KR20090018630A - Crystalline Form of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine in Combination with Serotonin and Norepinephrine Reuptake Inhibitors for the Treatment of Neuropathic Pain - Google Patents

Abstract

Crystalline forms of 4- [2- (4-methylphenylsulfanyl) and salts thereof are provided for the treatment of neuropathic pain, for example.

Description

Crystalline form of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine in combination with serotonin and norepinephrine reuptake inhibitors for the treatment of neuropathic pain {CRYSTALLINE FORMS OF 4- [2- (4- METHYLPHENYLSULFANYL) -PHENYL] -PIPERIDINE WITH COMBINED SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITION FOR THE TREATMENT OF NEUROPATHIC PAIN}

Perception of pain is more complex than direct transmission of signals from the damaged part of the body to specific receptors in the brain, where the perceived pain is proportional to the injury. Rather, peripheral tissue damage and nerve damage can result in alterations in the central nervous system involved in pain perception that affect pain sensitivity accordingly. Such neuroplasticity can lead to sensitization in response to longer lasting noxious stimuli, for example, as chronic pain, ie the perception of pain, remains after the noxious stimulus has stopped. , Or hyperalgesia, ie, an increased response to painful stimuli in general. One more incomprehensible and dramatic example of this is the "phantom limb symptom", ie the persistence of the pain present before the amputation of the limbs. Recent articles on central neuroplasticity and pain include Melzack et al . , Ann. NY Acad. Sci ., 933, 157-174, 2001.

Chronic pain, such as neuropathic pain, is found to be different from other types of pain, for example somatic or visceral pain. The pain is often described as shooting, burning, pins and needls, numb, or stabbing. Common causes of neuropathic pain include alcoholism, amputation, back, leg and buttock problems, chemotherapy, diabetes, HIV, multiple sclerosis, spinal surgery, and shingles virus infection.

The main component for chronic pain may explain why chronic pain, such as neuropathic pain, for example, often responds poorly to traditional analgesics such as non-steroidal anti-inflammatory drugs (NSAIDS) and opioid analgesics. Can be. Tricyclic antidepressants (TCAs), represented by amitriptyline, have become the standard for the treatment of neuropathic pain, and this effect is mediated by the combined inhibitory effects on serotonin transporters and norepinephrine transporters. Clin Ther., 26, 951-979, 2004. More recently, so-called dual action antidepressants, which have 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 are often referred to as SNRIs.

Although data on the use of selective serotonin reuptake inhibitors (SSRIs) for neuropathic pain are rare, generally limited effects are suggested [ Bas. Clin. Pharmacol ., 96, 399-409, 2005]. In fact, it is hypothesized that SSRIs are only mild anti-irritants on their own but inhibition of serotonin transporters increases the anti-irritant effect of norepinephrine reuptake inhibition. This concept is supported by the review of 22 animal and five human studies, which showed that SNRI had superior anti-irritancy compared to norepinephrine reuptake inhibitors, that is, it was superior to SSRI [ Pain Med. 4, 310-316, 2000].

5-HT ₃ antagonist for the last five data sets Ron (ondansetron) suggest that the 5-HT ₃ antagonist can have the analgesic effect, and therefore useful for the treatment of neuropathic pain [Anesth.Analg., 97, 1474-1478, 2003].

However, the use of tricyclic antidepressants is associated with known anticholinergic side effects such as, for example, drowsiness, anxiety, restlessness, and cognitive and memory difficulties. Thus, there is a need in the art to find alternative methods of treating neuropathic pain.

International patent applications published as WO 2003/029232 disclose, for example, 4- [2- (4-methylphenylsulfanyl) phenyl] piperidine compounds and the corresponding HCl salts as free bases. The compounds have been reported as inhibitors of serotonin transporters and serotonin receptor 2C (5-HT _2C ), which have been shown to be useful for the treatment of emotional disorders such as depression and anxiety.

Summary of the Invention

The inventors have surprisingly added that, in addition to the already known pharmacological profile, 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine is a potent inhibitor of serotonin reuptake and norepinephrine reuptake, serotonin receptor 3 (5 It was found that antagonists of -HT ₃ ), antagonists of serotonin receptor 2A (5-HT _2A ), and inhibitors of α ₁ adrenergic receptors, which compounds may be useful, for example, in the treatment of chronic pain. Accordingly, the present invention relates to crystalline Compound I, ie 4- [2- (4-methylphenyl-sulfanyl) phenyl] piperidine and pharmaceutically acceptable salts thereof, provided that the compound is 4- [2- (4 -Methylphenyl-sulfanyl) phenyl] -piperidine hydrochloride addition salt is provided on condition that it is not.

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

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 present invention relates to a pharmaceutical composition comprising compound I.

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

1: X-ray diffraction pattern of the HBr addition salt of Compound I

2: X-ray diffraction pattern of the HBr addition salt solvate of Compound I

3: X-ray diffraction pattern of palmitic acid addition salt of Compound I

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

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

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

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

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

9: malonic acid addition salt of compound I (1: 1), α-form X-ray diffraction pattern

10: Malonic acid addition salt of Compound I, X-ray diffraction pattern of β-form

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

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

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

14: X-ray diffraction pattern of L-malic acid addition salt (1: 1), α-form of Compound I

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

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

FIG. 17: X-ray diffraction pattern of L-aspartic acid addition salt (1: 1) of Compound I mixed with L-aspartic acid

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

19: X-ray diffraction pattern of glutamic acid addition salt (1: 1) of Compound I mixed with glutamic acid monohydrate

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

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

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

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

Figure 24: Acetylcholine levels in the prefrontal cortex for administration of the compounds of the present invention

25A + B: Acetylcholine levels in the prefrontal cortex and ventral hippocampus for administration of the compounds of the invention

The present invention relates to crystalline compound I, i.e. 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine and pharmaceutically acceptable salts thereof, provided that the compound is not a hydrochloric acid addition salt It is done. The structure of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine is as follows.

The pharmacological profile of the compounds of the present invention is described in the Examples, but can be summarized as follows. The compound as an inhibitor of serotonin and norepinephrine reuptake; It inhibits serotonin receptors 2A, 2C and 3; inhibits α-1 adrenergic receptors.

In one embodiment, the pharmaceutically acceptable salt is an acid addition salt of a nontoxic acid. The salts include organic acids such as maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, malic acid. Lonic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, and 8-halophylline, for example Salts formed from 8-bromotheophylline. The salts may also be formed from inorganic acids such as hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. Additionally useful salts are listed in the table of Example 1d (Table 1).

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

In one embodiment, the compounds of the invention are DL-lactic acid addition salts, in particular 1: 1 salts.

In one embodiment, the compounds of the present invention are L-aspartic acid addition salts, in particular 1: 1 salts.

In one embodiment, the compounds of the invention are glutamic acid addition salts, in particular 1: 1 salts.

In one embodiment, the compounds of the present invention are glutaric acid addition salts, in particular 1: 1 salts.

In one embodiment, the compounds of the present invention are malonic acid addition salts, in particular 1: 1 salts, which are found to exist in two polymorphic modifications, α and β, of which β forms a low solubility. It is considered to be the most stable by reference.

In one embodiment, the compounds of the present invention are in purified form. The term “purified form” is optionally where the compound is essentially free from other compounds or other forms, ie polymorphs of the compound.

Oral dosage forms, and in particular tablets and capsules, are often preferred to patients and physicians because of their ease of administration and consequently better compliance. For tablets and capsules, it is preferred that the active ingredient is crystalline.

Crystals of the present invention may exist as solvates, ie crystals in which solvent molecules form part of the crystal structure. The solvate may be formed from water, in which case the solvate is often referred to as a hydrate. Alternatively, the solvate may be formed from other solvents such as ethanol, acetone, or ethyl acetate. The exact amount of solvate often depends on the conditions. For example, hydrates typically free water when the temperature is increased or the relative humidity is decreased. Under conditions such as changes in humidity, for example, compounds that do not change or change little are generally considered to be more suitable for pharmaceutical formulations. HBr addition salts do not form hydrates when precipitated from water, while compounds such as succinate, maleate and tartrate acid addition salts are known to form hydrates.

Some compounds are hygroscopic, ie they absorb water when exposed to moisture. Hygroscopicity is generally considered an undesirable property for compounds present in pharmaceutical formulations, especially dry formulations such as tablets or capsules. In one embodiment, the present invention provides crystals with low hygroscopicity.

