JP7179035B2 - 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for treating cognitive impairment Piperazine - Google Patents

Description

The present invention provides serotonin receptor 1A (5-HT _1A ) and serotonin receptor 3 (5-H)
For compounds that exhibit serotonin reuptake inhibitory activity combined with activity on T ₃ ), these compounds are useful in the treatment of CNS-related diseases.

Selective serotonin reuptake inhibitors (SSRIs) are more efficacious, better tolerated and have a favorable safety profile than the compounds used before, namely the classical tricyclics. It has long been the drug of choice for the treatment of certain CNS-related disorders, particularly depression, anxiety and social phobia.

Nonetheless, therapeutic treatment with SSRIs is hampered by a significant proportion of non-responders, ie patients who do not respond or respond only to a limited extent to SSRI therapy. Moreover, SSRI treatment typically does not begin to show an effect until several weeks after treatment.

To circumvent some of these drawbacks of SSRI treatment, psychiatrists sometimes employ augmentation strategies. Antidepressant potentiation can be achieved, for example, by combining mood stabilizers such as lithium carbonate or triiodothyronine, or in combination with electroshock therapy.

It is known that a combination of inhibition of the serotonin transporter (SERT) and activity on one or more serotonin receptors can be beneficial. To date, combinations of serotonin reuptake inhibitors and compounds with 5-HT _2C antagonistic or inverse agonistic activity (compounds with negative potency at the 5-HT _2C receptor) have been
5-HT (serotonin) in terminal regions as measured in microdialysis experiments
It has been found to result in a considerable increase in levels (US Pat. This is due to the relatively short-term onset of antidepressant effects in the clinic and the use of serotonin reuptake inhibitors (SRIs)
This may have suggested an enhanced or synergistic effect of the therapeutic effect of

Similarly, it has also been reported that a combination of pindolol, a partial agonist of 5-HT _1A , and a serotonin reuptake inhibitor results in rapid onset of effects (Non-Patent Document 1).

CNS-related diseases such as depression, anxiety and schizophrenia are often co-morbid with other disorders or dysfunctions such as cognitive impairment or dysfunction (2, 3).

WO 01/41701 pamphlet

Psych. Res. , 125, 81-86, 2004 Scand. J. Psych. , 43, 239-251, 2002 Am. J. Psych. , 158, 1722-1725, 2001

Several neurotransmitters have been speculated to be involved in the neurological events that modulate this cognition. In particular, the cholinergic system plays an important role in cognition and thus
Compounds that affect the cholinergic system are potentially useful in treating cognitive dysfunction. 5-H
Compounds that affect the T1A and/or ₅ - _HT3 receptors are known to affect the cholinergic system and as such they may be used in the treatment of cognitive dysfunction. can be useful.

For this reason, compounds that function with 5-HT _1A and/or 5-HT ₃ receptor activity could be expected to be useful in treating cognitive dysfunction. SER on it
Compounds that also function T activity would be particularly useful in treating cognitive impairment in depressed patients, as such compounds would also provide rapid onset of therapeutic benefit in the treatment of depression.

WO 03/029232 discloses for example the compound 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Example 1e) as a compound with SERT activity.

Surprisingly, we found that 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine inhibited SERT, 5-HT ₃ antagonism and 5-HT _1A .
It was found to exert a combination of partial agonism. Accordingly, in one embodiment, the present invention provides 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]
Provided is Compound I, which is piperazine, and a pharmaceutically acceptable salt thereof, provided that said compound is not the free base in amorphous form.

In one embodiment, the invention provides the use of Compound I in therapy.

In one embodiment, the present invention provides pharmaceutical compositions comprising Compound I.

In one embodiment, the invention provides a method of treatment comprising administering an effective amount of Compound I to a patient in need of treatment.

In one embodiment, the invention provides use of compound I in the manufacture of a medicament.

XRPD of the crystalline base. XRPD of alpha hydrobromide. XRPD of hydrobromide in beta form. XRPD of gamma hydrobromide. XRPD of hydrobromide in hemihydrate form. XRPD of a mixture of ethyl acetate solvate and alpha hydrobromide. XRPD of hydrochloride. XRPD of hydrochloride in monohydrate form. XRPD of mesylate. XRPD of fumarate salt. XRPD of Maleate. XRPD of the meso-tartrate salt. XRPD of L-(+)-tartrate. XRPD of D-(-)-tartrate. XRPD of sulfate salt. XRPD of phosphate. XRPD of nitrate. 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 (seconds) spent licking the paw. Responses within a time period of 0-5 minutes. 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 (seconds) spent licking the paw. Response within a time period of 20-30 minutes. Extracellular acetylcholine levels in the prefrontal cortex of freely moving rats upon administration of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt. Extracellular acetylcholine levels in the ventral hippocampus of freely moving rats upon administration of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt. Effects of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 60 minutes prior to acquisition. Freezing behavior was scored (pre-shock acquisition) during the 58 sec habituation period preceding the footshock US (white bars). Freezing behavior was measured 24 hours after training (retention test) (black bars). Effects of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 1 hour prior to retention testing. Freezing behavior was scored (acquired) for 58 seconds prior to footshock US (white bars). Freezing behavior was measured 24 hours after training (retention test) (black bars). Effects of AA21004 on contextual fear conditioning in Sprague-Dawley rats when given immediately after acquisition. Freezing behavior was scored for 58 seconds prior to footshock US (pre-shock acquisition) (white bars). Freezing behavior was measured 24 hours after training (memory retention test) (black bars).

The present invention, whose structure is

Compound I, 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and pharmaceutically acceptable salts of Compound I thereof, provided that Compound I is the free base in amorphous form Make it not exist.

In one embodiment, the pharmaceutically acceptable salts mentioned above are acid addition salts of non-toxic acids. Such salts include those derived from organic acids such as maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid. , tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid,
Includes salts formed from benzenesulfonic acid, theophyllineacetic acid, and 8-haloteophylline, such as 8-bromoteophylline. Also, such salts may be formed from inorganic bases, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. In particular, methanesulfonic acid, maleic acid, fumaric acid,
Salts formed from meso-tartaric acid, (+)-tartaric acid, (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorous acid and nitric acid may be mentioned. Hydrobromide can be mentioned as a special case.

Oral dosage forms, especially tablets, are often preferred by patients and medical practitioners because they are easy to administer and result in good compliance. In tablets it is preferred that the active ingredient is crystalline. In one embodiment, the compounds of the invention are crystalline.

In one embodiment, the crystals of the invention are solvates, ie crystals in which solvent molecules form part of the crystal structure. This solvate may be formed from water, in which case they are often referred to as hydrates. Alternatively, these solvates may be formed from other solvents such as ethanol, acetone or ethyl acetate. The exact amount of solvation often depends on those conditions. For example, hydrates will typically lose water when the temperature is increased or the relative humidity is decreased.

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

Some compounds are hygroscopic, ie they absorb water when exposed to moisture. Hygroscopicity is generally considered an undesirable property for compounds that are to be present in pharmaceutical formulations, particularly dry formulations such as tablets. In one embodiment, the present invention provides crystals with low hygroscopicity. In the case of oral dosage forms using crystalline active ingredients, it is also beneficial that the crystals are well defined.
In this context, the term "well-defined" specifically means that the stoichiometry is well-defined, i.e. between the ions forming the salt Ratios are meant to be ratios between small integers, such as 1:1, 1:2, 2:1, 1:1:1, and so on. In one embodiment, the compounds of the invention are well-defined crystals.

The crystalline compounds of the present invention may exist in more than one form, ie they may exist in polymorphic forms. Polymorphic forms exist when a compound can crystallize in more than one form. The present invention is meant to comprehend all such polymorphic forms, whether in pure compounds or mixtures of compounds thereof.

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

In one embodiment, the present invention provides crystalline salts of the compounds of the present invention having XRDP's as shown in FIGS. 1-17, particularly FIGS.

The table below shows the main XRDP reflections for the compounds of the invention.

Selected X-ray peak positions (°2θ), all values +−0.1°

As evidenced for example by Figures 2-5, the compounds of the invention, in this case the hydrobromide salt, can exist in several forms, i.e. polymorphs. . These polymorphic forms have different properties, as shown in Example 4d. The beta form of the hydrobromide has increased stability as indicated by its higher DSC melting point and lower solubility. Moreover, the aforementioned beta form has an attractive combination of low hygroscopicity and solubility, which makes this compound particularly suitable for tablet manufacture. Accordingly, in one embodiment, the present invention provides approximately 6.89, 9.73
, 13.78 and 14.62 (°2θ), 1-[2-(2,4-dimethylphenylsulfanyl)-
A hydrobromide salt of phenyl]piperazine is provided.

The solubility of an active ingredient is also important in choosing a dosage form, as it can directly affect bioavailability. For oral dosage forms, higher solubility of the active ingredient is generally considered beneficial as it enhances bioavailability.

Cortical and hippocampal cholinergic neurotransmission are critical for cognition, and numerous preclinical observations point to the importance of serotonin receptor 1A (5-HT _1A ) for this system. T. Koyama, Neurosci. Lett. , 265, 33-3
6, 1999, reported that the 5-HT _1A agonist BAYX3702 increased acetylcholine efflux from rat cortex and hippocampus. Interestingly,
The 5-HT _1A antagonist WAY-100635 was able to abrogate the effect of BAYX3702, indicating that the effect of BAYX3702 is 5-HT _1A mediated.

Numerous studies have reported the effects of modulators of 5- _HT1A on cognitive impairment. A. Menese, Neurobiol. Learn. Memory,
71, 207-218, 1999, are partial 5-HT _1A agonists (±)
-8-hydroxy-2-(di-n-propylamino)-tetralin, HCl(8-OH-
DPAT) promotes learning consolidation in normal rats and also normalizes cognitive function in cognitively impaired rats.

These preclinical observations appear to be reflected in the clinic as well. T. Sumiy
oshi is Am. J. Psych. , 158, 1722-1725, 2001, in which patients were treated with typical antipsychotics such as haloperidol, sulpiride and pimozide in combination with placebo or the 5-HT _1A agonist tandospirone ( all lacking 5-HT _1A activity). Patients receiving tandospirone in addition to antipsychotics showed improved cognitive performance,
Patients who received placebo, on the other hand, showed no improvement. Similarly, the same 5-HT _1A
Agonist atypical antipsychotics, such as clozapine, also enhance cognition in schizophrenic patients, whereas typical antipsychotics without 5- _HT1A activity, such as haloperidol, do not. (Y. Chung, Brain Res., 1023,
54-63, 2004).

As mentioned above, the cholinergic system is thought to be involved in neurological events that regulate cognition, and the cholinergic system is responsible for serotonin receptor 3 (5-HT ₃
) [Giovannini et al., J. Am.
Pharmacol. Exp. Ther. , 1998, 285:1219-1225;
ostall and Naylor, Current Drug Targets--CNS
& Neurobiol. Disord. 2004, 3:27-37].

