BRPI0712758A2 - pharmaceutically acceptable compound and salts thereof, pharmaceutical composition, method of treating a disease. and, use of compsoto - Google Patents

Abstract

COMPOSITION AND PHARMACEUTICALLY ACCEPTABLE SALES OF THE SAME, PHARMACEUTICAL COMPOSITION, METHOD OF TREATING A DISEASE, AND USE OF THE COMPOUND. Crystalline forms of 4- [2- (4-methyl-phenyl-sulfanyl) -phenyl] -piperidine and their salts provided e.g. for the treatment of neuropathic pain.

Description

"COMPOUND AND PHARMACEUTICALLY ACCEPTABLE SALTS OF THE SAME, PHARMACEUTICAL COMPOSITION, DISEASE TREATMENT METHOD, AND USE OF THE COMPOUND"

Perception of pain is more complicated than direct transmission of signals from an injured part of the body to specific receptors in the brain, in which perceived pain is proportional to the injury. Rather, peripheral tissue damage and nerve damage can cause changes in central neural structures involved in pain perception affecting subsequent pain sensitivity. This neuroplasticity may lead to central sensitization in response to longer-term nontoxic stimuli, which may manifest as eg chronic pain, ie that the perception of permanent pain even after the nontoxic stimulus has stopped, or as hyperalgesia, ie an increased response. to a stimulus, which is usually painful. One of the most mysterious and dramatic examples of this is the "phantom limb syndrome", i.e. the persistence of pain that existed in a limb prior to its amputation. For a review of central neuroplasticity and pain see Melzack et al in Ann. Ν Y. Acad. Sci., 933, 157-174, 2001.

Chronic pain such as neuropathic odor manifests differently from other types of pain, e.g. somatic or visceral pain. The pain is often described as acute, burning, tingling, numb or penetrating. Common causes of neuropathic pain include alcoholism, amputation, back, leg and hip problems, chemotherapy, diabetes, HIV, multiple sclerosis, backbone surgery, and herpes zoster virus infection.

The central component to chronic pain may explain why chronic pain, such as e.g. neuropathic pain, often responds poorly to classic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDS) and opioid analgesics. Amitrillin-typified tricyclic antidepressants (TCAs) have become standard 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 dual-acting antidepressants having an inhibitory effect on both serotonin and norepinephrine reuptake have been used clinically for the treatment of neuropathic pain [Human Psychopharm., 19, S21-S25, 2004]. Examples of dual 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 (SSRI) for neuropathic pain are scarce but generally suggest a limited effect [Bas. Clin. Pharmacol., 96, 399-409, 2005]. Indeed, it has been hypothesized that SSRTs are only weakly antinociceptive in and of themselves but that serotonin transporter inhibition increases the antinociceptive effect of norepinephrine reuptake inhibition. This notion is supported by a review of 22 animal studies and five human studies showing that SNRTs have superior antinociceptive effect compared to norepinephrine reuptake inhibitors, which are again superior to SSRI [Pain Med. 4, 310-316, 2000].

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

The use of tricyclic antidepressants is, however, associated with known anticholinergic side effects, such as e.g. drowsiness, anxiety, restlessness, and cognitive and memory difficulties. Consequently, there is a need in the art to find alternative ways of treating neuropathic pain.

International patent application published as WO 2003/029232 describes e.g. 4- [2- (4-methyl-phenylsulfanyl) -phenyl] -piperidine as a free base and the corresponding HCl salt. The compound is reported to be a serotonin transporter and serotonin receptor 2C (5-HT2c) inhibitor, said to be useful for treating affective disorders, e.g. depression and anxiety.

Summary of the invention

The present inventors have surprisingly found in addition to the well-known pharmacological profile that 4- [2- (4-methyl-phenylsulfanyl) -phenyl] -piperidine is a potent inhibitor of serotonin reuptake and norepinephrine reuptake, a drug antagonist. serotonin receptor 3 (5-HT 3), a serotonin receptor 2A antagonist (5-HT 2a), and an α 1 adrenergic receptor inhibitor, and the compound may therefore be useful in the treatment of chronic pain. Accordingly, the invention to compound I, which is 4- [2- (4-methyl-phenylsulfanyl) -phenyl] -piperidine and pharmaceutically acceptable salts thereof in a crystalline form provided that said compound is not an addition salt of 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine hydrochloride.

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

In one embodiment, the invention relates to a method of treatment comprising administering 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 manufacture of a medicament. Figures

Figure 1: X-ray diffraction pattern of compound I HBr addition salt

Figure 2: X-ray diffraction pattern of solvate and HBr addition salt of compound I

Figure 3: X-ray diffraction pattern of the palmitic acid addition salt of compound I

Figure 4: X-ray diffraction pattern of DL-lactic acid addition salt of compound I

Figure 5: X-ray diffraction pattern of adipic acid addition salt (1: 1) of compound I (α + β form)

Figure 6: X-ray diffraction pattern of adipic acid addition salt (2: 1) of compound I

Figure 7: X-ray diffraction pattern of fumaric acid addition salt (1: 1) of compound I

Figure 8: X-ray diffraction pattern of glutaric acid addition salt (1: 1) of compound I

Figure 9: X-ray diffraction pattern of the malonic acid addition salt (1: 1) of compound I forms it

Figure 10: X-ray diffraction pattern of compound I malonic acid addition salt, β-form

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

Figure 12: X-ray diffraction pattern of sebacoinic acid addition salt (2: 1) of compound I

Figure 13: X-ray diffraction pattern of the succinic acid addition salt (2: 1) of compound I

Figure 14: X-ray diffraction pattern of L-malic acid addition salt (1: 1) of compound I, form it Figure 15: X-ray diffraction pattern of L-malic acid addition salt (1: 1) of compound I, β-form

Figure 16: X-ray diffraction pattern of D-tartaric acid addition salt (1: 1) of compound I

Figure 17: X-ray diffraction pattern of L-aspartic acid addition salt (1: 1) of compound I in admixture with L-aspartic acid

Figure 18: X-ray diffraction pattern of L-aspartic acid addition salt hydrate (1: 1) of compound I in admixture with L-aspartic acid

Figure 19: X-ray diffraction pattern of glutamic acid addition salt (1: 1) of compound I in admixture with glutamic acid monohydrate

Figure 20: X-ray diffraction pattern of the citric acid addition salt (2: 1) of compound I

Figure 21: X-ray diffraction pattern of HCl acid addition salt of compound I

Figure 22: X-ray diffraction pattern of phosphoric acid addition salt (1: 1) of compound I

Figure 23: Dopamine levels in prefrontal cortex under administration of compounds of the present invention.

Figure 24: Acetylcholine level in prefrontal cortex under administration of compounds of the present invention.

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

Detailed Description of the Invention

The present invention relates to compound I, which is 4- [2- (4-methyl-phenylsulfanyl) -phenyl] -piperidine and pharmaceutically acceptable salts thereof in a crystalline form provided that said compound is not the salt of hydrochloride addition. The structure of 4- [2- (4-methyl-phenylsulfanyl) -phenyl] -piperidine is

<formula> formula see original document page 7 </formula>

The pharmaceutical profile of the compounds of the present invention is shown in the examples, but may be summarized as follows. The compounds are serotonin and norepinephrine reuptake inhibitors; inhibit serotonin 2 A, 2C and 3 receptors; and inhibit the α-1 adrenergic receptor.