It is also beneficial if the crystals are well defined for oral dosage forms using crystalline active ingredients. In the present context, the term “well defined” is particularly well defined in terms of stoichiometry, ie the ratio between small integers between ions forming salts, such as 1: 1, 1: 2, 2: 1, 1: 1. : 1 or the like. In one embodiment, the compounds of the present invention are well defined crystals.

Solubility of the active ingredient is also important for the choice of dosage form as it may directly affect bioavailability. For oral dosage forms, it is believed that high solubility active ingredients generally increase the bioavailability. Some patients, such as elderly patients, may have difficulty swallowing tablets, and oral drops may be a suitable alternative avoidance of the need to swallow tablets. In order to limit the volume of oral drops, it is necessary to have a high concentration of the active ingredient in the solution, ie high solubility of the compound is required. As shown in Table 3, DL-lactic acid, L-aspartic acid, glutamic acid, glutaric acid and malonic acid addition salts have exceptionally high solubility.

The crystalline form affects the filtration and processing properties of the compound. Needle-shaped crystals tend to be more difficult to handle in production environments because they are more difficult and time consuming to filter. The exact crystal form of a given salt may vary depending, for example, on the conditions under which the salt precipitates. The HBr acid addition salts of the present invention grow as needle-shaped solvated crystals when precipitated from ethanol, acetic acid and propanol, but are not needle-shaped, which provide excellent filtration properties for HBr addition salts precipitated from water. Grows into crystals in non-hydrate form.

Table 3 also describes the pH obtained, ie the pH in a saturated solution of salt. This property is important because moisture cannot be completely avoided during storage, and the accumulation of moisture can cause a decrease in pH in or on tablets containing low obtained pH salts, which can reduce shelf life. In addition, salts with a low obtained pH can cause corrosion of the process equipment when the tablet is made by wet granules. The data in Table 3 suggest that HBr, HCl and adipic acid addition salts can be superior in this respect.

In one embodiment, the compounds of the invention are HBr addition salts in crystalline form, especially in purified form. In a further embodiment, the HBr salt has peaks at approximately 6.08 °, 14.81 °, 19.26 ° and 25.38 ° 2θ in the X-ray powder diffraction pattern (XRPD), in particular the HBr salt is XRPD as shown in FIG. 1. Has

In one embodiment, the compounds of the invention are DL-lactic acid addition salts (1: 1) in crystalline form, especially in purified form. In a further embodiment, the DL-lactic acid addition salt has peaks at approximately 5.30 °, 8.81 °, 9.44 ° and 17.24 ° 2θ in XRPD, in particular the DL lactic acid addition salt has an XRPD as shown in FIG. 4.

In one embodiment, the compounds of the invention are L-aspartic acid addition salts (1: 1) in crystalline form, especially in purified form. In a further embodiment, the L-aspartic acid addition salt is unsolvated and has peaks at approximately 11.05 °, 20.16 °, 20.60 °, 25.00 ° 2θ in XRPD, in particular the L-aspartic acid salt mixed with L-aspartic acid If so, it has an XRPD as shown in FIG. In one embodiment, the L-aspartic acid addition salt is a particularly hydrate in purified form. In a further embodiment, the L-aspartic acid addition salt hydrate has peaks at approximately 7.80 °, 13.80 °, 14.10 °, 19.63 ° 2θ in XRPD, in particular the L-aspartic acid addition salt hydrate is mixed with L-aspartic acid Case, it has an XRPD as shown in FIG.

In one embodiment, the compounds of the invention are glutamic acid addition salts in crystalline form, especially in purified form. In a further embodiment, the glutamic acid addition salt has peaks at approximately 7.71 °, 14.01 °, 19.26 °, 22.57 ° 2θ in XRPD, especially when the glutamic acid salt is mixed with glutamic acid monohydrate, as shown in FIG. 19. Has XRPD.

In one embodiment, the compounds of the invention are malonic acid addition salts (1: 1) in crystalline form, especially in purified form. In further embodiments, the malonic acid addition salt has a peak at approximately 10.77 °, 16.70 °, 19.93 °, 24.01 ° 2θ in the XRPD in α-form, or the malonic acid addition salt is approximately 6.08 in XRPD in β-form Peaks at °, 10.11 °, 18.25 °, 20.26 ° 2θ, in particular the malonic acid addition salt has an XRPD as shown in FIG. 9 or 10.

In one embodiment, the compounds of the present invention are glutaric acid addition salts (1: 1) in crystalline form, especially in purified form. In a further embodiment, the glutaric acid addition salt has peaks at approximately 9.39 °, 11.70 °, 14.05 ° and 14.58 ° 2θ in XRPD, in particular the glutaric acid addition salt has XRPD as shown in FIG. 8. .

As mentioned above, the compounds of the present invention are particularly well suited for the treatment of chronic pain. Chronic pain includes, for example, annular pain, neuropathic pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex site pain syndrome (CPRS), tertiary (trigeminal) neuralgia / trigeminus neuralgia / tic douloureux, surgical intervention (e.g. postoperative analgesics), diabetic angiopathy, capillary or diabetic symptoms associated with insulin salts, associated with angina Pain, Menstrual Pain, Cancer Pain, Toothache, Headache, Migraine, Tension Headache, Trigeminal Neuralgia, Temporomandibular Syndrome, Myofascial Muscle Injury, Fibromyalgia Syndrome, Bone and Joint Pain (osteoarthritis), Rheumatoid Arthritis, Burn Related Mental Rheumatoid arthritis and swelling, osteoarthritis, osteoporosis, sprains or fracture pain due to unknown reasons, gout, resulting from trauma, Mastitis, myofascial pain, thoracic outlet syndrome, back upper or lower back pain (back pain from systemic, local, or primary spinal disease (neuromyopathy)), pelvic pain, angina chest pain, non-angina chest pain, spinal cord injury ( Signs such as SCI) -related pain, central stroke pain, cancer neuropathy, AIDS pain, sickle cell pain or senile 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 signs listed above.

Pain is defined by the International Association for the Study of Pain (IASP) as "unpleasant sensory and emotional experiences that are described in terms of or associated with actual or potential tissue damage" (IASP). Classification of chronic pain, 2 ^nd Edition, IASP Press (2002), 210). Pain is always subjective but the cause or syndrome can be classified. “Neuropathic pain” is a subtype defined by the IASP as “pain caused or caused by primary damage or dysfunction in the nervous system”.

Different subtypes of neuropathic pain were approved by the IASP, as follows:

Allodynia, defined as "pain from irritation that normally does not cause pain".

-Defined as causalgia, "continuous burning pain, allodynia and hyperalgesia syndrome", often after traumatic nerve injury and nutritional changes combined with vasomotor and sweating neuropathy.

-Hypersensitivity, defined as "increased sensitivity to stimulation, except sensation".

Neuralgia, defined as "distribution to nerves or nerves".

Neuritis, defined as "inflammation of nerves or nerves".

Neuropathy, defined as "confusion or pathological change in function in nerves: mononeuropathy in one neuron, when diffuse, multiple mononeuropathy in several neurons, and double, multiple neuropathy". Neuropathy can be associated with diabetes, for example, in which case it is described as diabetic neuropathy.

Sensory hypersensitivity, defined as "increased response to normally painful stimuli".

Hyperalgesia, defined as "a pain syndrome characterized by irritation, in particular an abnormal pain response to repeated stimuli and increased thresholds".

The stimulus that causes 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 not directly related to chronic pain. For example, 5-HT _2C receptors located on dopaminergic neurons will exert a strain inhibitory effect on dopamine release upon activation, and 5-HT _2C antagonists will increase dopamine levels. The data presented in Example 2E show that the compounds of the present invention actually result in an increased dose dependency of extracellular dopamine levels in the brain. Based on this, it can be hypothesized that 5-HT _2C antagonists are particularly suitable for the treatment of refractory depression in the treatment with selective serotonin reuptake inhibitors [ Psychopharmacol. Bull ., 39, 147-166, 2006]. This hypothesis is supported by several clinical studies showing that the combination of mirtazapine and SSRI is superior to SSRI alone for the treatment of depressed patients with inappropriate clinical responses (treatment depression, TRD, or refractory depression). Is found [ Psychother. Psychosom ., 75, 139-153, 2006]. Mirtazapine is also a 5-HT ₂ and 5- HT ₃ antagonist, and the compound which causes the 5-HT ₂ and 5-HT ₃ antagonist, serotonin reuptake inhibitory action in combination with, for example, the compounds of the present invention, the treatment of TRD It is useful for, that is, treatment resistance can increase the remission rate of patients suffering from depression.