In the habituation test in mice, the T-maze forced alternation test in rats (T-maze r
in the enforced alteration task) and in object discrimination in marmosets (obje
ct discrimination) and reversal learning tasks, ondansetron reduced dysfunction caused by the muscarinic antagonist scopolamine or lesions of cholinergic pathways emerging from the ganglia basalis (Barnes et al., Pharmacol. Bioc.
hem. Behav. 1990, 35:955-962; Carey et al., Pharmac
ol. Biochem. Behav. 1992, 42:75-83). Boast et al.
eurobiol. Learn. Mem. 1999, 71:259-271), NMD
MK-801, a non-competitive antagonist of A receptors, was used to perturb the cognitive performance of rats trained in the delayed sample nonmatching radial maze task. Ondansetron has been shown to block cognitive impairment. Moreover, in a study on the amnestic effect of ethanol in a passive avoidance task in mice, this amnestic effect of ethanol was partially restored toward normal by ondansetron (Napiorkowska-Paw
lak et al., Fundam. Clin. Pharmacol. 2000, 14:125-1
31). Thus, enhancement of cholinergic transmission by ₅ -HT3 antagonism after cholinergic dysfunction in preclinical models (Diez-Ariza et al., Psychopher
macology, 2003, 169:35-41; Gil-Bea et al., Neuroph
armcol. 2004, 47:225-232) suggest rationale for using this treatment in the treatment of cognitive impairment.

An assessment of verbal and spatial memory and attention span performed in a randomized, double-blind, cross-over study in healthy male subjects showed that the ₅ -HT3 antagonist alosetron improved verbal and spatial memory. shown to attenuate scopolamine-induced impairment (Preston, Recent Advances in the
treatment of neurodegenerative disorders
and cognitive function, 1994, (eds.) Racagn.
i and Langer, Basel Karger, p. 89-93).

In conclusion, compounds that exert 5-HT _1A partial agonist activity in combination with 5-HT ₃ antagonist activity are believed to be particularly useful in the treatment of cognitive impairment. Furthermore, compounds that exert serotonin reuptake inhibition may be useful in reducing cognitive impairment associated with depression, as serotonin reuptake inhibition combined with 5- _HT1A partial agonism leads to a more rapid onset of therapeutic effect in depression. It would be exceptionally useful in therapy.

As shown in Example 1, the compounds of the invention are potent inhibitors of the human serotonin transporter, ie they inhibit serotonin reuptake. Moreover, these compounds are potent antagonists at mouse, rat, guinea pig and dog ₅ -HT3 receptors. At the human ₅ -HT3 receptor cloned in oocytes, these compounds were antagonistic at low concentrations (IC ₅₀ =˜30 nM), while at higher concentrations they exhibited agonistic properties. (ED ₅₀ =2.
1 μM). Subsequent application of the compounds of the invention at higher concentrations did not show any agonist response, suggesting rapid desenitisation in vitro.
Or it could have been due to direct antagonism. Thus, at low concentrations, compounds of the invention exhibit significant antagonism at human ₅ -HT3 receptors similar to that observed with ₅ -HT3 receptors from other species.

The compounds of the present invention are effective in reducing 5-HT _1A in both rat and mouse brain homogenates.
Binds to receptors with low affinity. However, the compounds of the present invention do not show human _5-
Binds to _HT1A receptors. Moreover, functional data indicate that the compounds of the invention are partial agonists at the human 5-HT _1A receptor, resulting in 85% efficacy.

The activity of the present invention at SERT, 5-HT ₃ receptors and 5-HT _1A receptors is expected to contribute to the in vivo profile of the compounds in humans.

As shown in Example 26, compounds of the invention produce increases in extracellular acetylcholine levels in the prefrontal cortex and ventral hippocampus in rats. These preclinical findings are expected to translate into clinical efficacy in treating cognitive impairment, such as Alzheimer's disease, compared to the use of acetylcholinesterase inhibitors in treating cognitive impairment. Further support for this view can be found in Example 27, where data show that compounds of the invention enhance contextual memory in rats. Overall, the pharmacological profile of the compounds of the invention in combination with their effects on acetylcholine levels and on memory in rats strongly suggest that the compounds of the invention are useful for treating cognitive impairment. there is

In one embodiment, the invention relates to a method for treating a cognitive disorder or cognitive dysfunction, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the invention. .

Cognitive impairment or cognitive dysfunction includes deterioration of cognitive function or cognitive domains, such as working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, such as executive function. , including decreased processing speed and/or social cognition. In particular, cognitive deficits or impairments are associated with lack of attention, disorganized thinking, and slow thinking.
ing), difficulty in understanding, poor concentration
, impairment of problem solving, poor memory
, difficulties in expressing thoughts and/or difficulties in integrating thoughts, feelings and behavior
ur), or difficulties in extinction of irrelevant thoughts
needs). The terms "cognitive impairment" and "cognitive impairment" are intended to denote the same and are used interchangeably.

In one embodiment, the patient has another CNS disorder, including affective disorders such as depression; generalized depression; major depressive disorder; general anxiety and panic disorders. obsessive-compulsive disorder; schizophrenia; Parkinson's disease; dementia;
Concomitant diagnoses such as dementia due to AIDS; ADHD; memory impairment due to aging; or Alzheimer's disease have also been made.

Cognitive impairment is one of the typical features of depression, eg major depressive disorder. Cognitive impairment is to some extent
It can be secondary to depression. However, there is also clear evidence that cognitive impairment is indeed independent of depression. For example, several studies have shown persistent cognitive impairment upon recovery from depression [J. Nervous Mental Disease
, 185, 748-754, 197]. Moreover, it provides further support for the notion that the differential effects of antidepressants on depression and cognitive impairment are independent of depression and cognitive impairment, even though they are often comorbid conditions. giving. Although serotonin and noradrenergic medications produce similar improvements in depressive symptoms, several studies have shown that modulation of the noradrenergic system did not improve cognitive function as much as serotonin modulation [Brain Res. Bull. , 58, 345-350, 2002;
sychpharmacol. , 8, 41-47, 1993].

Treatment of cognitive impairment in depressed patients by administering the compounds of the invention may be of particular advantage. Multimodal pharmacology of the compounds of the invention, especially SERT, 5-HT
₃ and 5-HT _1A activity are expected to provide improved cognitive function combined with rapid therapeutic onset of depression.

Cognitive impairment is a particularly important consideration in the elderly. Cognitive impairment normally progresses with aging, but it also progresses with depression. Accordingly, in one embodiment, the patient to be treated for cognitive impairment is the elderly, particularly the elderly with depression.

Cognitive function is often impaired in schizophrenic patients, as mentioned above. Also, several studies have shown that cognitive function is vocational function in schizophrenia.
ning) [Scizophrenia Res. , 45
, 175-184, 2000]. In one embodiment, the patient being treated for cognitive impairment is a schizophrenic patient.

5-HT3 receptor antagonists are also used for the treatment of various diseases such as emesis _, chemotherapy-induced emesis, craving, substance abuse, pain, irritable bowel syndrome (IBS), schizophrenia and eating disorders. [Eur. J. Pharmacol. , 56
0, 1-8, 2007; Pharmacol. Therapyut. , 111, 855~
876, 2006; Alimentary Pharmacol. Ther. , 24, 1
83-205, 2006].

One clinical study showed that mirtazipine in combination with SSRIs was superior to SSRIs for treating depressed patients with inadequate clinical response (treatment-resistant depression (TRD) or refractory depression). has been shown to be superior to the use of Ps alone [Ps
ychother. Psychosom. , 75, 139-153, 2006]. Mirtazapine is a 5-HT ₂ and 5-HT ₃ antagonist, which supports the notion that the compounds of the invention are useful for treating TRD.

Hot flushes are a symptom associated with the menopause transition. In some women, this hot flush can interfere with sleep or general activities to the extent that treatment is required. For decades, hormone replacement therapy with estrogen has been the treatment of choice, but recently concerns have been expressed about side effects such as breast cancer and cardiac events. Clinical trials with SSRIs have shown that these compounds are effective against hot flushes, although not as effectively as estrogen [J. Am. Med. Ass. , 295, 2057-2071, 2006]. However, treatment of hot flushes with compounds that inhibit serotonin reuptake, such as compounds of the present invention, is an alternative treatment for women who cannot or cannot tolerate estrogen.

Sleep apnea or obstructive sleep apnea-hypopnea syndrome or obstructive sleep disordered breathing is a disorder for which effective pharmacotherapy remains to be identified. However, some studies in animals suggest that ₅ -HT3 antagonists, such as the compounds of the present invention, may be effective in treating these diseases [Sleep, 21, 131-136
, 1998; Sleep, 8, 871, 878, 2001].

Major depressive disorder; postpartum depression; depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease. anxiety; generalized anxiety disorder; social anxiety disorder; obsessive-compulsive disorder; panic disorder; ADHD; melancholy; PTSD; hot flushes; sleep apnea; alcohol, nicotine or carbohydrate cravings; and comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the invention. In one embodiment, said patient being treated for any of the above-listed diseases has first been diagnosed with that disease.

It is well known that treatment with antidepressants in general, and SSRIs in particular, is associated with sexual dysfunction, often leading to cessation of treatment. 30 of patients treated with SSRI
As many as ∼70% of patients complain of impaired sexual function [J. Clin. Psych. , 6
6, 844-848, 2005], these disorders include diminished libido, delayed, reduced or absent orgasm, decreased sexual arousal and erectile dysfunction. A total of 114 subjects were administered compounds of the invention in clinical trials; of these 114 subjects, only 1 subject complained of sexual dysfunction. These data suggest that clinical intervention with the compounds of the invention is associated with a surprisingly low number of sexual dysfunctions.

As mentioned above, the compounds of the invention are particularly well suited for the treatment of chronic pain. Chronic pain includes phantom limb pain, neuropathic pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex regional pain syndrome (CPRS), neuralgia of the trigeminal nerve/trigeminal Neuralgia/painful tics, surgical interventions (e.g., postoperative analgesics), diabetic angiopathy, capillary resistance or diabetic conditions with insulitis, angina-related pain, menstrual-related pain, cancer-related pain, toothache, headache, migraine, tension pain, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscular inj
ury), fibromyalgia syndrome, bone joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid arthritis and edema due to trauma with burns, osteoarthritis, osteoporosis, bone metastasis or unknown reason Sprain or fracture bone pain, gout, fibromyalgia, myofascial pain, thoracic outlet syndrome, upper or lower back pain (where this back pain is systemic, focal or major spinal disease (neural radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury (SCI)-related pain, central post-stroke pain, cancer neuropathy, pain due to AIDS,
Indications include sickle cell pain, or geriatric pain.

The data presented in Example 16 demonstrate that the compounds of the present invention are useful for treating pain and that they may even have an analgesic effect, and further demonstrate that these compounds are useful in treating neuropathic pain in animals. Studies in models confirm this view.

As used herein, the term "therapeutically effective amount" of a compound cures clinical symptoms of a given disease and its complications in a therapeutic intervention involving administering a compound as described above, It means an amount sufficient to relieve or partially arrest. An amount adequate to accomplish this is defined as "therapeutically effective amount." Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. Determination of the proper dose is routine by constructing a matrix of numbers and testing at various different points on that matrix, all of which are within the ordinary skill of a trained physician. It will be appreciated that this can be accomplished with reasonable experimentation.

As used herein, the terms "treatment" and "treating" refer to the management and care of a patient aimed at combating a condition, such as a disease or disorder. The term applies to the full spectrum of treatments for a given condition with which the patient is suffering, e.g. to alleviate or alleviate the disease, and/or to cure or eliminate the disease, disorder or condition, as well as to prevent the condition,
Intended to include the administration of active compounds, etc., where prophylaxis is to be understood to mean the management and care of a patient aimed at combating a disease, condition or disorder, the symptoms thereof. or administration of active compounds to prevent the development of complications. Although,
Prophylactic treatment (treatment intended to prevent) and therapeutic treatment (treatment intended to cure) are two separate aspects of the present invention. The patient to be treated is preferably a mammal, especially a human.

Typically, treatment according to the invention will involve daily administration of a compound of the invention. This may involve once daily administration, or twice daily administration or even more frequent administrations.