In one embodiment, said pharmaceutically acceptable salts are acid addition salts which are non-toxic. Said salts include prepared salts of organic acids such as maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylene-salicylic, methanesulfonic, ethanesulfonic, acetic, propionic, tartaric, salicylic, citric, glyconic acids , lactic, malic, malonic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino benzoic, glutamic, benzene sulfonic, theophylline acetic, as well as 8-halo theophyllines, for example 8 -bromo-theophylline. Said salts may also be prepared from inorganic acids such as hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Additional useful salts are listed in the table in example 1d (table 1).

In one embodiment, the compound of the present invention, i.e. the compound of formula I, is the HBr salt.

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

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

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

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

In one embodiment, the compound of the present invention is the malonic acid addition salt, and in particular the 1: 1 salt which is found to exist in two polymorphic modifications α and β of which the β form is believed to be the most stable based on lower solubility.

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

Oral dosage forms, and in particular tablets and capsules, are often preferred by patients and the physician because of ease of administration and consequently better compliance. For tablets and capsules, it is preferable that the active ingredients be crystalline.

Crystals of the present invention may exist as solvates, i.e. crystals in which solvent molecules form part of the crystal structure. The solvate may be formed from water, in which case solvates are often referred to as hydrates. Alternatively, solvates may be formed from other solvents, such as e.g. ethanol, acetone, or ethyl acetate. The exact amount of solvate often depends on the conditions. For example, hydrates will typically lose water as the temperature is increased or relative humidity is decreased. Compounds, which do not change or that change only slightly when conditions such as e.g. moisture change are generally considered to be best suited for pharmaceutical formulations. It is observed that the HBr addition salt does not form hydrates when precipitated from water whereas compounds such as succinate, maleate and tartrate acid addition salts form. Some compounds are hygroscopic, i.e. absorb water when exposed to moisture. Hygroscopicity is generally regarded as an unwanted property for compounds which are to be present in a pharmaceutical formulation, in particular in a dry formulation such as tablets or capsules. In one embodiment, the invention provides crystals with low hygroscopicity.

For oral dosage forms using crystalline active ingredients it is also beneficial if said crystals are well defined. In the present context, the term "well defined" in particular means that the stoichiometry is well defined, ie that the ratio of ions forming salt is the ratio of small integers 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 significance for choosing the dosage form because it can have a direct impact on bioavailability. For oral dosage forms, it is believed that higher solubility of the active ingredient is generally beneficial because it increases bioavailability. Some patients, e.g. elderly patients may have difficulty swallowing tablets, and oral drop solutions may be a suitable alternative avoiding the need to swallow tablets. In order to limit the volume of an oral droplet solution, 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, DL-lactic acid addition salts , L-aspartic acid, glutamic acid, glutaric acid and malonic acid have exceptionally high solubility.

Crystal shapes influence the processing and filtration properties of a compound. Needle-shaped crystals tend to be more difficult to handle in a production environment because filtration becomes more difficult and time consuming. The exact crystalline form of a given salt may depend e.g. conditions under which the salt was precipitated. The HBr acid addition salt of the present invention grows as solvated crystals, in the form of needles when precipitated from ethanol, acetic acid and propanol, but crystals of a non-hydrated form, which are not in the form of needles, when the salt of addition of HBr is precipitated from water, provide superior filtration properties.

Table 3 also shows the resulting pH, i.e. the pH in the saturated salt solution. This property is important because moisture can never be completely avoided during storage and moisture buildup will cause a pH decrease in or on the tablet comprising a resulting low pH salt which can shorten shelf life. In addition, a salt with a resulting low pH may cause corrosion of process equipment if tablets are prepared by wet granulation. The data in Table 3 suggest that the adipic acid, HCl, and HBr addition salts may be higher in this regard.

In one embodiment, the compound of the present invention is the HBr salt in a crystalline form, in particular in a purified form. In another embodiment, said HBr salt has peaks on a powder X-ray diffractogram (XRPD) at approximately 6.08 °, 14.81 °, 19.26 ° and 25.38 ° 2Θ, and in particular cited. HBr salt has an XRPD as shown in Figure 1.

In one embodiment, the compound of the present invention is the DL-lactic acid addition salt (1: 1) in a crystalline form, in particular in a purified form. In another embodiment, said DL-lactic acid addition salt has peaks in an XRPD at approximately 5.30 °, 8.81 °, 9.44 ° and 17.24 ° 2Θ, and in particular said DL-lactic acid has an XRPD as shown in Figure 4.

In one embodiment, the compound of the present invention is the L-aspartic acid addition salt (1: 1) in a crystalline form, in particular in a purified form. In another embodiment, said L-aspartic acid addition salt is unsolvated and has peaks in an XRPD at approximately 11.05 °, 20.16 °, 20.60 °, 25.00 ° 20, and in particular cited above. L-aspartic salt, when mixed with L-aspartic acid, has an XRPD as shown in Figure 17. In one embodiment, said L-aspartic acid addition salt is a hydrate, in particular it is in a purified form. In another embodiment, said L-aspartic acid addition salt hydrate has peaks in an XRPD at approximately 7.80 °, 13.80 °, 14.10 °, 19.63 ° 2Θ, and in particular said L-Aspartic acid addition salt, when mixed with L-aspartic acid, has an XRPD as shown in Figure 18.

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

In one embodiment, the compound of the present invention is the malonic acid addition salt (1: 1) in a crystalline form, in particular in a purified form. In another embodiment, said malonic acid addition salt is the α-form and has peaks in an XRPD at approximately 10.77 °, 16.70 °, 19.93 °, 24.01 ° 20, or said Malonic acid addition is the β-form and has peaks in an XRPD at approximately 6.08 °, 10.11 °, 18.25 °, 20.26 ° 2Θ and in particular cited malonic acid addition salt has an XRPD as shown in Figure 9 or 10.

In one embodiment, the compound of the present invention is the glutaric acid addition salt (1: 1) in a crystalline form, in particular in a purified form. In another embodiment, said glutaric acid addition salt has peaks in an XRPD at approximately 9.39 °, 11.70 °, 14.05 °, and 14.58 ° 2Θ, and in particular said acid addition salt. glutaric has an XRPD as shown in Figure 8.

As mentioned above, compounds of the present invention are in particular well suited for treating chronic pain. Chronic pain includes indications such as phantom limb pain, neuropathic pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuralgia, complex regional pain syndrome (CPRS), trigeminal neuralgia / neuralgia trigeminus / tic pain, surgical intervention (eg postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, pain associated with menstruation, pain associated with cancer, dental pain, headache, migraine , tension-type headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fractured bone pain due to osteoarthritis, osteoporosis, bone metastasis or unknown reasons, go fibrositis, myofascial pain, chest output syndromes, upper back pain, or lower back pain (in which back pain results from primary, regional, or systematic backbone disease (radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest pain, backbone injury (IBS) pain, central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain or geriatric pain.

In particular, the compounds of the present invention are useful for treating 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 emotional and sensory experience associated with actual or potential tissue damage, or described in terms of such damage (IASP Classification of chronic pain, 2nd Edition, IASP Press (2002), 210) Although pain is always subjective its cause or syndromes can be classified as "Neuropathic pain" as a subtype is defined by the IASP as "pain initiated or caused by a dysfunction or primary injury to the nervous system".

