1-[2[(2,4-dimethylphenylsulfanyl)-phenyl]piperazine as compound with combined serotonin reuptake 5-HT3 and 5-HT1a activity for treatment of cognitive impairment

Abstract

To provide a compound extremely useful for a treatment of cognitive impairment in depression patients.SOLUTION: 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine has strong activity on SERT, 5-HT3 and 5-HT1A, and is useful for a treatment of cognitive impairment, especially cognitive impairment in depression patients.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for detecting serotonin receptor 1A (5-HT 1A ) and serotonin receptor 3 (5-H The present study concerns compounds that exhibit serotonin reuptake inhibitory activity combined with activity on T3 Thus, these compounds are useful in treating CNS-related disorders. [Background technology]

[0002] Selective serotonin reuptake inhibitors (SSRIs) are compounds that were previously used , i.e., more effective, better tolerated, and with a favorable safety profile compared to classical tricyclic compounds. Due to its gender profile, it has been used for many years to treat certain CNS-related diseases, especially It was the first-line drug used to treat depression, anxiety and social phobia.

[0003] Nevertheless, therapeutic treatment with SSRIs results in a significant proportion of non-responders, i.e. , hampered by patients who do not respond or only respond to SSRI treatment to a limited extent. Moreover, SSRI treatments typically do not begin to have an effect until several weeks after treatment. .

[0004] To avoid some of these drawbacks of SSRI treatment, psychiatrists sometimes recommend increased Augmentation strategies are used. Augmentation of antidepressants can be achieved by, for example, administering mood stabilizers such as rituximab to patients with depression. By combining it with tetrahydrofuran carbonate or triiodothyronine, or This can be achieved by combining it with Ki-Shock Therapy.

[0005] Inhibition of the serotonin transporter (SERT) and one or more serotonin receptors It is known that combinations of serotonin and steroids with activity on the immune system can be beneficial. Tonin reuptake inhibitors and 5-HT 2C Has antagonist or inverse agonist effects Compounds that 2C The combination of 5-HT (serotonin) in terminal areas as measured by microdialysis experiments It has been found that this significantly increases the level of erythrocytes (Patent Document 1). The relatively short duration of antidepressant effects and serotonin reuptake inhibitors (SRIs) This may have suggested an enhancement or synergistic effect of the therapeutic effects of

[0006] Similarly, 5-HT 1A Pindolol, a partial agonist of serotonin reuptake It has also been reported that combination with an inhibitor results in rapid onset of efficacy (Non-Patent Document 1).

[0007] CNS-related disorders, such as depression, anxiety and schizophrenia, are often associated with other disorders or It is often accompanied by cognitive impairment or dysfunction, such as cognitive impairment or impairment (Non-Patent Document 2, Non-Patent Document 3, Permitted document 3). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 01 / 41701 Brochure [Non-patent literature]

[0009] [Non-Patent Document 1] Psych.Res., 125, 81-86, 2004 [Non-Patent Document 2] Scand.J.Psych., 43, 239-251, 2002 [Non-Patent Document 3] Am.J.Psych., 158, 1722-1725, 2001 Summary of the Invention [Problem to be solved by the invention]

[0010] Several neurotransmitters are thought to be involved in the neurological events that regulate this cognition. In particular, the cholinergic system plays an important role in cognition and therefore Compounds that affect the cholinergic system are potentially useful in the treatment of cognitive impairment. T 1A Compounds that affect the 5-HT3 receptor and / or the 5-HT4 receptor have an effect on the cholinergic system. As such, these compounds are known to have cognitive impairment effects. These may be useful in treating

[0011] For this reason, 5-HT 1A and / or activate 5-HT3 receptors The compounds may be expected to be useful in the treatment of cognitive impairment. Compounds that also activate T activity may be useful in treating depression, as such compounds have rapid therapeutic efficacy. This is thought to be a useful treatment for cognitive impairment in patients with depression. It would be exceptionally useful.

[0012] WO 03 / 029232 describes compounds with SERT activity, e.g. As the compound 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine The present inventors have disclosed a method for producing the same (Example 1e). [Means for solving the problem]

[0013] Surprisingly, the inventors have found that 1-[2-(2,4-dimethylphenylsulfanyl )phenyl]piperazine exhibits SERT inhibition, 5-HT3 antagonism and 5-HT 1A It has been found that the combination of partial agonism exerts a In particular, the present invention relates to 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] The present invention provides Compound I, which is a piperazine, and pharma- ceutical acceptable salts of the compound, wherein It is understood that the compounds described above are not free bases in amorphous form.

[0014] In one embodiment, the present invention provides the use of Compound I in therapy.

[0015] In one embodiment, the present invention provides a pharmaceutical composition comprising Compound I.

[0016] In one embodiment, the present invention provides a method of treatment, the method comprising administering to a patient in need of treatment The method includes administering an effective amount of Compound I to a patient suffering from the condition.

[0017] In one embodiment, the present invention provides the use of Compound I in the manufacture of a medicament. . [Brief description of the drawings]

[0018] [Figure 1] XRPD of the crystalline base. [Diagram 2] XRPD of the alpha hydrobromide salt. [Diagram 3] XRPD of the beta hydrobromide salt. [Figure 4] XRPD of the gamma hydrobromide salt. [Diagram 5] XRPD of the hydrobromide salt in the hemihydrate form. [Figure 6]XRPD of a mixture of the ethyl acetate solvate and the hydrobromide salt of the alpha form. [Figure 7] XRPD of the hydrochloride salt. [Figure 8] XRPD of the hydrochloride salt in monohydrate form. [Figure 9] XRPD of the mesylate salt. [Figure 10] XRPD of the fumarate salt. [Figure 11] XRPD of the maleate salt. [Figure 12] XRPD of the meso-tartrate salt. [Figure 13] XRPD of L-(+)-tartrate salt. [Figure 14] XRPD of D-(-)-tartrate salt. [Figure 15] XRPD of sulfate salt. [Figure 16] XRPD of phosphate salts. [Figure 17] XRPD of nitrate. [Figure 18a] Effect of compounds of the invention in the intradermal formalin test. X-axis indicates the amount of compound administered; Y-axis indicates the amount of time spent licking the paw (seconds). Responses within the 0-5 min time period. [Figure 18b] Effect of compounds of the invention in the intradermal formalin test. The X-axis indicates the amount of compound administered; the Y-axis indicates the amount of time spent licking the paw (in seconds). Responses within a 20-30 minute time period. [Figure 19a] Extracellular acetylcholine levels in the prefrontal cortex of freely moving rats upon administration of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt. [Figure 19b] Extracellular acetylcholine levels in the ventral hippocampus of freely moving rats upon administration of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt. [Figure 20]Effect of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 60 min before acquisition. Freezing behaviour was scored during a 58 s habituation period preceding the footshock US (pre-shock acquisition) (white bars). Freezing behaviour was measured 24 h after training (retention test) (black bars). [Figure 21] Effect of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 1 h before the retention test. Freezing behavior was scored for 58 s prior to the footshock US (acquisition) (white bars). Freezing behavior was measured 24 h after training (retention test) (black bars). [Figure 22] Effect of AA21004 on contextual fear conditioning in Sprague-Dawley rats when given immediately after acquisition. Freezing behavior was scored for 58 s prior to the footshock US (pre-shock acquisition) (white bars). Freezing behavior was measured 24 h after training (retention test) (black bars). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present invention relates to a method for producing a

[0020] [ka]

[0021] Compound I, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyridine Perazine and its pharma- ceutically acceptable salts of Compound I, provided that Compound I is amorphous. It is not intended to be a free base in its original form.

[0022] In one embodiment, the pharma- ceutically acceptable salts are acid addition salts of non-toxic acids. Such salts include those formed from organic acids, such as maleic acid, fumaric acid, benzoic acid, etc. , 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 Acid, Lactic Acid, Malic Acid, Mandelic Acid, Cinnamic Acid, Citraconic Acid, Aspartic Acid, Stearyl Acid acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetate, and 8-halotheophylline, e.g. Such salts include salts derived from inorganic salts such as lomotheophylline. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid may be used. Particular examples include methanesulfonic acid, maleic acid, fumaric acid, Meso-tartaric acid, (+)-tartaric acid, (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorous acid and and nitric acid. It is possible.

[0023] Oral dosage forms, especially tablets, are easy to administer and result in good compliance. In tablets, the active ingredient is crystalline. In one embodiment, the compounds of the present invention are crystalline. .

[0024] In one embodiment, the crystals of the present invention are solvates, i.e., solvent molecules are not included in the crystal structure. The solvate may be formed from water, in which case it is These solvates are often referred to as hydrates. Alternatively, these solvates may be formed from other solvents. The solvent may be, for example, ethanol, acetone, or ethyl acetate. The exact amount of solvation of often depends on those conditions. For example, hydrates typically will lose moisture if the temperature is increased or the relative humidity is decreased.

[0025] In one embodiment, the compounds of the invention are crystalline in unsolvated form.

[0026] Some compounds are hygroscopic, that is, they absorb water when exposed to moisture. Hygroscopicity is generally a problem in pharmaceutical formulations, particularly in dry formulations, such as tablets. This is considered an undesirable property for a compound that should be present in the In an embodiment, the present invention provides a crystal having low hygroscopicity. For oral dosage forms, it is also beneficial that the crystals are well defined. In this context, the term "well-defined" specifically refers to a compound whose stoichiometry is clearly defined. This means that the salt is precisely defined, i.e. the ratio between the ions forming the salt is small. Ratios between small integers, e.g. 1:1, 1:2, 2:1, 1:1:1, etc. In one embodiment, the compounds of the invention are well-defined crystals.

[0027] The crystalline compounds of the present invention may exist in more than one form, i.e. A substance may exist in polymorphic forms. Polymorphic forms are when a compound crystallizes in more than one form. The present invention relates to either pure compounds or mixtures of these compounds. In these cases, all such polymorphic forms are intended to be encompassed.

[0028] In one embodiment, the compounds of the invention are in purified form. The term "form" refers to a compound that, in some cases, is identical to another compound or to another form of it. "Contains essentially no compounds."

[0029] In one embodiment, the present invention relates to a method for manufacturing a semiconductor device according to the present invention. The present invention provides a crystalline salt of a compound of the present invention having an XRDP as shown in the table below.

[0030] The following table shows the main XRDP reflections for the compounds of the present invention. is.

[0031] Selected X-ray peak positions (°2θ), all values ​​+-0.1°

[0032] [Table 1]

[0033] For example, as evidenced by Figures 2-5, the compounds of the present invention, in this case brominated The hydrochloride salt can exist in several forms, i.e., it can be polymorphic. The morphological forms have different properties, as shown in Example 4d. The hydrochloride salt has high activity as indicated by its higher DSC melting point and lower solubility. Moreover, the beta form has an attractive combination of low hygroscopicity and solubility. The complex properties of this compound make it particularly suitable for the production of tablets. Thus, in one embodiment, the present invention provides a method for producing a 100% 150% ... , 13.78 and 14.62 (°2θ), in particular the XRDP reflections at 1-[2-(2,4-dimethylphenylsulfanyl)- The hydrobromide salt of [phenyl]piperazine is provided.

[0034] The solubility of the active ingredient can also have a direct effect on bioavailability. This is important in choosing the dosage form. For oral dosage forms, the higher solubility of the active ingredient is important. is generally considered beneficial because it increases bioavailability. .

[0035] Cholinergic neurotransmission in the cortex and hippocampus is crucial for cognition and is also involved in the regulation of Many preclinical observations suggest that serotonin receptor 1A (5-HT 1A The importance of T. Koyama, Neurosci.Lett., 265, 33-3 6, 1999, 5-HT 1A The agonist BAYX3702 inhibited the rat cortex and increased acetylcholine efflux from the hippocampus. 5-HT 1A The antagonist WAY-100635 abrogates the effect of BAYX3702. This suggests that the effect of BAYX3702 is to inhibit 5-HT 1A Being mediated It shows.

[0036] Numerous studies have demonstrated the effect of 5-HT on cognitive impairment. 1A About the effect of the modulator A. Meneses, Neurobiol.Learn.Memory, 71, 207-218, 1999, Partial 5-HT 1AAgonist (±) -8-Hydroxy-2-(di-n-propylamino)-tetralin, HCl(8-OH- DPAT promotes learning consolidation and cognitive function in normal rats It has been reported that it normalizes cognitive function in rats with cognitive impairment.

[0037] These preclinical observations appear to be mirrored in the clinic. Oshi, Am. J. Psych., 158, 1722-1725, 2001 They report on a study in which patients were given either a placebo or 5-HT 1A a In combination with the agonist tandospirone, a typical antipsychotic, e.g. haloperidol , sulpiride and pimozide (all of which are 5-HT 1A (lacking activity) was administered Patients who received tandospirone in addition to antipsychotics showed improved cognitive performance, Patients who received the placebo did not show any improvement. 1A Atypical antipsychotics such as clozapine, which are agonists, also have cognitive impairment in schizophrenia patients. Increases intelligence, but 5-HT 1A Inactive typical antipsychotics, e.g., Haloperidol Dolls and other such devices do not enhance cognition (Y. Chung, Brain Res., 1023, 54-63, 2004).

[0038] As mentioned above, the cholinergic system is involved in the neurological events that regulate cognition. The cholinergic system is thought to be involved in the regulation of the serotonin receptor 3 (5-HT3 ) is thought to be susceptible to inhibitory control [Giovannini et al., J. Pharmacol.Exp.Ther., 1998, 285:1219~1225;C ostall and Naylor, Current Drug Targets-CNS &Neurobiol.Disord.2004, 3:27~37].

[0039] In the habituation test in mice, the T-maze forced alternation test in rats in the forced alternation task and in object discrimination in marmosets. Ondansetron inhibited muscarinic discrimination and reversal learning in rats. Dysfunction caused by the antagonist scopolamine or arising from the basal ganglia (Barnes et al., Pharmacol. Biol. 2003, 144:1311-1323) hem.Behav.1990, 35:955~962;Carey et al., Pharmac ol. Biochem. Behav. 1992, 42:75-83). Boast et al. (N eurobiol. Learn. Mem. 1999, 71:259-271) Delayed sample unmatched emission using MK-801, a noncompetitive antagonist of A receptors Ondansetron disrupted the cognitive performance of rats trained in a 3-dose maze task. Moreover, ethanol has been shown to block the effects of ethanol on passive avoidance in mice. In a study on the amnesic effect of ethanol, the amnesic effect of ethanol was Partially restored to normal by Tron (Napiorkowska-Paw lak et al., Fundam.Clin.pharmacol.2000, 14:125~1 31) Thus, the role of 5-HT3 antagonism in the treatment of cholinergic dysfunction in preclinical models is unclear. Facilitation of cholinergic transmission by stimuli (Diez-Ariza et al., Psychopharmacology, 2011). macology, 2003, 169:35-41; Gil-Bea et al., Neuroph armcol. 2004, 47:225-232) has demonstrated the efficacy of this procedure in the treatment of cognitive impairment. This suggests a rationale for using

[0040] Conducted in a randomized, double-blind, crossover study in healthy male subjects Verbal and spatial memory and sustained attention were assessed using 5-HT3 antagonists. Alosetron, a novel neurotransmitter, attenuates scopolamine-induced impairments in verbal and spatial memory. (Preston, Recent Advances in the treatment of neurodegenerative disorders and cognitive function, 1994, (eds.)Racagn i and Langer, Basel Karger, pp. 89-93).

