disease, cognitive insufficiency, THFA, melancholy, PTSD, flushes, sleep apnea, alcoholism, nicotine dependence or carbohydrate bulimia, drug dependence, alcoholism or drug dependence, vomiting, eating disorders, IBS, affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, Parkinson's psychosis or disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia or stress urinary incontinence, the method comprising administration to a patient in need thereof a therapeutically effective amount of compound I. E In one embodiment, said patient who is being treated for any of the diseases listed above has been initially diagnosed with said disease.

In one embodiment, the invention relates to a method for the treatment of chronic pain, the method comprising administering to a patient in need thereof a therapeutically effective amount of compound I. In one embodiment, said chronic pain is selected from the pain. of the phantom limb, diabetic neuropathy, protein-herpetic neuralgia (NPH), carpal tunnel syndrome (STC), HIV neuropathy, complex regional pain syndrome (CPRS), trigeminal trigeminal neuralgia / trigeminal / tic neuralgia, surgical intervention ( e.g., postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina pectoris, pain associated with menstruation, pain associated with cancer, dental pain, migraine, migraine, migraine headache tension type, trigemic neuralgia, temporomandibular joint syndrome, muscle injury with myofascial pain, fib syndrome romyalgia, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or bone fracture pain due to osteoarthritis, osteoporosis, bone metastasis

or for unknown reasons, gout, fibrositis, myofascial pain, external thoracic syndromes, upper back pain or lower back pain (in which the back pain comes from general, regional or primary spine disease (radiculopathy ), pelvic pain, heart pain in the chest, non-cardiac pain in the chest, pain associated with spinal cord injury (SCI), pain after the central stroke, cancer neuropathy, AIDS pain, sickle cell pain or geriatric pain .

In one embodiment, said chronic pain is neuropathic pain.

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In one embodiment, said neuropathic pain is selected from hyperpathy, hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, hyperesthesia, causalgia and allodynia.

In one embodiment, the compound of the invention is administered in an amount of about 0.001 to about 100 mg / kg body weight per day.

A typical oral dose is in the range between about 0.001 and about 100 mg / kg of body weight per day, preferably from about 0.01 to about 50 mg / kg of body weight per day, administered in one or more doses such as 1 to 3 doses The exact dose will depend on the frequency and mode of administration. The sex, age, weight and general condition of the treated patient, the nature and severity of the treated disease and any corresponding disease to be treated and other obvious factors for those skilled in the art.

A typical oral dose for adults is in the range of 1 to 100 mg / day of a compound of the present invention, such as 1 to 30 mg / day or 5 to 25 mg / day. This can usually be achieved by administering 0.1 to 50 mg such as 1 to 25 mg, such as 1, 5, 10, 15, 20 or 25 mg of the compound of the present invention once or twice daily.

A "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially stop the clinical manifestations of the given disease and its complications in a therapeutic intervention comprising the administration of said compound. An adequate amount to accomplish this is defined as a "therapeutically effective amount." The term also includes sufficient amounts to cure, alleviate and partially stop the clinical manifestations of a given disease and its complications in a treatment comprising the administration of said compound. The effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general condition of the patient. It should be understood that determining an appropriate dose can be achieved using routine experimentation by constructing a matrix of values and different test points, which are all within the ordinary skills of a trained physician.

The term "treatment" as used herein means the management and care of a patient in order to combat a condition, such as a disease or disorder. The term is intended to include the full spectrum of treatments for a given disease that the patient is suffering from, such as the administration of an active compound to relieve symptoms or complications, to retard the evolution of the disease, disorder or condition, to relieve or mitigate the symptoms and complications and / or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, in which prevention should be understood as the management and care of a patient in order to combat the disease, condition or disorder and includes the administration of active compounds to prevent the onset of symptoms or complications. However, prophylactic (preventive) and therapeutic (curative) treatment are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human being.

In one embodiment, the invention relates to the use of the present invention in the preparation of a medicament for the treatment of chronic pain, depression in patients who respond in part, treatment-resistant depression, Alzheimer's disease, cognitive insufficiency, THFA , melancholy, PTSD, flushes, sleep apnea, alcoholism, nicotine dependence or carbohydrate bulimia, drug dependence, alcoholism or drug dependence, vomiting, eating disorders, IBS, affective disorders, depression, major depressive disorder, postnatal depression , depression associated with bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia or urinary incontinence because of stress

In one embodiment, the invention relates to the use of the present invention in the preparation of a medicament for the treatment of chronic pain, such as neuropathic pain.

In one embodiment, the invention relates to compounds of the present invention for use as medicaments for the treatment of chronic pain, depression in patients who respond in part, treatment-resistant depression, Alzheimer's disease, cognitive insufficiency, THFA, melancholy, PTSD, flushes, sleep apnea, alcoholism, nicotine dependence or carbohydrate bulimia, drug dependence, alcoholism or drug dependence, vomiting, eating disorders, IBS, affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia or urinary incontinence stress.

In one embodiment, the invention relates to compounds of the present for use as a medicament for the treatment of chronic pain, such as neuropathic pain.

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The compounds of the present invention can be administered alone in the form of a pure compound or in combination with pharmaceutically acceptable carriers or excipients, in a single or multiple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents as well as any other adjuvants and excipients known according to conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be formulated specifically for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular) , intrathecal, intravenous and intradermal) with the oral route being preferred. It will be appreciated that the preferred route depends on the general disease and the age of the patient to be treated, the nature of the disease to be treated and the active ingredient selected. Pharmaceutical compositions for oral administration include solid pharmaceutical forms, such as capsules, tablets, grajeas, pills, pills, powders and granules, where appropriate can be prepared with coatings.

Liquid pharmaceutical formulas for oral administration include solutions, emulsions suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, solutions or emulsions as well as sterile powders to be redissolved in injectable solutions or dispersions before use.

Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalers, skin patches, implants, etc.

Conveniently, the compounds of the invention are administered in a unit dosage form comprising said compounds in an amount of about 0.1 to 50 mg, such as 1 mg, 5 mg, 10 mg, 15 mg, 20 or 25 mg of a compound of the present invention.

By parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, the doses are generally in the order of approximately half of the dose used for oral administration.