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

• Allodynia which is defined as "a pain due to a stimulus that normally does not cause pain".

• Causalgia which is defined as "a syndrome of prolonged burn pain, allodynia and hyperpathy after a traumatic nerve injury, often combined with vasomotor or sudomotor dysfunction and subsequent trophic changes".

• Hyperesthesia, which is defined as "increased sensitivity to stimulation excluding the senses".

• 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 disorder of function or pathological change in a nerve: in mononeuropathy of a nerve, in multiplex multiplex mononeuropathy, whether diffuse or bilateral, polyneuropathy". Neuropathy may be associated with e.g. diabetes in which case it is called diabetic neuropathy.

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

Hyperpathy, which is defined as "a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased limit."

The evoking stimuli of neuropathic pain can be mechanical or thermal.

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. 5-HT2c receptors are located e.g. in dopaminergic neurons where activation exerts a tonic inhibitory influence on dopamine release, and 5-HT2c antagonists will effect an increase in dopamine level. Data shown in example 2E shows that the compounds of the present invention actually effect a dose dependent increase in extracellular dopamine levels in the brain. Based on this background it can be hypothesized that 5-HT2c antagonists are in particular well suited 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 showing that a combination of mirtazipine and SSRI is superior to SSRI alone for treating depressed patients with an inadequate clinical response (treatment resistant depression, TRD, or refractory depression) [Psychother. Psychosom., 75, 139-153, 2006]. Mirtazapine is also a 5-HT2 and 5-HT3 antagonist, indicating that compounds exerting serotonin reuptake inhibition in combination with 5-HT2 and 5-HT3 antagonism, such as compounds of the present invention, are useful for TRD treatment, ie will increase the remission rate for patients suffering from treatment-resistant depression.

Data presented in example 2F and 2G show that the compounds of the present invention cause an increase in the extracellular level of acetylcholine in the prefrontal cortex and ventral hippocampus. There is lasting clinical evidence that increased levels of acetylcholine in the brain is a way of treating Alzheimer's disease and general cognitive impairment, cf. the use of acetylcholine esterase inhibitors in the treatment of Alzheimer's disease. Based on this background, it is believed that the compounds of the present invention are useful in the treatment of Alzheimer's disease and cognitive impairment, as well as mood disorders such as depression associated with Alzheimer's disease and cognitive impairment.

A segment of depressed patients will respond to treatment with e.g. SSRI in the sense that they will improve on clinically relevant depression scales such as MADRD and HAMD but where other symptoms such as sleep disturbance and cognitive impairment remain. In the present context, these patients are referred to as partial responders. Due to the effects discussed above on acetylcholine levels, the compounds of the present invention are expected to be useful in treating cognitive impairment in addition to depression. Clinical studies have shown that the compound Prazosine, which is an α-1 adrenergic receptor antagonist, reduces sleep disorders [Biol. Psychiatry, 61, 928-934, 2007]. In addition, it is also believed that the 5-HT2a and 5-HT2c antagonism of the compounds of the present invention has a sedative, sleep enhancing effect [Neuropharmacol, 33, 467-471, 1994] because the compounds of the present invention are useful for treating partial responders, or otherwise said that treating depressed patients with the compounds of the present invention will reduce the fraction of partial responders.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurobehavioral disorders. ADHD is characterized by the presence of a triad of communicative weaknesses with restricted, repetitive or stereotyped behaviors. ADHD usually begins in childhood or adolescence, but symptoms may continue into adulthood. Atomoxetine is currently the only FDA approved non-stimulant for the treatment of ADHD [Drugs, 64, 205-222, 2004]. Atomoxetine is a norepinephrine reuptake inhibitor, and this suggests that the compounds of the present invention may be used in the treatment of ADHD. In addition, the compounds of the present invention may have a sedative effect due to the α-1 adrenergic receptor and 5HT2 antagonism discussed above, which is beneficial in the treatment of ADHD.

Melancholy is a particular subtype of depression often linked to severe depression; This type of depression is also referred to as melancholic depression. Melancholy is associated with anxiety, fear of the future, insomnia, and loss of appetite. Compounds that inhibit reuptake of both serotonin and norepinephrine, such as e.g. venlafaxine, have been shown to be particularly effective in treating patients with severe depression and melancholy [Depres. Anxiety, 12, 50-54, 2000]. As discussed above, compounds exerting 5-HT2C antagonism increase the level of dopamine, therefore such compounds would be expected to be effective in treating melancholy [Psychpharm. Bull., 39, 147-166, 2006]. In addition, the α-1 adrenergic receptor and 5-HT 2 antagonism of the compounds of the present invention are expected to help normalize sleep, so said compounds are useful in treating melancholy.

FDA has recently approved sertraline and paroxetine, two SSRTs, for the treatment of posttraumatic stress disorder (PTSD). In addition, compounds having 5-HT2A antagonistic activity are useful because they are expected to be capable of containing agitation, insomnia and susceptibility to explode in PTSD patients [Curr opinion Invest. Drug, 4, 37-41, 2003]. Accordingly, the compounds of the present invention are expected to be useful in the treatment of PTSD.

Hot flushes are a symptom associated with menopausal transition. Some women may suffer from this to an extent where it interferes with sleep or general activities, and where treatment is needed. Estrogen hormone replacement therapy has been the established practice for decades, however, recent concerns have been expressed about side effects such as breast cancer and cardiac events. Clinical trials with SSRI and SNRI have shown that these compounds have an effect on hot flushes, although they are less than estrogen [J.Am.Med.Ass., 295, 2057-2071, 2006]. Treatment of hot flushes with serotonin and / or norepinephrine reuptake inhibitor compounds, e.g. compounds of the present invention could, however, be an alternative treatment for women who cannot or will not accept estrogen.

Sleep apnea or obstructive sleep apnea-hyponea syndrome or obstructive sleep disordered breathing is a disorder for which effective pharmacotherapy remains to be identified. Several animal studies, however, suggest that 5-HT 3 antagonists, e.g. compounds of the present invention may be effective in a therapeutic intervention [Sleep, 21, 131-136, 1998; Sleep, 8, 871, 878, 2001],

It has recently been shown that the 5-HT3 odansetron antagonist is effective in the treatment of craving and alcohol and drug abuse [Drug Alc.Depend., 84, 256-263, 2006; Pharmacol Therapeut., 111, 855-876, 2006]. This would seem to support the notion that 5-HT 3 antagonists, e.g. compounds of the present invention may be useful in treating craving, such as craving for alcohol, nicotine or carbohydrate; and drug and alcohol abuse.

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

It is further expected that the compounds of the present invention having a unique pharmacological profile will be useful in the treatment of affective disorders, depression, major depressive disorder, postpartum 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 and stress urinary incontinence.

In one embodiment, the invention relates to a method of treating chronic pain, depression in partial responders, treatment-resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholy, PTSD, hot flushes, sleep apnea, alcohol craving. , nicotine or carbohydrate, substance abuse, alcohol or drug abuse, emesis, eating disorders, IBS, affective disorders, depression, major depressive disorder, postpartum depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis or ill 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, the method comprising administering to a patient in need thereof a therapeutically effective amount of compound I. In one embodiment, said patient being treated for any of the diseases Those listed above have been initially diagnosed with the aforementioned disease.