In one embodiment, the present invention provides for affective disorders; depression; major depressive disorder; postpartum depression; depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, aging or Parkinson's disease; Generalized Anxiety Disorder; Social Anxiety Disorder; Obsessive-Compulsive Disorder; Panic Disorder; Panic Attacks; treatment-resistant depression; Alzheimer's disease; cognitive impairment; ADHD;
hot flushes; sleep apnea; alcohol, nicotine or carbohydrate cravings; substance abuse;

In one embodiment, the present invention is useful for treating affective disorders, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis, cancer, depression associated with aging or Parkinson's disease, anxiety, Generalized Anxiety Disorder, Social Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorder, Panic Attacks, Phobia, Social Phobia, Agoraphobia, Stress Incontinence, Vomiting, IBS, Eating Disorders, Chronic Pain, Partial Responders , treatment-resistant depression, Alzheimer's disease, cognitive impairment, ADHD,
A compound of the present invention for use in the treatment of a disorder selected from melancholia, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, or alcohol or drug abuse.

The effect of the compounds of the invention on human cognition can be assessed in a number of ways. The effect is determined by administration of the compound to healthy volunteers followed by accepted tests such as the Auditory Verbal Learning Test (AVLT), Wi
Tests that measure cognitive performance, such as the sconsin Card Sorting Test (WCST), or sustained attention [Psycopharmacol. , 163, 106-1
10, 2002; Psychiatry Clin. Neurosci. , 60, 70~
76, 2006]. The effect may of course be evaluated in patients suffering from cognitive impairment using the same type of test. Alternatively, a cognitive model may be used in which cognitive impairment is induced in healthy volunteers and the restorative effects of the compounds of the invention are measured. Cognitive dysfunction can be induced by, for example, scopolamine, sleep deprivation, alcohol, and tryptophan depletion.

The pharmaceutical formulations of the present invention can be manufactured by conventional methods in the art. Referring specifically to tablets, tablets can be prepared by mixing the active ingredient with conventional adjuvants and/or diluents and then compressing the mixture in a conventional tablet press. Examples of adjuvants or diluents are: anhydrous calcium hydrogen phosphate, PVP, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, maize starch, mannitol, potato starch, talcum, magnesium stearate, gelatin, lactose, gums. and so on. any other adjuvants or additives commonly used for such purposes,
For example, coloring agents, flavoring agents, preservatives and the like may also be used provided they are compatible with the active ingredients.

Injectable solutions are prepared by dissolving the active ingredient and possible excipients in a portion of an injectable solvent, preferably distilled water, adjusting the solution to the desired volume, sterilizing the resulting solution and dissolving it in suitable ampoules. Alternatively, it can be manufactured by filling in a vial. Any suitable additives commonly used in the art, such as tonicity agents, preservatives, antioxidants, etc., may be added.

The pharmaceutical composition of the present invention or the pharmaceutical composition prepared according to the present invention can be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups and the like. Alternatively, they may be administered parenterally in the form of injectable solutions. Various methods well known in the art may be used to produce such compositions,
Also, any pharmaceutically acceptable carrier, diluent, excipient or other additives commonly used in the art can be used.

Conveniently, the compounds of the present invention are administered in unit dosage form containing from about 1 mg to 50 mg of the compound. The upper limit is believed to be set by the concentration dependence of ₅ -HT3 activity. A total daily dose will generally range from about 1 to 20 mg of a compound of the invention, such as from about 1 mg to up to 10 mg, from about 5 to 10 mg, from about 10 to 20 mg or from about 10 to 15 mg of a compound of the invention. be. 5 mg as a special daily dose
, 10 mg, 15 mg or 20 mg.

Tablets containing a compound of the present invention may conveniently be prepared by wet granulation. Using this method, dry solids (active ingredients, fillers, binders, etc.) are blended and moistened with water or other wetting agents (e.g., alcohols), and the moist solids form agglomerates or granules. be built. Wet agglomeration is continued until the desired uniform particle size is achieved, after which the granulated product is dried. The compounds of the invention are typically mixed with lactose monohydrate, corn starch and copovidone with water in a high shear mixer. After formation of granules, these granules may be sieved through a sieve with a suitable sieve size and dried. These resulting dry granules are then mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate before tablets are compressed. Alternatively, wet granulation of the compounds of the invention employs mannitol, corn starch and copovidone, and the granules are mixed with microcrystalline cellulose, sodium starch glycolate and magnesium stearate prior to tablet compression. may be achieved by Alternatively, wet granulation of the compounds of the present invention employs anhydrous calcium hydrogen phosphate, corn starch and copovidone, and the granules are mixed with microcrystalline cellulose, sodium starch glycolate (Type A) prior to tablet compression. , talc and magnesium stearate. Copovidone is a PVP-VA copolymer.

In one embodiment, the compound of the invention is, for example, the beta hydrobromide salt,
Suitable tablets may consist of the following (percentages given are w/w %):
HBr salt: 2-20%
Lactose monohydrate: 30-50%
Starch: 15-30%
Copovidone: 3-5%
Microcrystalline cellulose: 15-25%
Croscarmellose sodium: 2-5%
Mg stearate: 0.5-5%.

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%
Mg 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%
Mg 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%
Mg stearate: 0.5-1%.

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%
Mg stearate: 0.25-5%, such as 0.25-2%.

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%
Mg 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%
Mg 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%
Mg 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%
Mg stearate: 0.5%.

In one embodiment the compound of the invention is the hydrobromide salt and a suitable tablet 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%.

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

Tablets with different amounts of active compound, e.g. 2.5 mg, 5 mg, 10 mg, 2
Tablets corresponding to 0 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg or 80 mg free base, etc. can be obtained by selecting the correct amount of a compound of the invention in combination with an appropriately sized tablet.

The size of the crystals used to make tablets containing the compounds of the invention is important. If the crystals are too small, they may stick to the tablet machine plunger. On the other hand, the crystals should not be too large. The rate of dissolution in the intestine decreases with increasing crystal size. Therefore, the bioavailability of the compound can be compromised if the crystals are too large. Quantiles such as D5%, D10%, D50%, D90%, D95% and D98% can be used to express the particle size distribution. As used herein, the term "particle size distribution" refers to Sy
Means the cumulative volume size distribution of equivalent spherical particle diameters as determined by laser diffraction at 1 bar dispersion pressure in an mpatec Helos apparatus.

In one embodiment, crystals of the compound of the invention, particularly crystals of hydrobromide in the beta form, have D98%: 650-680 μm; D50%: 230-250 μm; and D5%:
It has a particle size distribution corresponding to 40-60 μm. In a further embodiment, the particle size distribution corresponds to D98%: 370-390 μm; D50%: 100-120 μm; and D5%: 5-15 μm. In a still further embodiment, the particle size distribution is D98%: 100-125 μm; D50%: 15-25 μm; and D5%: 1-3
corresponds to μm. In a still further embodiment, the particle size distribution is D98%:5
0-70 μm; D50%: 3-7 μm; and D5%: 0.5-2 μm.

The free bases of the present invention can be prepared as disclosed in WO2003/029232. Salts of the invention can be prepared by dissolving the free base in a suitable solvent, adding the relevant acid, followed by precipitation. Precipitation is
This can be accomplished either by addition of a second solvent and/or evaporation and/or cooling. Alternatively, the free bases of the invention and ultimately the compounds of the invention can also be synthesized in a palladium catalyzed reaction as described below.

Formation of aromatic carbon-heteroatom bonds can be accomplished by nucleophilic aromatic substitution or copper-mediated Ullman reaction. More recently, palladium has been associated with the formation of such bonds,
In particular, it has been shown to be a strong catalyst in the formation of C—N and C—S bonds (see, eg, US Pat. No. 5,573,460).

In one embodiment, the invention provides

is provided, which method comprises compound II

[wherein R′ represents hydrogen or a monovalent metal ion] in the presence of a solvent, a base, and a palladium catalyst consisting of a palladium source and a phosphine ligand, at a temperature between 60° C. and 130° C. at temperature, formula III

compounds of the formula [wherein X ₁ and X ₂ independently represent halogen], and formula IV

[wherein R represents hydrogen or a protecting group].

In one embodiment, the method is divided into subprocesses in which compound II and compound III are reacted in a first reaction to form

yields a compound of This compound, optionally after purification to a suitable degree, is then reacted with compound IV to provide 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.

One-pot syntheses, ie, syntheses in which all reactants are mixed together at the beginning of the reaction or process, are particularly useful because of their inherent simplicity. On the other hand, the number of possible undesired side reactions increases dramatically, which again increases the number and/or amount of undesired side products and correspondingly increases the yield of the desired product. It means that it can be lowered. Specifically, it can be observed that for the present method the piperazine has two nitrogens, potentially each nitrogen participating in the formation of a C—N bond. Surprisingly, it has been found that the present process can be carried out as a one-pot synthesis, ie a process in which compound II, compound III and compound IV are mixed from the beginning while maintaining high yields of pure compounds.

Compound II is a thiol or the corresponding thiolate. Judging from an occupational health point of view, thiolates such as Li ⁺ , Na
⁺ or K ⁺ thiolate, etc. may be beneficial. However, in one embodiment, R' is hydrogen.

Compound III is a 1,2-dihalogen-activated benzene, the halogens of which are Cl,
Either Br or I may be used. In particular, compound II is 1-bromo-2-iodo-
Benzene or 1,2-dibromo-benzene.

The solvent used in the process of the present invention may be selected from aprotic organic solvents having boiling points within the reaction temperature range, ie from 60 to 130° C., or mixtures of such solvents. Typically, the solvent is selected from toluene, xylene, triethylamine, tributylamine, dioxane, N-methylpyrrolidone, or any mixture thereof. In particular, toluene can be mentioned as a solvent.

Central to the process is the use of a palladium catalyst without which the reaction does not occur. This palladium catalyst consists of a palladium source and a phosphine ligand. Useful palladium sources include palladium in various different oxidation states, such as 0 and II. Examples of palladium sources that can be used in the method of the invention are Pd ₂ dba ₃ , Pddba
₂ and Pd(OAc) ₂ . dba is an abbreviation for dibenzylideneacetone. In particular, Pddba ₂ and Pd ₂ dba ₃ may be named. This palladium source is
Typically it is applied in an amount of 0.1 to 10 mol %, such as 1 to 10 mol %, such as 1 to 5 mol %. Throughout this application, mole percents are calculated with respect to the limiting reactant.

A large number of phosphine ligands, both monodentate and bidentate, are known. Useful phosphine ligands include racemic 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (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'-dicyclohexylphosphanyl-biphenyl-2- yl)-dimethyl-amine, [2'-(di-
t-Butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and dicyclohexyl-(2′,4′,6′-tri-propyl-biphenyl-2-yl)-phosphane. In addition, carbene ligands such as 1,3-bis-(2,6-di-isopropyl-phenyl)-3H-imidazol-1-ium; chloride can be used instead of phosphine ligands. In one embodiment, the phosphine ligand is rac
- BINAP, DPPF or DPEphos, especially rac-BINAP. The phosphine ligand is usually applied in an amount of between 0.1 mol % and 10 mol %, such as between 1 mol % and 5 mol %, typically in an amount of about 1-2 mol %. applied in

A base is added to the reaction mixture to raise the pH. In particular, NaOt-Bu, KO
Bases selected from t-Bu and Cs ₂ CO ₃ are useful. organic base, e.g. 1,8
-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO), etc. can be applied as well. Mention may be made in particular of 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, such as 2-3 equivalents.