For parenteral administration, the solutions of the compound of the invention in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil can be employed. Such aqueous solutions should be adequately buffered if necessary and the first liquid diluent would be made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. The sterile aqueous media employed are all readily available by conventional techniques known to those skilled in the art.

Suitable pharmaceutical carriers include diluents or fillers, inert solids, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar-agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid vehicles are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by combining the compound of the invention and the acceptable pharmaceutical vehicles are then easily administered in various pharmaceutical forms suitable for the administration routes disclosed.

Formulations of the present invention suitable for oral administration may be presented as described units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. In addition, orally available formulations may be in the form of powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or a liquid oil-in-water or water-in-oil liquid emulsion.

If a solid vehicle is used for oral administration, the preparation may be a tablet, e.g. eg, placed in a hard gelatin capsule powder or in the form of granules or in the form of a grajea or tablet. The amount of solid vehicle may vary but will usually be from about 25 mg to about 1 g.

If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, hard gelatin capsule or sterile injectable liquid such as a suspension or aqueous liquid solution

or not watery.

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The tablets may be prepared by mixing the active ingredient with ordinary adjuvants or diluents followed by compression of the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, rubbers and the like. Any other adjuvant or additive used for such purposes such as dyes, flavorings, preservatives, etc. They can be used as long as they are compatible with the active ingredients.

Capsules comprising a compound of the present invention can be prepared by mixing a powder comprising said compound with microcrystalline cellulose and magnesium stearate and placing said powder in a hard gelatin capsule. Optionally said capsule can be colored by means of a suitable pigment. Generally, the capsules will comprise 0.25-20% of a compound of the present invention, such as 0.5 to 1.0%, 3.0 to 4.0%, 14.0 to 16.0% of a compound of the present invention. These powers can be used to conveniently administer 1, 5, 10, 15, 20 and 25 mg of a compound of the present invention in a unit dosage form.

Solutions for injections can be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterilized water, adjusting the solution to the desired volume, sterilizing the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art can be added, such as tonicity agents, preservatives, antioxidants, etc.

Compound I can be prepared as outlined in WO 2003/029232. The salts of compound I can by addition of an appropriate acid followed by precipitation. Precipitation can cause p. eg, cooling, solvent removal, addition of another solvent or a mixture thereof.

All references including all publications, patent applications and patents, cited herein are incorporated by reference in their entirety and to the same extent as if each reference was indicated individually and specifically to be incorporated by reference and published in its entirety herein (to the fullest extent permitted by law), regardless of any incorporation provided separately from particular documents prepared anywhere in this report.

The use of the terms "a" and "a" and "the" and "the" and their similar referents in the context of the description of the invention should be considered to cover both the singular and the plural, unless indicated in otherwise in this report or that is clearly contradicted by the context. For example, the phrase "the compound" which is to be understood to refer to several "compounds" of the invention or to a specific aspect described unless otherwise indicated.

Unless stated otherwise, all the exact values provided herein are representative of the corresponding approximate values (e.g., all exact illustrative values provided with respect to a specific factor or measurement may also be considered to provide a corresponding approximate measurement, modified by “approximately”, where applicable).

The description herein of any aspect or aspect of the invention using terms such as "comprising", "having", "including" or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of", "consists essentially of" or "substantially comprises" that the particular element or elements, unless otherwise indicated or clearly contradicted by the context (e.g. eg, a composition described herein comprising a particular element should be understood as also describing a composition consisting of this element, unless otherwise indicated or clearly contradicted by the context).

Examples

Analytical methods

X-ray powder diffractograms (DPRX) were measured on a PANalytical X’Pert PRO X-ray diffractometer using CuKα1 radiation. Samples were measured in reflection mode in the range 2θ 50-40 ° using an accelerator detector of X.

The elementary composition (CHN) was measured on an Elementar Vario EL instrument of Elementar. Approximately 4 mg of the sample was used for each measurement and the results are given as average values of two measurements.

Example 1a HBr salt of compound I

To 442 grams of 4- (2-p-tolylsulfanyl-phenyl) -piperidine-1-carboxylic acid ethyl ester stirred slightly (approx. At 45 ° C) as oil 545 ml of 33% by weight of HBr in AcOH was added (5.7 M, 2.5 eqv.). This mixture provides an exotherm of 10 ° C. After the final addition the reaction mixture is heated to 80 ° C and left for 18 hours. A sample is removed and analyzed by HPLC and if it is not completed further, 33% HBr by weight in AcOH should be added. Otherwise the mixture is cooled to 25 ° C causing the 4- (2-p-tolylsulfanyl-phenyl) -piperidine hydrobromide product to precipitate. After one hour at 25 ° C the thick suspension is added 800 ml of diethyl ether. Stirring is continued for another hour before isolating the product by filtration, washed with 400 ml of diethyl ether and dried under vacuum at 40 ° C overnight. The hydrobromide of compound I was isolated as a white solid.

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Example 1b HBr salt of compound I

2- (4-Tolylsulfanyl) -phenyl bromide

In a reactor covered with stirred nitrogen, the N-methyl.pyrrolidone NMP (4.5 L) was sprayed with nitrogen for 20 minutes. 4-Methylbenzenethiol (900 g, 7.25 mol) was added and then 1,2-dibromobenzene (1709 g, 7.25 mol). Finally, potassium tert-butoxide (813 g, 7.25 mol) was added as the last reactant. The reaction was exothermic providing a temperature increase of the reaction mixture to 70 ° C. The reaction mixture was then heated at 120 ° C for 2 to 3 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (4 L) and aqueous sodium chloride solution (15%, 2.5 L) were added. The mixture was stirred for 20 minutes. The aqueous phase was separated and extracted with another fraction of ethyl acetate (2 L). The aqueous phase was separated and the organic phases were combined and washed with sodium chloride solution (15%, 2.5 L). The organic phase was separated, dried with sodium sulfate and evaporated under reduced pressure to a red oil containing 20 to 30% NMP. The oil was diluted to twice the volume with methanol and the mixture was heated to reflux. More methanol was added until a light red solution was obtained. The solution was cooled slowly to room temperature while sowing. The product crystallizes in the form of faded white crystals, isolated by filtration and washed with methanol and dried at 40 ° C in a vacuum oven to constant weight.