[0041] In conclusion, 5-HT in combination with 5-HT3 antagonist activity 1A Partial Agony Compounds that exhibit anti-cognitive activity are believed to be particularly useful in the treatment of cognitive impairment. Furthermore, compounds that exert serotonin reuptake inhibition include 5-HT 1A Partial agonism and Combined serotonin reuptake inhibition produces faster onset of depression treatment This may be particularly useful for treating cognitive impairment associated with depression.

[0042] As shown in Example 1, the compounds of the present invention inhibit the human serotonin transporter. They are potent inhibitors, i.e., they inhibit serotonin reuptake. These compounds have been shown to inhibit 5-HT3 receptor activity in mice, rats, guinea pigs and dogs. It is a potent antagonist of the human 5-HT3 receptor cloned in oocytes. At low concentrations, these compounds are antagonists (IC 50 = approx. 30 nM), and On the other hand, at higher concentrations, the compounds exhibit agonistic properties (ED 50 =2. Subsequent application of the compounds of the invention at higher concentrations was found to have no agonistic effect. The mice did not show any rapid desensitization in vitro. Or it could have been due to direct antagonism. At the same time, the compounds of the present invention exhibit binding properties similar to those observed at 5-HT3 receptors from other species. , and also shows significant antagonism at the human 5-HT3 receptor.

[0043] The compounds of the present invention inhibited the 5-HT2+ receptor agonist activity in brain homogenates of both rats and mice. 1A The compounds of the present invention bind to the receptor with low affinity, however, with a K i Human 5- HT 1A Moreover, functional data are available for the compounds of the present invention. The object is human 5-HT 1A Partial agonist at the receptor, resulting in 85% efficacy This indicates that.

[0044] SERT, 5-HT3 receptors and 5-HT 1A The activity of the present invention at the receptor is This is expected to contribute to the in vivo profile of the compound in

[0045] As shown in Example 26, the compounds of the present invention have been shown to inhibit the prefrontal cortex and These preclinical findings result in increased extracellular acetylcholine levels in the ventral hippocampus and the ventral hippocampus. The findings compare favorably with the use of acetylcholinesterase inhibitors in the treatment of cognitive impairment. , which may translate into clinical benefits in the treatment of cognitive impairment, e.g., in the treatment of Alzheimer's disease. Further support for this view can be found in Example 27, where The data show that the compounds of the present invention enhance contextual memory in rats. Ultimately, the effects on acetylcholine levels in rats and The pharmacological profile of the compounds of the invention in combination with their effects on memory is These results strongly suggest that the compound may be useful in treating cognitive impairment.

[0046] In one embodiment, the present invention provides a method for treating cognitive impairment or cognitive dysfunction. The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the present invention. This includes giving.

[0047] Cognitive impairment or impairment of cognitive function includes a decline in a cognitive function or domain, such as impaired working memory. Memory, Attention and Vigilance, Verbal Learning and Memory, Visual Learning and Memory, Logical Thinking and and problem solving, including impairments in executive function, processing speed and / or social cognition. Cognitive impairment or impairment of cognitive function is characterized by lack of attention, disorganized thinking, slow thinking, ing), difficulty in understanding, poor concentration , impairment of problem solving, poor memory , difficulties in expressing thoughts and / or feelings Difficulties in integrating thoughts, feelings and behavior ur, or difficulties in extinction of irrelevant thoughts The terms "cognitive impairment" and "cognitive impairment" refer to the same thing. are intended to indicate the same thing and are used interchangeably.

[0048] In one embodiment, the patient is suffering from another CNS disorder, e.g., an affective disorder, e.g., anxiety. depression; generalised depression; major depressive disorder; generalised anxiety disorder and anxiety disorders including panic disorder; obsessive-compulsive disorder; schizophrenia; Parkinson's disease; dementia; Diagnosis of dementia due to AIDS; ADHD; memory loss due to aging; or Alzheimer's disease The decision was also made at the same time.

[0049] Cognitive impairment is a typical feature of depression, for example major depressive disorder. Intellectual disability is to some extent related to the improvement of depression, in the sense that improvement of cognitive impairment also leads to improvement. It may be secondary to depression, but cognitive impairment is actually independent of depression. For example, several studies have shown that recovery from depression This indicates continued cognitive impairment [J. Nervous Mental Disease , 185, 748-754, 197]. Furthermore, the effects of anti-angiogenic drugs on depression and cognitive impairment The differential effects of medications on depression and cognitive function, even though these conditions are often comorbid, This provides further support for the idea that serotonin and neurotransmitters are independent of the disorder. Although adrenaline medications produce similar improvements in depressive symptoms, some studies have shown that noradrenaline showed that modulation of the adrenergic system did not improve cognitive function as much as modulation of serotonin. [Brain Res. Bull., 58, 345-350, 2002;Hum P psychopharmacol., 8, 41–47, 1993].

[0050] Treatment of cognitive impairment in depressed patients by administering the compounds of the present invention is particularly The multifaceted pharmacology of the compounds of the present invention, particularly the inhibition of SERT and 5-HT 3- and 5-HT 1A Activity is a cognitive function combined with rapid onset of therapeutic effects in depressive states. It is expected to result in improved functionality.

[0051] Cognitive impairment is a particularly important consideration in older adults. It normally progresses with age, but also with depression. In this case, patients treated for cognitive impairment are elderly, especially those with depression. It is.

[0052] Cognitive function, as mentioned above, is often impaired in people with schizophrenia. In addition, some studies have shown that cognitive functioning may affect vocational functioning in schizophrenia. They also concluded that the condition is associated with aging [Scizophrenia Res., 45 In one embodiment, the treatment of cognitive impairment is The patients involved are those with schizophrenia.

[0053] 5-HT3 receptor antagonists are further used for the treatment of various disorders, e.g., emesis, chemotherapy, Act-induced vomiting, cravings, substance abuse, pain, irritable bowel syndrome (IBS), schizophrenia and eating disorders It has also been suggested that it can be used to treat eating disorders [Eur. J. Pharmacol., 56 0, 1~8, 2007;Pharmacol.Therapeut., 111, 855~ 876, 2006;Alimentary Pharmacol.Ther., 24, 1 83-205, 2006].

[0054] A clinical study has shown that patients with depression who have an inadequate clinical response (treatment-resistant depression (TRD) or To treat treatment-refractory depression, mirtazapine is combined with an SSRI. The study showed that combining SSRIs with serotoninib was superior to using SSRIs alone [Ps ychother.Psychosom., 75, 139–153, 2006]. Mirta Zapine is a 5-HT2 and 5-HT3 antagonist, which means that the compounds of the present invention This supports the concept that it may be useful in treating TRD.

[0055] Hot flushes are a symptom associated with menopause. For some women, the hot flushes affect their ability to sleep. or to the point where it interferes with normal activities and requires treatment. Hormonal replacement therapy using strogen has been the default treatment, but recently, Concerns have been expressed about side effects, including cardiac events. These compounds have been shown to be effective against hot flashes, although not as effective as trogen. [J.Am.Med.Ass., 295, 2057-2071, 2006]. The present invention also provides a method for treating facial flushing using a compound that inhibits serotonin reuptake, such as the compound of the present invention. Treatment is for women who cannot or will not tolerate estrogen. It is an alternative treatment.

[0056] Sleep apnea or obstructive sleep apnea-hypopnea syndrome or obstructive sleep breathing disorder However, it remains a disorder for which effective pharmacological treatments remain to be identified. Several studies in the literature have demonstrated that 5-HT3 antagonists, such as the compounds of the present invention, are effective in treating these It has been suggested that it may be effective in treating the disease [Sleep, 21, 131-136 , 1998;Sleep, 8, 871, 878, 2001].

[0057] In one embodiment, the present invention provides a method for treating affective disorders; depression; major depressive disorder; postpartum depression. Bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease depression; anxiety; generalized anxiety disorder; social anxiety disorder; obsessive-compulsive disorder; panic disorder; blackouts;phobia;social phobia;agoraphobia;stress incontinence;vomiting;IBS;eating disorders chronic pain; partial responders; treatment-resistant depression; Alzheimer's ADHD; Melancholia; PTSD; Hot flashes; Sleep apnea; alcohol, nicotine or carbohydrate cravings; substance abuse; and alcohol or drug abuse The present invention relates to a method of treating a disease selected from the group consisting of the above-mentioned diseases, which method comprises administering to a patient in need of treatment. In one embodiment, the method comprises administering to the patient a therapeutically effective amount of a compound of the present invention. The aforementioned patients being treated for any of the diseases listed in The diagnosis of the disease has been made.

[0058] Treatment with antidepressants in general, and SSRIs in particular, is often associated with sexual dysfunction. It is well known that this often leads to treatment discontinuation. Thirty percent of patients treated with SSRIs As many as 70% of patients complain of sexual dysfunction [J. Clin. Psych., 6 6, 844-848, 2005], these disorders include decreased libido, delayed orgasm, , reduced or absent sexual arousal, and erectile dysfunction. In total, 114 subjects received a compound of the invention; of these 114 subjects, only Only one subject reported sexual dysfunction. These data are consistent with the results of the study using the compounds of the present invention. These results suggest that clinical interventions associated with a surprisingly small number of sexual dysfunctions are associated with

[0059] As mentioned above, the compounds of the present invention are particularly well suited for the treatment of chronic pain. Chronic pain is caused by phantom limb pain, neuropathic pain, diabetic neuropathy, and post-herpetic neuropathy. Pain (PHN), Carpal Tunnel Syndrome (CTS), HIV Neuropathy, Complex Regional Pain Syndrome (CPRS), trigeminal neuralgia / trigeminal neuralgia / painful tics, surgical intervention (e.g. postoperative analgesics), diabetic vasculopathy, capillary resistance or diabetic symptoms with insulitis, angina pain related to menstruation, pain related to cancer, toothache, headache, migraine, tension Pain, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscle injury ury), fibromyalgia syndrome, osteoarthritis, rheumatoid arthritis, burns Chronic rheumatoid arthritis and edema due to trauma, osteoarthritis, osteoporosis, and metastasis to bones are also or bone pain from sprains or fractures of unknown origin, gout, fibromyalgia, myofascial pain, thoracic Outlet syndrome, upper or lower back pain (where the back pain is systematic, localized or Primary spinal disease (radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord Injury (SCI)-related pain, central post-stroke pain, cancer neuropathy, AIDS-related pain, Indications include sickle cell pain, or geriatric pain.

[0060] The data presented in Example 16 demonstrate that compounds of the invention are useful in the treatment of pain and They also show that these compounds may even have analgesic effects, and may even be useful in treating neuropathic pain. Studies in animal models of inflammatory bowel disease confirm this notion.

[0061] As used herein, the term "therapeutically effective amount" of a compound refers to the amount of the compound administered. Therapeutic interventions include administering a therapeutic agent to treat the clinical signs of a given disease and its complications. "Amount sufficient to prevent, mitigate, or partially arrest the A therapeutically effective amount is defined as an amount sufficient to treat a particular disease or condition. The appropriate use will depend on the severity of the injury, as well as the weight and general condition of the individual. The determination of the quantity is done by constructing a matrix of numbers and then calculating the to test (all of which is within the normal technical competence of a trained physician) It will be appreciated that this can be accomplished with routine experimentation.

[0062] As used herein, the terms "treatment" and "treating" refer to the treatment of a condition, e.g. This term refers to the management and care of a patient with the objective of combating a disease or disorder, for example. The term refers to the full spectrum of treatments for a given condition that a patient is suffering from, e.g. Slow the progression of the disease, disorder or condition so as to alleviate its symptoms or complications to alleviate or relieve the symptoms and complications of, and / or , for curing or eliminating a disorder or condition, or even for preventing the condition; and the like, where prophylaxis is intended to include the administration of an active compound, should be understood to mean the management and care of patients with the aim of combating the disorder. , including the administration of an active compound to prevent the onset of those symptoms or complications. Preventive treatment (treatment aimed at prevention) and therapeutic treatment (treatment aimed at cure) These are two separate aspects of the invention. The patient to be treated is preferably a mammal, particularly is human.

[0063] Typically, the treatment of the present invention will involve daily administration of the compound of the present invention. may be administered once daily, or even twice daily or more frequently. It may include.

[0064] In one embodiment, the present invention provides a method for treating affective disorders; depression; major depressive disorder; postpartum depression. Bipolar disorder, Alzheimer's disease, psychosis, cancer, caries associated with aging or Parkinson's disease depression;anxiety;generalized anxiety disorder;social anxiety disorder;obsessive-compulsive disorder;panic disorder;panic attack ;Phobia;Social Phobia;Agoraphobia;Stress Incontinence;Vomiting;IBS;Eating Disorders;Chronic Pain;Partial responders;Treatment-resistant depression;Alzheimer's disease;Cognitive impairment;ADHD; Melancholia; PTSD; hot flashes; sleep apnea; alcohol, nicotine or carbohydrate Manufacture medications to treat alcohol or drug abuse; substance cravings; The present invention relates to the use of the compounds of the present invention for treating

[0065] In one embodiment, the present invention relates to a method for treating affective disorders, depression, major depressive disorder, postpartum depression, dementia, bipolar disorder, Alzheimer's disease, psychosis, cancer, caries associated with aging or Parkinson's disease Depression, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, panic attacks , phobias, social phobia, agoraphobia, stress incontinence, vomiting, IBS, eating disorders, chronic Pain, partial responders, treatment-resistant depression, Alzheimer's disease, cognitive impairment, ADHD, Melancholia, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrates In the treatment of disorders selected from the group consisting of addiction craving, substance abuse, or alcohol or drug abuse. The present invention relates to a compound of the present invention for use in

[0066] The effects of the compounds of the invention on human cognition can be assessed in a number of ways. The effects of the compound are evaluated by administering it to healthy volunteers and then testing them in recognized tests, e.g. For example, Auditory Verbal Learning Test (AVLT), Wi Measure cognitive ability using the Sconsin Card Sorting Test (WCST) or sustained attention [Psycopharmacol., 163, 106-1 10, 2002; Psychiatry Clin. Neurosci., 60, 70~ 76, 2006]. The effect can be evaluated by a test that measures the same Cognitive impairment may be assessed in patients with cognitive impairment using the following tests: A model may be used in which cognitive impairment is induced in healthy volunteers. The ameliorative effect of the compound of the present invention is measured. It can be induced by sleep deprivation, alcohol, and tryptophan depletion.

[0067] The pharmaceutical formulation of the present invention can be prepared by conventional methods known in the art. In particular, tablets are made by mixing the active ingredient with conventional adjuvants and / or diluents. The mixture can then be compressed in a conventional tablet machine. Examples of diluents are: anhydrous calcium hydrogen phosphate, PVP, PVP-VA copolymer, microcrystalline cellulose, Crystalline cellulose, sodium starch glycolate, corn starch, mannitol , Potato Starch, Talcum, Magnesium Stearate, Gelatin, Lactose any other adjuvants or additives commonly used for such purposes; For example, colouring agents, flavourings, preservatives etc. may be used, provided they are compatible with the active ingredient. and can be used.

[0068] Injectable solutions are prepared by dissolving the active ingredient and possible additives in a portion of an injection solvent, preferably distilled water. The solution is dissolved in water, adjusted to the desired volume, and the resulting solution is sterilized and dispensed into suitable ampoules or bags. The method can be prepared by filling the vial with water. Any suitable additives may be added, such as tonicity agents, preservatives, antioxidants, etc. .

[0069] The pharmaceutical composition of the present invention or the pharmaceutical composition produced according to the present invention can be administered via any suitable route. It can be administered orally, for example in the form of tablets, capsules, powders, syrups, etc. It may be administered orally or parenterally in the form of an injectable solution. Various methods well known in the art may be used to prepare such compositions, In addition, any pharma- ceutically acceptable carrier, diluent, excipient, or any other suitable carrier or excipient commonly used in the art may be used. Other additives which have been used in the art may be used.