Compound IV is a piperazine compound. Piperazine has two nitrogens, only one of which participates in the formation of the CN bond. In one embodiment, bond formation to a second nitrogen is avoided by using a mono-protected piperazine, ie, by using embodiments where R is a protecting group. Many protecting groups are known in the art and useful examples include boc, Bn, Cbz, C(=O)O and Me, especially b
is oc. Bn is the abbreviation for benzyl; boc is the abbreviation for t-butyloxycarbonyl; cbz is the abbreviation for benzyloxycarbonyl. If a protected form of piperazine is used in these reactions, the protecting group must be removed in a subsequent step, typically by adding aqueous acid. When methyl is used as a protecting group, the methyl may be removed by reaction with a carbamate and subsequent removal of the group.

Surprisingly, it has been found that unprotected piperazines can be used as well, without the formation of unwanted bonds to the second nitrogen. Protected and unprotected piperazines have different solubilities in a variety of different solvents;
Piperazine is practically insoluble in toluene, whereas boc-protected piperazine is highly soluble in toluene. One would normally expect the ready solubility of all reactants in the applied solvent to be a prerequisite for successful reaction. Nevertheless, the method of the present invention uses toluene as solvent and the unprotected form of piperazine, i.e.
It has been found to work in good yields with the piperazine embodiment in which R is hydrogen. Thus, in one embodiment, the solvent is toluene and compound IV is piperazine. In a further embodiment, this combination of conditions is used in a one-pot synthesis.

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

In one embodiment, 1-[2-(2,4-dimethyl-phenylsulfanyl)
A phenyl]-piperazine is prepared by a method comprising the following steps:
a. dissolving or dispersing 1-1.5 equivalents of compounds II, III and IV in toluene to obtain mixture A;
b. 1-2 mol % of Pddba ₂ and 1-2 mol % of rac-BINAP, optionally dispersed or dissolved or dispersed in toluene, were added to mixture A together with 2-3 equivalents of NaOt-Bu to form mixture B. until complete conversion of compounds II and III.
heating the mixture B to about 100° C., typically for 5-10 hours;
c. increasing the temperature of the mixture obtained in step b to about 120° C. until compound IV is completely converted, typically for 16-32 hours; and d. Optionally, when compound III is a protected form of piperazine, removing its protecting group by adding an aqueous acid solution.

Optionally, the above sequence of reaction steps may include a purification step.

In one embodiment, 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-2-iodobenzene (or 1,2-dibromo-benzene) and piperazine are dispersed in toluene followed by and 2-5 equivalents, such as 3 equivalents of N dispersed in toluene.
aOt-Bu and 1-2 mol % of Pd ₂ dba ₃ and rac-BINAP are added to give a mixture which is refluxed for 2-10 hours, typically 3-5 hours to give 1-[2-(
2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine is obtained. Optionally, this product can be further reacted with aqueous HBr to give the corresponding hydrobromic acid addition salt.

In one embodiment, 2-5 equivalents of NaOt-Bu, 2-5 equivalents of piperazine,
0.2-0.6 mol % of Pddba ₂ and 0.6-1 mol % of rac-BINAP were dispersed in toluene to give a mixture A′ to which about 1 equivalent of 2-bromo-iodobenzene was added. is added to give a mixture B′, to the mixture is added 1 equivalent of 2,4-dimethylthiophenol and the resulting mixture is heated to reflux for 3-7 hours, such as 4-6 hours, and 1-
[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine is obtained.
Optionally, this product can be further reacted with aqueous HBr to give the corresponding hydrobromic acid addition salt.

In some situations, 1-[2-(2,4-dimethyl-
It may be desirable to obtain the acid addition salt of phenylsulfanyl)-phenyl]-piperazine. Acid addition salts may be obtained in a further process step, in which the free base obtained 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 the free base may first be purified to some suitable degree prior to such step. If the free base is isolated as a dry compound, it may be necessary to use a solvent to bring the free base into solution prior to reaction with the acid. In one embodiment, the aqueous hydrobromic acid solution is added directly to the reaction mixture without any initial purification of its free base.

In methods where a protected form of piperazine is used, the protecting group must be removed by adding an aqueous acid solution, as explained above. In one embodiment, the aqueous acid solution described above may be selected such that it can accomplish two transformations: deprotection of the protected piperazine and formation of the acid addition salt. In particular, aqueous hydrobromic acid can be used to deprotect the protected piperazine and to obtain the hydrobromic acid addition salt in one process step.

The notion applies to all reactions and reaction mixtures mentioned herein that it may be advantageous to purge them with an inert gas or to run them under a blanket of inert gas. Nitrogen is an example of an inert gas that is inexpensive and readily available.

All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entireties and elsewhere herein. To the same extent that each reference was individually and specifically indicated to be incorporated by reference, and the entire contents of this specification, regardless of the incorporation of any specific document given separately, incorporated herein to the same extent (to the fullest extent permitted by law) as set forth herein.

The use of the terms "a", "an" and "the" and similar referents in the context of describing the present invention is expressly disclaimed unless otherwise indicated herein or by context. should be construed to cover both singular and plural forms unless otherwise specified. For example, the phrase "the compound" should be understood to refer to various compounds of the invention or particular described embodiment, unless otherwise indicated.

Unless otherwise indicated, all exact values given herein are representative of corresponding approximate values (e.g., all exact values given for a particular factor or measure , can be viewed as changing to "about" where appropriate, and also giving corresponding approximate measurements).

"comprising", "ha", referring to one or more elements
Any description herein of any embodiment or aspect of the invention using terms such as "ving", "including" or "containing" includes, unless stated otherwise, , or “consisting of,” “consisting essentially of (such components) with respect to that particular component or components, unless the context clearly contradicts
"consisting of" or "consisting substantially of (such components)" are intended to provide support for similar aspects or aspects of the invention (e.g., Any composition described in should also be understood to describe a composition consisting of its constituents, unless otherwise stated or clearly contradicted by context. be).

Analysis method
¹ H NMR spectrum at 500.13 MHz with Bruker Avance
Recorded on the DRX500 device. Dimethylsulfoxide (99.8% D) is used as solvent and tetramethylsilane (TMS) as internal reference standard.

Melting points are measured using Differential Scanning Calorimetry (DSC). The instrument was a TA-Instruments DSC-Q10 calibrated at 5°/min to give the melting point as the starting value.
00. Approximately 2 mg of sample is heated at 5°/min in a loosely closed pan under nitrogen flow.

Thermogravimetric analysis (TGA), used to estimate the solvent/water content of dried materials, is performed using a TA-Instruments TGA-Q500. 1-10mg
of the sample is heated at 10°/min in an open pan under nitrogen flow.

A powder X-ray diffraction pattern was obtained from the PANalytical X'Per using CuK _α1 radiation.
t PRO X-Ray Diffractometer. The sample is
Measurements were made in reflection mode in the 2θ-range 5-40° using a 'celerator detector.

Example 1: In Vitro Receptor Pharmacology Rat Serotonin Transporter: IC ₅₀ 5.3 nM (Block of 5-HT Uptake)
Human serotonin transporter: IC ₅₀ 40 nM (blocking 5-HT uptake)
Human 5-HT _1A receptor: with partial agonism, K _i 40 nM (85% potency)
Rat 5-HT ₃ receptor: IC ₅₀ 0.2 nM (antagonism in functional assay)
Human 5-HT _3A receptor: IC ₅₀ approx. 20 nM (antagonism in functional assay).
At higher concentrations, the compound exhibits agonistic activity with an ED ₅₀ of 2.1 μM. Compounds of the invention also showed high affinity for the human 5HT3 receptor (Ki 4.5 nM) in an in vitro binding assay.

Example 2: Cognitive Effect As discussed above, compounds of the invention interact with the cholinergic system, and in in vivo models, effects on one or more of the following: would be expected.

5-choice reaction time test (5-CSRT) (useful for demonstrating effects on continuous attention)
Spatial Y-maze test (useful for demonstrating effects on short-term, long-term and working memory)
• Attentional set shifting model (useful for demonstrating effects on executive function, ie, reasoning and problem-solving).

Example 3a: Preparation of the free base of Compound I 10 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide was mixed with a stirred mixture of 100 ml of 3M NaOH and 100 ml of ethyl acetate. Treated for 10 minutes. The organic phase was separated and 100 ml of 15% wt N
_aCl (aq), dried over MgSO4, filtered and concentrated in vacuo to give 7.7 grams (98%) of Compound I base as a clear colorless oil. .
NMR fits the structure.

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

Example 3c: Characterization of Compound I of the Crystalline Base This base, prepared as in Example 3b, is crystalline (XRPD) - see FIG.
This crystalline base has a melting point of about 117°C. Also, this base is not hygroscopic and has a solubility of 0.1 mg/ml in water.

Example 4a: Preparation of the alpha hydrobromide salt of Compound I Dissolve 2.0 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine in 30 ml of hot ethyl acetate. and 0.73 ml of 48% wt H
Br(aq) was added. This addition resulted in the formation of a thick slurry and an additional 10 ml of ethyl acetate was added to ensure proper stirring. The slurry was stirred at room temperature for 1 hour. Filtration and drying under vacuum (20° C.) overnight gave 2.0 grams of product as a white solid (80%). NMR fits the structure. Elemental analysis: 57
. 05% C, 7.18% N, 6.16% H (theory for 1:1 salt: 56.9
9% C, 7.39% N, 6.11% H).

Example 4b: Characterization of the alpha hydrobromide of Compound I This alpha hydrobromide, prepared as in Example 4a, is crystalline (
XRPD) - see FIG. This crystalline hydrobromide has a melting point of about 226°C. This hydrobromide also absorbs about 0.3% water when exposed to high relative humidity and has a solubility of 2 mg/ml in water.

Example 4c: Preparation of the beta hydrobromide salt 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 was stirred overnight at room temperature. Filtration and drying under vacuum (50° C.) overnight gave 29.6 grams of product as a white solid (47%).
NMR fits the structure. Elemental analysis: 56.86% C, 7.35% N, 6.24% H (Theory for 1:1 salt: 56.99% C, 7.39% N, 6.11 % H)
.

Example 4d: Characterization of the beta hydrobromide of Compound I This hydrobromide beta, prepared as in Example 4c, is crystalline (X
RPD)--see FIG. This crystalline hydrobromide has a melting point of about 231°C. This hydrobromide also absorbs about 0.6% water when exposed to high relative humidity and has a solubility of 1.2 mg/ml in water.

Example 4e: Preparation of the gamma hydrobromide salt of Compound I Added to 20 ml of water and heated to 85°C. The solution was almost clear. The solution became clear by adding 1 drop of HBr. HBr was added until a cloud point was observed. The solution was cooled to room temperature and dried. NMR fits the structure. Elemental analysis: 56.63% C, 7.18% N, 6
. 21% H (theory for 1:1 salt: 56.99% C, 7.39% N, 6.1
1% H).

Example 4f: Characterization of the gamma hydrobromide of Compound I This hydrobromide, prepared as in Example 6e, is crystalline (XRPD)-
See FIG. 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. This crystalline hydrobromide absorbs about 4.5% water when exposed to high relative humidity and about 2% water at room temperature and 30% RH.

Example 4g: Preparation of Hydrobromide Hydrate of Compound I 1.4 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine oil was added to 20 ml of water and heated to 60°C. heated. p using 48% HBr
H was adjusted to 1. The solution was cooled to room temperature and dried. NMR fits the structure. Elemental analysis: 55.21% C, 7.16% N, 6.34% H (Theoretical for 1:1 salt hemihydrate: 55.68% C, 7.21% N , 6.23% H).