In one embodiment, the invention relates to a method for treating 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 chronic pain. phantom limb, neuropathic pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuralgia, complex regional pain syndrome (CPRS), trigeminal neuralgia / trigeminus neuralgia / painful tic, surgical intervention ( (eg postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, pain associated with menstruation, pain associated with cancer, dental pain, headache, migraine, tension-type headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, bone and joint pain action (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis, and edema resulting from trauma associated with burns, sprains, or fractured bone pain due to osteoarthritis, osteoporosis, bone metastasis, or unknown reasons, gout, fibrositis, myofascial pain, thoracic outlet syndromes, pain upper back or lower back pain (in which back pain results from primary, regional, or systematic backbone disease (radiculopathy), pelvic pain, cardiac chest pain, noncardiac chest pain, pain associated with backbone injury) (ICS), central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain or geriatric pain.

In one embodiment, said chronic pain is neuropathic pain.

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 from about 0.001 to about 100 mg / kg body weight per day.

A typical oral dose is within the range of from about 0.001 to about 100 mg / kg body weight per day, preferably from about 0.01 to about 50 mg / kg body weight per day administered on one or more. doses such as 1 to 3 dosages. Exact dosage will depend on the frequency and mode of administration, gender, age, weight and general condition of the treated individual, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident for those experienced in the art.

A typical adult oral dosage is within the range of 1-100 mg / day of a compound of the present invention, such as 1-30 mg / day, or 5-25 mg / day. This can typically be achieved by administration of 0.1-50 mg, such as 1-25 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 interrupt the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising administering said compound. An amount suitable to accomplish this is defined as a "therapeutically effective amount". The term also includes sufficient amounts to cure, alleviate or partially interrupt the clinical manifestations of a given disease and its complications in a treatment comprising administering said compound. Actual amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general condition of the individual. It will be appreciated that determination of an appropriate dosage can be achieved using routine experimentation, constructing a matrix of values and testing different points in the matrix, which are all within the ordinary capabilities of a trained physician.

The terms "treating" and "treating" as used herein mean the management and care of a patient for the purpose of combating a condition, such as a disease or disorder. The term is intended to include the full spectrum of treatments for a given condition of which the patient is suffering, such as administration of the active compound to alleviate symptoms or complications, to slow the progression of the disease, disorder or condition, to alleviate or alleviate symptoms and complications, and / or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, in which prevention is to be understood as the management and care of a patient for the purpose. to combat disease, condition, or disorder and include administration of the 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 manufacture of a medicament for treating chronic pain, depression in partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholy, PTSD, flushing. hot, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse, alcohol or drug abuse, emesis, eating disorders, IBS, affective disorders, depression, major depressive disorder, postpartum depression, depression associated with disorder 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 stress urinary incontinence.

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

In one embodiment, the invention relates to the compounds of the present invention for use as a medicament for the treatment of chronic pain, depression in partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholy, PTSD, flushing. hot, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse, alcohol or drug abuse, emesis, eating disorders, IBS, affective disorders, depression, major depressive disorder, postpartum depression, depression associated with disorder 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 stress urinary incontinence.

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

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

Pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will depend upon the general condition and age of the subject being treated, the nature of the condition being treated and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, pills, pills, tablets, powders and granules. Where appropriate, they may be prepared with coatings. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous or non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted into sterile injectable solutions or dispersions prior to use.

Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, etc.

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

For parenteral routes such as intravenous, intrathecal, intramuscular, and the like, typically doses are on the order of about half the dose employed for oral administration.

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

Suitable pharmaceutical carriers include solid fillers or diluents, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkylethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by the combination of the compound of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the administration routes described.

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

If a solid carrier is used for oral administration, the preparation may be a tablet, e.g. added into a hard gelatin capsule in powder or pellet form or in the form of a tablet or tablet. The amount of solid carrier 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 a syrup, emulsion, soft gelatin capsule or sterile injectable liquid as an aqueous or non-aqueous liquid solution or suspension.

Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and / or diluents followed by compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: Cornstarch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives commonly used for such purposes as colorants, flavorings, preservatives etc. may be employed provided they are compatible with the active ingredients.

Capsules comprising a compound of the present invention may be prepared by mixing a powder comprising said compound with microcrystalline cellulose and magnesium stearate and adding said powder into a hard gelatin capsule. Optionally, said capsule may be colored by a suitable pigment. Typically, capsules will comprise 0.25-20% of a compound of the present invention, such as 0.5-1.0%, 3.0-4.0%, 14.0-16.0% of a compound of the present invention. invention. These concentrations may be used to conveniently release 1.5, 10, 15, 20 and 25 mg of a compound of the present invention in a unit dosage form.

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

Compound I may be prepared as described in WO 2003/029232. Salts of compound I may be prepared by the addition of an appropriate acid followed by precipitation. Precipitation may be performed e.g. by cooling, solvent removal, addition of another solvent or a mixture thereof.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference herein and are set forth herein in their entirety (to the fullest extent permitted by law), regardless of any separately provided incorporation of particular documents made. here elsewhere.

Uses of the terms "one", "one", "o" and "a" and similar references in the context of the description of the invention are to be understood to cover both singular and plural unless otherwise indicated. or clearly contradicted by context. For example, the phrase "the compound" is to be understood as referring to various "compounds" of the invention or particular aspect described, unless otherwise indicated.

Unless otherwise indicated, all exact values provided herein are representative of the corresponding approximate values (eg, all exemplary exact values provided with respect to a particular factor or measurement may be considered to also provide approximate measurement). corresponding, modified by "about" where appropriate).

The description herein of any aspect or aspect of the invention using terms such as "comprising", "possessing", "including", or "containing" with reference to an element or elements, unless otherwise stated or clearly contradicted by context (eg, a composition described herein as comprising a particular element is to be understood as also describing a composition consisting of that element, unless stated or clearly contradicted by the context).

Examples

Analytical Methods

Powder X-ray diffractograms (XRPD) were measured on a PANalytical X1Pert PRO X-ray Diffractometer using CuKal radiation. Samples were measured in reflection mode in the 20-40 ° range-20 using an X'celerator detector.

Elemental composition (CHN) was measured on an Elementar Vario EL instrument from Elementar. About 4 mg of sample was measured for each measurement, and the results are given as mean values of two measurements.