The data presented in Examples 2F and 2G show that the compounds of the present invention result in increased levels of extracellular acetylcholine in the prefrontal cortex and ventral hippocampus. There is many years of clinical evidence that increasing acetylcholine levels in the brain is a way to treat Alzheimer's disease and general cognitive impairment (as compared to the use of acetylcholine esterase inhibitors in the treatment of Alzheimer's disease). Based on this, the compounds of the present invention are believed to be useful for the treatment of Alzheimer's disease and cognitive disorders, and also depression associated with mood disorders such as Alzheimer's disease and cognitive disorders.

Some of the depressed patients may respond to treatment with, eg, SSRIs in that they may be improved for clinically relevant depression measures such as MADRD and HAMD, but other symptoms, such as sleep disorders and cognitive disorders, remain. In this context, these patients are referred to as partial responders. Because of the effects on acetylcholine levels discussed above, the compounds of the present invention are expected to be useful in the treatment of cognitive disorders in addition to depression. Clinical studies have shown that the compound prazosin, an α-1 adrenergic receptor antagonist, reduces sleep disorders [ Biol. Psychiatry , 61, 928-934, 2007]. In addition, 5-HT _2A and 5-HT _2C antagonism of the compounds of the present invention are also believed to have a sedative, sleep-improving effect [ Neuropharmacol , 33, 467-471, 1994], and therefore the compounds of the present invention are partially reactive. Useful in the treatment of a child or in other words, treatment of a depressed patient with a compound of the present invention may reduce some of the partial responders.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common nervous system disorders. ADHD is characterized by the presence of three signs of social and communication disorders with limited, repeated or homotyped behavior. ADHD typically begins in childhood or puberty, but symptoms can persist until adulthood. Atomoxetine is the only non-irritant recently approved by the FDA for the treatment of ADHD [ Drugs , 64, 205-222, 2004]. Atomoxetine norepinephrine reuptake inhibitor, suggesting that the compounds of the present invention can be used in the treatment of ADHD. In addition, the compounds of the present invention may have beneficial sedative effects in the treatment of ADHD because of the α-1 adrenergic receptor and 5-HT ₂ antagonism discussed above.

Melancholia is a subtype of depression, particularly often associated with severe depression; This type of depression is also referred to as melancholic depression. Melancholia is associated with anxiety, fear of the future, insomnia, and loss of appetite. Compounds that inhibit both serotonin and norepinephrine reuptake, eg venlafaxine, have been shown to be particularly effective in treating patients with severe depression and melancholia [ Depres. Anxiety , 12, 50-54, 2000]. As discussed above, compounds that cause 5-HT _2C antagonism increase dopamine levels, so such compounds may be expected to be effective in the treatment of melancholia [ 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 aid normalized sleep, and therefore the compounds are useful for the treatment of melancholia.

The FDA recently approved two SSRIs, sertraline and paroxetine for the treatment of post-traumatic stress disorder (PTSD). In addition, compounds with 5-HT _2A antagonistic activity are useful because they are expected to suppress excitement, insomnia and explosiveness in PTSD patients [ Curr opinion Invest . Drug, 4, 37-41, 2003]. Thus, the compounds of the present invention are expected to be useful for the treatment of PTSD.

Hot flashes are a symptom associated with menopause conversion. Some women may suffer to the extent that this usually interferes with sleep or activity and requires treatment. Hormone replacement therapies with estrogen have been practiced for decades, but recent attention has been directed to side effects such as breast cancer and heart events. Clinical trials using SSRIs and SNRIs have shown that the compounds are effective in hot flushes, although lower than estrogens. J. Am . Med . Ass ., 295, 2057-2071, 2006. Treatment of facial flushing with a compound that inhibits serotonin and / or norepinephrine reuptake, eg, a compound of the present invention, may be an alternative treatment for women who may or may not receive estrogen.

Sleep apnea or obstructive sleep apnea-low breathing syndrome or obstructive breathing related sleep disorder is a disorder in which effective pharmacotherapy remains to be demonstrated. However, studies in some animals suggest that 5-HT ₃ antagonists, such as the compounds of the present invention, may be effective in therapeutic intervention [ Sleep , 21, 131-136, 1998; Sleep , 8, 871, 878, 2001.

5-HT ₃ antagonist ondansetron has recently been shown to be 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 is because 5-HT ₃ antagonists, for example compounds of the invention, are craving, such as alcohol, nicotine or carbohydrate craving; And support for the concept that it may be useful in the treatment of alcohol and drug abuse.

Other suggested 5-HT ₃ antagonists include vomiting, particularly vomiting-induced chemotherapy, eating disorders such as bulimia, and irritable bowel syndrome (IBS) [ Exp. Opin. Ther. Targets , 11, 527-540, 2007].

Compounds of the present invention endowed with unique pharmacological profiles are also useful for emotional disorders, depression, major depressive disorders, postpartum depression, bipolar disorder, Alzheimer's disease, depression associated with psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, It is expected to be useful for the treatment of OCD, panic disorder, panic attack, phobia, social phobia, agoraphobia and stress incontinence.

In one embodiment, the present invention relates to chronic pain, depression in partial responders, treatment resistance depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, Alcohol or drug abuse, vomiting, eating disorders, IBS, emotional disorders, depression, major depressive disorders, postpartum depression, bipolar disorder, Alzheimer's disease, depression associated with psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder A method of treating a disorder, panic disorder, panic attack, phobia, social phobia, agoraphobia or stress incontinence, comprising administering a therapeutically effective amount of Compound I to a patient in need thereof. In one embodiment, the patient receiving treatment of any of the diseases listed above was initially diagnosed with the disease.

In one embodiment, the present invention relates to a method for the treatment of chronic pain comprising administering a therapeutically effective amount of Compound I to a patient in need thereof. In one embodiment, the chronic pain is annular pain, neuropathic pain, diabetic neuropathy, shingles neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex site pain syndrome (CPRS), tertiary Neuralgia / trigeminal neuralgia / circulating teak, surgical interventions (e.g. postoperative painkillers), diabetic angiopathy, capillary or diabetic symptoms associated with insulin salts, pain associated with angina, pain associated with menstruation, cancer-related Pain, toothache, headache, migraine, tension headache, trigeminal neuralgia, temporomandibular syndrome, fascia pain muscle damage, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema resulting from mental trauma associated with burns, Osteoarthritis, osteoporosis, bone metastasis or sprain or fracture pain due to unknown causes, gout, fibromyalitis, fascia pain, thoracic outlet syndrome, Upper back pain or lower back pain (back pain from systemic, local, or primary spinal disease (neuromyopathy)), pelvic pain, angina chest pain, non-angina chest pain, spinal cord injury (SCI) -related pain, post central stroke Pain, cancer neuropathy, AIDS pain, sickle cell pain or senile pain.

In one embodiment, the chronic pain is neuropathic pain.

In one embodiment, the neuropathic pain is selected from hyperalgesia, hypersensitivity, neuropathy, diabetic neuropathy, neuritis, neuralgia, hypersensitivity, burning pain, and allodynia.

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

Typical oral dosages are administered in one or more doses per day, such as 1-3 doses, and range from about 0.001 to about 100 mg / kg body weight, preferably from about 0.01 to about 50 mg / kg body weight per day Is in. The exact dosage will vary depending on the frequency and method of administration, the sex, age, weight and general condition of the subject being treated, the nature and severity of the condition being treated and any disease that is to be treated and other factors apparent to those skilled in the art. .

Typical oral dosages for adults are in the range of 1-100 mg / day, such as 1-30 mg / day, or 5-25 mg / day of the compound of the invention. This can usually 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 invention once or twice daily.