Example 4h: Characterization of the Hydrobromide Hemihydrate of Compound I This hydrate, prepared as in Example 4g, is crystalline (XRPD) - see FIG. Moisture content strongly depends on relative humidity. At room temperature and 95% RH, the moisture content is about 3.7%. Dehydration occurs by heating to about 100°C.

Example 4i: Preparation of Ethyl Acetate Solvate of Hydrobromide Salt of Compound I 0.9 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine oil was added to 35 ml of Dissolved in ethyl acetate and added 0.5 ml of 48% wt HBr(aq). This addition resulted in the formation of a thick slurry which was stirred overnight at room temperature. After filtering and washing with 30 ml of diethyl ether, vacuum (50° C.
) to give 1.0 grams (65%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine HBr EtOAc solvate. NMR fits the structure. Elemental analysis: 56.19% C, 6.60% N, 6.56%
H (Theoretical for 1:1 salt when corrected for 8% ethyl acetate and 0.5% water as determined by TGA and KF: 56.51% C, 6. 76% N, 6.38% H).

Example 4j: Characterization of Ethyl Acetate Solvate of Hydrobromide of Compound I This ethyl acetate solvate prepared as in Example 4i is crystalline (X
RPD)--see FIG. The batch contains a mixture of solvate and alpha forms of Compound I, presumably because drying caused partial desolvation. This desolvation is carried out at 10°
/min starts at about 75°C. After desolvation the alpha form is formed. Exposure to high relative humidity displaces ethyl acetate with water, which is then released when the humidity is lowered. The resulting solid is hygroscopic, absorbing 3.2% moisture at high relative humidity.

Example 5a: Preparation of Hydrochloride Salt of Compound I 1.0 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine oil was added to 20 ml with gentle heating (30°C). of ethyl acetate. When a clear solution was obtained, a solution of 2M HCl in diethyl ether was slowly added until the pH was about 1-2. Spontaneous precipitation was observed during this addition. After the last addition, the suspension was stirred for 1 hour, then filtered and vacuumed (4
A white precipitate was isolated by drying overnight at 0°C. 1.1 grams (99%
) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrochloride was isolated.
NMR fits 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: 64.13% C, 8.31% N, 6.95% H).

Example 5b: Characterization of the Hydrochloride of Compound I This hydrochloride, prepared as in Example 5a, is crystalline (XRPD)-
See FIG. This crystalline hydrochloride has a melting point of about 236°C. This hydrochloride also absorbs about 1.5% water when exposed to high relative humidity and has a solubility of 3 mg/ml in water.

Example 5c: Preparation of Hydrochloride Monohydrate of Compound I 11.9 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]
The piperazine oil was dissolved in 100 ml ethanol with heating. Addition of 3.5 ml concentrated HCl(aq), which was done when a homogeneous solution was obtained, caused immediate precipitation of a white solid. The resulting suspension was first stirred for 5 minutes and then stirred on the ice bath for a further 1 minute.
After stirring for an hour, it was filtered. Pour the white solid into 100 ml of fresh cold ethanol (-
2 hours in the freezer at 18° C.), 50 ml acetone and finally 50 ml
of diethyl ether and dried under vacuum (50° C.) overnight. 5.
One gram (38%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine HCl was isolated.
NMR fits 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).

Example 5d: Characterization of Hydrochloride Monohydrate of Compound I This hydrochloride monohydrate prepared as in Example 5c is crystalline (XR
PD) - see FIG. The crystalline monohydrate begins to lose water at about 50°C. Further heating causes several thermal events, possibly rearrangements, and the monohydrate melts at about 230°C, followed by recrystallization and melting at about 236°C. This crystalline monohydrate does not absorb any additional amount of water when exposed to high relative humidity, and the water bound to this hydrate does not increase when the relative humidity is below 10% RH at room temperature. It won't release until it drops. This crystalline monohydrate has a solubility of about 2 mg/ml in water.

Example 6a: Preparation of the mesylate salt of Compound I 1.0 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine oil was heated (70°C) to 20 ml of ethyl Dissolved in acetate. When a clear solution was obtained, 0.35 grams of methanesulfonic acid (1.1 eq) was added slowly. After the final addition, the solution was cooled on ice and diethyl ether was added slowly resulting in precipitation of the product. After stirring the suspension on ice for 2 hours, the resulting white precipitate was isolated by filtration and dried under vacuum (40° C.) overnight. 1.1 grams (85%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine mesylate was isolated. NMR fits the structure. Elemental analysis: 57
. 81% C, 6.81% N, 6.68% H (Theory for 1:1 salt: 57.8
1% C, 7.10% N, 6.64% H).

Example 6b: Characterization of the Mesylate of Compound I This mesylate, prepared as in Example 7a, is crystalline (XRPD) - Figure 9
reference. This crystalline mesylate has a melting point of about 163°C. The mesylate is also hygroscopic (absorbs approximately 8% water when exposed to 80% relative humidity, which
Converted to hydrated form. The last 6% of the water absorbed is at a relative humidity of 10% RH
It will not be released until This crystalline mesylate has a very high solubility in water (>45 mg/ml).

Example 7a: Preparation of the fumarate of compound I In a mixture of 50 ml of methanol and 50 ml of ethyl acetate, 5.5
A gram of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine oil was heated to reflux. The addition of 2.1 grams of fumaric acid shortly after the solution was allowed to cool caused an exothermic reaction resulting in the precipitation of a white solid. The resulting suspension was stirred while it was allowed to cool to room temperature, followed by cooling at -18°C in a freezer for 2 hours. The white solid was collected by filtration, washed with 20 ml cold ethyl acetate and dried under vacuum (50° C.) overnight. 3.1 grams (44%) of product was isolated.

NMR fits the structure. Elemental analysis: 63.42% C, 6.64% N, 6.42%
of H (theory for 1:1 salt: 63.74% C, 6.76% N, 6.32% H
).

Example 7b: Characterization of the Fumarate of Compound I This fumarate prepared as in Example 7a is crystalline (XRPD) - Figure 1
See 0. This crystalline fumarate has a melting point of about 194°C. Its solubility in water is 0.4 mg/ml.

Example 8a: Preparation of Maleate of Compound I 2.5 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine oil was dissolved in 50 ml of ethyl acetate and heated to 60°C. After heating,1.
One gram of maleic acid was added. The mixture was heated again to reflux for 5 minutes and allowed to cool to room temperature while stirring. Precipitation began during cooling and was terminated by placing in the freezer (-18°C) for 4 hours. The white solid was collected by filtration, washed with 50 ml of diethyl ether and dried under vacuum (50° C.) overnight. This makes 1
. 3 grams of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine maleate (38%) were obtained by treating the maleate with 40 ml of ethyl acetate and 5 ml of methanol at reflux. recrystallized. The clear solution was cooled to room temperature, followed by cooling in a freezer (−18° C.) for 2 hours before filtering and adding 10 ml
of cold ethyl acetate and then dried under vacuum (50° C.) for 2 days. 0.9 grams (69%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine maleate was isolated. NMR fits the structure. Elemental analysis: 63.57% C, 6.79% N, 6.39% H (theory for 1:1 salt: 6
3.74% C, 6.76% N, 6.32% H).

Example 8b: Characterization of Maleate of Compound I This maleate prepared as in Example 8a is crystalline (XRPD) - Figure 1
See 1. This crystalline fumarate has a melting point of about 152°C. Its solubility in water is approximately 1 mg/ml.

Example 9a: Preparation of the meso-tartrate of Compound I 11.1 ml of a 0.30 M solution of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine in acetone was dissolved in 5 ml of acetone. 0.5
Gram meso-tartaric acid. The resulting mixture was stirred at room temperature for 30 minutes during which time precipitation occurred. Filtration and washing first with 5 ml of acetone and then with 3 ml of diethyl ether gave the product as a white solid which was dried under vacuum (50° C.) overnight. 1.4 grams (93%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine meso-tartaric acid was isolated. NMR fits the structure.
Elemental analysis: 58.58% C, 6.29% N, 6.40% H (Theoretical for 1:1 salt: 58.91% C, 6.25% N, 6.29 % H).

Example 9b: Characterization of the meso-tartrate of Compound I This meso-tartrate, prepared as in Example 9a, is crystalline (XRPD
)--see FIG. This crystalline meso-tartrate has a melting point of about 164°C. Its solubility in water is approximately 0.7 mg/ml.

Example 10a: Preparation of L-(+)-Tartrate of Compound I 0.5 dissolved in acetone
treated with grams of L-(+)-tartaric acid. The resulting mixture was stirred at room temperature for 30 minutes during which time precipitation occurred. Filtration and washing first with 5 ml of acetone and then with 3 ml of diethyl ether gave the product as a white solid which was dried under vacuum (50° C.) overnight. 1.2 grams (81%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine (+)-tartaric acid was isolated. NMR fits the structure. Elemental analysis: 58.86% C, 6.30% N, 6.38% H (Theoretical for 1:1 salt: 58.91% C, 6.25% N, 6.29 % H).

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

Example 11a: Preparation of D-(-)-Tartrate of Compound I 0.5 dissolved in acetone
gram of D-(-)-tartaric acid. The resulting mixture was stirred at room temperature for 30 minutes during which time precipitation occurred. Filtration and washing first with 5 ml of acetone and then with 3 ml of diethyl ether gave the product as a white solid which was dried under vacuum (50° C.) overnight. 1.0 grams (68%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine D-(-)-tartaric acid was isolated. NMR fits the structure. Elemental analysis: 58.90% C, 6.26% N, 6.35% H (Theoretical for 1:1 salt: 58.91% C, 6.25% N, 6.29 % H).

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

Example 12a Preparation of _Sulfate of Compound _I .2 ml of 3M
treated with solution. The resulting mixture was stirred at room temperature for 30 minutes and then stirred on an ice bath for an additional 4 hours to cause and terminate the precipitation. Filtration and washing first with 5 ml of acetone and then with 3 ml of diethyl ether gave the product as a white solid which was dried under vacuum (50° C.) overnight. 0.51 grams (39%) of 1-[
2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine sulfate was isolated. NMR fits the structure. Elemental analysis: 54.53% C, 7.22% N,
6.28% H (theoretical for 1:1 salt: 54.52% C, 7.07% N, 6.52% C;
10% H).

Example 12b: Characterization of the Sulfate of Compound I This sulfate, prepared as in Example 12a, is crystalline (XRPD)-
See FIG. This crystalline sulfate has a melting point of about 166°C. Its solubility in water is approximately 0.1 mg/ml.

Example 13a Preparation of Phosphate of Compound I 11.1 ml of 0.30 M solution of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine in acetone was treated with 0.2 ml of 65% H ₃ . PO4 ₍ aq
). The resulting mixture was stirred at room temperature for 30 minutes during which time precipitation occurred. Filtration and washing first with 5 ml of acetone and then with 3 ml of diethyl ether gave the product as a white solid which was dried under vacuum (50° C.) overnight. 1.
23 grams (94%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine phosphate were isolated. NMR fits the structure. Elemental analysis: 54.
21% C, 7.15% N, 6.43% H (theory for 1:1 salt: 54.53
% C, 7.07% N, 6.36% H).

Example 13b: Characterization of the Phosphate of Compound I This phosphate, prepared as in Example 13a, is crystalline (XRPD)-
See FIG. This crystalline phosphate has a melting point of about 224°C. Its solubility in water is approximately 1 mg/ml.