Example Ia An HBr salt of compound I

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

Example 1b HBr decomposed salt I

2- (4-Tolylsulfanyl) phenyl bromide

In a stirred N-methylpyrrolidone nitrogen-reactor, NMP (4.5L) was subjected to nitrogen flow for 20 minutes. 4-Methyl benzenethiol (900 g, 7.25 mol) was added and then 1,2-dibromo-benzene (1709 g, 7.25 mol). Potassium tert-butoxide (813 g, 7.25 mol) was finally added as the last reagent. The reaction was exothermic giving a temperature rise of the reaction mixture to 70 ° C. The reaction mixture was then heated at 120 ° C for 2-3 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (4L) was added and aqueous sodium chloride solution (15%, 2.5L). The mixture was stirred for 20 minutes. The aqueous phase was separated and extracted with another portion of ethyl acetate (2L). The aqueous phase was separated and the organic phases were combined and washed with sodium chloride solution (15%, 2.5L). The organic phase was separated, dried with reduced pressure sodium sulfate to a red oil containing 20-30% NMP. The oil was diluted to twice the volume with methanol and the mixture was slowly cooled to room temperature while sown. The product crystallizes as off-white crystals, they were 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 nitrogen cover 2- (4-tolylsulfanyl) phenyl bromide (600 g, 2.15 mol) was suspended in heptane (4.5 L). At room temperature BuLi IOM in hexane (235 mL, 2.36mol) was added over 10 minutes. Only a small exotherm was noted. The suspension was stirred for 1 hour at room temperature and then cooled to -40 ° C. 1-Carbethoxy-4-piperidone (368 g, 2.15 mol) dissolved in THF (1.5 L) was added at a not very rapid flow rate so that the reaction temperature was maintained at -40 ° C. When the reaction reached completion, it was warmed to 0 ° C and HCl IM (IL) was added keeping the temperature below 10 ° C. The acidic aqueous phase was separated and extracted with ethyl acetate (1L). The organic phases were combined and extracted with sodium chloride solution (15%, 1L). The organic phase was dried over sodium sulfate and evaporated to a semi-crystalline mass. It was slurried with ethyl ether (250 mL) and filtered. Dries in a vacuum oven at 40 ° C to constant weight.

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

Trifluoroacetic acid (2.8kg, 24.9mol) and triethyl silane (362 g, 3.1 mol) were charged to a reactor with an efficient stirrer. Ethyl 4- hydroxy-4- (2- (4-tolylsulfanyl) -phenyl) piperidin-1-carboxylate (462 g, 1.24 mol) was added via a portioned powder funnel. The reaction was slightly exothermic. The temperature rose to 50 ° C. Upon 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 portion 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 which was further processed in the next step.

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

Crude ethyl 4- (2- (4-tolylsulfanyl) phenyl) piperidin-1-carboxylate as a red oil from Example 3 was mixed in a stirred reactor with hydrobromic acid in acetic acid (40%, 545 mL 3.11 mol). The mixture was heated at 80 ° C for 18 hours. The reaction mixture was cooled to room temperature. During cooling the product crystallizes. 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 1 c Recrystallization of HBr salt of compound I

A 10.0 gram mixture of the HBr salt of compound I, e.g. prepared as above, was heated to reflux in 100 ml H 2 O. The mixture became transparent and was fully dissolved at 80-90 ° C. To the clear solution was added 1 gram of charcoal and reflux was continued for 15 minutes before being filtered and allowed to cool spontaneously to room temperature.

During cooling white solid precipitation occurs and the suspension was stirred for 1 hour at room temperature. Filtration and vacuum drying at 40 ° C overnight yielded 6.9 grams (69%) of HBr acid addition salt of compound I. See Figure 1 for XRPD. Elemental analysis: 3.92% N, 59.36% C, 6.16% H (theory: 3.85% N, 59.34% C, 6.09% H)

Example Id Preparing Free Base Stock Solutions

To a mixture of 500 ml ethyl acetate and 200 ml H 2 O were added 50 grams of the HBr salt of compound I producing a two phase slurry. Approximately 25 ml of conc. which caused the formation of a clear two-phase solution (measured pH 13-14). The solution was stirred for 15 minutes and the organic phase was separated. The organic phase was washed with 200 ml H 2 O, dried over Na 2 SO 4, filtered and evaporated in vacuo at 60 ° C yielding the free base in 38 grams (99%) yield as an almost colorless oil.

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

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

Example 1 and Salt Formation Using Free Base Stock Solutions

The given aliquots were added to test tubes and while shaking the appropriate amount of acid was added as indicated in Table 1. If the acid was a liquid it was added neat otherwise it was dissolved in the given solvent prior to addition. After mixing and precipitation stirring was continued overnight and the precipitate collected by filtration. Prior to vacuum drying at 30 ° C a small reference sample was taken and dried at room temperature without vacuum. This procedure was included for the purpose of testing solvates. Some results are shown in Table 1. XRPD diffractograms are shown in Figures 1-22, and selected peak positions are tabulated in Table 2. Table 3 shows the solubilities of the compounds of the present invention in water along with pH in the resulting saturated solution. The "Precipitate" column shows whether the isolated precipitate after solubility determination is identical to the dissolved compound, which is indicative of hydrate formation.

Table 1

<table> table see original document page 31 </column> </row> <table>

Table 2: Selected X-ray peak positions (° 2Θ), 2: 1 means 2 bases for 1 acid. All values ± 0.1 °

<table> table see original document page 31 </column> </row> <table> <table> table see original document page 32 </column> </row> <table>

Table 3

<table> table see original document page 32 </column> </row> <table> Example 2A Serotonin (5-HT) and norepinephrine (NE) reuptake inhibition

Aliquots of test compound and rat cortical synaptosome preparation were prepared for 10 min / 37 ° C, and then added [3 H] NE or [3 H] 5-HT (10 nM final concentration). Non-specific uptake was determined in the presence of talsupram or citalopram 10μΜ and total uptake was determined in the presence of buffer. Aliquots were incubated for 15 minutes at 37 ° C. Following incubation [3H] NE or [3H] 5-HT captured by synaptosomes was separated by filtration through Unifilter GF / C, pre-soaked in 0.1% PEI for 30 minutes using a Tomtec Cell Harvester program. Filters were washed and counted in a Wallac MicroBeta counter.

In NET compounds of the present invention exhibit an IC 50 value of 23 nM. In SERT compounds of the present invention exhibit an IC 50 value of 8 nM.

Example 2B 5-HT2a Antagonism

Compounds of the present invention were tested for serotonin receptor affinities and found to exhibit an affinity antagonist profile at 5-HT 2a receptors (54 nM Ki). Affinity is calculated from Y = 100 / (1 + 10 (X-logIC50) where Y denotes% binding and X denotes compound concentration. 5 Compound concentrations (1, 10, 30, 100, 1,000 nM) were used to Calculating the IC50-Ki value was calculated from the Cheng-Prusoff equation Ki = (IC50 / (1+ ([L] / Kd)). Affinity was determined in MDL Pharmaservices catalog number 271650.

In mammalian cells expressing human 5-HT 2a receptors compounds of the present invention exhibit competitive antagonistic properties. The compounds bind to 5-HT 2a receptors with a Ki of <100 nM and in a functional assay the compounds antagonize 5-HT-evoked Ca 2+ release from intracellular deposits with a Kb of 67 nM. Schild analysis revealed antagonism with a 100 nM Kb.