[0070] Conveniently, the compound of the present invention is provided in an amount of about 1 mg to 50 mg of the compound. The upper limit is a concentration-dependent increase in 5-HT3 activity. The total daily dose is usually in the range of about 1 to 20 mg. The compound of the present invention may be, for example, about 1 mg to 10 mg, about 5 mg to 10 mg, about 10 mg to 20 mg. or about 10 to 15 mg of the compound of the present invention per day. , 10 mg, 15 mg or 20 mg.

[0071] Tablets containing the compounds of the invention may conveniently be prepared by wet granulation. When this method is used, dry solids (active ingredients, fillers, binders, etc.) are blended. , moistened with water or other moistening agent (e.g. alcohol) and solidified with the moistened solids. Agglomerates or granules are built up. Wet agglomeration continues until the desired uniform particle size is achieved. After the desired particle size is achieved, the granulated product is dried. Typically, lactose monohydrate, corn maltose, and maltose are mixed together in a high shear mixer with water. The granules are mixed with starch and copovidone. After formation of the granules, the granules are passed through a suitable sieve. The resulting mixture may then be sieved through a sieve having a size and dried. These dried granules are made of microcrystalline cellulose, croscarmellose sodium and magnesium. The compound of the present invention is mixed with sodium stearate and then compressed into tablets. The wet granulation process uses mannitol, corn starch and copovidone to compress tablets. Before shrinking, the granules were mixed with microcrystalline cellulose, sodium starch glycolate and This may be achieved by mixing with magnesium stearate and magnesium stearate. The wet granulation of the compound is carried out with anhydrous calcium hydrogen phosphate, corn starch and The granules were mixed with microcrystalline cellulose, sodium chloride, and copovidone prior to compression into tablets. Mixed with starch glycolate (type A), talc and magnesium stearate This may be achieved by copovidone, a PVP-VA copolymer.

[0072] In one embodiment, the compound of the invention is, for example, the beta hydrobromide salt, A suitable tablet may consist of the following (percentages given are w / w%): be): HBr salt: 2-20% Lactose monohydrate: 30-50% Starch: 15-30% Copovidone: 3-5% Microcrystalline cellulose: 15-25% Croscarmellose sodium: 2-5% Magnesium stearate: 0.5~5%.

[0073] In particular, the tablet may consist of: HBr salt: 3-4% Lactose monohydrate: 44-46% Starch: 22-23% Copovidone: 3-4% Microcrystalline cellulose: 20-22% Croscarmellose sodium: 3-3.5% Magnesium stearate: 0.5~1% or HBr salt: 15-16% Lactose monohydrate: 35-38% Starch: 18-20% Copovidone: 3-4% Microcrystalline cellulose: 20-22% Croscarmellose sodium: 3-3.5% Magnesium stearate: 0.5~1% or HBr salt: 1-2% Lactose monohydrate: 44-46% Starch: 20-24% Copovidone: 3-4% Microcrystalline cellulose: 22-24% Croscarmellose sodium: 3-4% Magnesium stearate: 0.5~1%.

[0074] In one embodiment, the compound of the invention is, for example, the beta hydrobromide salt, A suitable tablet may consist of: HBr salt: 2-30% Mannitol: 25-45% Corn starch: 10-20% Copovidone: 2-4% Microcrystalline cellulose: 22-27% Sodium starch glycolate: 4-5% Magnesium stearate: 0.25-5%, for example 0.25-2%.

[0075] In particular, the tablet may consist of: HBr salt: 20-22% Mannitol: 35-36% Corn starch: 10-12% Copovidone: 2.5-3% Microcrystalline cellulose: 24-25% Sodium starch glycolate: 3-4% Magnesium stearate: 0.25~1% or HBr salt: 12-13% Mannitol: 36-37% Corn starch: 18-19% Copovidone: 3-4% Microcrystalline cellulose: 24-25% Sodium starch glycolate: 3-4% Magnesium stearate: 0.25~1% or HBr salt: 25-27% Mannitol: 27-29% Corn starch: 13-15% Copovidone: 3-4% Microcrystalline cellulose: 24-25% Sodium starch glycolate: 3-5% Magnesium stearate: 0.25~1% or HBr salt: 3-4% Mannitol: 40-42% Corn starch: 20-22% Copovidone: 3-4% Microcrystalline cellulose: 26-28% Sodium starch glycolate: 3-5% Magnesium stearate: 0.5%.

[0076] In one embodiment, the compound of the invention is the hydrobromide salt and a suitable tablet formulation is as follows: It may consist of: HBr salt: 3-8% Anhydrous calcium hydrogen phosphate: 35-45% Corn starch: 15-25% Copovidone: 2-6% Microcrystalline cellulose: 20-30% Sodium starch glycolate: 1-3% Talc: 2-6% Magnesium stearate: 0.5-2%.

[0077] In particular, the tablet may consist of: HBr salt: approx. 5% Anhydrous calcium hydrogen phosphate: approx. 39% Corn starch: approx. 20% Copovidone: approx. 3% Microcrystalline cellulose: approx. 25% Sodium starch glycolate: approx. 3% Talc: approx. 4% Magnesium stearate: about 1%.

[0078] Tablets having various different amounts of active compound, e.g. 2.5 mg, 5 mg, 10 mg, 2 0mg, 25mg, 30mg, 40mg, 50mg, 60mg or 80mg of free base Such tablets are prepared by combining the correct amount of the compound of the present invention in a tablet of appropriate size. It can be obtained by selection.

[0079] The size of the crystals used to prepare tablets containing the compounds of the present invention is important. If the crystals are too small, they will stick to the plunger of the tablet press. On the other hand, the crystals should not be too large. The dissolution rate decreases with increasing crystal size. Therefore, if the crystals are too large, may impair the bioavailability of the compound. For example, particle size distribution can be done using D5%, D10%, D50%, D90%, D95% and D98%. As used herein, the term "particle size distribution" refers to the The measurements were performed by laser diffraction at a dispersion pressure of 1 bar in an mpatec Helos instrument. The cumulative volumetric size distribution refers to the diameter of equivalent spherical particles when a given particle size distribution is determined.

[0080] In one embodiment, crystals of the compounds of the present invention, particularly the beta form of the hydrobromide salt, are prepared. The crystals are D98%: 650-680 μm; D50%: 230-250 μm; and D5%: In a further embodiment, the particle size distribution falls within the range of 40 to 60 μm. The particle size distribution of D98%: 370-390 μm; D50%: 100-120 μm; and D5%: 5 to 15 μm. In yet another embodiment, the particle size distribution D98%: 100-125μm; D50%: 15-25μm; and D5%: 1-3 In yet a further embodiment, the particle size distribution is D98%:5 μm. 0~70μm; D50%: 3~7μm; and D5%: 0.5~2μm.

[0081] The free base of the present invention is disclosed in WO 2003 / 029232. The salts of the present invention can be prepared by dissolving the free base in a suitable solvent. The precipitation can be carried out by dissolving the carboxylic acid in a hexane-containing solution, adding the relevant acid, and then precipitation. This can be accomplished by either adding a second solvent, and / or evaporating, and / or cooling. Alternatively, the free bases and ultimately the compounds of the invention can be prepared by the methods described below. It can also be synthesized in a palladium catalyzed reaction as described.

[0082] Aromatic carbon-heteroatom bond formation can be achieved by aromatic nucleophilic substitution or the copper-mediated Ullman reaction. More recently, palladium has been used to form such bonds, In particular, it has been shown to be a powerful catalyst in the formation of CN and CS bonds (e.g. (See U.S. Patent No. 5,573,460).

[0083] In one embodiment, the present invention provides

[0084] [ka]

[0085] The present invention provides a method for preparing compound II,

[0086] [ka]

[0087] [wherein R' represents hydrogen or a monovalent metal ion] in the presence of a solvent, a base, and palladium. In the presence of a palladium catalyst consisting of a source of ruthenium and a phosphine ligand, At temperatures between 100° C. and 130° C., the compound of formula III

[0088] [ka]

[0089] wherein X1 and X2 independently represent a halogen; and a compound of formula IV

[0090] [ka]

[0091] wherein R represents hydrogen or a protecting group.

[0092] In one embodiment, the method is divided into sub-processes, is a compound represented by the formula:

[0093] [ka]

[0094] This compound is then optionally purified to an appropriate extent. Then, 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine was added. This is reacted with compound IV to give

[0095] One-pot synthesis, i.e., all reactants are mixed together at the start of the reaction or process Syntheses are particularly useful due to their inherent simplicity. The number of undesirable side reactions increases dramatically, which again increases the number of undesirable by-products and It is understood that the amount and / or amount of aldehydes may increase and the yield of the desired product may correspondingly decrease. Specifically, in the present method, piperazine has two nitrogen atoms and is latent. It can be observed that essentially each nitrogen participates in the formation of a C-N bond. In particular, the present method allows for one-pot synthesis, i.e., optimal synthesis, while maintaining high yields of pure compounds. The method can be carried out as a method in which compound II, compound III and compound IV are mixed from the beginning. It was discovered that...

[0096] Compound II is a thiol or the corresponding thiolate. To avoid the odor problems associated with thiols, thiolates, e.g., Li + , Na + or K + It may be advantageous to use thiolates, etc. However, in one embodiment In this embodiment, R' is hydrogen.

[0097] Compound III is a 1,2-dihalogen activated benzene, the halogens of which are Cl, Br and I. In particular, compound II is 1-bromo-2-iodo- Benzene or 1,2-dibromo-benzene.

[0098] The solvent used in the process of the present invention is capable of reacting in the reaction temperature range, i.e., at a boiling point of 60 to 130°C. The solvent may be selected from aprotic organic solvents having the above properties or a mixture of such solvents. Typically, the solvent is toluene, xylene, triethylamine, tributylamine, diethylamine, oxane, N-methylpyrrolidone, or any mixture thereof. In particular, toluene can be mentioned as a solvent.

[0099] Central to the method is the use of a palladium catalyst without which the reaction would not occur. The palladium catalyst comprises a palladium source and a phosphine ligand. Suitable palladium sources include palladium in a variety of different oxidation states, e.g., 0 and II. Examples of palladium sources that can be used in the process of the present invention are Pd2dba3, Pddba 2 and Pd(OAc)2. dba is the abbreviation for dibenzylideneacetone. , Pddba2 and Pd2dba3. The palladium source can be Typically, it is 0.1 to 10 mol%, for example, 1 to 10 mol%, for example, 1 to 5 mol%. Throughout this application, mole percent refers to the limiting reactant. It is calculated in relation to

[0100] Numerous phosphine ligands, both monodentate and bidentate, are known. The ligand is racemic 2,2'-bis-diphenylphosphanyl-[1,1']binaphthalene. Nyl (rac-BINAP), 1,1'-bis(diphenylphosphino)ferrocene (D PPF), bis-(2-diphenylphosphinophenyl) ether (DPEphos), Tri-t-butyl-phosphine (Fu's salt), Biphenyl-2-yl-di-t-butyl -phosphine, biphenyl-2-yl-dicyclohexyl-phosphine, (2'-dicyclohexyl 2'-(di-hexylphosphanyl-biphenyl-2-yl)-dimethyl-amine, t-Butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and diphenyl Cyclohexyl-(2',4',6'-tripropyl-biphenyl-2-yl)-phosph Further, carbene ligands, such as 1,3-bis-(2,6-diisopropyl -phenyl)-3H-imidazol-1-ium, etc.; chloride instead of phosphine ligand In one embodiment, the phosphine ligand is rac -BINAP, DPPF or DPEphos, in particular rac-BINAP The phosphine ligand is usually present in an amount of from 0.1 mol % to 10 mol %, for example 1 mol % to 5 mol %, and typically is applied in an amount of about 1-2 mol %.

[0101] To increase the pH, a base is added to the reaction mixture. In particular, NaOt-Bu, KO Bases selected from t-Bu and Cs2CO3 are useful. Organic bases, such as 1,8 -Diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabi Cyclo[2.2.2]octane (DABCO) can be similarly applied. , NaO(t-Bu) and KO(t-Bu). Typically, The base is added in an amount of about 1-5 equivalents, such as 1-3 equivalents, for example 2-3 equivalents. is added in an amount of

[0102] Compound IV is a piperazine compound. Piperazine has two nitrogens. Only one of them is involved in forming a C-N bond. In one embodiment, the second nitrogen The formation of the bond to the aryl group can be achieved by using a mono-protected piperazine, i.e., This is avoided by using an embodiment in which the protecting group is a substituted aryl group. Many protecting groups are known in the art. Examples of useful compounds include boc, Bn, Cbz, C(=O)O, and Me, especially oc. Bn is the abbreviation for benzyl; boc is the abbreviation for t-butyloxycarbonyl. where cbz is the abbreviation for benzyloxycarbonyl. If the protected piperazine is If used in these reactions, the protecting group must be removed in a subsequent step. It is not a protecting group and is typically removed by the addition of aqueous acid. If the methyl group is substituted, it can be converted to methyl by reaction with a carbamate and subsequent removal of this group. may be removed.

[0103] Surprisingly, the unprotected pyridine derivatives were synthesized without the formation of undesired bonds to the second nitrogen. It has been found that piperazine can be used as well. Perazine has different solubilities in various different solvents; for example: Piperazine is practically insoluble in toluene, whereas the boc-protected piperazine Generally, all reactants are readily available in the applied solvent. One would expect that solubility in water would be a necessary condition for the success of the reaction. First, the method of the present invention uses toluene as a solvent and is carried out using an unprotected piperazine, i.e. It has been found to be carried out in high yields using piperazine embodiments in which R is hydrogen. Thus, in one embodiment, the solvent is toluene and compound IV is pipera. In a further embodiment, this combination of conditions is a one-pot synthesis. Used in.

[0104] In one embodiment, the temperature for carrying out the method is from about 80° C. to about 120° C. do.

[0105] In one embodiment, 1-[2-(2,4-dimethyl-phenylsulfanyl) Phenyl]-piperazine is prepared by a process comprising the steps of: a. Dissolve or disperse 1 to 1.5 equivalents of compounds II, III and IV in toluene. to obtain mixture A; b. 1 to 2 mole percent of optionally dispersed or dissolved or dispersed in toluene Pddba2 and 1-2 mol% rac-BINAP were mixed with 2-3 equivalents of NaOt-Bu. Add both to mixture A to obtain mixture B until compounds II and III are completely converted. heating mixture B to about 100° C., typically for 5 to 10 hours; c. Compound IV obtained in step b is reacted with the mixture until it is completely converted, typically for 16-32 hours. increasing the temperature of the mixture to about 120° C.; and d. Optionally, when compound III is a protected piperazine, adding an aqueous acid solution. removing the protecting group by

[0106] Optionally, a purification step may be included in the above reaction sequence.

[0107] In one embodiment, 1 to 1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo 1,2-dibromo-2-iodobenzene (or 1,2-dibromo-benzene) and piperazine 2 to 5 equivalents, e.g., 3 equivalents of N-dimethylformamide dispersed in toluene followed by 2 to 5 equivalents, e.g., 3 equivalents of N-dimethylformamide dispersed in toluene. Addition of aOt-Bu and 1-2 mol% Pd2dba3 and rac-BINAP A mixture is obtained, and the mixture is refluxed for 2 to 10 hours, typically 3 to 5 hours, to obtain 1-[2-( 2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine is obtained. This product was then further reacted with aqueous HBr to give the corresponding hydrobromide addition salt. It can also be done.