Ethyl 4-hydroxy-4- (2- (4-tolylsulfanyl) phenyl) -piperidin-1-carboxylate

In a stirred reactor under a nitrogen layer, 2- (4-tolylsulfanyl) -phenyl bromide (600 g, 2.15 mol) in heptane (4.5 L) was suspended. At room temperature BuLi (235 ml, 2.36 mol) 10 M in hexane was added at room temperature for 10 minutes. Only a small exotherm was observed. The suspension was stirred for 1 hour at room temperature and then cooled to -40 ° C. 1-Carbetoxy-4-piperidone (368 g, 2.15 mol) was dissolved in THF (1.5 L) at a rate no faster than the reaction temperature was kept below -40 ° C. When the reaction was completed, it was heated to 0 ° C and 1M HCl (1 L) was added at 0 ° C keeping the temperature below 10 ° C. The aqueous acid phase was separated and extracted with ethyl acetate (1 L). The organic phases were combined and extracted with sodium chloride solution (15%, 1 L). The organic phase was dried over sodium sulfate and evaporated to a semicrystalline mass. It was suspended with ethyl ether (250 ml) and filtered. It was dried under vacuum in an oven at 40 ° C to constant weight.

Ethyl 4- (2- (4-tolylsulfanyl) phenyl) -piperidin-1-carboxylate

Trifluoroacetic acid (2.8 kg, 24.9 mol) and triethylsilane (362 g, 3.1 mol) were loaded into a reactor with an efficient stirrer. Ethyl 4-hydroxy-4- (2- (4-tolylsulfanyl) phenyl) -piperidin-1-carboxylate (462 g, 1.24 mol) was added by a funnel to fractional powder. The reaction was slightly exothermic. The temperature rose to 50 ° C. After completion of the addition, the reaction mixture was heated at 60 ° C for 18 hours. The reaction mixture was cooled to room temperature.

Toluene (750 ml) and water (750 ml) were added. The organic phase was isolated and the aqueous phase was extracted with another fraction of toluene (750 ml). The organic phases were combined and washed with sodium chloride solution (15%, 500 ml) and dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was evaporated under reduced pressure to a red oil that was further processed in the next step.

4- (2- (4-Tolylsulfanyl) phenyl) -piperidine hydrobromide

 The ethyl 4- (2- (4-tolylsulfanyl) phenyl) -piperidin-1-carboxylate in the form of red oil of Example 3 was mixed in a stirred reactor with hydrobromic acid in acetic acid (40%, 545 ml, 3, 11 moles) The mixture was heated at 80 ° C for 18 hours. The reaction mixture was cooled to room temperature. During cooling the product crystallized. After 1 hour at room temperature ethyl ether (800 ml) was added to the reaction mixture, and the mixture was stirred for another hour. The product was filtered, washed with ethyl ether and dried in a vacuum oven at 50 ° C to constant weight.

Example 1c Recrystallization of the HBr salt of compound I

A mixture of 10.0 grams of the HBr salt of compound I, p. eg, as before, it was heated to reflux in 100 ml of H2O. The mixture became clear and dissolved completely at 80-90 ° C. To the clear solution 1 gram of charcoal was added and reflux was continued for 15 minutes before filtering and allowed to cool spontaneously at room temperature. During cooling, precipitation of the white solid occurred and the suspension was stirred for 1 hour at room temperature. Filtration and drying under vacuum at 40 ° C overnight produced 6.9 grams (69%) of the HBr acid addition salt of compound I. For XRPD see Figure 1. Elemental analysis: 3.92% N, 59 , 36% C, 6.16% H (in theory: 3.85% N, 59.34% C, 6.09% H).

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Example 1d Preparation of free base stock solutions

To a mixture of 500 ml of ethyl acetate and 200 ml of H2O, 50 grams of the HBr salt of compound I was added producing a two-phase suspension. To this suspension was added approximately 25 ml of conc. NaOH, which caused the formation of a transparent solution in two phases (the pH was measured at 13-14). The solution was stirred vigorously for 15 minutes and the organic phase was separated. The organic phase was washed with 200 ml of H2O, dried over Na2SO4, filtered and evaporated in vacuo at 60 ° C yielding the free base in 38 grams of yield (99%) as an almost colorless oil.

Dissolving 10 grams of the oil and adjusting the volume to 150 ml using ethyl acetate produced a 0.235 M stock solution in ethyl acetate of which 1.5 ml aliquots (100 mg of the free base) were used.

Dissolving 10 grams of the oil and adjusting the volume to 100 ml using 96% vol EtOH. a 0.353 M stock solution in EtOH was produced from which 1.0 ml aliquots (100 mg of the free base) were used.

Example 1e Salt formation using free base stock solutions

The given aliquots were placed in test tubes and while stirring the appropriate amount of acid was added as indicated in Table 1. If the acid was a liquid, pure was added but dissolved in the given solvent before the addition. After mixing and precipitation, stirring was continued overnight and the precipitate was collected by filtration. Before drying under vacuum at 30 ° C, a small reference sample was removed and dried at room temperature without vacuum. This procedure was included to test the solvates. Some results are presented in Table 1. XRPD diffractograms are presented in Figures 1 to 22 and the positions of the selected peak are tabulated in Table 2. Table 3 presents the solubilities of the compounds of the present invention in water together with the pH in the resulting saturated solution. The "precipitate" column shows whether the isolated precipitate after the determination of solubility is identical to the dissolved compound, which is indicative of hydrate formation.