The experiment was performed as follows. 2 or 3 Days prior to the experiment CHO cells expressing 250 fmol / mg human 5-HT2a receptors are plated at a density sufficient to give a confluent monolayer on the day of the experiment. The cells are loaded with dye (Molecular Devices kit-Ca2 +) for 60 minutes at 37 ° C in a 5% CO2 incubator in 95% humidity. Basal fluorescence was monitored on a fluorometric or FLIPR plate reader from Molecular Devices (Sunnyvale, CA) with an excitation wavelength of 488 nm and an emission range of 500 to 560 nm. Laser intensity was adjusted to an appropriate level to obtain baseline values of approximately 8,000-10,000 fluorescence units. The variation in basal fluorescence should be less than 10%. EC50 values are evaluated using increasing concentrations of test compound covering at least 3 decades. PA2 values are evaluated by challenging total 5-HT dose-response curves with four different compound concentrations (150, 400, 1500, and 4000 nM). Kb values have also been evaluated challenging 2 decades of 5-HT EC85 test substance concentrations. 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 human 5-HT homomeric 5-HT3A receptors activates currents with an EC50 of 2,600 nM. This stream may be antagonized with classical 5-HT 3 antagonists such as ondansetron. Ondansetron displays a Ki value below 1 nM in this system. Compounds of the present invention exhibit potent antagonism at low concentrations (0.1 nM - 100 nM) (IC50 ~ 10 nM / Kb ~ 2 nM) and agonistic properties when applied at higher concentrations (100 - 100,000 nM) (EC50 ~ 2,600 nM ) reaching a maximum current of approximately 70-80% of the maximum current induced by 5-HT itself. In oocytes expressing 5-HT rat homomeric 5-HT3A receptors activates currents with an EC50 of 3.3 μΜ. The experiments were performed as follows. Oocytes were surgically removed from mature female anesthetized Xenepus laevis in 0.4% MS-222 for 10-15 min. The oocytes were then digested at room temperature for 2-3 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 escaped from the follicle layer were selected and incubated for 24 hours in Modified Barth Saline Buffer [88 mM NaCl, 1 mM KCl, 15 mM HEPES, 2.4 mM NaHCO3, 0.41 mM CaCl2, 0.82 mM MgSO4, 0.3 mM Ca (NO3) 2] supplemented with 2 mM sodium pyruvate, 0.1 U penicillin / l and 0.1 μl streptomycin. Stage IV-IV oocytes were identified and injected with 12-48 nl nuclease-free water containing 14 - 50 pg cRNA encoding human 5-HT3A receptors and incubated at 18 ° C until used for electrophysiological readings (1 -7 days after injection). Human 5-HT3 receptor-expressing oocytes were left in a 1 ml 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 impaled with agar bound on 0.5-1 ΜΩ electrodes containing 3 M KCl and clamped at -90 mV voltage by a GeneClamp 500B amplifier. Oocytes were continuously perfused with Ringer's buffer and drugs were applied to the perfused. 5-HT agonist solutions were applied for 10 - 30 s. The potencies of 5-HT3 receptor antagonists were examined by measuring concentration response against 10 μΜ 5-HT stimulation.

Example 2DA1A Receptor Antagonism

Compounds of the present invention were tested for α1A receptor affinities and were found to exhibit a medium affinity antagonist profile for aiA receptors (Ki = 34 nM).

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

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. Non-specific binding is determined in the presence of WB-4101 10μΜ and total binding is determined in the presence of buffer. After incubation, bound ligand is separated from unbound by filtration through Unifilter GF / B, pre-soaked in 0.1% PEI for 30 minutes, using a Tomtec Cell Harvester program (D4,2., 4). 96 wells. Filters are washed 3 with 1 ml of cold buffer, dried at 50 ° C and 35 µl scintillation / well liquid is added to the filters. Turned on radioactivity is counted in a Wallac OY 1450 MicroBeta. Affinity is calculated from Y = 100 / (1+ io (x-logIC50) where Y denotes binding% and X denotes compound concentration. Compound concentrations covering 2 decades were used to calculate the IC 50 value. Ki was calculated from Cheng-Prusoff Ki equation (IC 50 / (1+ ([L] / Kd)).

In a functional assay compounds of the present invention antagonize adrenaline-evoked Ca2 + release from cell stocks and a functional assay revealed that the compounds were antagonists.

These experiments were performed essentially as described below.

Cells were cultured in DMEM medium supplemented with 10% BCS, 4 mM L-glutamine (or 2 mM for COS-7), and 100 units / ml penicillin plus 100 µg / ml streptomycin at 37 ° C. in CO2 5%.

Twenty-four hours prior to assay, CHO cells expressing alpha1A_7 receptors were seeded in 384-well poly-D-lysine coated black wall microtiter plates. Culture medium was aspirated and cells were loaded with 1.5 µΜ Fluo-4 stain in Hank's Balanced Salt Solution assay buffer (138 mM NaCl, 5 mM KCl, 1.3 mM CaCl2, 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 probenicide (2.5 mM 50 µl / well) for 1 hour in 5% CO 2 at 37 ° C. After excess dye was discarded, cells were washed in assay buffer and layered with a final volume of 45 μΐ / well (or 30 μl / well for antagonist assay). In case of evaluation of antagonist, antagonist or vehicle was added at this point as a 15 μl aliquot in buffer containing 4% DMSO at 4x final concentration (final DMSO = 1%), followed by a 20 min incubation. Basal fluorescence was monitored on a fluorometric or FLIPR ™ plate reader from Molecular Devices (Sunnyvale, CA) with an excitation wavelength of 488 nm and an emission range of 500 to 560 nm. Laser excitation energy was adjusted so that the basal fluorescence readings were approximately 8,000 relative fluorescent units (RFU). Cells were then stimulated at room temperature with agonists diluted in assay buffer (15 μl), and RFU were measured at 1.5 second intervals over a period of 2.5 min. Maximum change in fluorescence was calculated for each well. Concentration-response curves derived from the maximum change in fluorescence were analyzed by nonlinear regression (Hill's equation). For antagonistic determinations, after 20 min of compound incubation (as above), fixed concentrations of standard serotonin agonist were added.

Example 2E Increase in Dopamine

A single dose-dependent injection of compounds of the present invention increased extracellular AD levels in rat frontal cortex. The compound of the present invention at 8.9mg / kg and 18mg / kg sc increased AD levels by approximately 100% and 150%, respectively, above baseline levels as shown in Figure 23. Quantities are calculated as free base.

Method.

Male Sprague-Dawley rats, initially weighing 275-300 g, were used. Animals were housed under a 12 h light / dark cycle under controlled conditions for regular internal temperature (21 ± 2 ° C) and humidity (55 ± 5%) with available ad libitum feed and tap water. For the three day treatment experiments osmotic minipumps (Alzet, 2ML1) were used. The pumps were filled under aseptic conditions and implanted subcutaneously under sevoflurance anesthesia. The experiments were performed with mini pumps on board. Blood samples to measure plasma levels of the test compound after 3 days of treatment were collected at the end of the experiments.

Surgery and microdialysis experiments.

Animals were anesthetized with hypnorm / dormicum (2 ml / kg) and intracerebral guide cannulae (CMA / 12) were sterotaxically implanted in the hippocampus, positioning 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 mater or frontal cortex (coordinates: 3.2 mm anterior to the bregma; lateral, 3.0 mm; 4.0 mm ventral to the dura mater). Acrylic cement were used for guide cannula fixation.The body temperature of the animals was monitored by rectal probe and kept at 37 ° C. The rats were allowed to recover from surgery for 2 days, individually housed in cages. The microdialysis probe (CMA / 12, 0.5 mm in diameter, 3 mm in length) was inserted through the guide cannula.The probes were connected via a dual channel spinner in a micro-injection pump. filtered Ringer's solution (NaCl 145 mm, 3 mM KCl, 1 mM MgCl2, 1.2 mM CaCl2) started immediately prior to probe insertion into the brain and continued during 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.

After the experiments the rats were killed by beheading, their brains were removed, frozen and sliced for probe placement verification.

Dialysate analysis.