Example 14a: Preparation of Nitrate of Compound I 11.1 ml of 0.30 M solution of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine in acetone was dissolved in 0.2 ml of 16.5 M HNO. ₃ (a
q). The resulting mixture was stirred at room temperature for 30 minutes during which time precipitation occurred. Filtration and washing first with 5 ml of acetone and then with 3 ml of diethyl ether gave the product as a white solid which was dried under vacuum (50° C.) overnight. 0
. 87 grams (73%) of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine nitrate were isolated. NMR fits the structure. Elemental analysis: 59.
80% C, 11.67% N, 6.51% H (Theory for 1:1 salt: 59.8
1% C, 11.63% N, 6.41% H).

Example 14b: Characterization of the Nitrate of Compound I This nitrate, prepared as in Example 14a, is crystalline (XRPD) - see FIG. This crystalline nitrate does not melt, but decomposes under an exothermic reaction at about 160°C. Its solubility in water is approximately 0.8 mg/ml.

Example 15: Tablets The following example provides representative examples of how tablets containing the compounds of the invention may be prepared. The beta form of hydrobromide was used in all examples.

Example 15a
63.55 g of this hydrobromide, 923.65 g of Lactosum 350M, 46
1.8 g of corn starch and 76.0 g of Kollidon VA64 were added to Di
Mixed for 2 minutes in an osna PP1 high shear mixer with an impeller speed of 1000 rpm. The impeller speed was then reduced to 800 rpm and 220 g of water were added in a short period of time. Massing was carried out for 7 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1383.5 g of granules were mixed with 400 g of Avicel PH200 and 60.
g of Ac-Di-Sol. After lubricating the blend by mixing with 15 g of magnesium stearate, the resulting powder blend was transferred to a tablet press.
Tablets with a target core weight of 200 mg and a diameter of 8 mm were produced in order to obtain a tablet with a target content corresponding to 5 mg of the free base.

Example 15b
317.75 g of this hydrobromide, 754.15 g of Lactosum 350M, 3
77.1 g of corn starch and 76.0 g of Kollidon VA64 were added to D
Mixed for 2 minutes in an iosna PP1 high shear mixer with an impeller speed of 1000 rpm. The impeller speed was then reduced to 800 rpm and 210 g of water were added in a short period of time. Agglomeration was carried out for 7 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1386.2 g of granules were mixed with 400 g of Avicel PH200 and 60 g of Ac-
Mixed with Di-Sol. After lubricating the blend by mixing with 15 g of magnesium stearate, the resulting powder blend was transferred to a tablet press. Tablets with a target core weight of 200 mg and a diameter of 8 mm were produced in order to obtain a tablet with a target content corresponding to 25 mg of the free base.

Example 15c
32.2 g of this hydrobromide, 944.82 g of Lactosum 350M, 472
. 4 g of corn starch and 76.0 g of Kollidon VA64 were added to the Dio
Mixed for 2 minutes in a sna PP1 high shear mixer with an impeller speed of 1000 rpm. The impeller speed was then reduced to 800 rpm and 220 g of water were added in a short period of time. Agglomeration was carried out for 7 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm sieve. Resulting 1317
g of granules were mixed with 400 g of Avicel PH200 and 60 g of Ac-Di-Sol. After lubricating the blend by mixing with 15 g of magnesium stearate, the resulting powder blend was transferred to a tablet press. Tablets with a target core weight of 208 mg and a diameter of 8 mm were produced in order to obtain a tablet with a target content corresponding to 2.5 mg of the free base.

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 were mixed in an Aeromatic-Fielder PMA1 high shear mixer at 1000 rpm.
was mixed for 2 minutes at an impeller speed of The impeller speed was then reduced to 800 rpm and 241.87 g of water was added during a short period of time. Agglomeration was carried out for 7 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. 1500 g of the resulting granules were added to 531.91 g of Avic
el PH200 and 85.11 g of Primojel. After lubricating the blend by mixing with 10.64 g of magnesium stearate, the resulting powder blend was transferred to a tabletting machine. Tablets with a target core weight of 125 mg and a diameter of 6 mm were produced in order to obtain a tablet with a target content corresponding to 25 mg of the free base.

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 A
Mixed for 2 minutes at an impeller speed of 1000 rpm in an erotic-Fielder PMA1 high shear mixer. then reduce the impeller speed to 800 rpm,
195 g of water were added in a short time. Agglomeration was carried out for 5.5 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1200.3 g of granules were mixed with 425.5 g of Avice.
l PH 200 and 68.09 g of Primojel. After lubricating the blend by mixing with 8.8 g of magnesium stearate, the resulting powder blend was transferred to a tabletting machine. Tablets with a target core weight of 100 and a diameter of 6 mm were produced in order to obtain a tablet with a target content corresponding to 10 mg of the free base.

Example 15f
504.85 g of this free base, 552.95 g of Pearlitol 50C, 276
. 53 g of corn starch and 65.7 g of Kollidon VA64 were mixed with Ae
Mixed for 2 minutes at an impeller speed of 1000 rpm in a romatic-Fielder PMA1 high shear mixer. The impeller speed was then reduced to 800 rpm and 182 g of water were added in a short period of time. Agglomeration was carried out for 5.5 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1250.7 g of granules were mixed with 443.31 g of Avice.
l PH 200 and 70.8 g of Primojel. After lubricating the blend by mixing with 8.92 g of magnesium stearate, the resulting powder blend was transferred to a tabletting machine. Tablets with a target core weight of 250 mg and a diameter of 8 mm were produced in order to obtain a tablet with a target content corresponding to 50 mg of the free base.

Example 15g
135.23 g of this hydrobromide, 863.2 g of Pearlitol 50C, 43
2.69 g of corn starch and 70.66 g of Kollidon VA64 were mixed in an Aeromatic-Fielder PMA1 high shear mixer at 1000 rpm.
was mixed for 2 minutes at an impeller speed of The impeller speed was then reduced to 800 rpm and 195 g of water was added in a short period of time. Agglomeration was carried out for 5.5 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1200 g of granules was added to 425.28 g of Avice.
l PH 200 and 68.2 g of Primojel. After lubricating the blend by mixing with 8.58 g of magnesium stearate, the resulting powder blend was transferred to a tabletting machine. Tablets with a target core weight of 100 mg and a diameter of 6 mm were produced in order to obtain a tablet with a target content corresponding to 5 mg of the free base.

Example 15h
67.6 g of this hydrobromide, 908.0 g of Pearlitol 50C, 453.
9 g of corn starch and 70.51 g of Kollidon VA64 were added to Dio
Mixed for 2 minutes in a sna PP1 high shear mixer with an impeller speed of 1000 rpm. The impeller speed was then reduced to 800 rpm and 195 g of water was added in a short period of time. Agglomeration was carried out for 5.5 minutes and the resulting granules were passed through a 4000 μm size sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1325 g of granules were mixed with 531.91 g of Avicel PH200 and 85.11.
g of Primojel. After lubricating the blend by mixing with 10.64 g of magnesium stearate, the resulting powder blend was transferred to a tabletting machine. To obtain a tablet with a target content corresponding to 5 mg of the free base, 207.8 mg
Tablets were manufactured with a target core weight of 1.5 mm and a diameter of 7 mm.

Example 15i
2290.1 g of this hydrobromide, 17568 g of anhydrous calcium hydrogen phosphate and 8783 g of corn starch and 1510 g of copovidone were added to Aeroma.
Mixed for 3 minutes in a tic-Fielder PMA100 high shear mixer with an impeller speed of 200 rpm. 5130 g of water were then added during 2 minutes at an impeller speed of 150 rpm. Agglomeration was carried out for 15 minutes and the resulting granules were subjected to 9.
It was passed through a conical mill operating at about 2700 rpm with a screen size of 525 mm. The granules are dried and with a screen size of 2.388 mm, approximately 15
It was passed through a conical mill operating at 00 rpm. The resulting 28747 g of granules was
Mixed with 1250 g microcrystalline cellulose, 1350 g sodium starch glycolate (type A) and 1800 g talc. After lubricating the blend by mixing with 450 g of magnesium stearate, the resulting powder blend was transferred to a tabletting machine. To obtain a tablet with a target content of the hydrobromide salt corresponding to 5 mg of the free base, tablets with a target core weight of 125 mg and a diameter of 6 mm were produced. In addition, tablets with a target core weight of 250 mg and a diameter of 8 mm were produced in order to obtain tablets with a target content of the hydrobromide salt corresponding to 10 mg of the free base.

Example 16: Pain effects in an intradermal formalin test in mice
In this model, mice receive an injection of formalin (4.5%, 20 μl) into the left hind paw. This formalin injection-evoked stimulus elicits a characteristic biphasic behavioral response, quantified by the amount of time spent licking the injured paw. The first phase (approximately 0-10 minutes) represents direct chemical stimulation and nociception, while the second phase (approximately 20-3
0 min) is considered to represent pain of neuropathic origin. These two phases are separated by a period of sedation during which behavior returns to normal. Efficacy of test compounds to reduce painful stimuli is assessed by timing the amount of time spent licking the injured paw during these two phases.

Compounds of the invention showed a significant reduction in pain scores in Phase 2 (Figure 18b), demonstrating efficacy against pain of neuropathic origin. Moreover, the compounds of the invention also showed a significant reduction in scores in the first phase (Fig. 18a), indicating that they have greater analgesic activity at the highest dose. Taken together, these results indicate that the compounds of the invention are likely to be effective in treating pain disorders.

Example 17

20 g of 2-bromoiodobenzene (71 mmol) and 9.8 g of 2,4-dimethylthiophenol (71 mmol) were dissolved in 100 ml of toluene. 324 mg Pd ₂ dba ₃ (0.35 mmol; 1 mol %) and 381 mg DPEPhos (
0.71 mmol; 1 mol %), the solution was purged with nitrogen. The reaction mixture was stirred for 5 minutes during which time the color changed from dark red to orange. 8.7g KOB
U ^t (78 mmol) was added and a heterogeneous mixture immediately formed. The suspension was heated to 100° C. under nitrogen. After 1 hour, the mixture was cooled to 0° C. and stirred for 2 hours before filtering the mixture through a pad of celite. The resulting filter cake is 2 x 50
ml of toluene and evaporation of the combined filtrates gave 21 g of an orange-reddish oil (99% yield), which was analyzed by HPLC and GC.
-MS found >96% pure.

Example 18

Place 500 ml of toluene in a 1 L 3-neck round bottle with a mechanical stirrer,
203 mg _Pddba2 (0.35 mmol; 0.1 mol%) and 760 mg D
PEPhos (1.5mmol; 0.4mol%) was added. After purging the dark red solution with nitrogen for 5 minutes, 100 g of 2-bromoiodobenzene (353 mmol) and 4
Addition of 8.9 g of 2,4-dimethylthiophenol (353 mmol) was made. 43
. Addition of 6 g of KOBu ^t (389 mmol) caused an exothermic reaction, raising the temperature from 20° C. to 36° C., with concomitant formation of a heterogeneous mixture. The suspension was heated to 100° C. under nitrogen. After 7 hours, the mixture was cooled to 0° C. and stirred for 2 hours before filtering the mixture through a pad of celite. The resulting filter cake is 2 x 200
ml of toluene and evaporation of the combined filtrates gave 104 g of an orange oil (105% yield) which was found to be 97% pure by HPLC. , and confirmed by NMR to be the desired structure. This oil solidified on standing at room temperature.