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Table 1

Acid (Base: acid)

P.M. (g / mol) Amount of acid (mg or μl) Solvent CHN (exp.) CHN (in theory)

Palmitic acid, hexadecanoic acid 1: 1

256.42 90.5 EtOAc 75.36 9.77 2.46 75.64 9.9 2.6

DL-lactic acid, DL-2-hydroxypropionic acid 1: 1

90.1 31.8 EtOAc 66.88 7.26 3.52 67.53 7.29 3.75

Adipic acid, 1,6: hexanedioic acid 1: 1

146.14 51.6 EtOAc 66.08 7.23 2.98 67.1 7.27 3.26

Adipic acid, 1,6: hexanedioic acid 2: 1

146.14 25.8 EtOAc 70.66 7.32 3.82 70.75 7.35 3.93

1: 1 fumaric acid

116.01 40.9 EtOH 65.71 6.41 3.35 66.14 6.31 3.51

Glutaric acid, 1,5: pentanedioic acid 1: 1

132.12 46.6 EtOAc 66.09 6.97 3.2 66.48 7.03 3.37

Malonic acid 1: 1

104.1 36.7 EtOAc 65.04 6.53 3.54 65.09 6.5 3.62

1: 1 oxalic acid

90.1 31.8 EtOH 64.28 6.41 3.61 64.32 6.21 3.75

Sebacoinic acid, 1,8-octanedioic acid 2: 1

202.02 35.6 EtOAc 71.79 7.86 3.58 71.83 7.86 3.64

Succinic acid, 1,4-butanedioic acid 2: 1

118.1 20.8 EtOAc 65.65 6.86 3.4 65.80 6.78 3.49 (1: 1 salt formed)

L-malic acid, L-2-hydroxybutanedioic acid 1: 1, α

134.1 47.3 EtOAc 62.87 6.20 3.22 63.29 6.52 3.36

L-malic acid, L-2-hydroxybutanedioic acid 1: 1, β

134.1 47.3 EtOH 62.99 6.66 3.13 63.29 6.52 3.36

D-tartaric acid, D2,3-dihydroxybutanedioic acid, 1: 1

150.1 53.0 EtOH 60.67 6.4 3.07 60.95 6.28 3.23

1: 1 L-aspartic acid

133.1 47.0 EtOH 59.31 6.7 7.1 (contains excess acid) 63.43 6.78 6.73

1: 1 glutamic acid

165.15 58.3 EtOH 56.38 6.88 7.35 (contains excess acid) 56.46 6.94 7.06 (for salt and acid 1: 1 monohydrate 1: 1)

Citric Acid 2: 1

192.13 33.9 EtOAc 65.93 6.72 3.44 66.46 6.64 3.69

1: 1 HCl / Et2O

2m 176.4 EtOH

1: 1 phosphoric acid

14.7 M 24.0 EtOAc 55.79 6.47 3.43 56.68 6.34 3.67

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Table 2: Selected positions of the peak by X-rays (º2θ), 2: 1 means 2 bases for 1 acid. All values ± 0.1º

Palmitate

 7.00 16.34  22.73 28.21

Stearate

6.70 15.52  21.81 28.91

Lactate

 5.30 8.18 9.44 17.24

Hydrated lactate

11.67  16.70 18.25 21.76

Hydroxyl isobutyrate

5.09  16.60 20.38 27.37

Sebacoinic acid salt

7.18  12.53 21.11 24.19

2: 1 adipinic acid salt

 8.03 13.52 17.90 24.60

1: 1 α adipic acid salt

 9.33 14.01 18.72 20.63

1: 1 β adipic acid salt

 15.69 21.53 25.81 31.18

1: 1 Glutarate

9.39 11.70  14.05 14.58

1: 1 succinate

11.74 14.33 17.75 26.84

1: 1 fumarate

8.90 11.47 19.25 22.33

Fumate 2: 1

8.49 12.48 17.78 23.97

1: 1 maleate

12.11 15.51  17.48 22.53

1: 1 hydrated maleate

12.81  18.76 20.53 27.71

Malonate α

 10.77 16.70 19.93 24.01

Β malonate

 6.08 10.11 18.25 20.26

Aspartate

11.05 20.01 20.60 25.00

Hydrated aspartate

7.80 13.80 14.10 19.63

Glutamate

 7.71 14.01  19.26 22.57

Oxalate

14.68 17.45  19.50 23.90

Malate 1: 1 α

 8.30 12.04 17.23 20.67

1: 1 β malate

 10.91 12.87 14.14 26.16

Hydrated malate

12.30  15.56 19.56 23.30

D-tartrate (from EtOH)

5.08 17.18 19.42 22.10

Hydrochloride

12.44 16.72 19.45 25.02

Hydrobromide

6.08 14.81  19.26 25.38

I-PrOH hydrobromide

6.57  13.12 19.07 24.77

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Table 3

Acid (Base: Acid)

Solubility (mg / ml) resulting pH Precipitate

Palmitic acid, hexadecanoic acid 1: 1

0.4  8.6 = Principle

DL-lactic acid, DL-2 hydroxypropionic acid 1: 1

> 150 6.1 = Principle (after evaporation)

Adipic acid, 1,6: hexanedioic acid 1: 1

2.5 4.0 Part 2: 1 salt

Adipic acid, 1,6: hexanedioic acid 2: 1

1.0  7.8 = Principle

1: 1 fumaric acid

0.2 3.3 = Principle

Glutaric acid, 1,5: pentanedioic acid 2: 1

13  4.6 = Principle

Malonic acid 2: 1 (α)

5.2 4.0 = new formulation (β)

1: 1 oxalic acid

1.1 2.7 = Principle

Sebacoinic acid, 1,8octanedioic acid 2: 1

0.7  5.5 = Principle

Succinic acid, 1,4-butanedioic acid 2: 1

2.0  4.0 Hydrate

L-malic acid, L-2-hydroxy butanedioic acid 1: 1, β

2.8  4.0 Hydrate

D-tartaric acid, D-2,3-dihydroxy butanedioic acid, 1: 1

1.8  3.5 Hydrate

1: 1 L-aspartic acid

39 4.3 Hydrate

1: 1 glutamic acid

> 35 4.6 -

Citric Acid 2: 1

0.5 4.7 = Principle

1: 1 phosphoric acid

6.0 2.0 ?

HCl

 4,5 6.8 = Principle

HBr

2.4 7.0 = Principle

Example 2A Inhibition of the reabsorption of serotonin (5-HT) and norepinephrine (NE)

Aliquots of the test compound were pre-incubated for 10 min at 37 ° C and a

5 preparation of rat cortical synaptosome and then [3H] NE or [3H] 5-HT (final concentration 10 nM) was added. Non-specific absorption was determined in the presence of 10 µM talsupram or citalopram and total absorption was determined in the presence of buffer. Aliquots were incubated for 15 minutes at 37 ° C. After incubation [3H] NE or [3H] 5-HT absorbed by the synaptosomes, they were filtered off through Unifilter GF / C previously soaked in 0.1% PEI for 30 minutes using a program

10 Tomtec Cell Harvester. The filters were washed and counted in a MicroBeta Wallac counter.

In NET the compounds of the present invention have an IC50 value of 23 mM. In that SRT the compounds of the present invention have an IC50 value of 8 mM.