As used herein, "therapeutically effective amount" means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention involving the administration of said compound. Appropriate amounts to achieve this are defined as "therapeutically effective amounts". The term also includes an amount sufficient to cure, alleviate or partially arrest the clinical signs of a given disease and its complications in a treatment involving the administration of the compound. Effective amounts for each purpose will depend on the severity of the disease or injury and the weight and general condition of the subject. It will be appreciated that determination of the appropriate dosage can be accomplished using customary experiments, all of which are within the ordinary skill of the skilled physician, that construct a matrix of values and test different points within the matrix.

As used herein, the terms "treatment" and "treating" means handling and caring for a patient for the purpose of fighting a condition, such as a disease or disorder. The term refers to all ranges of treatment of a given condition where a patient suffers, such as to alleviate symptoms or complications, to delay progression of a disease, disorder or condition, to alleviate or alleviate symptoms and complications, and / or to disease To prevent or treat a disorder or condition, and to prevent a condition (here, prevention is understood to treat and care for a patient for the purpose of the struggle against a disease, condition, or disorder, which is intended to prevent the development of symptoms or complications). To the administration of the active compound). Nevertheless, prophylactic (prophylactic) and therapeutic (therapeutic) treatments are two separate aspects of the present invention. The patient to be treated is preferably a mammal, in particular a human being.

In one embodiment, the invention relates to chronic pain, depression in partial responders, treatment resistance depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, alcohol Or depression associated with substance abuse, vomiting, eating disorders, IBS, emotional disorders, depression, major depressive disorders, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder And the use of the invention in the manufacture of a medicament for the treatment of panic disorder, panic attack, phobia, social phobia, agoraphobia or stress incontinence.

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

In one embodiment, the invention relates to chronic pain, depression in partial responders, treatment resistance depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, alcohol Or depression associated with substance abuse, vomiting, eating disorders, IBS, emotional disorders, depression, major depressive disorders, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder The present invention relates to a compound of the present invention for use as a medicament for the treatment of panic disorder, panic attack, phobia, social phobia, agoraphobia or stress incontinence.

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

The compounds of the present invention can be administered in single or multiple doses, as pure compounds, alone or in combination with pharmaceutically acceptable carriers or excipients. Pharmaceutical compositions according to the invention are, for example, pharmaceutically acceptable according to conventional techniques disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. It may be formulated with a possible carrier or diluent and any other known auxiliaries and excipients.

The pharmaceutical composition may be administered in any suitable route, such as oral, rectal, nasal, pulmonary, topical (including oral and sublingual), intradermal, intratracheal, intraperitoneal, vaginal and parenteral (subcutaneous, intramuscular, Specifically for the administration by the intradural, intravenous and intradermal routes), the oral route is preferred. It will be appreciated that the preferred route may vary depending on the general condition and age of the subject being treated, the nature of the condition being treated and the active ingredient selected.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders, and granules. If appropriate, they can be prepared by coating.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injections, dispersions, suspensions or emulsions and sterile powders reconstituted in sterile injections or dispersions prior to use.

Other suitable dosage forms include suppositories, sprays, ointments, creams, gels, inhalants, transdermal patches, implants, and the like.

Preferably, the compound of the invention is in unit dosage form containing the compound in an amount of about 0.1 to 50 mg, such as 1 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg of the compound of the invention. Administered.

For parenteral routes such as intravenous, intradural, intramuscular and similar administration, the dose is typically about half of the dose used for oral administration.

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

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, white earth, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Thereafter, the pharmaceutical compositions formulated in combination with the compounds of the present invention and pharmaceutically acceptable carriers are readily administered in a variety of dosage forms suitable for the disclosed routes of administration.

Suitable formulations of the present invention for oral administration may be presented as discrete units, such as capsules or tablets, containing a predetermined amount of active ingredient and may contain suitable excipients. In addition, orally available formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions. have.

If a solid carrier is used for oral administration, the preparation may be in the form of a tablet, powder or pellet, or in the form of a troche or lozenge, for example, in a hard gelatin capsule. The amount of solid carrier can vary but typically can 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, such as an aqueous or non-aqueous liquid suspension or solution.

Tablets may be prepared by mixing the active ingredient with conventional adjuvants and / or diluents and then compacting the mixture in a conventional tablet machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other auxiliaries or additives conventionally used for this purpose, such as colorants, flavors, preservatives and the like, may be used provided they are compatible with the active ingredient.

Capsules containing a compound of the present invention may be prepared by mixing a powder comprising the compound with microcrystalline cellulose and magnesium stearate and placing the powder in a hard gelatin capsule. Optionally, the capsule can be colored using a suitable pigment. Typically, the capsule may comprise 0.25-20% of the compound of the present invention, such as 0.5-1.0%, 3.0-4.0%, 14.0-16.0% of the compound of the present invention. Such strength can be used to facilitate delivery of compounds 1, 5, 10, 15, 20 and 25 mg of the invention in unit dosage form.

Solutions for injection dissolve the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, adjust the solution to the desired volume, sterilize the solution and place in a suitable ampoule or vial. Can be prepared by filling. Any suitable additive commonly used in the art may be added, such as isotonic agents, preservatives, antioxidants, and the like.

Compound I can be prepared as outlined in WO 2003/029232. Salts of compound I may precipitate after the addition of the appropriate acid. Precipitation can be obtained, for example, by cooling, removal of the solvent, addition of other solvents or mixtures thereof.

All citations, including publications, patent applications, and patents cited herein, are hereby incorporated in their entirety and in their respective citations independently of any reference merger to a particular document, if otherwise set forth herein in another instance. In particular, it is hereby incorporated by reference by reference, the entirety of which is hereby incorporated by reference in the same range as described herein (to the maximum extent permitted by law).

The use of the singular forms and the like in the context of the present invention should be construed to cover both the singular and the plural unless the context clearly dictates otherwise or unless the context clearly indicates otherwise. For example, the phrase "compound" should be understood to refer to the various "compounds" of the present invention or particularly described aspects, unless stated otherwise.

Unless stated otherwise, all exact values provided herein are representative of that approximation (e.g., any precise representative value provided in connection with a particular factor or measurement may also be considered to provide that approximate measurement and , Where appropriate, "about").

The terminology used herein in connection with an element or elements in aspects or any aspect of the invention, such as “comprising”, “having”, “comprising”, or “comprising”, unless stated otherwise Unless expressly denied in the context, it is intended to be provided to support a similar aspect or aspect of the invention of "comprising", "essentially" or "essentially containing" a particular element or elements (eg For example, a composition described herein, in particular comprising an element, should be understood as describing a composition consisting of that element, unless otherwise indicated or unless clearly stated in the context).

Analytical Method

X-ray powder diffraction pattern (XRPD) was measured on a PANalytical X'pert PRO X-ray diffractometer using CuK _α1 radiation. The samples were measured in reflection mode in the 2θ-range 5-40 ° using an X'celerator detector.

Elemental composition (CHN) was measured on an Elementar Vario EL instrument from Elementar. About 4 mg of sample was used for each measurement and the results are shown as the average value of the two measurements.

Example 1a HBr Salts of Compound I

442 grams of 33 (wt) in 545 ml of AcOH to 4- (2-p-tolylsulfanyl-phenyl) -piperidine-1-carboxylic acid ethyl ester as a stirred and slightly heated (approx. 45 ° C.) oil. % HBr (5.7 M, 2.5 equiv) was added. The mixture exhibited 10 ° C. exotherm. After the final addition, the reaction mixture was heated to 80 ° C and left for 18 hours. Samples were collected and analyzed by HPLC, and if not terminated, further 33 wt-% HBr in AcOH was added. Alternatively, the mixture was cooled to 25 ° C. to precipitate the product 4- (2-p-tolylsulfanyl-phenyl) -piperidine hydrobromide. After 1 hour at 25 ° C., 800 ml diethyl ether was added to the thick suspension. Stirring was continued for another hour, purified with 400 ml diethyl ether and dried overnight at 40 ° C. under vacuum before the product was isolated by filtration. Hydrobromide of Compound I was isolated as a white solid.