Example 19

To a solution of 10 grams of 1-(2-bromo-phenylsulfanyl)-2,4-dimethyl-benzene (34 mmol) in 50 ml of dry toluene was added 7 grams of boc-piperazine (38 mmol) and degassed with nitrogen for 5 minutes. 312 mg of Pd ₂ dba ₃ (2
mol %) and 637 mg of rac-BINAP (3 mol %) were added and degassed for an additional 5 minutes before adding 3.9 grams of But ^ONa (41 mmol) and heating to 80° C. for 15 hours. The reaction mixture was cooled to room temperature and extracted twice with 20 ml of 15% brine,
Dry over Na ₂ SO ₄ , add activated charcoal, reflux for 15 min, filter through celite and evaporate to give 14.2 g of a brownish oil with a purity of 95% as determined by NMR. product (4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-BOC-piperazine) was obtained. This crude oil was dissolved in 200 ml MeOH and 20 ml 6M HCl (aq.) and refluxed for 1 hour after which HPLC indicated complete deprotection. After cooling to room temperature, the methanol is removed by vacuum on a rotary evaporator,
20 ml of concentrated NaOH (pH was 13-14) was added, then the resulting mixture was stirred with 100 ml of EtOAc for 15 minutes. The organic phase was collected and 30 ml of 1
Extracted twice with 5% brine, dried over Na ₂ SO ₄ and added 5.2 g fumaric acid (44 mmol) in 30 ml MeOH. A homogeneous solution forms during heating to reflux and rapid precipitation occurs from the solution during either further heating or cooling. The precipitate was collected, washed with 20 ml of EtOAc and 20 ml of acetone, and dried under vacuum to give 9.3 grams of 1- as a white powder in 66% overall yield.
[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine fumarate (22 mmol) was obtained with a purity of 99.5% by LC-MS.

Example 20

100 g of 1,2-dibromobenzene (424 mmol) and 58.6 g of 2,4-
Dimethylthiophenol (424 mmol) is dissolved in 800 ml of toluene. 4.
6 g Pddba ₂ (8 mmol; 2 mol %) and 13.1 g rac-BINAP
(21 mmol; 5 mol %) the solution is purged with nitrogen. 5 times the reaction mixture
Stir for a minute, during which time the color changes from dark red to orange. 61 g of NaOBu ^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 brought to 60°C.
after cooling to 102.6 g of boc-piperazine (5
51 mmol) and another 61 g of NaOBu ^t (636 mmol) are added. After purging the reaction mixture with nitrogen, another portion of 4.6 g of Pddba ₂ (8 mmol; 2 mol) was
%) and 13.1 g of rac-BINAP (21 mmol; 5 mol %) were added. The mixture was then heated to reflux (110° C.) for an additional 6 hours or until HPLC indicated complete conversion. After cooling the resulting reaction mixture on ice for 2 hours, the mixture was filtered through a pad of celite. The filter cake obtained is washed with 2×200 ml of toluene and 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 before complete deprotection was detected by HPLC. The mixture was cooled, 1000 ml of EtOAc was added and MeOH was removed by evaporation. Addition of 1000 ml Et ₂ O caused precipitation. 2 at room temperature
After continuing to stir for hours, the slurry was left in the freezer overnight (-18°C). filtered, 2
17 by washing twice with 00 ml Et ₂ O and drying under vacuum at 40°C.
2 g of brownish solid was obtained. The brownish solid was added to 1500 ml of boiling H
After treatment with ₂ O for 1 hour, it was cooled to room temperature over an additional 2 hours. Filtration and drying under vacuum at 40° C. overnight gave 98 g of 4-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (61%).

Example 21

102 g of 2-bromo-iodobenzene (362 mmol) and 50 g of 2,4-dimethylthiophenol (362 mmol) are dissolved in 1000 ml of toluene. To this solution was added 81 g of BOC-piperazine (434 mmol) followed by 2.08 g of P
ddba ₂ (1 mol %) and 4.51 g rac-BINAP (2 mol %) were added. After purging the mixture with nitrogen for 5 minutes, a slurry of 87 g of NaOBu ^t (905 mmol) in 300 ml of toluene was added. The resulting suspension was heated to 100° C. overnight under nitrogen. GCMS analysis indicated complete conversion to the intermediate product (1-(2-bromo-phenylsulfanyl)-2,4-dimethyl-benzene) and the temperature was raised to reflux (120°C) for an additional 24 hours. . HPLC analysis showed intermediate (1-BOC-4-[2
-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine). After cooling the reaction mixture on ice for 1 hour, the mixture was filtered. The resulting filter cake was washed with 2 x 200 ml toluene and 80 ml
of HBr (aq.) was added, followed by heating to reflux for 18 hours, after which HP
Complete deprotection was detected by LC. The resulting mixture was cooled on ice for 2 hours and filtered. The brownish solid was added to 1000 ml of boiling H ₂ O with activated charcoal (25 g).
for 1 hour, filtered while hot and allowed to cool. The resulting precipitate was collected by filtration and dried under vacuum at 40° C. overnight to give 49 g of 4 as a white solid.
-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (36%) was obtained.

Example 22

Place 500 ml of toluene in a 1 L 3-neck round bottle with a mechanical stirrer,
809 mg _{Pd2dba3 (} 0.88 mmol; 0.5 mol%) and 952 mg DPEPhos (1.77 mmol; 0.5 mol%) were added. After purging the dark red solution with nitrogen for 5 minutes, the addition of 100 g of 2-bromoiodobenzene (353 mmol) and 48.9 g of 2,4-dimethylthiophenol (353 mmol) was performed.
Addition of 43.6 g of KOBu ^t (389 mmol) caused an exothermic reaction, raising the temperature to 20°C.
C. to 42.degree. C., at the same time resulting in the formation of a heterogeneous mixture and changing its color from dark red to orange/brownish. The suspension was placed under nitrogen for 10
Heated to 0°C. After only 20 min HPLC showed 1-(2-bromo-phenylsulfanyl)
It showed complete conversion to -2,4-dimethyl-benzene. the mixture is 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 phase was washed with 2x100ml toluene. The combined organic phases were washed with 100 ml 2 M HCl (aq.), 100 ml 15 wt % NaCl, dried over Na ₂ SO ₄ , refluxed with activated charcoal (10 g) for 15 min and filtered twice. was evaporated to give 107.3 g of an orange-red oil (103%), which was purified by HPL
C was found to be 98% pure.

90 grams of the above orange-red oil in 500 ml of dry toluene (
57 grams of boc-piperazine (307 mmol) was added to a solution of
Degas with nitrogen for 5 min and 1.4 g of Pd ₂ dba ₃ (1.53 mmol; 0.5 mol %)
and 2.9 g of rac-BINAP (4.6 mmol; 1.5 mol %) were added and degassed for an additional 2 minutes before adding 35.4 g of But ^ONa (368 mmol) and heating to 80° C. for 18 hours. . HPLC showed complete conversion and the reaction mixture was cooled to room temperature, filtered and the filter cake was washed with 2 x 100 ml of toluene. The combined filtrates were extracted twice with 2×150 ml of 15 wt % NaCl, dried over Na ₂ SO ₄ , added with activated charcoal, refluxed for 30 minutes, filtered twice and evaporated to give 140. 7
grams of brownish oil (4-[2-(2,4-dimethyl-phenylsulfanyl)
-Phenyl]-BOC-piperazine) was obtained. This crude oil was diluted with 300 ml of MeO.
H and 200 ml 6M HCl (aq.) and refluxed for 1 hour before HPLC
C showed complete deprotection. After cooling to room temperature, methanol was removed by vacuum on a rotary evaporator, 200 ml of concentrated NaOH (pH was 13-14) was added, then the resulting mixture was stirred with 1000 ml of EtOAc for 15 minutes. . collecting the organic phase,
Extracted with 300 ml of 15 wt % brine, dried over Na ₂ SO ₄ and added to a solution of 46.3 g of fumaric acid (399 mmol) in 300 ml of MeOH. The mixture was heated to reflux, cooled to room temperature and then left in the freezer overnight (-18°C).
). The resulting precipitate was collected, washed with 100 ml of EtOAc and 100 ml of acetone, and dried under vacuum (50° C.) to give 1 as a white powder in 81% overall yield.
03.2 g of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine fumarate (249 mmol) was obtained, which had a purity of 99% by LC-MS. . The fumarate was treated with the free base (1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-) using EtOAc/H ₂ O/conc. NaOH.
piperazine), the organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and a white solid precipitated by adding 34 ml of 48 wt % HBr (aq.) to the filtrate. was triggered. The solid was collected, treated with 1000 ml of boiling H ₂ O, and cooled to room temperature to form a slurry. This final product (1-[2-(
2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide)
was collected by filtration and dried under vacuum (50° C.) to give 83 g of white powder (71% overall yield) [CHN(teo.) 56.99;6.11;7 .3
9; CHN (found) 57.11; 6.15; 7.35].

Example 23

815 g NaOBu ^t (8.48 mol), 844 g 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 minutes. then 8
40 g of 2-bromo-iodobenzene (2.97 mol) was added with 1.5 L of toluene, stirring was continued for 30 minutes and finally 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 and kept at reflux for 5 hours. The reaction mixture was allowed to cool overnight. After adding 2 L of water and stirring for 1 hour, the mixture was filtered through filter aid. The resulting filtrate was then washed with 3×1 L of brine. After this, the combined aqueous phase was extracted with 600 ml of toluene.
After this, the combined toluene phases were heated to 70° C. followed by 329.2 ml of 48
wt % HBr (aq.) and 164.6 ml of water were added. The resulting mixture was cooled to room temperature overnight. The final product (1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried under vacuum (60° C.).
) gave 895 g (84% yield) of product.

Example 24

40.76 g NaOBu ^t (424.1 mol), 0.33 g Pddba ₂ (0.
57 mmol) and 0.68 g of rac-BINAP (1.09 mmol)
1 of toluene. Then 42 g of 2-bromo-iodobenzene (362
mmol) and 19.54 g of 2,4-dimethylthiophenol (362 mmol) were added along with 50 ml of toluene. The suspension was heated to reflux and kept refluxing overnight. HPLC analysis indicated intermediate product (1-(2-bromo-phenylsulfanyl)-2,4-
dimethyl-benzene). The reaction mixture was cooled to room temperature and filtered through filter aid. The filtrate was treated with 40.76 g of NaOBu ^t (424.1 mmol).
), 42.2 g piperazine (489.9 mmol), 0.33 g Pddba ₂ (0.
57 mmol) and 0.68 g of rac-BINAP (1.09 mmol) and heated to reflux for 2 hours. The reaction mixture was allowed to cool overnight. 100 ml of water were added and the aqueous phase was separated off. filtering the organic phase through a filter aid, then
The filtrate obtained was washed with 3×80 ml of brine. After this time, the combined aqueous phase was
Extracted with 0 ml of toluene. The combined toluene phase is then heated to 70° C.,
Subsequently, 16.5 ml of 48 wt% HBr (aq.) and 8.25 ml of water were added. The resulting mixture was cooled to room temperature overnight. The final product (1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried under vacuum (60° C.) to yield 40.18 g of An off-white powder was obtained (75% yield).

Example 25

40.76 g NaOBu ^t (424.1 mmol), 0.33 g Pddba ₂ (0
. 57 mmol) and 0.68 g of rac-BINAP (1.09 mmol) in 200
Stirred with ml of toluene. Then 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 kept refluxing overnight. HPLC analysis showed intermediate product (1-(2-bromo-phenylsulfanyl)
-2,4-dimethyl-benzene). The reaction is cooled to 50° C. and 42
. 2 g piperazine (489.9 mmol) was added along with 100 ml toluene. The resulting mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature overnight.
100 ml of water was added and the reaction mixture was filtered through filter aid. The filter cake obtained was then washed with 50 ml of toluene.