[0108] In one embodiment, 2 to 5 equivalents of NaOt-Bu, 2 to 5 equivalents of piperazine, 0.2-0.6 mol% Pddba2 and 0.6-1 mol% rac-BINAP were added. The mixture was dispersed in toluene to obtain a mixture A', and about 1 equivalent of 2-bromo-iodobenzene was added to the mixture. Add 1 equivalent of 2,4-dimethylthiophenol to the mixture B' to obtain mixture B'. and the resulting mixture is heated to reflux for 3-7 hours, e.g., 4-6 hours, and 1- [2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is obtained. Optionally, this product is further treated with aqueous HBr to give the corresponding hydrobromide addition salt. It can also be reacted with

[0109] In some circumstances, rather than as the free base, 1-[2-(2,4-dimethyl- In some cases it may be desirable to obtain an acid addition salt of phenylsulfanyl-phenyl-piperazine. The acid addition salt may be obtained in a further process step, in which The resulting free base is reacted with a suitable acid, such as fumaric acid, sulfuric acid, hydrochloric acid, or hydrobromic acid. The acid may be added directly to the reaction mixture or, alternatively, Alternatively, the free base may first be purified to any suitable extent prior to such steps. If the free base is isolated as a dry compound, it should be dried prior to reaction with the acid. It may be necessary to use a solvent to put the free base into solution. In the form, aqueous hydrobromic acid is reacted without any initial purification of the free base. It is added directly to the mixture.

[0110] In the methods in which protected piperazines are used, the acid is The protecting group must be removed by adding an aqueous solution. In this regard, the aqueous acid solution described above can carry out two transformations, namely, deprotection of the protected piperazine and formation of an acid addition salt. In particular, the formation of In one process step, the protected piperazine is deprotected and the hydrobromic acid addition salt is formed. can be obtained.

[0111] For all reactions and reaction mixtures described herein, they were gassed under inert gas. It may be advantageous to purge or carry them out under a blanket of inert gas. Nitrogen is an example of a cheap and readily available inert gas. .

[0112] All references cited herein, including publications, patent applications and patents, are the property of their respective owners. The entire contents of which are hereby incorporated by reference, as well as all of the claims made elsewhere in this specification. Each reference, without regard to the incorporation of any separately given specific document, to the same extent as if each of the preceding claims was individually and specifically indicated to be incorporated by reference. and to the same extent as if fully set forth herein (as provided by law). to the fullest extent permitted by applicable law).

[0113] The terms "a," "an," and "the" in the context of describing the present invention, Use of similar referents shall apply unless otherwise indicated in this specification or by context. Unless expressly stated otherwise, the terms "a," "the," "the," and "the" shall be construed as covering both the singular and the plural. For example, the phrase "the compound" should be used interchangeably with other Unless otherwise indicated, the various compounds of the invention or specific disclosed embodiments are represented by the following formulas: It should be understood that

[0114] Unless otherwise indicated, all precise values ​​given herein are relative values. are representative of approximate values ​​that may be applicable (e.g., given for a particular factor or measure) All precise illustrative values ​​have been amended to "about" where appropriate and the corresponding approximate measurements have been added. can be considered as a given.

[0115] "Comprising," "having," or "having" in relation to a component or components Use terms such as "containing," "including," or "including" The description herein of any embodiment or aspects of the invention may be used interchangeably with other embodiments or aspects of the invention unless otherwise stated. Unless otherwise stated or clearly contradicted by the context, or "consists of," "essentially consists of," or "consists of" several specific components. Similar aspects or inventions that "consist of" or "substantially comprise" The disclosure is intended to provide support for certain aspects of the invention (e.g., to include certain components). The compositions described herein as such are intended to be used interchangeably unless otherwise stated or the context dictates. Unless expressly denied by the should be understood as such). EXAMPLES

[0116] Analysis method 1 H NMR spectrum at 500.13MHz from Bruker Avance The data was recorded on a DRX500 instrument. Dimethyl sulfoxide (99.8% D) was used as the solvent. and tetramethylsilane (TMS) is used as the internal reference standard.

[0117] The melting points are measured using differential scanning calorimetry (DSC). The instrument uses TA-Instruments DSC-Q10 calibrated at 5° / min to give melting points Approximately 2 mg of sample was placed in a loosely closed pan under nitrogen flow. The plate is heated at 5° / min.

[0118] Thermogravimetric analysis (TGA) is used to estimate the solvent / water content of the dried material. , performed using a TA-Instruments TGA-Q500. The samples are heated at 10° / min in an open pan under nitrogen flow.

[0119] The powder X-ray diffraction pattern is CuK α1 PANalytical X'Per using radiation The samples were measured using a t PRO X-Ray Diffractometer. Measured in reflection mode in the 2θ-range 5-40° using a 'Celerator' detector It was done.

[0120] Example 1: In vitro receptor pharmacology Rat serotonin transporter:IC 50 5.3 nM (blockade of 5-HT uptake) ) Human serotonin transporter:IC 50 40nM (blocks 5-HT uptake) Human 5-HT 1A Receptor: Partial agonism, K i 40nM (85% potency) Rat 5-HT3 receptor: IC 50 0.2nM (antagonism in functional assays) Human 5-HT 3A Receptor: IC 50 Approximately 20 nM (antagonism in functional assays). At higher concentrations, the compound had an ED of 2.1 μM. 50 exhibits agonistic activity In addition, the compounds of the present invention bind to human 5HT3 receptors in an in vitro binding assay. It also showed high affinity for the antibody (Ki 4.5 nM).

[0121] Example 2: Cognitive effects As discussed above, the compounds of the present invention interact with the cholinergic system and also inhibit the innate immune system. In vivo models, it is expected that one or more of the following effects will be observed: Let's do it.

[0122] Five-choice reaction time test (5-CSRT) (useful for demonstrating effects on continuous attention) for) Spatial Y-maze test (demonstrating effects on short-term, long-term and working memory) (useful for Attentional set shifting model (executive function, i.e., reasoning) (useful for demonstrating effects on logical thinking and problem solving).

[0123] Example 3a: Preparation of the free base of Compound I 10 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperidine Dissolve arazine hydrobromide in 100 ml of 3M NaOH and 100 ml of ethyl acetone. The organic phase was separated and washed with 100 ml of 15% wt. N by washing with aCl(aq), drying over MgSO4, filtering and concentrating in vacuo. This gave 7.7 grams (98%) of Compound I base as a clear, colorless oil. NMR is consistent with the structure.

[0124] Example 3b: Preparation of the crystalline base of Compound I 3.0 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyrimidine The colorless oil of perazine was treated with 70 ml of acetonitrile and heated to reflux. The almost clear solution of is filtered and the resulting clear filtrate is cooled spontaneously. Precipitation began shortly after. The mixture was stirred at room temperature (22° C.) for 2 hours, and the resulting product The product was isolated by filtration and dried overnight under vacuum (40° C.). 2.7 grams (90%) of white The crystalline base was isolated as a colored solid. NMR is consistent with the structure. Elemental analysis: 72.4 0% C, 9.28% N, 7.58% H (theoretical value: 72.26% C, 9.36% N, 7.42% H).

[0125] Example 3c: Characterization of the Crystalline Base of Compound I This base, prepared as in Example 3b, is crystalline (XRPD) - see Figure 1. The crystalline base has a melting point of about 117° C. The base is also not hygroscopic and It has a solubility of 0.1 mg / ml in water.

[0126] Example 4a: Preparation of the hydrobromide salt of the alpha form of Compound I 2.0 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyridine Perazine was dissolved in 30 ml of hot ethyl acetate and 0.73 ml of 48% wt. Br(aq) was added. This addition resulted in the formation of a thick slurry, which could be stirred properly. An additional 10 ml of ethyl acetate was added to ensure complete dissolution. The slurry was allowed to stand at room temperature for 1 hour. The mixture was stirred for 1 h. The mixture was filtered and dried overnight under vacuum (20° C.) to give a white solid. 2.0 grams of product was obtained (80%). NMR is consistent with the structure. Elemental analysis: 57 .05% C, 7.18% N, 6.16% H (theoretical value for 1:1 salt: 56.9 9% C, 7.39% N, 6.11% H).

[0127] Example 4b: Characterization of the hydrobromide of the alpha form of Compound I The alpha form of this hydrobromide, prepared as in Example 4a, is crystalline ( XRPD) - see Figure 2. This crystalline hydrobromide has a melting point of about 226°C. In addition, this hydrobromide absorbs approximately 0.3% water when exposed to high relative humidity, and It has a solubility of 2 mg / ml in water.

[0128] Example 4c: Preparation of the hydrobromide salt of the beta form of compound I 49.5 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] The colorless oil of piperazine was dissolved in 500 ml of ethyl acetate and 18.5 ml of 48% wt HBr(aq) was added. This addition resulted in the formation of a thick slurry, which The slurry was stirred at room temperature overnight. It was filtered and dried under vacuum (50°C) overnight. This gave 29.6 grams of product as a white solid (47%). NMR is consistent with the structure. Elemental analysis: 56.86% C, 7.35% N, 6.24% H (theoretical for 1:1 salt: 56.99% C, 7.39% N, 6.11% H) .

[0129] Example 4d: Characterization of the beta-form hydrobromide of compound I The beta form of this hydrobromide, prepared as in Example 4c, is crystalline (X RPD) - see Figure 3. This crystalline hydrobromide has a melting point of about 231°C. This hydrobromide absorbs about 0.6% water when exposed to high relative humidity; and It has a solubility of 1.2 mg / ml in water.

[0130] Example 4e: Preparation of the hydrobromide salt of the gamma form of compound I 1 g of 1-[2-(2,4-dimethylphenylsulfuryl) Add 1,2-diphenylpiperazine hydrobromide to 20 ml of water and heat to 85°C. The solution was almost transparent. Adding one drop of HBr made the solution transparent. The solution became bright. HBr was added until a cloud point was observed. The solution was cooled to room temperature and dried. The NMR is consistent with the structure. Elemental analysis: 56.63% C, 7.18% N, 6 .21% H (theoretical for 1:1 salt: 56.99% C, 7.39% N, 6.1 1% H).

[0131] Example 4f: Characterization of the hydrobromide of the gamma form of compound I This hydrobromide, prepared as in Example 6e, is crystalline (XRPD)- See Figure 4. This DSC curve shows several thermal events at about 100°C, possibly a change in crystal form. The hydrobromide then melts at about 220°C. Dolobromide absorbs approximately 4.5% water when exposed to high relative humidity and at room temperature At 30% RH, approximately 2% water is absorbed.

[0132] Example 4g: Preparation of the hydrobromide hydrate of compound I 1.4 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyridine The perazine oil was added to 20 ml of water and heated to 60° C. 48% HBr was used to The H was adjusted to 1. The solution was cooled to room temperature and dried. NMR is consistent with the structure. Elemental analysis: 55.21% C, 7.16% N, 6.34% H (1:1 salt hemihydrate) Theoretical values ​​for: 55.68% C, 7.21% N, 6.23% H).

[0133] Example 4h: Characterization of the Hemihydrate of the Hydrobromide of Compound I This hydrate, prepared as in Example 4g, is crystalline (XRPD) - see Figure 5. The moisture content is highly dependent on the relative humidity. At room temperature and 95% RH, the moisture content is approximately The dehydration rate is 3.7%. Heating to about 100°C causes dehydration.

[0134] Example 4i: Preparation of the ethyl acetate solvate of the hydrobromide salt of Compound I 0.9 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyridine The perazine oil was dissolved in 35 ml of ethyl acetate and 0.5 ml of 48% wt. HBr(aq) was added. This addition resulted in the formation of a thick slurry, which was then cooled to 100° C. The mixture was stirred at room temperature overnight. It was filtered, washed with 30 ml of diethyl ether, and then cooled under vacuum (50°C). 1.0 g (65%) of 1-[2-(2,4-dimethylphenyl)-2,4-dimethyl-1,2,3-tetramethylphenyl]-2,4-dimethylphenyl]-2,5-dichloro ... (phenylsulfanyl)-phenyl]piperazine HBrEtOAc solvate was obtained. NMR is consistent with the structure. Elemental analysis: 56.19% C, 6.60% N, 6.56% H (8% ethyl acetate and 0.5% water as determined by TGA and KF) Theoretical values ​​for the 1:1 salt when corrected for: 56.51% C, 6.76% N, 6.38% H).

[0135] Example 4j: Characterization of the Ethyl Acetate Solvate of the Hydrobromide of Compound I This ethyl acetate solvate, prepared as in Example 4i, is crystalline (X RPD) - see Figure 6. The batch was 0.1%. Therefore, it contains a mixture of solvates and the alpha form of compound I. This desolvation occurs at 10°C. When heated at 1000 K / min, it begins at about 75°C. After desolvation, the alpha form is formed. When exposed to humidity, the ethyl acetate is replaced by water, and when the humidity is then reduced The resulting solid is hygroscopic and loses its moisture at high relative humidity. It absorbs 3.2% of moisture.

[0136] Example 5a: Preparation of the hydrochloride salt of compound I 1.0 gram of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyridine The perazine oil was dissolved in 20 ml of ethyl acetate with gentle heating (30°C). When a clear solution was obtained, 2M HCl in diethyl ether was added. The solution was added slowly until the pH was about 1-2. During this addition, spontaneous precipitation occurred. After the last addition, the suspension was stirred for 1 h, then filtered and concentrated under vacuum (4 A white precipitate was isolated by drying overnight at 0° C. 1.1 grams (99% ) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydride The chloride was isolated. NMR is consistent with the structure. Elemental analysis: 64.18% C, 8.25% N, 6.96% H (for 1:1 salt when corrected for 0.66% water as determined by TGA) Theoretical values: 64.13% C, 8.31% N, 6.95% H).

[0137] Example 5b: Characterization of the Hydrochloride of Compound I This hydrochloride, prepared as in Example 5a, is crystalline (XRPD)- See Figure 7. This crystalline hydrochloride has a melting point of about 236°C. When exposed to high relative humidity, chlorine absorbs about 1.5% water and dissolves in water. It has a solubility of 3 mg / ml in water.

[0138] Example 5c: Preparation of the hydrochloride monohydrate of compound I 11.9 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] The piperazine oil was dissolved in 100 ml of ethanol with heating. When a solution was obtained, the addition of 3.5 ml of concentrated HCl(aq) gave the immediate formation of a white solid. The resulting suspension was first stirred for 5 min and then cooled for an additional 1 h on an ice bath. After stirring for 1 hour, the white solid was filtered. The white solid was dissolved in 100 ml of fresh cold ethanol (- (placed in freezer for 2 hours at 18°C), 50 ml of acetone and finally 50 ml After washing with diethyl ether, it was dried overnight under vacuum (50°C). 5. 1 gram (38%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl ]Piperazine HCl was isolated. NMR is consistent with the structure. Elemental analysis: 61.23% C, 7.91% N, 7.16% H (theoretical for 1:1 salt monohydrate: 61.26% C, 7.94% N, 7.14 %H).

[0139] Example 5d: Characterization of the hydrochloride monohydrate of compound I This hydrochloride monohydrate, prepared as in Example 5c, is crystalline (XR PD) - see Figure 8. This crystalline monohydrate begins to lose water at about 50°C. Further heating Several thermal events, possibly rearrangements, occur and the monohydrate melts at about 230°C, followed by The crystalline monohydrate recrystallizes and melts at approximately 236°C when exposed to high relative humidity. The water bound to this hydrate does not absorb any additional moisture when it is hydrated, and the ... It is not released until the humidity drops below 10% at room temperature. It has a solubility of approximately 2 mg / ml.