Example 2B Antagonism 5-HT2A

Affinity to serotonin receptors in the compounds of the

The present invention was found to have an antagonist profile with affinity to 5-HT2A receptors (Ki 54 nM). The affinity is calculated from Y = 100 / (1 + 10 (X-log IC50)) in which Y indicates% bond and X indicates the concentration of the compound. 5 concentrations of the compound (1, 10, 20, 30, 100, 1000 nM) were used to calculate the IC50 value. Ki was calculated from the Cheng Prusoff equation Ki = (IC50 / (1 + ([L] / Kd)) .Pharmaservices MDL catalog number 271650 was determined.

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In the mammalian cells expressing the human 5-HT2A receptors the compounds of the present invention have competitive antagonistic properties. The compounds bind to 5-HT2A receptors with a Ki <100 mM and in a functional analysis the compounds antagonize the 5-HT release of Ca2 + from intracellular stores with a Kb of 67 nM. A Schild analysis revealed the competitive antagonism with a Kb of 100 nM.

The experiment was performed as follows. 2 or 3 days before the experiment with CHO cells expressing 250 fmoles / mg of human 5-HT2A receptors are placed at a density sufficient to give a confluent monolayer on the day of the experiment. The cells are loaded with dye (Ca2 + kit from Molecular Devices) for 90 minutes at 37 ° C in an incubator with 5% CO2 at 95% humidity. The reference fluorescence was monitored on a fluorometric image detector or FLIPR384 from Molecular Devices (Sunnyvale, CA) with an excitation wavelength of 488 nM and a mission range between 500 and 560 nM. The laser intensity was set at an appropriate level to obtain reference values of approximately 8,000 to 10,000 fluorescence units. The variation in the reference fluorescence should be less than 10%. EC50 values are evaluated using increasing concentrations of the test compound that span at least 3 decades. The pA2 values are evaluated by performing the provocation test of the response curves at the full doses of 5-HT with four different concentrations of compound (150, 400, 1500 and 4000 nM). Kb values were also evaluated by performing the challenge test of two decades of concentration of test substances with EC85 of 5-HT. Test substances are added to the cells 5 minutes before 5-HT. Ki values are calculated using the Cheng Prusoff equation.

Example 2C 5-HT3A receptor antagonism

In oocytes expressing the 5-HT 5-HT human homomeric 5-HT receptors activates the currents with EC50 of 2600 nM. This current can be antagonized with classic 5-HT antagonists such as ondansetron. Ondansetron has a Ki value of less than 1 nM in this system. The compounds of the present invention exhibit potent antagonism at low concentrations (0.1 nM -100 nM) (IC50 ~ 10 nM / Kb ~ 2 nM) and antagonistic properties when applied at higher concentrations (100 100,000 nM) ((EC50 ~ 2600 nM) reaching a maximum current of approximately 70 to 80% of the maximum current produced by the 5-HT itself In oocytes expressing 5-HT3A rat homomeric 5-HT receptor activates currents with an EC50 of 3.3 μM The experiments were performed as follows: The oocytes were surgically removed from the mature female Xenepus laevis anesthetized in 0.4% MS-222 for 10 to 15 minutes.The oocytes were then digested at room temperature for 2 to 3 hours with 0.5 mg / ml collagenase (type IA Sigma-Aldrich) in OR2 buffer (82.5 mN NaCl, 2.0 mM KCl, 1.0 mM MgCl2 and 5.0 mM HEPES, pH 7.6 ) Oocytes devoid of the follicle layer were selected and incubated for 24 hours in saline buffer or modified Barth [88 mM NaCl, 1 mM KCl, 15 mM HEPES, 2.4 mM NaHCO3, 0.41 mM CaCl2, 0.82 mM MgSO4, Ca (NO3) 2 0.3 mM] enriched with 2 mM sodium pyruvate , 0.1 U / l of penicillin and 0.1 μg / l of streptomycin. Stage IV-IV oocytes were identified and injected with 12 to 48 nl of water-free nuclease containing 14 to 50 pg of cRNA encoding human 5-HT3A receptor receptors and incubated at 10 ° C until They were used for electrophysiological records (1 to 7 days after injection). The oocytes with expression of human 5-HT3A receptors were placed in 1 ml of a bath and perfused with Ringer's buffer (115 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1.8 mM CaCl2, 0.1 MgCl2 mM, pH 7.5). Cells were blocked with 0.5 to 1 MΩ electrodes blocked with agar-agar containing 3M KCl and a voltage locked to -90 mV via a GeneClamp 500 B amplifier. The oocytes were continuously perfused with Ringer's buffer and the drugs they were applied in the perfused. 5-HT agonist solutions were applied for 10 to 30 s. The potencies of the 5-HT3 receptor antagonists were examined by measuring the response to concentration versus stimulation of 10 µM 5-HT.

Example 2D Antagonism of the α1A receptor

In the compounds of the present invention the affinities for the α1A receptor were determined and it was observed that they have an antagonistic profile with affinity of the medium for the α1A receptors (Ki = 34 mM).

On the day of the experiments on the membranes (see below the description of the membrane preparation) they were thawed and homogenized in buffer using an ultra turrax and diluted to the desired concentration (5 μg / well ~ 5 μg / 900 μl , they are stored on ice until they are used).

The experiment is started by mixing 50 µl of test compound, 50 µl of [3H] -Prazosin and 900 µl of membranes, and the mixture is incubated for 20 minutes at 25 ° C. The non-specific bond is determined in the presence of 10 µM WB-4101 and the total bond is determined in the presence of buffer. After incubation, the bound ligand is separated from the unbound by filtration through Unifilter GF / B, previously soaked in 0.1% PBI for 30 minutes, using the Tomtec Cell Harvester program (D42..4). 96 wells The filters were washed 3 times with 1 ml of ice-cold buffer, dried at 50 ° C and 35 µl of scintillation fluid / well was added to the filters. The linked radioactivity is counted in a Wallac OY 1450 of MicroBeta. The affinity is calculated from Y = 100 / (1 + 10 (X-log IC50)) in which Y indicates% bond and X indicates the concentration of the compound. The compound concentrations that span two decades were used to calculate the IC50 value. Ki was calculated from the Cheng Prusoff equation Ki = (IC50 / (1 + ([L] / Kd)).

image17

In a functional analysis the compounds of the present invention antagonize the release of Ca2 + caused by adrenaline from intracellular stores and a functional analysis showed that the compounds were antagonists.