Example 1b HBr Salts of Compound I

2- (4-tolylsulfanyl) -phenyl bromide

In a reactor filled with stirred nitrogen, N-methyl-pyrrolidone, NMP (4.5 L) was charged with nitrogen for 20 minutes. 4-methylbenzenethiol (900 g, 7.25 mol) was added followed by 1,2-dibromobenzene (1709 g, 7.25 mol). Potassium tert-butoxide (813 g, 7.25 mol) was finally added as the final reactant. The reaction showed an exotherm which raised the temperature of the reaction mixture to 70 ° C. The reaction mixture was then heated to 120 ° C. for 2-3 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (4 L) was added and aqueous sodium chloride solution (15%, 2.5 L) was added. The mixture was stirred for 20 minutes. The aqueous phase was separated and extracted with another portion of ethyl acetate (2 L). The aqueous phase was separated and the organic phase was combined and washed with sodium chloride solution (15%, 2.5 L). The organic phase was separated, dried over sodium sulfate and evaporated under reduced pressure to give a red oil containing 20-30% NMP. The oil was diluted to twice the volume with methanol and the mixture was refluxed. More methanol was added until a clear red solution was obtained. The solution was slowly cooled to room temperature while seeding. The product was crystallized as off-white crystals which were isolated by filtration and washed with methanol and dried in a vacuum oven to constant weight at 40 ° C.

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

In a stirred reactor filled with nitrogen, 2- (4-tolylsulfanyl) -phenyl bromide (600 g, 2.15 mol) was suspended in heptane (4.5 L). At room temperature, 10M BuLi (235 mL, 2.36 mol) in hexanes was added over 10 minutes. Only slight fever was observed. The suspension was stirred at ambient temperature for 1 hour and then cooled to -40 ° C. 1-Carbetoxy-4-piperidone (368 g, 2.15 mol) dissolved in THF (1.5 L) was added at a rate not faster than the reaction temperature was maintained below −40 ° C. At the end of the reaction, 1 M HCl (1 L) was added while warming to 0 ° C. and keeping the temperature below 10 ° C. The acid aqueous 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 slurried with ethyl ether (250 mL) and filtered. In a vacuum oven, it dried to 40 weight at 40 degreeC.

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

Trifluoroacetic acid (2.8 kg, 24.9 mol) and triethylsilane (362 g, 3.1 mol) were charged into a reactor equipped with an efficient stirrer. Ethyl 4-hydroxy-4- (2- (4-tolylsulfanyl) phenyl) -piperidine-1-carboxylate (462 g, 1.24 mol) was added in portions via a powder funnel. The reaction was slightly exothermic. The temperature rose to 50 ° C. After the addition was complete, the reaction mixture was warmed to 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 extracted with another portion of toluene (750 mL). The organic phase was combined and washed with sodium chloride solution (15%, 500 mL) and dried over sodium sulfate. The sodium sulfate was filtered and the filtrate was evaporated at reduced pressure to give a red oil which was further processed in the next step.

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

From Example 3, crude ethyl 4- (2- (4-tolylsulfanyl) phenyl) -piperidine-1-carboxylate as a red oil was hydrobromic acid (40%, 545 mL) in acetic acid in a stirred reactor. , 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 crystallized out. After 1 hour, ethyl ether (800 mL) was added to the reaction mixture at room temperature and the mixture was stirred for another 1 hour. The product was filtered, washed with ethyl ether and dried to 50 wt at 50 ° C. in a vacuum oven.

Example 1c Recrystallization of HBr Salts of Compound I

For example, a mixture of 10.0 grams of the HBr salt of Compound I, prepared as above, was heated to reflux in 100 ml H ₂ O. The mixture became clear and completely dissolved at 80-90 ° C. 1 gram of charcoal was added to the clear solution, refluxed for 15 minutes, filtered and allowed to cool spontaneously to room temperature. A precipitate of white solid formed during cooling and the suspension was stirred for 1 hour at room temperature. Filtration and drying overnight at 40 ° C. under vacuum yielded 6.9 grams (69%) of HBr acid addition salt of Compound I. See XRPD. Elemental analysis: 3.92% N, 59.36% C, 6.16% H (Theoretical values: 3.85% N, 59.34% C, 6.09% H).

Example 1d Preparation of Free Base Stock Solution

A biphasic slurry was prepared by adding 50 grams of the HBr salt of Compound I to a mixture of 500 ml ethyl acetate and 200 ml H ₂ O. Approximately 25 ml concentrated NaOH was added to the slurry, which resulted in the formation of a clear biphasic solution (pH measured from 13-14). The solution was stirred vigorously 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 dried at 60 ° C. under vacuum to give 38 grams (99%) of free base as an almost colorless oil.

Ethyl acetate was used to dissolve 10 grams of oil and the volume was adjusted to 150 ml to prepare a 0.235 M stock solution in ethyl acetate from which 1.5 ml aliquot (100 mg free base) was used.

Dissolve 10 grams of oil using 96-vol% EtOH and adjust the volume to 100 ml to prepare a 0.353 M stock solution in EtOH from which 1.0 ml aliquot (100 mg free base) was used.

Example 1e Formation of Salt Using Stock Solution of Free Base

A given aliquot was placed in a test tube and the appropriate amount of acid was added as shown in Table 1 with stirring. If the acid is a liquid, it is added neat, otherwise it is dissolved in the given solvent before addition. After mixing and precipitation, stirring was continued overnight and the precipitate was collected by filtration. Prior to drying at 30 ° C. under vacuum, a small amount of standard sample was collected and dried at room temperature rather than in vacuum. This procedure was included for testing for solvates. Some results are shown in Table 1. XRPD diffraction patterns are shown in FIGS. 1-22 and selected peak positions are tabulated in Table 2. Table 3 shows the solubility in water of the compounds of the present invention with the pH in the saturated solution obtained. The “precipitate” column indicates whether the precipitate isolated after the solubility determination is the same as the dissolved compound, which indicates the formation of a hydrate.

Example 2A Serotonin (5-HT) and Norepinephrine (NE) Reuptake Inhibitors

Aliquots of test compounds and rat cortical synaptosome preparations were pre-incubated at 37 ° C. for 10 minutes before [ ³ H] NE or [ ³ H] 5-HT (final concentration 10 nM) was added. Non-specific uptake was determined in the presence of 10 μM dehydrated or citalopram and total uptake was determined in the presence of buffer. Aliquots were incubated at 37 ° C. for 15 minutes. After incubation, [ ³ H] NE or [ ³ H] 5-HT absorbed by the synaptosomes was isolated by filtration through Unifilter GF / C, pre-soaked in 0.1% PEI for 30 minutes, using the Tomtec Cell Harvester program. It was. The filter was washed and counted with a Wallac MicroBeta counter.

In NET the compound of the present invention showed an IC ₅₀ value of 23 nM. Compounds of the invention in the SERT exhibit an IC ₅₀ value of 8 nM.

Example 2B 5-HT _2A  Antagonism

Compounds of the invention were tested for affinity for serotonin receptors and found to exhibit antagonistic profiles with affinity at the 5-HT _2A receptor (K _i 54 nM). The affinity was calculated from Y = 100 / (1 + 10 ^(X-logIC ₅₀ ⁾ ), where Y represents% binding and X represents the concentration of the compound. IC ₅₀ values were calculated using 5 concentrations of compound (1, 10, 30, 100, 1000 nM). Ki was calculated from the Cheng Prusoff equation Ki = (IC ₅₀ / (1+ ([L] / Kd)) The affinity was determined in MDL Pharmaservices (Cat. No. 271650).

In mammalian cells expressing the human 5-HT _2A receptor, the compounds of the present invention exhibited competitive antagonistic properties. The compound bound the 5-HT _2A receptor with a Ki of <100 nM and in a functional assay the compound antagonized 5-HT induced Ca ²⁺ release from intracellular storage to Kb of 67 nM. Shield analysis showed competitive antagonism with a Kb of 100 nM.

The experiment was performed as follows. Two or three days before the experiment, CHO cells expressing 250 fmol / mg human 5-HT _2A receptor were plated at sufficient density to obtain a mono-confluent layer on the day of the experiment. The cells were stained for 60 minutes at 37 ° C., at 95% humidity in a 5% CO ₂ incubator (Ca ²⁺ -Kit, manufactured by Molecular Devices). Base fluorescence was monitored by excitation at wavelength 488 nm and emission in the range 500-560 nm in a fluorescence image plate reader or FLIPR ³⁸⁴ (manufactured by Molecular Devices (Sunnyvale, Calif.)). The laser intensity was set at a level suitable to obtain a base value of approximately 8000-10000 fluorescent units. Strain in base fluorescence should be less than 10%. EC ₅₀ values were assessed using increased concentrations of test compound, covering at least 3 decades. pA2 values were assessed using 5-HT of the full dose response curve with four different concentrations of compound (150, 400, 1500 and 4000 nM). Kb values were also evaluated using test substances at concentrations of 2 decades with 5-HT of EC ₈₅ . Test substance was added to the cells 5 minutes before 5-HT. K _i values were calculated using the Cheng-Prusoff equation.