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

Example 2F Increase in acetylcholine

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

Male Wistar rats (280-350 g; Harlan, Zeist, Netherlands) were used for the experiments. Rats were initially housed in plastic cages (30 cm χ 30 cm χ 40 cm) and had ad libitum access to food and water.

Rats were anesthetized using isoflurane (2%, 400 mL / min N 2 O, 400 mL / min O 2). Lidocaine (10% m / v) was used for local anesthesia. Each animal was positioned on a sterotaxic frame (Kopf Instruments, USA), and home-prepared I-shaped probes (Hospal AN 69 membrane, 4 mm exposed surface) were inserted into the prefrontal mediate cortex (mPFC) using atlas of brain brain of Paxinos and Watson (1982). Coordinates for the probe tip were mPFC [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 24-48 hours after surgery. On the day of the experiment, rats were connected with PEEK flexible tubing to the 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 into mini-flasks containing 55 μL of 0.02 M formic acid for acetylcholine determination. Samples were collected by an automatic fraction collector (CMA 142), and stored at -80 ° C until analyzed. After completing the experiments the rats were motorcycles. The brains were removed and cured in paraformaldehyde solution (4% w / v). The positioning of each probe was histologically verified according to Paxinos and Watson (1982), by performing coronal sections of the brain.

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

Acetylcholine concentrations were determined by tandem mass spectrometry (MS / MS) detection HPLC.

Aliquots (25 μΕ) were injected into the HPLC column by an automatic sample injector (PerkinElmer Instruments, 200 series). Chromatographic separation was performed on a 150 mm χ 2.00 mm (4 μm) reverse phase analytical column (Phenomenex Synergy MAX-RP, Bester) protected by a 4 mm χ 2.0 mm guard column (Phenomenex Synergy MAX-RP). 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%). Mobile phase was run through the system at a flow rate of 0.300 mL / min by an HPLC pump (PerkinElmer Instruments, 200 series micro pump).

LC / MS analyzes were performed using an API 4000 MS / MS system consisting of an API 4000 MS / MS detector and a Turbo Ion Spray interphase (both from Applied Biosystems, Netherlands). Acquisitions were performed in positive ionization mode, with electron spray voltage set at 5.5 kV, nebulizer gas pressure at 345 kPa (relative) (on a SCIEX scale of 0-90) with a probe temperature of 600 ° C. The instrument was operated in multiple reaction monitoring (MRM) mode for acetylcholine detection (precursor 146.1 Da, product 86.8 Da). The collision energy was 21.0 eV, and the collision gas (nitrogen) pressure was maintained at 7 (on a SCIEX scale of 0-12). Data were calibrated and quantified using the Analysttm data system (Applied Biosystem, version 1.2).

Two consecutive microdialysis samples with variation less than 50% were taken as baseline levels and adjusted to 100%. Changes in acetylcholine concentration were expressed as percentage of baseline within the same object.

The data are shown in Figure 24.

Example 2G Increase in acetylcholine

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

Male Sprague-Dawley rats, initially weighing 275-300 g, were used. Animals were housed under a 12-hour light / dark cycle under controlled conditions for regular internal temperature (21 ± 2 ° C) and humidity (55 ± 5%) with available ad libitum feed and tap water. Surgery and microdialysis experiments

Animals were anesthetized with hypnorm / dormicum (2 ml / kg) and intracerebral guide cannulae (CMA / 12) were sterotaxically implanted in the hippocampus, aiming at the positioning of the dialysis probe tip in the ventral hippocampus (coordinates: 5.6 mm anterior to the bregma). , lateral -5.0 mm, 7.0 mm ventral to dura mater or frontal cortex (coordinates: 3.2 mm anterior to bregma; lateral, 0.8 mm; 4.0 mm ventral to dura mater). anchorage and acrylic cement were used for guide cannula fixation.The body temperature of the animals was monitored by rectal probe and kept at 37 ° C. The rats were allowed to recover from surgery for 2 days, housed individually in cages. A microdialysis probe (CMA / 12, 0.5 mm in diameter, 3 mm in length) was inserted through the guide cannula.

The probes were connected via a dual channel spinner to a microinjection pump. Perfusion of microdialysis probe with filtered Ringer's solution (145 mm NaCl, 3 mM KCl, 1 mM MgCl2, 1.2 mM CaCl2 containing 0.5 μΜ neostigmine) was initiated immediately prior to insertion of the probe into the brain and continued during the experiment. at a constant flow rate of 1 μl / μm. After 180 min of stabilization, the experiments were started. Dialysates were collected every 20 min. After the experiments the rats were killed by beheading, their brains were removed, frozen and sliced for probe placement verification. Analysis of acetylcholine in dialysate

Acetylcholine (ACh) concentration in the dialysates was analyzed by electrochemical detection HPLC using a mobile phase consisting of 100 mM disodium hydrogen phosphate, 2.0 mM octane sulfonic acid, 0.5 mM tetramethyl ammonium chloride and MB (ESA) 0.005%, pH 8.0. A pre-column enzyme reactor (ESA) containing immobilized choline oxidase eliminated choline from the injected sample (10 μl) prior to separation of ACh into the analytical column (ESA ACH-250); flow rate 0.35 ml / min, temperature: 35 ° C. After the analytical column, the sample passed through a post-column solid phase reactor (ESA) containing immobilized acetylcholine esterase and choline oxidase. The last reactor converted ACh into choline and subsequently choline into betaine and H2O2. The latter was detected electrochemically by the use of a platinum electrode (Analytical cell: ESA, model 5040).

Data Presentation

In single injection experiments the mean value of 3 consecutive ACh samples immediately preceding compound administration served as the baseline level for each experiment and data were converted to percentage of baseline (average baseline pre-injection values normalized to 100%). Data are presented in Figures 25a and 25b.

The data presented in Figure 24 show surprising drops in acetylcholine levels (see e.g. 8 mg / kg) which are difficult to explain and which are attributed to experimental uncertainty. In general, both data sets of examples 2F and 2G show the same, i.e. a dose dependent increase in extracellular acetylcholine levels in the brain. This preclinical finding is expected to translate into an improvement in cognition in a useful clinical setting e.g. in the treatment of diseases characterized by cognitive impairment, such as e.g. Alzheimer's patients, partial responders, cognitive impairment etc.

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 are injected with formalin (4.5%, 20 μl) on the plantar surface of the left hind paw and then placed in individual glass beakers (2 L capacity) for observation. The irritation caused by formalin injection generates a characteristic biphasic behavioral response as quantified by the amount of time consumed by licking the injured. The first phase (-0-10 minutes) represents direct chemical irritation and nociception, while the second phase (20-30 minutes) is considered to represent pain of neuropathic origin. The two phases are separated by a quiescent period in which the behavior returns to normal. Measurement of the amount of time consumed by licking the injured paw in both phases assesses the effectiveness of the test compounds in reducing painful stimuli.

Eight C57 / B6 mice (ca. 25g) were tested per group. Table 4 below shows the amount of time spent licking the injured paw in the two phases, i.e. 0-5 minutes and 20-30 minutes after formalin injection. The amount of compound administered is calculated as the free base.

Table 4

<table> table see original document page 44 </column> </row> <table>

The data in Table 4 shows that the compound of the present invention has little effect in the first phase representing direct chemical irritation and nociception. Most notably, the data also show a clear and dose-dependent decrease in time spent licking paws in the second phase indicating an effect of the compound of the present invention in the treatment of neuropathic pain.