These experiments were performed essentially as described below.

All cells were cultured in DMEM medium enriched with 10% BCS, 4 mM L-glutamine (or 2 mM in the case of COS-7) and 100 units / ml of penicillin plus 100 μg / ml of streptomycin, at 37 ° C in 5% CO2

Twenty-four hours before the analyzes, CHO cells expressing human alpha1A-7 receptors were plated on 384-well black wall microtiter plates coated with poly-D-lysine. The culture medium was aspirated and the cells were loaded colored with 1.5 μM Fluo-4 in assay buffer composed of Hank's balanced saline solution (138 mM NaCl, 5 mM KCl, 1.3 mM CaCl2, 0 MgCl2, 5 mM, 0.4 mM MgSO4, 0.3 mM KH2PO4, 0.3 mM Na2HPO4, 5.6 mM glucose) plus 20 mM HEPES, pH 7.4, 0.05% BSA and 2.5 mM probenicide ( 50 μl / well) for 1 hour in CO2 at 37 ° C. Once the excess dye was discarded, the cells were washed in assay buffer and covered with a final volume equal to 45 μl / well (or 30 μl / well by antagonist analysis). In the case of the evaluation of the antagonist, antagonist or vehicle was added at this time in the form of a 15 μl aliquot in buffer containing 4% DMSO at 4 times the final concentration (final DMSO = 1%), followed by about 20 min incubation The reference fluorescence was monitored in a detector of plate readers by the fluorometric image or FLIPRTM of Molecular Devices (Sunnyvale, CA) with an excitation wavelength of 488 nm and an emission range between 500 and 560 nm. The laser excitation energy was adjusted so that the reference fluorescence readings were approximately 8,000 relative fluorescence units (UFR). The cells were then stimulated at room temperature with agonists diluted in assay buffer (15 μl) and the UFRs were measured at 1.5 second intervals over a period of 2.5 min. The maximum change in fluorescence for each well was calculated. The concentration response curves from the maximum change by non-linear regression (Hill equation) were analyzed. For antagonistic determinations, after 20 min incubation of the compound (as above) fixed concentrations of conventional agonist serotonin were added.

Example 2E Increase of dopamine

A single injection of compounds of the present invention increased as a function of the dose of extracellular DA in the rat frontal cortex. The compound of the present invention at 8.9 mg / kg and 18 mg / kg sc, increased the DA concentrations by approximately 100% and 150%, respectively, above the reference concentrations as depicted in Figure 23. The quantities are calculated as free base.

Method

Male Sprague-Dawley rats were used, initially weighing 275 to 300 g. The animals were housed in conditions controlled by the 12 h light / dark cycle. to regulate the indoor temperature (21 ± 2ºC) and humidity (55 ± 5%) with food and running water available at discretion. During the three-day treatment experiments, osmotic mini pumps (Alzet, 2 ML1) were used. The pumps were filled under aseptic conditions and implanted subcutaneously under sevofluoran anesthesia. The experiments were performed with the mini pumps on board. Blood samples were collected to measure the plasma concentrations of the test compound after 3 days of treatment at the end of the experiments.

Surgery and microdialysis experiments.

Animals were anesthetized with hypnorm-dormicum (2 ml / kg) and cannulas with intracerebral guidance (CMA / 12) were stereotaxically implanted in the hippocampus, placing the tip of the dialysis probe in the ventral hippocampus (coordinates: 5.6 mm anterior to the bregma, lateral -5.0 mm, 7.0 mm ventral to the dura or in the frontal cortex (coordinates: 3.2 mm prior to the bregma; lateral, 3.0 mm; 4.0 mm ventral to the dura ) Anchoring screws and acrylic cement were used to fix the guide cannulas.The body temperature of the animals was controlled by rectal catheter and maintained at 37 ° C. The rats were allowed to recover from the surgical intervention for 2 days, each one was housed in cages. On the day of the experiment a microdialysis probe (CMA / 12, 0.5 mm in diameter, 3 mm in length) was inserted through the guide cannula. The probes were connected by a rotating channel bend to a microinjection pump. The infusion of the mic probe Rhodialysis with the filtered Ringer's solution (145 mM NaCl, 3 mM KCl, 1 mM MgCl2, 1.2 mM CaCl2) was started shortly before insertion of the probe into the brain and continued throughout the experiment at a constant flow rate of 1 (1.3) μl / min. After 180 min of stabilization, the experiments were started. Dialysates were collected every 20 (30) min.

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After the experiments, the rats were sacrificed by decapitation, their brains were extracted, frozen and cut into sections for verification of probe placement.

Dialysate Analysis

The concentration of dopamine in dialysates was analyzed by HPLC with electrochemical detection. Monoamines were separated by reverse phase liquid chromatography (ODS 150 x 3 mm, 3 μM). Dopamine: mobile phase consisting of 90 mM NaH2PO4, 50 mM sodium citrate, 367 mg / l of sodium 1-octanosufonic acid, 50 μM EDTA and 8% acetonitrile (pH 4.0) at a flow rate of 0.5 ml / min. Electrochemical detection was performed using a colorimetric detector; potential set at 250 mM (cell stored at 350 mV) (Coulochem II, ESA).

Example 2F Increase in acetylcholine

The experiment was designed to evaluate the effects of the compounds of the present invention on extracellular concentrations of acetylcholine in the prefrontal cortex of freely moving rats.

Male Wistar rats (280-350 g; Harlan Zeist, The Netherlands) were used for the experiments. The rats were individually housed in plastic cages (30 x 30 x 40 mm) and had access to food and water at their discretion.