Example 2C 5-HT _3A  Receptor antagonism

In oocytes expressing the human-isomorphic 5-HT _3A receptor, 5-HT activated an electric current with an EC ₅₀ of 2600 nM. The current can be antagonized with traditional 5-HT ₃ antagonists such as ondansetron. Ondansetron showed a Ki value of less than 1 nM in this system. The compounds of the present invention a low concentration (0.1 nM - 100 nM) ( IC 50 ~ 10 nM / Kb ~ 2 nM) showed a strong antagonistic activity, higher concentration in the (100 - 100000 nM) (EC 50 ~ 2600 nM) When applied, the agonist properties reached a maximum current of approximately 70-80% of the maximum current induced by 5-HT itself. In oocytes expressing the rat-isotype 5-HT _3A receptor, 5-HT activated an electric current with an EC ₅₀ of 3.3 μM. The experiment was performed as follows. Oocytes were surgically removed from mature female Xenepus laevis anesthetized in 0.4% MS-222 for 10-15 minutes. The oocytes were then subjected to 0.5 mg / ml collagenase (type IA Sigma-) in OR2 buffer (82.5 mN NaCl, 2.0 mM KCl, 1.0 mM MgCl ₂ and 5.0 mM HEPES, pH 7.6) for 2-3 hours at room temperature. Aldrich). Oocytes without follicle layer were selected and modified Barth saline buffer added with 2 mM sodium pyruvate, 0.1 U / l penicillin and 0.1 μg / l streptomycin [88 mM NaCl, 1 mM KCl, 15 mM HEPES, 2.4 mM NaHCO ₃ , 0.41 mM CaCl ₂ , 0.82 mM MgSO ₄ , 0.3 mM Ca (NO ₃ ) ₂ ] for 24 hours. When identifying oocytes of stage IV-IV and injecting 12-48 nl of nuclease-free water containing 14-50 pg of cRNA encoding human 5-HT3A receptor and using for electrophysiological recordings Incubated at 18 ° C. until (1-7 days after injection). Oocytes expressing human 5-HT3 receptors were placed in 1 ml containers and perfused with Ringer's buffer (115 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1.8 mM CaCl ₂ , 0.1 mM MgCl ₂ , pH 7.5). The cells were stabbed with a 0.5-1 MΩ electrode clogged with agar containing 3 M KCl and the voltage clamped at −90 mV with a GeneClamp 500B amplifier. The oocytes were continuously perfused with Ringer's buffer and the drug was applied in the perfusate. 5-HT agonist-solution was applied for 10-30 seconds. The effect of 5-HT ₃ receptor antagonist was examined by concentration-response measurements on 10 μM 5-HT stimulation.

Example 2D α _1A  Receptor antagonism

The compounds of the present invention to test the affinity for the α _1A receptor was found to represent the antagonistic profile with medium affinity also for the α _1A receptors (Ki = 34 nM).

On the day of the experiment thaw the membrane (see membrane preparation techniques below), homogenize in buffer using ultra turrax, and store the desired concentration (5 μg / well to 5 μg / 900 μl on ice before use). Dilution).

The experiment was initiated with a mix of 50 μl test compound, 50 μl [ ³ H] -prazosin and 900 μl membrane and the mixture was incubated at 25 ° C. for 20 minutes. Non-specific binding was determined in the presence of 10 μM WB-4101 and total binding was determined in the presence of buffer. After incubation, the bound ligand was unbound from the Tomtec Cell Harvester program (D4.2..4). 96 wells were used to separate by filtration through Unifilter GF / B, pre-soaked in 0.1% PEI for 30 minutes. The filter was washed three times with 1 ml ice-cold buffer, dried at 50 ° C. and 35 μl scintillation liquid / well was added to the filter. Bound radioactivity was calculated with Wallac OY 1450 MicroBeta. The affinity was calculated from Y = 100 / (1 + 10 ^(X-logIC ₅₀ ⁾ ), where Y represents% binding and X represents the concentration of the compound. IC ₅₀ values were calculated using a concentration of compound encompassing 2 decades. Ki was calculated from the Cheng Prusoff equation Ki = (IC ₅₀ / (1+ ([L] / Kd)).

In a functional assay, the compounds of the present invention antagonized adrenergic induced Ca ²⁺ release from intracellular storage, and the functional assay indicated that the compound was an antagonist.

The experiment was performed essentially as described below.

All cells were 37 ° C. in 5% CO 2 in DMEM medium supplemented with 10% BCS, 4 mM L-glutamine (or 2 mM for COS-7), and 100 μg / ml streptomycin in addition to 100 units / ml penicillin Incubated at.

24 hours before the assay, CHO cells expressing human alpha _1A-7 receptor were seeded on 384-well black wall microtiter plates coated with poly-D-lysine. The culture medium is aspirated and the cells are Hank's Balanced Salt Solution (138 mM NaCl, 5 mM KCl, 1.3 mM CaCl ₂ , 0.5 mM MgCl ₂ , 0.4 mM MgSO ₄ , 0.3 mM KH ₂ PO ₄ , 0.3 in 5% CO ₂ with 1.5 μM Fluo-4 in assay buffer consisting of 20 mM HEPES, pH 7.4, 0.05% BSA and 2.5 mM probebenid (50 μl / well) in addition to mM Na ₂ HPO ₄ , 5.6 mM glucose). Staining was performed at 37 ° C. for 1 hour. After removing excess dye, cells were washed in assay buffer and layered to a final volume of 45 μl / well (or 30 ul / well for antagonist assay). For antagonist evaluation, the antagonist or vehicle was added in 15 μl aliquots in 4% DMSO-containing buffer at 4 times the final concentration (final DMSO = 1%) and then incubated for 20 minutes. Base fluorescence was monitored by excitation at wavelength 488 nm and emission in the range 500-560 nm in a fluorescence image plate reader or FLIPR ^™ (manufactured by Molecular Devices (Sunnyvale, Calif.)). By adjusting the laser excitation energy, the resulting fluorescence recording was approximately 8,000 relative fluorescence units (RFU). Cells were then stimulated with agonists diluted in assay buffer (15 μl) at room temperature and RFU was measured at 1.5 second intervals over a period of 2.5 minutes. 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 equation). For antagonistic determination, after 20 minutes of compound incubation (as above), a fixed concentration of standard agonist serotonin was added.

Example 2E Increase of Dopamine

Single injections of the compounds of the invention increased dose-dependently extracellular DA levels in the rat frontal lobe. Compounds of the present invention improved DA levels at 8.9 mg / kg and 18 mg / kg s.c. above the baseline as shown in FIG. 23, approximately 100% and 150%, respectively. The amount was calculated as the free base.

Way

Initially male Sprague-Dawley rats weighing 275-300 g were used. The animals were housed under 12-hour light / dark cycles under controlled conditions of normal room temperature (21 ± 2 ° C.) and humidity (55 ± 5%), where food and tap water were optionally available. For three days of treatment experiments, an osmotic small pump (Alzet, 2ML1) was used. The pump was filled under sterile conditions and implanted subcutaneously under Sebofluran anesthesia. The experiment was performed using a small pump on board. Blood samples for measuring plasma levels of test compounds were collected at the end of the experiment 3 days after treatment.

Surgical Procedures and Microdialysis Experiments

Animals are anesthetized with hyponorm / dormicum (2 ml / kg) and dialysis probe tips are ventral hippocampus (coordination: 5,6 mm in front of parietal point, lateral -5,0 mm, ventral meninges in ventral side) 7,0 mm) or frontal lobe (coordinating: parietal point 3,2 mm; flank, 3.0 mm; ventral meninges 4,0 mm) and intracranial guide cannula (CMA / 12) was stereotactically implanted into the hippocampus . Anchor screws and acrylic cement were used for fixing the guide cannula. The body temperature of the animal was monitored with a rectal probe and maintained at 37 ° C. The rats were allowed to recover from surgical treatment for 2 days and housed alone in cages. On the day of the experiment microdialysis probes (CMA / 12, diameter 0,5 mm, length 3 mm) were inserted through the guide cannula. The probe was connected to the microinjection pump via a dual channel swivel. Perfusion of the microdialysis probe with filtered Ringer's solution (145 mm NaCl, 3 mM KCl, 1 mM MgCl ₂ , 1,2 mM CaCl ₂ ) started just before insertion of the probe into the brain, 1 (1,3) μL It continued during the experiment at a fixed flow rate of / min. After 180 minutes of stabilization, the experiment was initiated. The dialysate was collected every 20 (30) minutes.