[0140] Example 6a: Preparation of the mesylate salt of Compound I 1.0 gram of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyridine Perazine oil was dissolved in 20 ml of ethyl acetate by heating (70°C). When a clear solution was obtained, 0.35 grams of methanesulfonic acid (1.1 equivalents) was added. After the last addition, the solution was cooled on ice and diethyl ether was added slowly. Addition of 100 ml of 100% NaOH resulted in precipitation of the product. The suspension was stirred on ice for 2 hours. The resulting white precipitate was then isolated by filtration and dried overnight under vacuum (40° C.). 1.1 g (85%) of 1-[2-(2,4-dimethylphenylsulfanyl)- 1,2-Diphenylpiperazine mesylate was isolated. NMR is consistent with the structure. Elemental analysis: 57 .81% C, 6.81% N, 6.68% H (theoretical value for 1:1 salt: 57.8 1% C, 7.10% N, 6.64% H).

[0141] Example 6b: Characterization of the mesylate of Compound I This mesylate, prepared as in Example 7a, is crystalline (XRPD) - FIG. The crystalline mesylate has a melting point of about 163°C. It is hygroscopic (absorbs approximately 8% water when exposed to 80% relative humidity, which The final 6% of absorbed water is converted to a hydrated form at a relative humidity of 10%. The crystalline mesylate has very high solubility in water and is not released until (>45mg / ml).

[0142] Example 7a: Preparation of the fumarate of compound I In a mixture of 50 ml of methanol and 50 ml of ethyl acetate, Grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine The oil was heated to reflux and the solution was allowed to cool shortly after which 2.1 grams of fluoride was obtained. The addition of malonic acid caused an exothermic reaction and resulted in the precipitation of a white solid. The resulting suspension was stirred while being cooled to room temperature and then stored in a freezer at -18°C. The white solid was collected by filtration and diluted with 20 mL of cold ethyl acetate. After washing with ethyl acetate, it was dried overnight under vacuum (50°C). The product was isolated.

[0143] NMR is consistent with the structure. Elemental analysis: 63.42% C, 6.64% N, 6.42% H (theoretical values ​​for 1:1 salt: 63.74% C, 6.76% N, 6.32% H ).

[0144] Example 7b: Characterization of the fumarate of Compound I This fumarate, prepared as in Example 7a, is crystalline (XRPD) - FIG. 0. This crystalline fumarate has a melting point of about 194°C. Its solubility in water is It is 0.4mg / ml.

[0145] Example 8a: Preparation of the Maleate of Compound I 2.5 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]pyrimidine The oily perazine was dissolved in 50 ml of ethyl acetate and heated to 60°C. 1 gram of maleic acid was added. The mixture was again heated to reflux for 5 minutes and stirred. The mixture was then left to cool to room temperature. During cooling, precipitation began, and the mixture was then placed in a freezer (-18°C). The reaction was terminated by placing the mixture in 50 mL of ethyl acetate for 4 hours. The white solid was collected by filtration and diluted with 50 mL of After washing with diethyl ether, it was dried overnight under vacuum (50°C). 0.3 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperane The maleate was refluxed with 40 ml of ethyl acetate to give 38% dimethyl sulphate. The clear solution was recrystallized by treating with 5 ml of ethyl acetate and 5 ml of methanol. The mixture was cooled to room temperature, then cooled in a freezer (-18°C) for 2 hours, filtered, and diluted with 10 ml Cold ethyl acetate twice and then dried under vacuum (50°C) for 2 days. 0.9 g (69%) of 1-[2-(2,4-dimethylphenylsulfanyl )-Phenyl]piperazine maleate was isolated. NMR is consistent with the structure. Elemental analysis : 63.57% C, 6.79% N, 6.39% H (theoretical value for 1:1 salt: 6 3.74% C, 6.76% N, 6.32% H).

[0146] Example 8b: Characterization of the Maleate of Compound I This maleate, prepared as in Example 8a, is crystalline (XRPD) - FIG. 1. The crystalline fumarate has a melting point of about 152°C. Its solubility in water is It is about 1mg / ml.

[0147] Example 9a: Preparation of meso-tartrate of compound I 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] in acetone ] 11.1 ml of a 0.30 M solution of piperazine was dissolved in 5 ml of acetone. The resulting mixture was stirred at room temperature for 30 minutes, during which time the precipitate The mixture was filtered and washed first with 5 ml of acetone and then with 3 ml of diethyl ether. The product was obtained as a white solid, which was then cooled to room temperature under vacuum (50°C). After drying overnight, 1.4 g (93%) of 1-[2-(2,4-dimethylphenylsulfonyl) (phenyl)-phenyl]piperazine meso-tartaric acid was isolated. NMR is consistent with the structure. Elemental analysis: 58.58% C, 6.29% N, 6.40% H (based on a 1:1 salt) Theoretical values: 58.91% C, 6.25% N, 6.29% H).

[0148] Example 9b: Characterization of meso-tartrate of Compound I The meso-tartrate, prepared as in Example 9a, is crystalline (XRPD ) - see Figure 12. This crystalline meso-tartrate has a melting point of about 164°C. The solubility in is approximately 0.7 mg / ml.

[0149] Example 10a: Preparation of L-(+)-tartrate of compound I 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] in acetone ] 11.1 ml of a 0.30 M solution of piperazine was dissolved in 5 ml of acetone. The mixture was stirred at room temperature for 30 minutes and then treated with 1 g of L-(+)-tartaric acid. Precipitation occurred during the period. The mixture was filtered and washed first with 5 ml of acetone and then with 3 ml of diethyl ether. The product was obtained as a white solid by washing, which was then cooled under vacuum (50°C) The mixture was dried overnight. 1.2 g (81%) of 1-[2-(2,4-dimethylphenyl Sulfanyl)-phenyl]piperazine(+)-tartaric acid was isolated. NMR was consistent with the structure. Elemental analysis: 58.86% C, 6.30% N, 6.38% H (in a 1:1 salt). vs. theory: 58.91% C, 6.25% N, 6.29% H).

[0150] Example 10b: Characterization of the L-(+)-tartrate of Compound I This L-(+)-tartrate, prepared as in Example 10a, is crystalline ( XRPD) - see Figure 13. This crystalline L-(+)-tartrate has a melting point of about 171°C. Its solubility in water is approximately 0.4 mg / ml.

[0151] Example 11a: Preparation of D-(-)-tartrate of Compound I 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] in acetone ] 11.1 ml of a 0.30 M solution of piperazine was dissolved in 5 ml of acetone. The resulting mixture was stirred at room temperature for 30 minutes and then Precipitation occurred during the period. The mixture was filtered and washed first with 5 ml of acetone and then with 3 ml of diethyl ether. The product was obtained as a white solid by washing, which was then cooled under vacuum (50°C) The mixture was dried overnight. 1.0 g (68%) of 1-[2-(2,4-dimethylphenyl Sulfanyl-phenyl]piperazine D-(-)-tartaric acid was isolated. NMR showed the structure Elemental analysis: 58.90% C, 6.26% N, 6.35% H (1:1 ratio) Theoretical values ​​for salt: 58.91% C, 6.25% N, 6.29% H).

[0152] Example 11b: Characterization of D-(-)-tartrate of Compound I This D-(+)-tartrate, prepared as in Example 11a, is crystalline ( XRPD) - see Figure 14. This crystalline D-(-)-tartrate has a melting point of about 175°C. Its solubility in water is approximately 0.4 mg / ml.

[0153] Example 12a: Preparation of the sulfate of compound I 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] in acetone ] Dissolve 11.1 ml of a 0.30 M solution of piperazine in 2.2 ml of 3 M H2SO4(aq). The resulting mixture was stirred at room temperature for 30 min and then incubated on an ice bath for an additional 4 h. Precipitation occurred upon stirring and was terminated by filtration and addition of first 5 ml of acetone and then 1 ml of acetone. Washing with 3 mL of diethyl ether gave the product as a white solid, which The product was dried under vacuum (50° C.) overnight. 0.51 g (39%) of 1-[ 2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine sulfate Isolated. NMR is consistent with the structure. Elemental analysis: 54.53% C, 7.22% N, 6.28% H (theoretical for 1:1 salt: 54.52% C, 7.07% N, 6. 10% H).

[0154] Example 12b: Characterization of the Sulfate of Compound I This sulfate, prepared as in Example 12a, is crystalline (XRPD)- See Figure 15. This crystalline sulfate has a melting point of about 166°C. The solution is approximately 0.1 mg / ml.

[0155] Example 13a: Preparation of the phosphate of compound I 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] in acetone ]11.1 ml of a 0.30 M solution of piperazine was added to 0.2 ml of 65% H3PO4(aq The resulting mixture was stirred at room temperature for 30 minutes, during which time precipitation occurred. The white solid was obtained by washing first with 5 ml of acetone and then with 3 ml of diethyl ether. The product was obtained as a solid and dried overnight under vacuum (50°C). 1. 23 grams (94%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl [1,3-difluorophenyl]piperazine phosphate was isolated. NMR is consistent with structure. Elemental analysis: 54. 21% C, 7.15% N, 6.43% H (theoretical value for 1:1 salt: 54.53 % C, 7.07% N, 6.36% H).

[0156] Example 13b: Characterization of the phosphate of Compound I This phosphate, prepared as in Example 13a, is crystalline (XRPD)- See Figure 16. This crystalline phosphate has a melting point of about 224°C. The solution is approximately 1 mg / ml.

[0157] Example 14a: Preparation of the nitrate of compound I 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] in acetone ] 11.1 ml of a 0.30 M solution of piperazine in 0.2 ml of 16.5 M HNO3 (a q). The resulting mixture was stirred at room temperature for 30 minutes, during which time precipitation occurred. Filtered. and washed first with 5 ml of acetone and then with 3 ml of diethyl ether to obtain a white The product was obtained as a solid and was dried under vacuum (50° C.) overnight. 0.87 g (73%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl Nyl]piperazine nitrate was isolated. NMR is consistent with structure. Elemental analysis: 59. 80% C, 11.67% N, 6.51% H (theoretical value for 1:1 salt: 59.8 1% C, 11.63% N, 6.41% H).

[0158] Example 14b: Characterization of the nitrate of compound I This nitrate, prepared as in Example 14a, is crystalline (XRPD) - FIG. 17. This crystalline nitrate does not melt, but undergoes an exothermic reaction at about 160°C. Its solubility in water is approximately 0.8 mg / ml.

[0159] Example 15: Tablets The following examples are representative of the methods by which tablets containing the compounds of the present invention may be prepared. In all examples the beta hydrobromide salt was used.

[0160] Example 15a 63.55g of this hydrobromide, 923.65g of Lactosum 350M, 46 1.8 g of corn starch and 76.0 g of Kollidon VA64 were added to the Mix in an osna PP1 high shear mixer for 2 minutes at an impeller speed of 1000 rpm The impeller speed was then reduced to 800 rpm and 220 g of water was added for a short period of time. Massing was carried out for 7 min and the resulting granules were milled to a size of 4000 μm. The granules were dried and passed through a 710 μm size sieve. Results The 1383.5 g of granules obtained as above was mixed with 400 g of Avicel PH200 and 60 Mix with 15g of Magnesium Stearate. After lubrication of the blend with , the resulting powder blend was transferred to a tablet press. To obtain a tablet with a target content equivalent to 5 mg of the free base, a target concentration of 200 mg was used. Tablets having a weight and a diameter of 8 mm were produced.

[0161] Example 15b 317.75g of this hydrobromide, 754.15g of Lactosum 350M, 3 77.1 g of corn starch and 76.0 g of Kollidon VA64 were added to the D Mix in an iosna PP1 high shear mixer for 2 minutes at an impeller speed of 1000 rpm. The impeller speed was then reduced to 800 rpm and 210 g of water was poured into the mixture for a short period of time. Agglomeration was carried out for 7 minutes and the resulting granules were sieved through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. 1386.2g of granules were mixed with 400g of Avicel PH200 and 60g of Ac- Mixed with Di-Sol. Mixed with 15g magnesium stearate. After lubrication of the blend, the resulting powder blend was transferred to a tablet press. To obtain tablets with a target content equivalent to the free base, a target core weight of 200 mg and and tablets having a diameter of 8 mm were produced.

[0162] Example 15c 32.2g of Hydrobromide, 944.82g of Lactosum 350M, 472 0.4g corn starch and 76.0g Kollidon VA64 in Dio Mix in a sna PP1 high shear mixer for 2 minutes at an impeller speed of 1000 rpm. The impeller speed was then reduced to 800 rpm and 220 g of water was added for a short period of time. Agglomeration was carried out for 7 minutes and the resulting granules were passed through a sieve with a size of 4000 μm. The granules were dried and passed through a 710 μm sieve. g of granules mixed with 400 g of Avicel PH200 and 60 g of Ac-Di-Sol. The blend was lubricated by mixing with 15 g of magnesium stearate. The resulting powder blend was then transferred to a tablet press. To obtain tablets with the target content of 208 mg and a diameter of 8 mm, Tablets having the following dimensions were produced.

[0163] Example 15d 540.85 g of this hydrobromide, 953.00 g of Pearlitol 50C, 2 96.22 g of corn starch and 70.5 g of Kollidon VA64 1000 rpm in an Aeromatic-Fielder PMA1 high shear mixer The mixture was mixed for 2 minutes at an impeller speed of 100 rpm. The impeller speed was then reduced to 800 rpm. 241.87 g of water was added in a short period of time. Agglomeration was carried out for 7 minutes, resulting in The granules were dried and passed through a sieve with a size of 710 μm. The resulting 1500 g of granules was passed through a sieve of size 1000. Mixed with 10.64g of maltitol PH200 and 85.11g of Primojel. After lubrication of the blend by mixing with magnesium stearate, the resulting powder The blend was transferred to a tablet press with a target content equivalent to 25 mg of the free base. To obtain tablets with a target core weight of 125 mg and a diameter of 6 mm, tablets were produced. It was done.

[0164] Example 15e 270.45 g of this hydrobromide, 772.0 g of Pearlitol 50C, 38 6.41 g of corn starch and 70.5 g of Kollidon VA64 were added to the In an eromatic-Fielder PMA1 high shear mixer at 1000 rpm The impeller speed was then reduced to 800 rpm and the mixture was mixed for 2 minutes. 195 g of water was added in a short period of time. Agglomeration was carried out for 5.5 minutes, and the resulting The granules were passed through a sieve with a size of 4000 μm. The granules were dried and passed through a sieve with a size of 710 μm. The resulting granules (1200.3 g) were passed through a 100 mm sieve and mixed with 425.5 g of Avice. Mixed with PH200 and 68.09g of Primojel. 8.8g of Magnesium After lubrication of the blend by mixing with umstearate, the resulting powder blend was The tablets were transferred to a tablet press with a target content equivalent to 10 mg of the free base. To obtain the formulation, tablets with a target core weight of 100 and a diameter of 6 mm were manufactured.

[0165] Example 15f 504.85g of this free base, 552.95g of Pearlitol 50C, 276 0.53g corn starch and 65.7g Kollidon VA64 The mixture was mixed in a romatic-Fielder PMA1 high shear mixer at 1000 rpm. The impeller speed was then reduced to 800 rpm and the mixture was mixed for 2 minutes. During this time, 182 g of water was added. The agglomeration was carried out for 5.5 minutes, and the resulting conjugates were The granules were passed through a sieve with a size of 4000 μm. The granules were dried and passed through a sieve with a size of 710 μm. The resulting granules (1250.7 g) were passed through a sieve of 443.31 g Avice. l pH 200 and mixed with 70.8g Primojel. 8.92g Magnesium After lubrication of the blend by mixing with umstearate, the resulting powder blend was The tablets were transferred to a tablet press with a target content equivalent to 50 mg of the free base. To obtain the formulation, tablets with a target core weight of 250 mg and a diameter of 8 mm were produced. .