Rats were anesthetized using isofluorane (2%, 400 ml / min N2O, 400 ml / min O2). Lidocaine (10% m / v for local anesthesia) was used. Each animal was placed in a stereotaxic frame (Kopf Instruments, USA) and domestic I-shaped probes (Hospal membrane AN 69, 4 mm exposed surface) were inserted into the middle prefrontal cortex (CPFm) using atlas rat brain of Paxinos and Watson (1982). The coordinates of the probe tip were CPFm [AP = 3.4 mm, L = -0.8 mm, V = 5.0 mm]. The probe was then fixed to the skull with dental cement and a screw. Flunixin (1 mg / kg s.c.) was administered as a postoperative analgesic. Experiments were performed 24 to 48 hours after surgery. On the day of the experiment, the rats with PEEK flexible tubing were connected to microperfusion pumps (CMA 102) and the dialysis probes were perfused with a Ringer buffer containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl2 and 1.2 mM MgCl2, at a flow rate of 1.5 μl / min. Microdialysis samples were collected at 30 min intervals in minivials containing 55 μl of 0.02 M formic acid for the determination of acetylcholine. Samples were collected with an automatic fraction collector (CMA 142) and stored at -80 ° C until analyzed. Once the experiments were finished, the rats were sacrificed. Brains were removed and cured in paraformaldehyde solution (4% m / v). Acda probe placement was histologically verified according to Paxinos and Watson (1982), practicing coronary sections of the brain.

The test compound was dissolved in 10% of 2-OH-propyl-beta-cyclodextrin and administration occurred by subcutaneous injections of volumes of 5 ml / kg in different doses.

Acetylcholine concentration was determined by HPLC with tandem mass spectrometry (MS / MS) detection.

Aliquots (25 μl) were injected into the HPLC column with an automatic sample injector (PerkinElmer Instruments, 200 series). Chromatographic separation was performed on a 150 x 2.00 mm (4 μm) reverse phase analytical column (Phenomenex Synergy MAX-RP, Bester) protected by a 4 x 2.0 mm guard column (Phenomenex Synergy MAX-RP AJO-6073, Bester), both maintained at a temperature of 30 ° C. The mobile (isocratic) phase consisted of ultrapurified water (UP) acetonitrile (ACN) and trifluoroacetic acid (TFA) (UP: ACN: TFA = 95.0: 0.5: 0.1 v / v / v%). The mobile phase was carried out through the system at a flow rate of 0.300 ml / min with an HPLC pump (PerkinElmer Instruments, 200 micropump series).

LC / MS analyzes were performed using an MS / MS API 4000 system consisting of an MS / MS API 4000 detector and a Turbo Ion Spray interface (both from Applied Biosytems, The Netherlands). Acquisitions were made in positive ionization mode, with an ionic spray voltage set at 5.5 kV, the pressure of the nebulizer gas at 344.750 Pa (50 psig) (on a SCIEX scale 0-90) with a temperature of 600 ° C probe. The instrument was operated in multiple reaction control mode (MRM) for the detection of acetylcholine (precursor 146.1 Da, product 86.8 Da). The collision energy was 21.0 eV and the pressure of the collision gas (nitrogen) was maintained at 7 (on a SCIEX scale from 0 to 12). Data were calibrated and quantified using the AnalystTM data system (Applaied Byosistem, version 1.2).

image19

Two consecutive microdialysis samples with less than 50% variation were taken as reference levels and set to 100%. Changes in acetylcholine concentration were expressed as a percentage of the reference of the same subject.

The data is presented in Figure 24.

Example 2G Increase of acetylcholine

The experiment was designed to evaluate the effects of the compounds of the present invention on extracellular concentrations of acetylcholine in the prefrontal cortex and ventral hippocampus of freely moving rats.

Male Sprague-Dawley rats were used, initially weighing 275 to 300 g. The animals were housed under a 12 h light / dark cycle. under controlled conditions to regulate the temperature inside (21 ± 2ºC) and humidity (55 ± 5%) with food and running water available at discretion.

Surgery and microdialysis experiments

Animals were anesthetized with hypnorm-dormicum (2 ml / kg) and cannulas with intracerebral guidance (CMA / 12) were stereotaxically implanted in the hippocampus, pointing to the dialysis probe in the ventral hippocampus (coordinates: 5.6 mm prior to bregma, lateral -5.0 mm, 7.0 mm ventral to the dura or in the frontal cortex (coordinates: 3.2 mm anterior to the bregma; lateral, 0.8 mm; 4.0 mm ventral to the dura). Anchoring screws and acrylic cement were used to fix the guide cannulas.The body temperature of the animals was controlled by rectal catheter and maintained at 37 ° C. The rats were allowed to recover from the surgical intervention for 2 days, they were housed individually in cages On the day of the experiment a microdialysis probe (CMA / 12, 0.5 mm in diameter, 3 mm in length) was inserted through the guide cannula.

The probes were connected by a double rotating channel to a microinjection pump. Perfusion of the microdialysis probe with the filtered Ringer's solution (145 mM NaCl, 3 mM KCl, 1 mM MgCl2, 1.2 mM CaCl2 containing 0.5 µM neostigmine) was started shortly before insertion of the probe into the brain and continued throughout the experiment at a constant flow rate of 1 μl / min. After 180 min of stabilization, the experiments were started. Dialysates were collected every 20 min.

After the experiments, the rats were sacrificed, their brains were extracted, frozen and cut into sections for verification of probe placement.

Acetylcholine dialysate analysis

The concentration of acetylcholine (ACh) in dialysates was analyzed by means of HPLC with electrochemical detection using a mobile phase consisting of 100 mM disodium basic phosphate, 2.0 mM octansulfonic acid, 0.5 mM tetramethylammonium chloride and 0.005% MB (ESA), pH 8.0. An enzyme precolumn reactor (ESA) containing immobilized choline oxidase removed choline from the injected sample (10 μl) before ACh separation from the analytical column (ESA ACH-250); flow rate 0.35 ml / min, temperature: 35 ° C. After the analytical column the sample passed through a solid phase back column (ESA) reactor containing immobilized acetylcholinesterase and choline oxidase. This last reactor turned ACh into choline and then choline into betaine and H2O2. The latter was detected electrochemically using a platinum electrode (analytical cell: ESA, model 5040).

Data presentation

In the experiments with a single injection the average value of 3 consecutive ACh samples that immediately precede the administration of the compound served as a reference concentration for each experiment and the data became reference% (average values of the previous reference injection normalized to 100%). The figures are presented in Figures 25a and 25b.