Example 4 Capsules

4- [2- (4-Methyl-phenylsulfanyl) -phenyl] -piperidine hydrobromide was mixed with microcrystalline cellulose in a first step. In a second step magnesium stearate was mixed. Capsules with four concentrations were prepared - the active ingredient is stated as the free base.

<table> table see original document page 45 </column> </row> <table>

10,000 Capsules were prepared from each batch.

Claims (32)

Pharmaceutical acceptable compound and salts thereof, characterized in that it is compound I which is 4- [2- (4-methyl-phenylsulfanyl) -phenyl] -piperidine <formula> formula see original document page 46 </ formula > in a crystalline form provided that said compound is not 4- [2- (4-methyl-phenylsulfanyl) -phenyl] -piperidine hydrochloride addition salt. Compound according to Claim 1, characterized in that it is the HBr salt. A compound according to claim 2, characterized by the peaks in an XRPD at approximately 6.08, 14.81, 19.26 and 25.38 ° 2Θ. A compound according to claim 2, characterized by an XRPD as shown in Figure 1. Compound according to Claim 1, characterized in that it is the DL-lactic acid addition salt. A compound according to claim 5, characterized by the peaks in an XRPD at approximately 5.30, 8.18, 9.44 and 17.24 ° 2Θ. A compound according to claim 5, characterized by an XRPD as shown in Figure 4. Compound according to claim 1, characterized in that it is the glutaric acid addition salt (1: 1). A compound according to claim 8, characterized by the peaks in an XRPD at approximately 9.39, 11.70, 14.05 and 14.58 ° 2Θ. A compound according to claim 8, characterized by an XRPD as shown in Figure 8. Compound according to Claim 1, characterized in that it is the malonic acid addition salt (1: 1). A compound according to claim 11, characterized by the peaks in an XRPD at 10.77 °, 16.70 °, 19.93 ° and 24.01 ° 2Θ, or at 6.08 °, - 10.11 ° , 18.25 ° and 20.26 ° 2Θ. A compound according to claim 11, characterized by an XRPD as shown in Figure 9 or 10. Compound according to claim 1, characterized in that it is L-aspartic acid addition salt (1: 1) or L-aspartic acid addition salt hydrate (1: 1). Compound according to claim 1, characterized in that it is the glutamic acid addition salt (1: 1) or the glutamic acid addition salt monohydrate. Compound according to any one of claims 1 to 15, characterized in that it is for use in therapy. Pharmaceutical composition, characterized in that it comprises the compound as defined in any one of claims 1 to 15 together with a pharmaceutically acceptable excipient. 18. Method of treating a selected disease of chronic pain, depression in partial responders, treatment-resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholy, PTSD, hot flushes, sleep apnea, alcohol craving, nicotine, or carbohydrate. , substance abuse, alcohol or drug abuse, emesis, eating disorders, IBS, affective disorders, depression, major depressive disorder, postpartum 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 stress urinary incontinence, characterized by understanding administering to a patient in need thereof therapeutically effective compound as defined in any one of claims 1 to 15. A method according to claim 18, characterized in that said disease is chronic pain. A method according to claim 19, characterized in that said chronic pain is selected from phantom limb pain, neuropathic pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), neuralgia. HIV, complex regional pain syndrome (CPRS), trigeminal neuralgia / trigeminus / painful tic neuralgia, surgical intervention (eg postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, associated pain with menstruation, cancer-associated pain, dental pain, headache, migraine, tension-type headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis) , rheumatoid arthritis, rheumatoid arthritis, and edema resulting from trauma associated with burns, sprains, or fractured bone pain due to osteoarthritis, osteoporosis, bone metastasis or unknown reasons, gout, fibrositis, myofascial pain, thoracic outlet syndromes, upper back pain or lower back pain (in which back pain results from primary, regional, or spinal disease) Systematic, pelvic pain, cardiac chest pain, non-cardiac chest pain, pain associated with backbone injury (SCI), central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain and geriatric pain. Method according to claim 20, characterized in that said chronic pain is neuropathic pain. A method according to claim 21, characterized in that said neuropathic pain is selected from hyperpathy, hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, hyperesthesia, causalgia, and allodynia. Use of the compound as defined in any one of claims 1 to 15, characterized in that it is in the manufacture of a medicament for the treatment of a selected disease of chronic pain, depression in partial responders, treatment resistant depression, Alzheimer's disease. , cognitive impairment, ADHD, melancholy, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse, alcohol or drug abuse, emesis, eating disorders, IBS, affective disorders, depression, depressive disorder major, postpartum 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, phobia agoraphobia or stress urinary incontinence. Use according to claim 23, characterized in that said disease is chronic pain. Use according to claim 24, characterized in that said chronic pain is selected from phantom limb pain, neuropathic pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), neuralgia. HIV, complex regional pain syndrome (CPRS), trigeminal neuralgia / trigeminus / painful tic neuralgia, surgical intervention (eg postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, associated pain with menstruation, cancer-associated pain, dental pain, headache, migraine, tension-type headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis) , rheumatoid arthritis, rheumatoid arthritis, and edema resulting from trauma associated with burns, sprains, or fractured bone pain due to steoarthritis, osteoporosis, bone metastasis or unknown reasons, gout, fibrositis, myofascial pain, chest output syndromes, upper back pain or lower back pain (in which back pain results from primary, regional, or systematic backbone disease (radiculopathy)) , pelvic pain, cardiac chest pain, noncardiac chest pain, pain associated with backbone injury (SCI), central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain and geriatric pain. Use according to claim 25, characterized in that said chronic pain is neuropathic pain. Use according to claim 26, characterized in that said neuropathic pain is selected from hyperpathy, hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, hyperesthesia, causalgia, and allodynia. Compound according to any one of claims -1 to 15, characterized in that it is for use in the treatment of a selected disease of chronic pain, depression in partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD. , melancholy, PTSD, hot flushes, sleep apnea, alcohol craving, nicotine or carbohydrate, substance abuse, alcohol or drug abuse, emesis, eating disorders, IBS, affective disorders, depression, major depressive disorder, post-depression childbirth, 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 incontinence urinary stress disorder. Compound according to claim 28, characterized in that it is for use in the treatment of chronic pain. A compound according to claim 29 for use in the treatment of phantom limb pain, neuropathic pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuralgia. , complex regional pain syndrome (CPRS), trigeminal neuralgia / trigeminus / painful tic neuralgia, surgical intervention (eg postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms associated with insulitis, pain associated with angina, pain associated with menstruation , pain associated with cancer, dental pain, headache, migraine, tension type headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis), arthritis rheumatoid, rheumatoid arthritis and edema resulting from trauma associated with burns, sprains or fractured bone pain due to osteoart ritis, osteoporosis, bone metastasis or unknown reasons, gout, fibrositis, myofascial pain, chest output syndromes, upper back pain, or lower back pain (in which back pain results from primary, regional, or systematic backbone disease (radiculopathy)) , pelvic pain, cardiac chest pain, non-cardiac chest pain, pain associated with backbone injury (SCI), central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain or geriatric pain. Compound according to claim 30, characterized in that it is for use in the treatment of neuropathic pain. A compound according to claim 31, characterized in that said neuropathic pain is selected from hyperpathy, hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, hyperesthesia, causalgia, and allodynia.