[0166] Example 15g 135.23 g of this hydrobromide, 863.2 g of Pearlitol 50C, 43 2.69 g corn starch and 70.66 g Kollidon VA64 1000 rpm in an Aeromatic-Fielder PMA1 high shear mixer The mixture was mixed for 2 minutes at an impeller speed of 100 rpm. The impeller speed was then reduced to 800 rpm. 195 g of water was added in a short period of time. Agglomeration was carried out for 5.5 minutes, and the resulting The granules were dried and passed through a sieve with a size of 710 μm. The resulting granules were passed through a sieve from No. 1200 and mixed with 425.28 g of Avice. Mixed with PH200 and 68.2g Primojel. 8.58g Magnesium After lubrication of the blend by mixing with umstearate, the resulting powder blend was The tablets were transferred to a tablet press with a target content equivalent to 5 mg of the free base. To obtain this, tablets with a target core weight of 100 mg and a diameter of 6 mm were manufactured.

[0167] Example 15h 67.6 g of this hydrobromide, 908.0 g of Pearlitol 50C, 453. 9 g corn starch and 70.51 g Kollidon VA64 in Dio Mix in a sna PP1 high shear mixer for 2 minutes at an impeller speed of 1000 rpm. The impeller speed was then reduced to 800 rpm and 195 g of water was added for a short period of time. Agglomeration was carried out for 5.5 min and the resulting granules were mixed to a size of 4000 μm. The granules were dried and passed through a 710 μm size sieve. The 1325g of granules was mixed with 531.91g of Avicel PH200 and 85.11 Mix with 10.64 g of Primojel. Mix with 10.64 g of Magnesium Stearate. After lubrication of the blend by ethanol, the resulting powder blend is transferred to a tablet press. To obtain a tablet with a target content equivalent to 5 mg of the free base, 207.8 mg Tablets were produced with a target core weight of 0.01g and a diameter of 7mm.

[0168] Example 15i 2290.1 ​​g of this hydrobromide, 17568 g of anhydrous calcium hydrogen phosphate and and 8783 g of corn starch and 1510 g of copovidone were added to Aeroma tic-Fielder PMA100 high shear mixer with impeller at 200 rpm The mixture was mixed at 100 rpm for 3 minutes, followed by 2 minutes at 150 rpm impeller speed. 5130 g of water was added. Agglomeration was carried out for 15 minutes and the resulting granules were mixed with 9. The mixture was passed through a cone mill with a screen size of 525 mm, operating at approximately 2700 rpm. The granules were dried and sieved through a sieve with a size of 2.388 mm for about 15 min. The resulting granules, 28,747 g, were passed through a cone mill operating at 100 rpm. 1250g microcrystalline cellulose, 1350g sodium starch glycolate (Thailand Mixed with 1800g of talc (group A) and 450g of magnesium stearate. After lubrication of the blend by mixing, the resulting powder blend is placed in a tablet press. Tablets were obtained with a target content of the hydrobromide salt equivalent to 5 mg of the free base. To achieve this, tablets were produced with a target core weight of 125 mg and a diameter of 6 mm. to obtain tablets with a target content of the hydrobromide salt equivalent to 10 mg of the free base. , tablets were produced with a target core weight of 250 mg and a diameter of 8 mm.

[0169] Example 16: Pain effects in the intradermal formalin test in mice In this model, mice were injected with formalin (4.5%, 20 μl) into the left hind paw. This formalin injection-induced stimulation induced a characteristic biphasic behavioral response. Phase I: (approximately 0–10 min) represents direct chemical stimulation and nociception, whereas the second phase (approximately 20–3 The first phase (0 min) is thought to represent pain of neuropathic origin. These two phases were separated by a sedative period. During this period of sedation, behavior returns to normal. The efficacy of the compound was evaluated by measuring the amount of time spent licking the injured paw during these two phases. It is evaluated by timing.

[0170] Compounds of the invention showed a significant reduction in pain scores in the second phase (Figure 18b), which It has been shown to be effective against pain of neuropathic origin. The compound also showed a significant reduction in the scores in the first phase (Figure 18a), which was seen at the highest dose In summary, these results show that nicotinamide has a higher analgesic effect in The results indicate that the compounds of the present invention are likely to be effective in treating pain disorders. do.

[0171] Example 17

[0172] [ka]

[0173] 20 g of 2-bromoiodobenzene (71 mmol) and 9.8 g of 2,4-dimethyl Thiophenol (71 mmol) was dissolved in 100 ml of toluene. Pd2dba3 (0.35 mmol; 1 mol%) and 381 mg of DPEPhos( The solution was purged with nitrogen prior to addition of 0.71 mmol; 1 mol%). The material was stirred for 5 minutes, during which time the color changed from dark red to orange. u t (78 mmol) was added and a heterogeneous mixture was immediately formed. The suspension was cooled to 100° C. with nitrogen. The mixture was heated to 100° C. under vacuum. After 1 hour, the mixture was cooled to 0° C. and stirred for 2 hours. After that, the mixture was filtered through a pad of Celite. The resulting filter cake was diluted with 2 x 50 1 ml of toluene and the combined filtrate was evaporated to obtain 21 g of oleic acid. An orange-red oil was obtained (99% yield), which was analyzed by HPLC and GC. -MS showed it to be >96% pure.

[0174] Example 18

[0175] [ka]

[0176] Put 500 ml of toluene into a 1 L three-necked round bottle equipped with a mechanical stirrer. 203 mg of Pddba2 (0.35 mmol; 0.1 mol%) and 760 mg of D PEPhos (1.5 mmol; 0.4 mol%) was added. The dark red solution was then purified with nitrogen. After purging for 5 min, 100 g of 2-bromoiodobenzene (353 mmol) and 4 An addition of 8.9 g of 2,4-dimethylthiophenol (353 mmol) was performed. .6g KOBu t The addition of (389 mmol) caused an exothermic reaction, raising the temperature from 20°C to The temperature was increased from 0.01 to 36°C, which simultaneously resulted in the formation of a heterogeneous mixture. The suspension was then purged with nitrogen. After 7 hours, the mixture was cooled to 0° C. and stirred for 2 hours. The mixture was then filtered through a pad of Celite. The combined filtrate was evaporated to give 104 g of toluene. An orange oil was obtained (105% yield) which was 97% pure by HPLC. The desired structure was confirmed by NMR. The oil solidified upon standing at room temperature.

[0177] Example 19

[0178] [ka]

[0179] 10 grams of 1-(2-bromo-phenylsulfa) in 50 ml of dry toluene A solution of 7 grams of boc-piperidine in 2,4-dimethylbenzene (34 mmol) was added. Add 38 mmol of dimethyl ether (DMSO) and degas with nitrogen for 5 minutes. Add 312 mg of Pd2dba3 (2 mol%) and 637 mg of rac-BINAP (3 mol%) were added and the mixture was degassed for another 5 min. After drying, 3.9 grams of Bu tAdd ONa (41 mmol) and heat at 80°C for 15 hours. The reaction mixture was cooled to room temperature and extracted twice with 20 ml of 15% brine. Dry over Na2SO4, add activated charcoal, reflux for 15 minutes, and filter through Celite. , 14.2 g, with a purity of 95% as determined by NMR, by evaporation A brownish oil (4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl The crude oil was diluted with 200 mL of MeOH and After dissolving in 20 ml of 6 M HCl (aq.) and refluxing for 1 h, HPLC showed complete After cooling to room temperature, the methanol was removed by vacuum on a rotary evaporator, 20 ml of concentrated NaOH (pH was 13-14) was added, and the resulting mixture was then The organic phase was collected and stirred with 100 ml of EtOAc for 15 min. Extract twice with 5% brine, dry over Na2SO4, and dissolve in 30 ml of MeOH. 5.2 g of fumaric acid (44 mmol) was added. The mixture was heated to reflux until a homogeneous solution was formed. A liquid is formed, from which rapid precipitation occurs during either further heating or cooling. The precipitate was collected, washed with 20 ml of EtOAc and 20 ml of acetone, and purified. Drying under reduced pressure gave 9.3 grams of 1- as a white powder in an overall yield of 66%. [2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine fumarate The fumarate (22 mmol) was obtained with a purity of 99.5% by LC-MS. had.

[0180] Example 20

[0181] [ka]

[0182] 100 g of 1,2-dibromobenzene (424 mmol) and 58.6 g of 2,4- Dissolve dimethylthiophenol (424 mmol) in 800 ml of toluene. 4. 6 g of Pddba2 (8 mmol; 2 mol%) and 13.1 g of rac-BINAP The solution was purged with nitrogen before the reaction mixture was stirred for 5 min. Stir for 10 minutes, during which the color changes from dark red to orange. t (6 36 mmol) and 200 ml of toluene were added, immediately forming a heterogeneous mixture. The suspension was heated to 80° C. under nitrogen. After 10 hours, the mixture was heated to 60° C. After cooling to 5°C, 102.6 g of boc-piperazine (5 51 mmol) and another 61 g of NaOBu t (636mmol) is added. The reaction After purging the mixture with nitrogen, another 4.6 g of Pddba2 (8 mmol; 2 mol %) and 13.1 g of rac-BINAP (21 mmol; 5 mol%) were added. The mixture was heated to reflux for an additional 6 h or until HPLC showed complete conversion. The resulting reaction mixture was cooled on ice for 2 hours, and then the mixture was poured into a ceramic dish. The resulting filter cake was washed with 2×200 ml of toluene. The combined filtrates are evaporated to give 242 g of a red oil. This oil was dissolved in 1000 ml of MeOH and 115 ml of 48 wt% HBr(a q.) was slowly added, followed by heating to reflux for 2 hours, after which complete cleavage was observed by HPLC. Deprotection was detected. The mixture was cooled, 1000 ml of EtOAc was added and evaporated. The MeOH was removed by addition of 1000 ml of Et2O, which caused precipitation. After stirring for 2 hours, the slurry was left in the freezer overnight (-18°C). The 17-membered cellulose was extracted by washing twice with 0.01 ml of Et2O and drying under vacuum at 40°C. 2 g of a brownish solid was obtained. The brownish solid was dissolved in 1500 ml of boiling H After being treated with 20 for 1 hour, it was cooled to room temperature for another 2 hours. 98 g of 4-[2-(2,4-dimethyl- To give 1,3-dihydro-1,4-diphenylsulfanyl-phenyl-piperazine hydrobromide (61%) was obtained.

[0183] Example 21

[0184] [ka]

[0185] 102 g of 2-bromo-iodobenzene (362 mmol) and 50 g of 2,4-di Methylthiophenol (362 mmol) is dissolved in 1000 ml of toluene. To the solution was added 81 g of BOC-piperazine (434 mmol), followed by 2.08 g of P Add ddba2 (1 mol%) and 4.51 g of rac-BINAP (2 mol%). The mixture was purged with nitrogen for 5 minutes, and then 87 g of toluene was dissolved in 300 ml of toluene. NaOBu t (905 mmol) was added to the slurry. The resulting suspension was stirred under nitrogen for 1 hour. The mixture was heated to 100° C. overnight. GCMS analysis revealed that the intermediate product (1-(2-bromo-phenylsulfonyl) The complete conversion of 2,4-dimethyl-phenylbenzene to 2,4-dimethyl-phenylbenzene was observed by increasing the temperature. The mixture was refluxed for another 24 hours (120°C). HPLC analysis revealed that the intermediate (1-BOC-4-[2 -(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine) The reaction mixture was cooled on ice for 1 h, and then the mixture was filtered. The filter cake was washed with 2 x 200 ml of toluene and the combined filtrate was added to 80 ml of 48 wt% HBr (aq.) was added, followed by heating to reflux for 18 hours. Complete deprotection was detected by LC. The resulting mixture was cooled on ice for 2 h and filtered. The brownish solid was dissolved in 1000 ml of boiling H2O together with activated charcoal (25 g). The mixture was dissolved in water for 1 hour, filtered while still hot, and allowed to cool. The resulting precipitate was collected by filtration. The mixture was collected and dried overnight under vacuum at 40° C. to give 49 g of 4 as a white solid. -[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride The bromide (36%) was obtained.

[0186] Example 22

[0187] [ka]

[0188] Put 500 ml of toluene into a 1 L three-necked round bottle equipped with a mechanical stirrer. 809 mg of Pd2dba3 (0.88 mmol; 0.5 mol%) and 952 mg of DPEPhos (1.77 mmol; 0.5 mol%) was added. The dark red solution was cooled to room temperature with nitrogen. After purging with nitrogen for 5 minutes, 100 g of 2-bromoiodobenzene (353 mmol) and and 48.9 g of 2,4-dimethylthiophenol (353 mmol) were added. 43.6g KOBu t The addition of (389 mmol) caused an exothermic reaction, raising the temperature to 20 The temperature was increased from 42°C to 42°C, which resulted in the formation of a heterogeneous mixture and the color The color changed from dark red to orange / brownish. The suspension was placed under nitrogen for 10 min. The mixture was heated to 0° C. After only 20 minutes, HPLC showed 1-(2-bromo-phenylsulfanyl) The mixture was cooled to 40° C., and the reaction mixture was cooled to 40° C., and the reaction mixture was cooled to 40° C. 600 ml of 15 wt% NaCl was added and stirred for 5 minutes. The organic phase was separated and the aqueous The organic phases were washed with 2×100 ml of toluene. The combined organic phases were then washed with 100 ml of 2M HCl (aq.), washed with 100 ml of 15 wt% NaCl, and dried over Na2SO4. The mixture was refluxed with activated charcoal (10 g) for 15 min, filtered twice, and evaporated. 107.3 g of an orange-red oil was obtained (103%), which was purified by HPLC. C was found to be 98% pure.

[0189] Dissolve 90 grams of the above orange-red oil ( To a solution of 57 grams of boc-piperazine (307 mmol), Degass with nitrogen for 5 min and add 1.4 g of Pd2dba3 (1.53 mmol; 0.5 mol%) and 2.9 g of rac-BINAP (4.6 mmol; 1.5 mol%) were added, After degassing for 2 minutes, 35.4 grams of Bu t Add ONa (368mmol) and heat to 80℃ Heated for 18 h. HPLC showed complete conversion and the reaction mixture was cooled to room temperature. Then, the mixture was filtered, and the filter cake was washed with 2×100 ml of toluene. The filtrate was extracted twice with 2 × 150 ml of 15 wt% NaCl and dried over Na2SO4. The mixture was refluxed for 30 minutes, filtered twice, and evaporated to give a final yield of 140.7 g. Grams of brownish oil (4-[2-(2,4-dimethyl-phenylsulfanyl) The crude oil was diluted with 300 mL of MeO H and 200 ml of 6M HCl (aq.), refluxed for 1 hour, and then C indicated complete deprotection. After cooling to room temperature, the methanol was removed by vacuum on a rotary evaporator. The solution was removed, 200 ml of concentrated NaOH (pH was 13-14) was added, and the resulting The mixture was stirred with 1000 ml of EtOAc for 15 min. The organic phase was collected and Extract with 300 ml of 15 wt% brine, dry over Na2SO4, and add 300 ml of A solution of 46.3 g of fumaric acid (399 mmol) in MeOH was added. The material was heated to reflux, cooled to room temperature, and then placed in the freezer overnight (-18°C). The resulting precipitate was collected and washed with 100 ml of EtOAc and 100 ml of acetone. and dried under vacuum (50 °C) to give 1H 2 O as a white powder in an overall yield of 81%. 03.2g of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-pi Perazine fumarate (249 mmol) was obtained, which was identified by LC-MS as The fumarate had a purity of 99%. The free base (1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazine), and the organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was filtered and 34 ml of 48 wt% HBr (aq.) was added to give a white This caused a solid to precipitate. The solid was collected and treated with 1000 ml of boiling H2O. When cooled to room temperature, a slurry was formed. 2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide was collected by filtration and dried under vacuum (50° C.) to give 83 g of white A powder (71% overall yield) was obtained [CHN(teo.) 56.99; 6.11; 7.3 9;CHN(actual value) 57.11;6.15;7.35].