The data presented in Figure 24 show unexpected drops in acetylcholine levels (see, eg, 8 mg / kg) that are difficult to explain and are attributed to experimental uncertainty. In general, both data sets in Example 2F and 2G have the same, that is, a dose-dependent increase in extracellular acetylcholine concentrations in the brain. This preclinical discovery is expected to translate into an improvement in knowledge in a useful clinical facility,

p. eg, in the treatment of diseases characterized by cognitive insufficiency, such as, e.g. eg, Alzheimer's patients, partially responding patients, cognitive impairment, etc.

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Example 3 Effect on neuropathic pain

To demonstrate efficacy against neuropathic pain, the compound of the present invention was tested in the neuropathic pain formalin model [Neuropharm., 48, 252-263, 2005; Pain, 51, 5-17, 1992]. In this model, mice receive an injection of formalin (4.5%, 20 μl) on the surface of the

5 plant of the left hind leg and then placed in individual glass beakers (2 l capacity) for observation. The irritation caused by the injection of formalin causes a characteristic response of biphasic behavior quantified by the amount of time spent licking the injured leg. The first phase (~ 0 to 10 minutes) represents direct chemical irritation and nocirreception, while the second phase (~ 20 to 30 minutes) is believed to represent the pain of origin

10 neuropathic The two phases are represented by a latent period in which the behavior becomes normal again. Measuring the amount of time elapsed by licking the injured leg in the two phases assesses the efficacy of the test compounds in reducing painful stimuli.

Eight C57 / B6 mice (approx. 25 g) were tested per group. Table 4 below shows the amount of time spent licking the injured leg in the two phases, that is, 0 to 5 minutes and 20 to 30 minutes after the formalin injection. The amount of compound administered is calculated referred to

to the free base.

Table 4

Vehicle

1.0 mg / kg 2.5 mg / kg 10 mg / kg

0 - 5 minutes (s)

42 37 30 37

20-30 minutes (s)

41 43 26 6

The data in Table 4 demonstrate that the compound of the present invention has little effect.

20 in the first phase representing direct chemical irradiation and nocirreception. More prominently, the data also show a clear and dose-dependent decrease in the time spent licking the legs in the second phase indicating an effect of the compound of the present invention in the treatment of neuropathic pain.

 Example 4 Capsules

4- 4- [2- (4-Methylphenylsulfanyl) -phenyl] piperidine hydrobromide was mixed with microcrystalline cellulose in a first stage. In a second stage, magnesium stearate was mixed. Capsules with four doses were prepared, the active ingredient is indicated referring to the free base.

1 mg

5 mg 25 mg

Active ingredient

12.85 g 64.25 g 321.25 g

Microcrystalline cellulose

2026.55 g 2034.55 g 1846.85 g

Magnesium stearate

20.6 g 21.2 g 21.9 g

Capsule content weight

206 mg 212 mg 219 mg

10,000 capsules of each batch were prepared.

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Claims (15)

1. Compound which is the HBr addition salt of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine image 1 in a crystalline form. 2. Compound according to claim 1, characterized by peaks in an XRPD at about 6.08, 14.81, 19.26 and 25.38 ° 2θ.

3.

Compound according to claim 1, which is characterized by an XRPD as depicted in Figure 1.

Four.

Compound which is the addition salt of DL-lactic acid 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine

10 in a crystalline form. image 1 5. Compound which is the addition salt of glutaric acid 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine (1: 1). image 1 6. Compound which is the addition salt of malonic acid 4- [2- (4-methylphenylsulfanyl) 15 phenyl] piperidine (1: 1) image 1 in a crystalline form. 7. Compound which is the addition salt of L-aspartic acid 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine (1: 1) image2 image 1 5 10 fifteen twenty 25 30 35 or the addition salt of hydrated L-aspartic acid (1: 1) in a crystalline form. 8. Compound which is the addition salt of glutamic acid 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine (1: 1) image 1 or the addition salt of glutamic acid monohydrate (1: 1) in a crystalline form. 9. Compound according to any of claims 1 to 8 for use in therapy.

10.

Pharmaceutical composition comprising a compound according to any one of claims 1 to 8 together with a pharmaceutically acceptable excipient.

eleven.

Compound according to any of claims 1 to 8 for use in the treatment of chronic pain, depression in patients who respond in part, treatment-resistant depression, Alzheimer's disease, cognitive impairment, THFA, melancholy, PTSD, flushes, apnea of sleep, alcoholism, nicotine or bulimia dependence on carbohydrates, drug dependence, alcoholism or drug dependence, vomiting, eating disorders, IBS, affective disorders, depression, major depressive disorder, postnatal depression, bipolar disorder associated depression, Alzheimer's, psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia or stress urinary incontinence.

12.

Compound according to claim 11 for use in the treatment of chronic pain.

13.

Compound according to claim 12 for use in the treatment of phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (NPH), carpal tunnel syndrome (STC), HIV neuropathy, pain syndrome regional complex (CPRS), trigeminal neuralgia / painful trigeminal / tic neuralgia, surgical intervention (e.g., postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina pectoris, Pain associated with menstruation, pain associated with cancer, dental pain, migraine, migraine, migraine headache, trigemic neuralgia, temporomandibular joint syndrome, muscle injury with myofascial pain, fibromyalgia syndrome, bone and joint pain (osteoarthritis) , rheumatoid arthritis, rheumatoid arthritis and edema associated with trauma associated with burns, sprains or pain due to fr Bone actura due to osteoarthritis, osteoporosis, bone metastases or for unknown reasons, gout, fibrositis, myofascial pain, external thoracic syndromes, upper back pain or lower back pain (in which the back pain comes from the disease of general, regional or primary spine (radiculopathy), pelvic pain, heart chest pain, non-cardiac chest pain, pain associated with spinal cord injury (SCI), central pain after stroke, cancer neuropathy, pain for AIDS, depranocitic pain or geriatric pain.

14.

Compound according to claim 13 for use in the treatment of neuropathic pain.

fifteen.

Compound according to claim 14, wherein said neuropathic pain is selected from hyperpathy, hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, hyperesthesia, causalgia and allodynia.