After the experiment, the rats were sacrificed by guillotine, their brains were removed, frozen and sliced for probe positioning.

Analysis of Dialysis Solution

The concentration of dopamine in the dialysate was analyzed using HPLC with electrochemical detection. Monoamines were separated by reverse phase liquid chromatography (ODS 150 × 3 mm, 3 μΜ). Dopamine: Mobile phase of flow rate 0.5 ml / min, consisting of 90 mM NaH ₂ PO ₄ , 50 mM sodium citrate, 367 mg / l sodium 1-octanesulfonic acid, 50 μM EDTA and 8% acetonitrile (pH 4.0). Electrochemical detection was performed using a stoichiometric detector; The potential was set at 250 mV (coliar cells at 350 mV) (Coulochem II, ESA).

Example 2 F Increase of Acetylcholine

This experiment was designed to evaluate the effect of the compounds of the present invention on the level of extracellular acetylcholine in the prefrontal cortex of freely moving rats.

Male Wistar rats (280-350 g; Harlan, Zeist, The Netherlands) were used for this experiment. Rats were individually housed in plastic cages (30 x 30 x 40 cm) and provided random 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 placed in a stereotactic frame (Kopf instruments, USA) and a homemade I-shaped probe (Hospal AN 69 membrane, exposed surface 4 mm) was placed in Paxinos and Watson rat brain atlas (1982). ) Into the center of the prefrontal cortex (mPFC). Coordination of the tip of the probe was 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 screws. Plunicin (1 mg / kg sc) was administered as postoperative analgesia.

Experiments were performed 24-48 hours after surgical treatment. On the day of the experiment, the rats were connected to the microperfusion pump (CMA 102) with an elastic PEEK tube and the dialysis probe was 1.5 with Ringer's buffer containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl ₂ , and 1.2 mM MgCl ₂ . Perfusion was carried out at a flow rate of μL / min. Microdialysis samples were collected into small-vials containing 55 μL 0.02 M formic acid at 30 minute intervals for acetylcholine measurements. Samples were collected with an automated fraction collector (CMA 142) and stored at −80 ° C. until analysis. After the end of the experiment, the rats were sacrificed. Brains were removed and treated in paraformaldehyde solution (4% m / v). The position of each probe was made histologically by preparing a coronal plane of the brain, according to Paxinos and Watson (1982).

Test compounds were dissolved in 10% 2-OH-propyl-beta-cyclodextrin and administered by subcutaneous injection at a volume of 5 mL / kg at different doses.

The concentration of acetylcholine was determined by HPLC with tandem mass spectrometry (MS / MS) detection.

Aliquots (25 μL) were injected onto HPLC columns by automated sample syringes (PerkinElmer instruments, series 200). Chromatographic separation was performed with a reversed phase 150 x 2.00 mm (4 μm) analytical column (Phenomenex Synergy MAX-RP, Bester) (two columns) protected with a 4 x 2.0 mm guide column (Phenomenex Synergy MAX-RP AJO-6073, Bester). All at a temperature of 30 ° C.). The mobile phase (isocratic) consisted of ultrapure water (UP), acetonitrile (ACN), and trifluoroacetic acid (TFA) (UP: ACN: TFA = 95.0: 0.5: 0.1 v / v / v%). Mobile phase was moved through the system at a flow rate of 0.300 mL / min by HPLC pump (PerkinElmer instruments, series 200 micropump).

LC / MS analysis was performed using an API 4000 MS / MS system consisting of an API 4000 MS / MS detector and a Turbo Ion Spray interface (both from Applied Biosystems, The Netherlands). Acquisition was carried out in positive ionization mode at an ion spray voltage of 5.5 kV, nebulizer gas pressure of 50 psig (SCIEX scale 0-90) and probe temperature of 600 ° C. The instrument was run in a complex-reaction-monitoring (MRM) mode for the detection of acetylcholine (precursor 146.1 Da, product 86.8 Da). The impact energy was 21.0 eV and the impact gas (nitrogen) pressure was fixed at 7 (SCIEX scale 0-12). Data was adjusted and quantified using the Analyst ^tm data system (Applied Biosystem, version 1.2).

Two consecutive microdialysis samples with less than 50% strain were taken at baseline level and set to 100%. Changes in acetylcholine concentration are expressed as percent of baseline within the same subject.

The data is shown in FIG.

Example 2 Increasing G Acetylcholine

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

Initially male Sprague-Dawley rats weighing 275-300 g were used. The animals were housed under 12-hour light / dark cycles under controlled conditions of normal room temperature (21 ± 2 ° C.) and humidity (55 ± 5%), where food and tap water were optionally available.

Surgical Procedures and Microdialysis Experiments

Rats are anesthetized with Hypnorm / Dormicum (2 ml / kg) and the dialysis probe tip is ventral hippocampus (coordination: 5,6 mm ahead of parietal point, lateral -5,0 mm, meninges 7,0 mm from ventral side) or An intracranial guide cannula (CMA / 12) was stereotactically implanted into the hippocampus for the purpose of positioning the frontal lobe (coordination: 3.2 mm anterior to the parietal point; lateral, 3.0 mm; meninges 4,0 mm from the abdomen). Anchor screws and acrylic cement were used for fixing the guide cannula. Body temperature of the animals was monitored with a rectal probe and maintained at 37 ° C. The rats were allowed to recover from surgical treatment for 2 days and housed alone in cages. On the day of the experiment microdialysis probes (CMA / 12, diameter 0,5 mm, length 3 mm) were inserted through the guide cannula.

The probe was connected to the microinjection pump via a dual channel swivel. Perfusion of the microdialysis probe using filtered Ringer's solution (145 mm NaCl, 3 mM KCl, 1 mM MgCl ₂ , 1,2 mM CaCl ₂ with 0.5 μM neostigmine) started just before insertion of the probe into the brain. The test was continued during the experiment at a fixed flow rate of 1 μL / min. After 180 minutes of stabilization, the experiment was initiated. The dialysate was collected every 20 minutes. After the experiment, the rats were sacrificed, their brains removed, frozen and sliced for probe location.

Analysis of Dialysis Solution Acetylcholine

The concentration of acetylcholine (ACh) in the dialysate was electrochemically detected using a mobile phase of pH 8.0 consisting of 100 mM disodium hydrogenphosphate, 2.0 mM octane sulfonic acid, 0.5 mM tetramethyl-ammonium chloride and 0.005% MB (ESA) Analysis using HPLC. Analytical column (ESA ACH-250) prior to ACh separation in a pre-column enzyme reactor (ESA) containing immobilized choline oxidase; Choline was removed from the sample (10 μl) injected on 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 acetylcholinesterase and choline oxidase. The latter reactor converted ACh to choline and then choline to betaine and H ₂ O ₂ . The latter reactor was electrochemically detected using platinum electrodes (analytical cells: ESA, model 5040).

Data display

In a single injection experiment, the mean value of three consecutive ACh samples of the immediately preceding compound dose is considered the basal level for each experiment and the data is expressed as a percentage of the basal (normalized mean basal pre-injection value to 100%). Switched. The data is shown in FIGS. 25A and 25B.

The data shown in FIG. 24 shows an unexpected drop in acetylcholine levels (see eg 8 mg / kg) which is difficult to explain and considered experimental uncertainty. In total, both data sets of Example 2F and 2G exhibit the same dose dependent increase in extracellular acetylcholine levels in the brain. Such preclinical findings are expected to translate into cognitive improvement in clinical conditions useful for the treatment of diseases characterized, for example, by cognitive disorders such as Alzheimer's patients, partial responders, cognitive disorders, and the like.