[0190] Example 23

[0191] [ka]

[0192] 815g of NaOBu t (8.48 mol), 844 g of piperazine (9.8 mol) , 6.6 g of Pd(dba)2 (11.48 mmol) and 13.6 g of rac-BI NAP (21.84 mmol) was stirred with 4 L of toluene for 50 min. 40 g of 2-bromo-iodobenzene (2.97 mol) with 1.5 L of toluene Add, continue stirring for 30 minutes, and finally add 390.8 g of 2,4-dimethylthiophenol ( 2.83 mmol) was added along with 1.5 L of toluene. The suspension was heated to reflux. The mixture was cooled overnight. 2 L of water was added and stirred for 1 hour. The mixture was then filtered through a filter aid. The filtrate was then poured into 3 x 1 L flasks. After this, the combined aqueous phase was extracted with 600 ml of toluene. The combined toluene phase was then heated to 70° C., followed by addition of 329.2 ml of 48 % HBr(aq.) and 164.6 ml of water were added. The resulting mixture was allowed to cool to room temperature. The final product (1-[2-(2,4-dimethyl-phenylsulfa The resulting mixture was collected by filtration and cooled under vacuum (60° C.). ) to give 895 g (84% yield) of product.

[0193] Example 24

[0194] [ka]

[0195] 40.76g NaOBu t (424.1 mol), 0.33 g of Pdddba2 (0. 57 mmol) and 0.68 g of rac-BINAP (1.09 mmol) in 200 ml The mixture was stirred with 42 g of 2-bromo-iodobenzene (362 mmol) and 19.54 g of 2,4-dimethylthiophenol (362 mmol). Along with 50 ml of toluene, the suspension was heated to reflux and kept at reflux overnight. HPLC analysis revealed that the intermediate product (1-(2-bromo-phenylsulfanyl)-2,4- The reaction mixture was cooled to room temperature and filtered. The filtrate was filtered through a filter aid and 40.76 g of NaOBu t (424.1 mmol ), 42.2 g of piperazine (489.9 mmol), 0.33 g of Pddba2 (0. 57 mmol) and 0.68 g of rac-BINAP (1.09 mmol). The reaction mixture was cooled overnight. 100 ml of water was added. The organic phase was filtered through a filter aid and then The filtrate was washed with 3 x 80 ml of brine. The combined aqueous phase was then The mixture was extracted with 100 ml of toluene. The combined toluene phase was then heated to 70° C. Subsequently, 16.5 ml of 48 wt % HBr(aq.) and 8.25 ml of water were added. The mixture was cooled to room temperature overnight. The final product (1-[2-(2,4-diphenyl Methyl-phenylsulfanyl-phenyl-piperazine hydrobromide was filtered off. The resulting mixture was collected and dried under vacuum (60°C) to give 40.18 g of off-white solid. A powder of tetramethylsilane was obtained (75% yield).

[0196] Example 25

[0197] [ka]

[0198] 40.76g NaOBu t (424.1 mmol), 0.33 g of Pddba2(0 0.57 mmol) and 0.68 g of rac-BINAP (1.09 mmol) were added to 200 The mixture was stirred with 42 g of 2-bromo-iodobenzene (14 8.5 mmol) and 19.54 g of 2,4-dimethylthiophenol (141.4 m mol) was added along with 50 ml of toluene. The suspension was heated to reflux and allowed to reflux overnight. The flow was continued. HPLC analysis revealed that the intermediate product (1-(2-bromo-phenylsulfanyl) The reaction was cooled to 50° C. and 42 0.2g of piperazine (489.9mmol) was added along with 100ml of toluene. The resulting mixture was heated to reflux for 4 hours. The reaction mixture was allowed to cool to room temperature overnight. 100 ml of water was added and the reaction mixture was filtered through a filter aid. The filter cake was washed with 50 ml of toluene.

[0199] After separating and removing the aqueous phase, the organic phase was diluted with 3×25 ml of brine and 25 The combined aqueous phase was then extracted with 30 ml of toluene. The combined toluene phase was then heated to 70° C., followed by addition of 16.46 ml of 48 % HBr(aq.) and 8.23 ​​ml of water were added. The resulting mixture was allowed to cool to room temperature. The final product (1-[2-(2,4-dimethyl-phenylsulfani The resulting mixture was collected by filtration and cooled under vacuum (60° C.) Drying at rt gave 46.8 g (87% yield) of product.

[0200] Example 26: Effects on extracellular levels of acetylcholine in the brain of freely moving rats method 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine in animals; HBr salt was administered.

[0201] animal Male Sprague-Dawley rats weighing 275-300 g at first weighing The animals were kept in a cage with free access to food and tap water. The room temperature (21±2°C) and humidity (55±5%) were controlled to obtain regular indoor temperatures. The mice were housed under controlled conditions with a 12-h light / dark cycle.

[0202] Surgery and microdialysis experiments Rats were anesthetized with Hypnorm / Dormicum (2 ml / kg) and then implanted in the ventral hippocampus (coordinates: 5.6 mm posterior to leguma, -5.0 mm lateral to dura, 7.0 mm ventral to dura) or prefrontal cortex (Coordinates: 3.2 mm anterior to bregma; 0.8 mm lateral; 4.0 mm ventral to dura). Intracerebral guide cannula (CMA / 12) for the purpose of positioning the probe tip The cerebrospinal fluid was stereotactically implanted into the brain. Anchor screws and acrylic cement were used to secure the cerebrospinal fluid to the brain. The guide cannula was fixed. The body temperature of the animals was monitored by a rectal probe and kept at 37 °C. The rats were allowed to recover from surgery for 2 days and were then housed in individual cages. On the day of the experiment, a microdialysis probe (CM) was inserted through the guide cannula described above. A / 12, diameter 0.5 mm, length 3 mm) was inserted.

[0203] These probes are connected to the microinjection pump via a dual channel swivel. The catheter was connected to a catheter tube. Filtered Ringer's solution (containing 0.5 μM neostigmine, 1 mL) was 45mM NaCl, 3mM KCl, 1mM MgCl2, 1.2mM CaCl2) Perfusion of the microdialysis probe with 1 μl / mL was started shortly before insertion of the probe into the brain. A constant flow rate of 180 min was continued for the duration of the experiment. After 180 min of stabilization, the experiment was started. Analyses were collected every 20 min. After the experiment, the animals were sacrificed and their brains were removed. The tissue was frozen at 4 °C and sectioned to confirm probe placement.

[0204] Compounds were dissolved in 10% HPbetaCD and injected subcutaneously (2.5-10 mg / mL). Doses are expressed as mg of salt / kg body weight. Compounds were administered in a volume of 2.5 ml / kg. was administered in doses.

[0205] Dialysate acetylcholine analysis The acetylcholine (ACh) concentration in the dialysate was 100 mM disodium hydrogen carbonate. Phosphate, 2.0 mM octanesulfonic acid, 0.5 mM tetramethylammonium Electrochemical analysis was performed using a mobile phase of pH 8.0 consisting of 1,2-dichloromethane and 0.005% MB(ESA). The enzyme was analyzed by HPLC with gas-chemical detection. The pre-column enzyme reactor (ESA) is connected to the analytical column (ESA ACH-250); flow rate 0. Prior to separation of ACh at 35 ml / min and temperature: 35°C, the injected sample (10 μl After the analytical column, the sample was purified by acetylcholine esterase (AES) which eliminated choline from the immobilized acetylcholine esterase. The enzyme was passed through a post-column solid phase reactor (ESA) containing esterase and choline oxidase. The latter reactor converted ACh to choline, which was then reacted with betaine and H2 The latter H2O2 was converted to O2 using a platinum electrode (analytical cell: ESA, model 5040). It was detected electrochemically by the presence of

[0206] Representing Data In single injection experiments, the three preceding consecutive ACh samples immediately prior to compound administration The mean value was used as the basal level in each experiment, and data were normalized to basal (100%). All data were converted to percentages of the mean basal pre-infusion value.

[0207] result The compound significantly increased extracellular levels of ACh in the prefrontal cortex and ventral hippocampus of rats. - see Figures 19a and 19b.

[0208] Example 27: Contextual fear conditioning in rats The compound administered in this experiment was 1-[2-(2,4-dimethylphenylsulfanyl) The compound was the [phenyl]piperazine HBr salt.

[0209] We investigated the effects of this compound on the acquisition, consolidation, and recall of contextual fear conditioning in rats. In this fear conditioning paradigm, animals are placed in a neutral environment. (context, training chamber, CS) as an aversive experience (electrical footshock, US). When exposed to the training chamber again, the animals The mice showed freezing behavior, which is considered a direct measure of their fear-related memory. [Pavlov J.Biol.Sci., 15, 177-182, 1980] The neuroanatomy of this contextual fear conditioning has been well studied, and several studies have , which shows that the hippocampus and amygdala are required for this memory formation [Hippoca mpus, 11, 8~17, 2001; J. Neurosci., 19, 1106~11 14, 1999;Behav.Neurosci., 106, 274~285, 1992 ].

[0210] Animals and Drugs Charles was housed two per cage under a 12-hour light / dark cycle. Adult male Sprague-Dawley mice were obtained from River Laboratories. Dawley rats (body weight at the time of training, 250-300 g) were used. The rats were allowed free access to water and water. They were used for one week after their arrival. The compounds were dissolved in 10% HPbetaCD and injected subcutaneously. A volume of 5 ml / kg was administered.

[0211] device Training and testing will be carried out in isolated rooms and connected to a ventilation system. The experiment was conducted in a soundproof chamber (30 × 20 × 40 cm) equipped with a 60-watt white light source. The floor of the chamber was made of metal that was attached to an electric shock generator. Prior to training and testing, the chamber was filled with 70% The samples were cleaned with a 100% ethanol solution. A video camera was used to train the samples for offline analysis. Observation and recording of session behavior was possible.

[0212] Acquisition and Retention Testing During acquisition, animals were allowed to freely explore the new environment for a 1-min habituation period. The 1-minute habituation period consisted of a single unavoidable challenge administered through an electrically chargeable grid floor. The footshock was terminated simultaneously with a rapid footshock (unconditioned stimulus, US). The duration was 2 seconds and the intensity was 0.75 mA. Animals were then monitored for an additional 60 seconds after the US. The rats were then placed in the conditioning chamber. The first 58 s (pre-shock acquisition; the experimenter was informed of group information) were used to determine whether the participants were in the same group or not. Freezing behavior was scored during acquisition (without the addition of the mouse). Once acquisition was completed, the animal was gently removed. After 24 hours, the same animals were placed in the training conditions described above. The subjects were then placed back into the fear conditioning chamber for a 2-minute retention test. No footshock was administered during the experiment. Freezing behavior was scored by the subject during the entire test period and was calculated as a percentage of the total test period. Presented as a rate.

[0213] Results and Discussion Effects of compounds on contextual fear conditioning in rats. The effects of compounds on contextual fear conditioning in rats were assessed by (i) acquisition (prior to acquisition) (ii) memory recall (drug application before the test, Fig. 21) and (ii i) Immobilization (drug application immediately after acquisition, FIG. 22) was investigated. In this first set of experiments In the study, the compounds (1 mg / kg, 5 mg / kg and 10 mg / kg) increased acquired session activity. The food shock was administered 1 hour before the training period. Figure 1 depicts the acquisition of freezing behavior during the first 24 h (seconds) and in the retention test 24 h later. Views observed: The compound increased baseline levels of GABA before footshock administration at all doses tested. Does not affect freezing behavior.

[0214] The compound at a dose of 5 mg / kg was administered in a memory retention test performed 24 hours after acquisition. There was a tendency for the subjects to increase the time spent freezing during the , n = 6, vs. 24.30 ± 4.40% in vehicle-treated animals, n = 16).

[0215] The compound at a dose of 10 mg / kg exhibited no significant effects during the retention test performed 24 hours after acquisition. significantly increased the time spent freezing in the rat (52.15 ± 5.68%, n = 10, vs , 24.30 ± 4.40% in vehicle-treated animals, n = 16, p < 0.01). .

[0216] This fear conditioning model, as depicted in Figure 20, has been used to study learning and memory. This is a standard procedure described in the literature. To clarify the The compound was administered 1 hour before the test. At a dose of 5 mg / kg, the compound suppressed freezing behavior during the memory test. The expression was observed to be suppressed (12.86 ± 3.57%, n = 9, vs. vehicle treatment). 33.61±4.29% in treated animals, n=13, p<0.05) (Figure 21).

[0217] As mentioned above, the compound by itself does not improve baseline levels of schizophrenia before US begins. Therefore, the most plausible hypothesis at first glance is that The hypothesis is that the effects observed in Figure 21 are due to anxiolytic effects. Memory was assessed by freezing behavior, a response that was reduced by compounds with potential anxiolytic properties. This study demonstrated that the compound has anxiolytic effects when given immediately before memory retrieval. Therefore, the increase in freezing behavior shown in FIG. 20 indicates the anxiogenicity of the compound. It is unlikely that this is due to an initiating effect.

[0218] The compound is not anxiogenic but has pro-cognitive potential. After the acquisition session, The compound was administered at doses of 10 mg / kg and 20 mg / kg. In rat experiments, the compound was administered on-board both during acquisition and throughout retention testing. Here, the compound at a dose of 5 mg / kg was not observed during the acquisition session. The results showed that the administration of 100 mg / kg / day increased the time spent freezing during the retention test 24 hours after the administration of 100 mg / kg / day. The observed (45.58 ± 4.50%, n = 8, vs. 2 in vehicle-treated animals) 5.26±3.57%, n=19, p<0.05). The percentage of resting time has been described as a measure of fear-related memory [Pavlov et al. J. Biol. Sci., 15, 177-182, 1980], and vehicle-treated animals. This is increased in compound-treated rats compared to 21) Taken together, these data suggest that this compound enhances contextual memory. This shows that. The present invention may include the following aspects. [1] 1-[2-(2,4-diphenylphosphine oxide]) Methylphenylsulfanyl)-phenyl]piperazine and its pharma- ceutically acceptable salts . [2] Compounds include hydrobromide, hydrochloride, mesylate, fumarate, maleate, meso-tartrate Tartrate, L-(+)-tartrate, D-(-)-tartrate, sulfate, phosphate or nitrate The compound according to claim 1, [3] 3. The compound of claim 1 or 2, wherein the compound is crystalline. [4] Claim 3: The compound has an XRDP as shown in any one of Figures 1-17. The compound according to claim 1, [5] Crystalline form of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperidine 2. The compound of claim 1 which is rhadine hydrobromide. [6] The compound has XR values ​​of approximately 6.89, 9.73, 13.78 and 14.64 (°2θ). The compound according to claim 5, having PD reflex. [7] 6. The compound of claim 5, wherein the compound has an XRDP as shown in FIG. [8] The compound is: D98%: 650~680μm; D50%: 230~250μm; and D5%: 40 ~60 μm; D98%:370~390;d50%:100~120μm;D5%:5~15μm; D98%: 100~125μm; D50%: 15~25μm; and D5%: 1~3μm m; or D98%: 50-70μm; D50%: 3-7μm; and D5%: 0.5-2, 7. The compound of claim 6, having a particle size distribution corresponding to: [9] 10. A compound according to any one of claims 1 to 8 for use in therapy.

[10] A medicament comprising a compound according to any one of claims 1 to 8 together with a pharma- ceutically acceptable excipient. composition.

[11] 11. The composition of claim 10 comprising a compound of claim 5 or 6.

[12] A tablet prepared by wet granulation and containing anhydrous calcium hydrogen phosphate, Corn starch, PVP-VA copolymer, microcrystalline cellulose, sodium denat. 11. The composition of claim 10, comprising punglycolate, talc and magnesium stearate. composition.

[13] HBr salt: 3-8% Anhydrous calcium hydrogen phosphate: 35-45% Corn starch: 15-25% PVP-VA copolymer: 2~6% Microcrystalline cellulose: 20-30% Sodium starch glycolate: 1-3% Talc: 2-6% Magnesium stearate: 0.5~2% 13. The composition of claim 12, comprising:

[14] HBr salt: approx. 5% Anhydrous calcium hydrogen phosphate: approx. 39% Corn starch: approx. 20% PVP-VA copolymer: approx. 3% Microcrystalline cellulose: approx. 25% Sodium starch glycolate: approx. 3% Talc: approx. 4% Magnesium stearate: approx. 1% 13. The composition of claim 12, comprising:

[15] Affective disorders, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, Depression, anxiety, generalized anxiety disorder, and social anxiety associated with cancer, aging, or Parkinson's disease Disorder, obsessive-compulsive disorder, panic disorder, panic attacks, phobias, social phobia, agoraphobia, stress urinary incontinence, vomiting, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression , Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, facial flushing, sleepiness Sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, and alcohol or substance abuse, comprising administering to a patient in need of treatment A method for treating a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 8. method.

[16] Affective disorders, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, Depression, anxiety, generalized anxiety disorder, and social anxiety associated with cancer, aging, or Parkinson's disease Disorder, obsessive-compulsive disorder, panic disorder, panic attacks, phobias, social phobia, agoraphobia, stress urinary incontinence, vomiting, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression , Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, facial flushing, sleepiness Sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, or alcohol Or the compound according to any one of claims 1 to 8 for producing a medicament for treating drug abuse. Use of compounds.

[17] Affective disorders, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, Depression, anxiety, generalized anxiety disorder, and social anxiety associated with cancer, aging, or Parkinson's disease Disorder, obsessive-compulsive disorder, panic disorder, panic attacks, phobias, social phobia, agoraphobia, stress urinary incontinence, vomiting, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression , Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, facial flushing, sleepiness Sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, and alcohol or any one of claims 1 to 8 for use in the treatment of a disease selected from drug abuse. The compound according to any one of claims 1 to 4.

[18] below: [ka] The process for preparing the compound of formula (I) comprises the steps of: in the presence of a palladium catalyst consisting of a ligand, at a temperature between 60°C and 130°C, Compound II [ka] [wherein R' represents hydrogen or a monovalent metal ion], [ka] wherein X1 and X2 independently represent halogen, and a compound of formula IV [ka] wherein R represents hydrogen or a protecting group.

[19] Compound II and compound III are reacted in a first reaction, and optionally said first reaction Reaction products at [ka] is isolated and purified, followed by subsequent reaction with said compound IV. 8. The method according to claim 8.

[20] Compound II, Compound III and Compound IV are mixed together at the start of the process; The method of claim 18. [twenty one] The compound according to any one of claims 18 to 20, wherein X1 and X2 independently represent Br or I. method. [twenty two] 22. The method of claim 21 , wherein X1 represents Br and X2 represents I. [twenty three] 23. The method according to claim 18, wherein the solvent is an aprotic solvent. [twenty four] The solvent may be toluene, xylene, triethylamine, tributylamine, dioxin, or or N-methylpyrrolidone. [twenty five] 25. The method of claim 24, wherein the solvent is toluene.

[26] The palladium source is selected from Pdddba2, Pd(OAc)2, or Pd2dba3. The method according to any one of claims 18 to 25,

[27] 27. The method of claim 26, wherein the palladium source is Pdddba2 or Pd2dba3. Law.

[28] The phosphine ligand 2,2'-Bis-diphenylphosphanyl-[1,1']binaphthalenyl (rac-B INAP); 1,1'-Bis(diphenylphosphino)ferrocene (DPPF); Bis-(2-diphenylphosphinophenyl) ether (DPEphos); Tri-t-butylphosphine (Fu's salt); Biphenyl-2-yl-di-t-butyl-phosphine; Biphenyl-2-yl-dicyclohexyl-phosphine; (2'-Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine ; [2'-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl- Min; and Dicyclohexyl-(2',4',6'-tri-propyl-biphenyl-2-yl)- phosphane; The method according to any one of claims 18 to 27, wherein the method is selected from the group consisting of:

[29] 29. The method of claim 28, wherein the phosphine ligand is rac-BINAP.

[30] The base is NaO(t-Bu), KO(t-Bu), Cs2CO3, DBU or DA The method according to any one of claims 18 to 28, wherein the compound is selected from BCO.

[31] 31. The method of claim 30, wherein the base is NaO(t-Bu).

[32] 32. The method of claim 18, wherein R represents hydrogen.

[33] R represents a protecting group selected from Boc, Bn, Cbz, C(=O)Oet or Me The method according to any one of claims 18 to 31.

[34] The method according to any one of claims 18 to 33, wherein R' is hydrogen.

[35] 35. The method according to claim 18, wherein the temperature is between about 80° C. and about 120° C. Method of posting.

[36] Follow these steps: a. Dissolve or disperse 1 to 1.5 equivalents of compounds I, II and III in toluene. obtaining mixture A; b. 1-2 mol% Pddba2 and 1-2 mol% rac-BINAP in 2-3 equivalents adding a quantity of NaO(t-Bu) to mixture A to obtain mixture B, Then, the mixture B is heated to about 100° C. until the compounds II and III are completely converted. Steps to be taken; c. The temperature of the mixture obtained in step b is increased to about 100° C. until the compound IV is completely converted. increasing the temperature to 20°C; and d. Optionally, when compound IV is a protected piperazine, adding an aqueous acid solution. removing the protecting group by 21. The method of claim 20, comprising:

[37] 1 to 1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-1-iodo-benzene ( or 1,2-dibromo-benzene) and piperazine in toluene, followed by 2-5 equivalents of NaO(t-Bu) and 1-2 mol% Pd2d dispersed in toluene ba3 and rac-BINAP are added to obtain a mixture, and the mixture is heated to 100-130°C. Heat for 2 to 10 hours to obtain the product 1-[2-(2,4-dimethyl-phenylsulfanyl)- 21. The method of claim 20, wherein the phenyl-piperazine is obtained.

[38] The mixture is heated to reflux for 3 to 5 hours, and the subsequent step is to obtain the resulting product. The product is further reacted with aqueous HBr to obtain the corresponding hydrobromide addition salt. 38. The method of claim 37, followed by a step.

[39] 2 to 5 equivalents of NaO(t-Bu), 2 to 5 equivalents of piperazine, 0.2 to 0.6 mol% Pddba2 and 0.6-1 mol% rac-BINAP were dispersed in toluene and mixed. and adding about 1 equivalent of 2-bromo-iodobenzene to the mixture A' to obtain mixture B. To the mixture B', 1 equivalent of 2,4-dimethylthiophenol is added, and the resulting mixture B' is The mixture was heated to reflux for 3 to 7 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl) 21. The method of claim 20, wherein the phenyl-piperazine is obtained.

[40] The resulting mixture is heated to reflux for 4 to 6 hours, and then the subsequent step of The resulting product was further reacted with aqueous HBr to give the corresponding hydrobromide addition salt. 40. The method of claim 39, followed by a step of:

[41] To obtain the corresponding hydrobromide salt, aqueous HBr was added to the product. [ka] wherein the product is optionally in purified form. The method according to any one of claims 18 to 37.

[42] 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine odor A method for producing a hydrochloric acid addition salt, comprising the steps of: ol, 1-bromo-1-iodo-benzene (or 1,2-dibromo-benzene) and and piperazine in toluene, followed by 2 to 5 equivalents of Na dispersed in toluene. O(t-Bu) and 1-2 mol% Pd2dba3 and rac-BINAP were added. A mixture is obtained, and the mixture is heated to reflux for 3 to 5 hours to obtain the product 1-[2-(2,4-dimethyl and further treating said piperazine with hydrobromide. The method as described above, further comprising reacting the compound with an aqueous solution of hydrochloric acid.

[43] 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine odor A process for preparing hydrochloric acid addition salts comprising the steps of: 2-5 equivalents of NaO(t-Bu), 2- 5 equivalents of piperazine, 0.2-0.6 mol% of Pddba2 and 0.6-1 mol% of r ac-BINAP was dispersed in toluene to obtain a mixture A', and about 1 equivalent of 2-Bromo-iodobenzene was added to obtain mixture B', and 1 equivalent of 2,4 -Dimethylthiophenol is added and the resulting mixture is heated to reflux for 4-6 hours. 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine was obtained. further reacting said piperazine with aqueous hydrobromic acid.

Claims

1. below: 【Chemistry 1】 The method for producing the compound of formula (I) comprises the steps of: From thi-diphenylphosphanyl-[1,1']binaphthalenyl (rac-BINAP) Compound I is reacted with a palladium catalyst having a temperature between 60° C. and 130° C. I 【Chemistry 2】 wherein R′ represents hydrogen or a monovalent metal ion, 【Chemistry 3】 [In the formula, X １ and X ２ and 【Chemistry 4】 wherein R represents hydrogen or a protecting group.

2. below: 【Chemistry 1】 The method for producing the compound of formula (I) comprises the steps of: From thi-diphenylphosphanyl-[1,1']binaphthalenyl (rac-BINAP) Compound I is reacted with a palladium catalyst having a temperature between 60° C. and 130° C. I 【Chemistry 2】 [0033] wherein R' represents hydrogen or a monovalent metal ion, and Compound III 【Chemistry 3】 [In the formula, X １ and X ２ each independently represents a halogen] is reacted in a first reaction, Reaction products in the first reaction 【Chemistry 5】 is isolated and subsequently reacted with a solvent, a base, and a palladium source and rac-BINAP. The reaction is carried out at a temperature between 60° C. and 130° C. in the presence of a palladium catalyst comprising Products and Compound IV 【Chemistry 4】 wherein R represents hydrogen or a protecting group.

3. Compound II, Compound III and Compound IV are mixed together at the start of the process; The method of claim 1.

4. X １ and X ２ The method according to any one of claims 1 to 3, wherein independently represents Br or I. 。

5. X １ represents Br; X ２ The method of claim 4 , wherein represents I.

6. The method according to any one of claims 1 to 5, wherein the solvent is an aprotic solvent.

7. The solvent may be toluene, xylene, triethylamine, tributylamine, dioxin, or 7. The method according to claim 1, wherein the solvent is selected from N-methylpyrrolidone or N-methylpyrrolidone.

8. The method of claim 7, wherein the solvent is toluene.

9. The palladium source is Pddba ２ , Pd(OAc) ２ or Pd ２ D.B.A. ３ Selected from The method according to any one of claims 1 to 8,

10. The palladium source is Pddba ２ or Pd ２ D.B.A. ３ The method according to claim 9, 。

11. The base is NaO(t-Bu), KO(t-Bu), Cs ２ CO ３ , DBU or DA The method according to any one of claims 1 to 10, wherein the carboxylate is selected from BCO.

12. The method of claim 11, wherein the base is NaO(t-Bu).

13. The method according to any one of claims 1 to 12, wherein R represents hydrogen.

14. R represents a protecting group selected from Boc, Bn, Cbz, C(=O)OEt or Me; The method according to any one of claims 1 to 12.

15. The method of any one of claims 1 to 14, wherein R' is hydrogen.

16. The method according to any one of claims 1 to 15, wherein the temperature is between 80°C and 120°C. Law.

17. Steps below: a. 1 to 1.5 equivalents of compounds II, III and IV are dissolved or dispersed in toluene. to obtain mixture A; b. 1 to 2 mol % Pddba ２ and 1 to 2 mol % of rac-BINAP in 2 to 3 equivalents. adding to mixture A together with an amount of NaO(t-Bu) to obtain mixture B, Then, the mixture B is heated to 100° C. until the compounds II and III are completely converted. The steps of: c. The temperature of the mixture obtained in step b is increased for 12 h until the compound IV is completely converted. increasing to 0° C.; and d. Optionally, when compound IV is a protected piperazine, adding an aqueous acid solution. removing said protecting group by The method of claim 3 , comprising:

18. 1 to 1.5 equivalents of 2,4-dimethyl-thiophenol, 1-bromo-2-iodo-phenol Phenol (or 1,2-dibromo-benzene) and piperazine are dispersed in toluene, followed by In the present study, 2-5 equivalents of NaO(t-Bu) and 1-2 mol % of P dispersed in toluene were used. d ２ D.B.A. ３ and rac-BINAP to obtain a mixture, and the mixture was diluted with 100 to 13 Heating at 0° C. for 2-10 hours gives the product 1-[2-(2,4-dimethyl-phenylsulfani The process according to claim 3, wherein the compound is a phenyl-piperazine.

19. The mixture is heated to reflux for 3-5 hours, and the subsequent step is to obtain the resulting product. The product is further reacted with aqueous HBr to obtain the corresponding hydrobromic acid addition salt.

20. The method of claim 18, followed by a step.

20. 2 to 5 equivalents of NaO(t-Bu), 2 to 5 equivalents of piperazine, 0.2 to 0.6 mol % Pddba ２ and 0.6 to 1 mol % of rac-BINAP dispersed in toluene and mixed. and adding 1 equivalent of 2-bromo-iodobenzene to the mixture A' to obtain mixture B'. To the mixture B', 1 equivalent of 2,4-dimethylthiophenol is added, and the resulting mixture B' is The mixture was heated to reflux for 3 to 7 hours to obtain 1-[2-(2,4-dimethylphenylsulfanyl)- 4. The method of claim 3, wherein the phenyl-piperazine is obtained.

21. The resulting mixture is heated to reflux for 4-6 hours, and then the subsequent step of The resulting product was further reacted with aqueous HBr to give the corresponding hydrobromic acid addition salt.

21. The method of claim 20, followed by a step of:

22. To obtain the corresponding hydrobromide salt, aqueous HBr was added to the product 【Chemistry 6】 wherein the product is optionally in purified form. The method according to any one of claims 1 to 18.

23. 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine odor A process for preparing hydrochloric acid addition salts comprising the steps of: phenol, 1-bromo-2-iodo-benzene (or 1,2-dibromo-benzene ) and piperazine dispersed in toluene, followed by 2-5 equivalents of toluene dispersed in of NaO(t-Bu) and 1-2 mol % of Pd ２ D.B.A. ３ and rac-BINAP Addition gives a mixture, and the mixture is heated to reflux for 3 to 5 hours to give the product 1-[2-(2,4-diphenyl methyl-phenylsulfanyl)-phenyl]-piperazine, The method described above, which comprises reacting with an aqueous hydrobromic acid solution.

24. 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine odor A process for preparing hydrochloric acid addition salts comprising the steps of: 2 to 5 equivalents of NaO(t-Bu), 2 to 5 equivalents of NaO(t-Bu), 5 equivalents of piperazine, 0.2-0.6 mol % of Pddba ２ and 0.6 to 1 mol % of r ac-BINAP was dispersed in toluene to obtain mixture A', and 1 equivalent of 2 was added to the mixture A'. -bromo-iodobenzene was added to obtain mixture B', and 1 equivalent of 2,4- Dimethylthiophenol was added and the resulting mixture was heated to reflux for 4-6 hours. -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, The process as described above, further comprising reacting the piperazine with aqueous hydrobromic acid.

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