Example 3 Effect on Neuropathic Pain

To demonstrate efficacy against neuropathic pain, the compounds of the present invention were tested in formalin models of neuropathic pain [ Neuropharm., 48, 252-263, 2005; Pain , 51, 5-17, 1992]. In this model, mice were injected with formalin (4.5%, 20 μl) into the plantar surface of the left hind paw and placed in individual glass beakers (2 l dose) for observation. Stimulation caused by formalin injection induced a characteristic two-phase behavioral response, quantified by the amount of time spent licking an injured foot. The first phase (˜0-10 minutes) exhibited direct chemical stimulation and pain, whereas the second phase (˜20-30 minutes) was believed to exhibit neuropathic pain. The two phases were separated by a dormant period in which the behavior returned to normal. The amount of time spent licking the damaged foot in the two phases was measured to assess the effectiveness of the test compound in reducing painful irritation.

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

The data in Table 4 shows that the compounds of the present invention have little effect on the first phase, which exhibits direct chemical stimulation and pain. More clearly, the data also shows a clear and dose dependent decrease in the time spent licking the feet in the second phase, indicating the effect of the compounds of the invention in the treatment of neuropathic pain.

Example 4 Capsules

In the first step 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine hydrobromide was mixed with microcrystalline cellulose. In the second step, magnesium stearate was mixed therein. Capsules of four strengths were prepared (the active ingredient was present as free base) and 10,000 capsules were made from each batch.

Claims (32)

Crystalline Compound I, i.e. 4- [2- (4-methylphenyl-sulfanyl) phenyl] piperidine

And pharmaceutically acceptable salts thereof, provided that the compound is not 4- [2- (4-methylphenylsulfanyl) phenyl] -piperidine hydrochloride addition salt. The compound of claim 1, wherein the compound is an HBr addition salt. The compound of claim 2, wherein the compound is characterized by an XRPD peak at approximately 6.08 °, 14.81 °, 19.26 °, and 25.38 ° 2θ. The compound of claim 2, wherein the compound is characterized by XRPD as shown in FIG. 1. The compound of claim 1, wherein the compound is a DL-lactic acid addition salt. The compound of claim 5, wherein the compound is characterized by XRPD peaks at approximately 5.30 °, 8.18 °, 9.44 °, and 17.24 ° 2θ. 6. The compound of claim 5, wherein the compound is characterized by XRPD as shown in FIG. A compound according to claim 1, wherein the compound is glutaric acid addition salt (1: 1). The compound of claim 8, wherein the compound is characterized by an XRPD peak at approximately 9.39 °, 11.70 °, 14.05 °, and 14.58 ° 2θ. The compound of claim 8, wherein the compound is characterized by XRPD as shown in FIG. 8. A compound according to claim 1, wherein the compound is malonic acid addition salt (1: 1). The compound of claim 11, wherein the compound is characterized by an XRPD peak at 10.77 °, 16.70 °, 19.93 ° and 24.01 ° 2θ, or 6.08 °, 10.11 °, 18.25 ° and 20.26 ° 2θ. 12. The compound of claim 11, wherein the compound is characterized by XRPD as shown in Figure 9 or 10. A compound according to claim 1, wherein the compound is L-aspartic acid addition salt (1: 1) or L-aspartic acid addition salt hydrate (1: 1). The compound according to claim 1, wherein the compound is glutamic acid addition salt (1: 1) or glutamic acid addition salt monohydrate. The compound according to any one of claims 1 to 15 for use in therapy. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient. Chronic pain, depression in partial responders, treatment resistance depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, alcohol or drug abuse, vomiting, eating disorders Depression, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attack, phobia associated with IBS, emotional disorders, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease A method of treating a disease selected from social phobia, agoraphobia or stress incontinence, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15. The method of claim 18, wherein said disease is chronic pain. 20. The method of claim 19, wherein the chronic pain is annular pain, neuropathic pain, diabetic neuropathy, post shingles neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex site pain syndrome (CPRS), Trigeminal neuralgia / trigeminal neuralgia / circulating teak, surgical interventions (e.g. postoperative painkillers), diabetic angiopathy, capillary or diabetic symptoms associated with insulin salts, pain associated with angina pectoris, pain associated with menstruation, cancer and Related pain, toothache, headache, migraine, tension headache, trigeminal neuralgia, temporomandibular syndrome, fascia pain muscle damage, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and swelling resulting from mental trauma associated with burns , Osteoarthritis, osteoporosis, bone metastasis or sprain or fracture pain due to unknown causes, gout, fibromyalitis, fascia pain, thoracic outlet symptoms Group, upper back pain or lower back pain (back pain resulting from systemic, local, or primary spinal disease (neuromyopathy)), pelvic pain, angina chest pain, non-angina chest pain, spinal cord injury (SCI) -related Method selected from pain, pain after central stroke, cancer neuropathy, AIDS pain, sickle cell pain and senile pain. The method of claim 20, wherein the chronic pain is neuropathic pain. The method of claim 21, wherein the neuropathic pain is selected from hyperalgesia, hypersensitivity, neuropathy, diabetic neuropathy, neuritis, neuralgia, hypersensitivity, burning pain, and allodynia. Chronic pain, depression in partial responders, treatment resistance depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, alcohol or drug abuse, vomiting, eating disorders Depression, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attack, phobia, IBS, emotional disorders, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for the treatment of a disease selected from social phobia, agoraphobia or stress incontinence. The use of claim 23, wherein said disease is chronic pain. The method of claim 24, wherein the chronic pain is annular pain, neuropathic pain, diabetic neuropathy, shingles neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex site pain syndrome (CPRS), Trigeminal neuralgia / trigeminal neuralgia / circulating teak, surgical interventions (e.g. postoperative painkillers), diabetic angiopathy, capillary or diabetic symptoms associated with insulin salts, pain associated with angina pectoris, pain associated with menstruation, cancer and Related pain, toothache, headache, migraine, tension headache, trigeminal neuralgia, temporomandibular syndrome, fascia pain muscle damage, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and swelling resulting from mental trauma associated with burns , Osteoarthritis, osteoporosis, bone metastases or sprains or osteopathic pain due to unknown causes, gout, fibritis, fascia pain, thoracic outlet syndrome Group, upper back pain or lower back pain (back pain resulting from systemic, local, or primary spinal disease (neuromyopathy)), pelvic pain, angina chest pain, non-angina chest pain, spinal cord injury (SCI) -related Use selected from pain, pain after central stroke, cancer neuropathy, AIDS pain, sickle cell pain and senile pain. The use of claim 25, wherein the chronic pain is neuropathic pain. 27. The use of claim 26, wherein the neuropathic pain is selected from hyperalgesia, hypersensitivity, neuropathy, diabetic neuropathy, neuritis, neuralgia, hypersensitivity, burning pain, and allodynia. Chronic pain, depression in partial responders, treatment resistance depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, alcohol or drug abuse, vomiting, eating disorders Depression, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attack, phobia, IBS, emotional disorders, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease The compound according to any one of claims 1 to 15, for use in the treatment of diseases selected from social phobia, agoraphobia or stress incontinence. 29. A compound according to claim 28 used for the treatment of chronic pain. 30. The method of claim 29, wherein annular pain, neuropathic pain, diabetic neuropathy, shingles neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex site pain syndrome (CPRS), trigeminal neuralgia / trigeminal Neuralgia / distributive teak, surgical interventions (e.g. postoperative analgesics), diabetic angiopathy, capillary or diabetic symptoms associated with insulin salts, pain associated with angina, pain associated with menstruation, pain associated with cancer, Toothache, headache, migraine, tension headache, trigeminal neuralgia, temporomandibular joint syndrome, fascia pain muscle damage, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and swelling resulting from mental trauma associated with burns, osteoarthritis, Sprain or fracture pain due to osteoporosis, bone metastasis or unknown causes, gout, fibromyalitis, fascia pain, thoracic outlet syndrome, upper pain, etc. Or lower back pain (back pain from systemic, local, or primary spinal disease (neuromyopathy)), pelvic pain, angina chest pain, non-angina chest pain, spinal cord injury (SCI) -related pain, after central stroke Compound used for the treatment of pain, cancer neuropathy, AIDS pain, sickle cell pain or senile pain. 31. The compound of claim 30, used for the treatment of neuropathic pain. 32. The compound of claim 31, wherein said neuropathic pain is selected from hyperalgesia, hypersensitivity, neuropathy, diabetic neuropathy, neuritis, neuralgia, hypersensitivity, burning pain, and allodynia.

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