After separating off the aqueous phase, the organic phase was washed with 3×25 ml of brine and 25 ml of
ml water. After this, the combined aqueous phase was extracted with 30 ml of toluene.
The combined toluene phase was then heated to 70° C. followed by 16.46 ml of 48
wt % HBr (aq.) and 8.23 ml water were added. The resulting mixture was cooled to room temperature overnight. The final product (1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried under vacuum (60°C).
46.8 g (87% yield) of product was obtained by drying at rt.

Example 26 Effects on Extracellular Levels of Acetylcholine in the Brain of Freely Moving Rats Methods Animals were treated with 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine,
HBr salts were administered.

Animals Male Sprague-Dawley rats weighing 275-300 g when initially weighed were used. The animals were kept under controlled conditions to provide regular room temperature (21±2° C.) and humidity (55±5%) with free access to food and tap water. , were kept under a 12-hour light/dark cycle.

Surgery and Microdialysis Experiments Rats were anesthetized with Hypnorm/Dormicum (2 ml/kg) and placed in the ventral hippocampus (coordinates: 5.6 mm posterior to bregma, −5.0 mm lateral, 7.0 mm ventral to dura) or An intracerebral guide cannula (CMA/12) was used to position the dialysis probe tip in the prefrontal cortex (coordinates: 3.2 mm anterior to bregma; 0.8 mm lateral; 4.0 mm ventral to the dura).
was stereotactically implanted in the brain. The guide cannula was fixed using an anchor screw and acrylic cement. Animal body temperature was monitored by a rectal probe,37
°C. The rats were allowed to recover from surgery for 2 days and housed individually in cages. On the day of the experiment, a microdialysis probe (CM
A/12, 0.5 mm diameter, 3 mm length) was inserted.

The probes were connected to microinjection pumps via dual channel swivels. Filtered Ringer's solution (containing 0.5 μM neostigmine, 1
45 mM NaCl, 3 mM KCl, ₁ mM MgCl2, _1.2 mM CaCl2)
Perfusion of the microdialysis probe at 1 μl/
A constant flow rate of minutes was maintained for the duration of the experiment. After 180 minutes of stabilization, the experiment was started. Dialysate was collected every 20 minutes. After the experiment, the animals were sacrificed and their brains removed, frozen, and sectioned to confirm probe placement.

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

Dialysate Acetylcholine Analysis The concentration of acetylcholine (ACh) in the dialysate was 100 mM disodium hydrogen phosphate, 2.0 mM octanesulfonic acid, 0.5 mM tetramethylammonium chloride and 0.005% MB (ESA). was analyzed by HPLC with electrochemical detection using a pH 8.0 mobile phase consisting of A pre-column enzymatic reactor (ESA) containing immobilized choline oxidase was added to an analytical column (ESA ACH-250);
Injected sample (10 μl
) eliminated choline. After the analytical column, the sample was passed through a post-column solid phase reactor (ESA) containing immobilized acetylcholinesterase and choline oxidase. _The latter reactor converts ACh to choline, which is then converted to betaine and H2.
Converted to _O2 . The latter H ₂ O ₂ was detected electrochemically by using a platinum electrode (analytical cell: ESA, model 5040).

Data representation In single-infusion experiments, the average value of the preceding three consecutive ACh samples immediately prior to compound administration was used as the basal level in each experiment, and the data were basal (mean basal infusion normalized to 100%). prior value).

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

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

We investigated the effects of this compound on the acquisition, fixation and recall of contextual fear conditioning in rats. In this fear conditioning paradigm, animals learn to associate a neutral environment (situation, training chamber, CS) with an aversive experience (electrical footshock, US). When re-exposed to the training chamber, the animals exhibited freezing behavior, which is believed to be a direct measure of their fear-related memory [Pavlov J. et al. Biol. Sci. , 15, 177-182, 1980]
. The neuroanatomy of this contextual fear conditioning is well studied, and several studies indicate that the hippocampus and amygdala are required for the formation of this memory [Hippoca
mpus, 11, 8-17, 2001; Neurosci. , 19, 1106-11
14, 1999; Behav. Neurosci. , 106, 274-285, 1992
].

Animals and Drugs Charles, housed 2 per cage under a 12 hour light/dark cycle
Adult male Sprague-Sprague, obtained from River Laboratories.
Dawley rats (weight at training, 250-300 g) were used. Food and water were available ad libitum. The rats were used one week after arrival. Compounds were dissolved in 10% HPbetaCD and injected subcutaneously. 2. Drugs.
A volume of 5 ml/kg was administered.

Equipment Training and testing were carried out in a soundproof chamber (30 x 20 x 40 cm) housed in an isolated room and connected to a ventilation system. Illumination was provided by a white light (60 watts). The floor of the chamber consisted of a metal grid attached to an electric shock generator. 70% of the chamber prior to training and testing
of ethanol solution. A video camera enabled observation and recording of training session behavior for offline analysis.

Acquisition and Retention Tests During acquisition, animals are allowed to freely explore the new environment for a 1-minute habituation period, which is provided through a chargeable grid floor. It ended simultaneously with 1 unavoidable footshock (unconditioned stimulus, US). The footshock had a duration of 2 seconds and an intensity of 0.75 mA. Animals remained in their conditioning chambers for an additional 60 seconds after US. Freezing was scored during the first 58 seconds (pre-shock acquisition; experimenter blinded to group information) to determine the baseline-freezing response to this situation. Once the acquisition was completed, the animals were gently removed and placed back in their cages. Twenty-four hours later, the same animals were placed again in the training situation described above (fear conditioning chamber) and a 2-minute retention test was performed. No footshock was applied during this period. Freezing behavior during the entire test period was scored by an experimenter blinded to the group and presented as a percentage of the total test period.

Results and Discussion Effect of Compounds on Contextual Fear Conditioning in Rats. Drug application prior to testing, Figure 21) and (ii)
i) was examined for fixation (drug application immediately after acquisition, FIG. 22). In this first set of experiments, compounds (1 mg/kg, 5 mg/kg and 10 mg/kg) were administered 1 hour prior to the acquisition session. Figure 20 shows the training period (58 days before food shock).
Seconds) and after 24 hours the acquisition of freezing behavior in the retention test is depicted. The following findings were observed:
• The compound does not affect baseline freezing behavior prior to footshock at any dose tested.

- The compound at a dose of 5 mg/kg has a tendency to increase the time spent freezing during a memory retention test performed 24 hours after acquisition (39.24 ± 13.76%
, n=6, vs. 24.30±4.40% in vehicle-treated animals, n=16).

- The compound at a dose of 10 mg/kg significantly increases the time spent in freezing behavior during a retention test performed 24 hours after acquisition (52.15±5.68%, n=10, vs. vehicle 24.30±4.40% in drug-treated animals, n=16, p<0.01)
.

This fear conditioning model, as depicted in FIG. 20, is a standard procedure described in the literature for learning and memory studies. To further elucidate the acute effects of this drug on memory retrieval, compounds (5 mg/kg, 10 mg/kg and 20 mg/kg) were applied 1 hour prior to retention testing. At a dose of 5 mg/kg, the compound was observed to suppress the development of freezing behavior during memory testing (12.86±3.57%, n=9, vs. 33.61±4.29%, n=13, p<0.05) (FIG. 21).

As noted above, the compound, by itself, did not affect baseline freezing behavior prior to initiation of US (FIG. 20), so the seemingly most plausible hypothesis is that
It is hypothesized that the effects observed in Figure 21 are due to anxiolytic effects. Conditioned memory is assessed by freezing behavior, a response that is reduced by compounds with potential anxiolytic effects. This experiment indicates that the compound given just prior to memory retrieval has anxiolytic effects, thus the increase in freezing behavior shown in Figure 20 is due to the anxiogenic effects of the compound. It's hard to imagine it being anything.

を製造するための方法であって、溶剤、塩基、ならびにパラジウム源およびホスフィン配
位子からなるパラジウム触媒の存在下において、６０℃から１３０℃までの間の温度で、
化合物ＩＩ

［式中、Ｒ’は水素または一価の金属イオンを表す］を、式ＩＩＩ

［式中、Ｘ_１およびＸ_２は独立してハロゲンを表す］の化合物および式ＩＶ

［式中、Ｒは水素または保護基を表す］の化合物と反応させることを含む、前記の方法。
［１９］
化合物ＩＩおよび化合物ＩＩＩが第一の反応で反応させられ、場合により前記第一反応
での反応生成物

が単離および精製され、続いて、前記化合物ＩＶとのその後の反応が行われる、請求項１
８に記載の方法。
［２０］
化合物ＩＩ、化合物ＩＩＩおよび化合物ＩＶが前記方法の開始時に一緒に混合される、
請求項１８に記載の方法。
［２１］
Ｘ_１およびＸ_２が独立してＢｒまたはＩを表す、請求項１８～２０のいずれかに記載の
方法。
［２２］
Ｘ_１がＢｒを表し、Ｘ_２がＩを表す、請求項２１に記載の方法。
［２３］
前記溶剤が非プロトン性溶剤である、請求項１８～２２のいずれかに記載の方法。
［２４］
前記溶剤がトルエン、キシレン、トリエチルアミン、トリブチルアミン、ジオキシンま
たはＮ－メチルピロリドンから選択される、請求項１８～２３のいずれかに記載の方法。
［２５］
前記溶剤がトルエンである、請求項２４に記載の方法。
［２６］
前記パラジウム源がＰｄｄｂａ_２、Ｐｄ（ＯＡｃ）_２またはＰｄ_２ｄｂａ_３から選択さ
れる、請求項１８～２５のいずれかに記載の方法。
［２７］
前記パラジウム源がＰｄｄｂａ_２またはＰｄ_２ｄｂａ_３である、請求項２６に記載の方
法。
［２８］
前記ホスフィン配位子が
２，２’－ビス－ジフェニルホスファニル－［１，１’］ビナフタレニル（ｒａｃ－Ｂ
ＩＮＡＰ）；
１，１’－ビス（ジフェニルホスフィノ）フェロセン（ＤＰＰＦ）；
ビス－（２－ジフェニルホスフィノフェニル）エーテル（ＤＰＥｐｈｏｓ）；
トリ－ｔ－ブチルホスフィン（Ｆｕ’ｓ塩）；
ビフェニル－２－イル－ジ－ｔ－ブチル－ホスフィン；
ビフェニル－２－イル－ジシクロヘキシル－ホスフィン；
（２’－ジシクロヘキシルホスファニル－ビフェニル－２－イル）－ジメチル－アミン
；
［２’－（ジ－ｔ－ブチル－ホスファニル）－ビフェニル－２－イル］－ジメチル－ア
ミン；および
ジシクロヘキシル－（２’，４’，６’－トリ－プロピル－ビフェニル－２－イル）－
ホスファン；
から選択される、請求項１８～２７のいずれかに記載の方法。
［２９］
前記ホスフィン配位子がｒａｃ－ＢＩＮＡＰである、請求項２８に記載の方法。
［３０］
前記塩基がＮａＯ（ｔ－Ｂｕ）、ＫＯ（ｔ－Ｂｕ）、Ｃｓ_２ＣＯ_３、ＤＢＵまたはＤＡ
ＢＣＯから選択される、請求項１８～２８のいずれかに記載の方法。
［３１］
前記塩基がＮａＯ（ｔ－Ｂｕ）である、請求項３０に記載の方法。
［３２］
Ｒが水素を表す、請求項１８～３１のいずれかに記載の方法。
［３３］
ＲがＢｏｃ、Ｂｎ、Ｃｂｚ、Ｃ（＝Ｏ）ＯｅｔまたはＭｅから選択される保護基を表す
、請求項１８～３１のいずれかに記載の方法。
［３４］
Ｒ’が水素である、請求項１８～３３のいずれかに記載の方法。
［３５］
前記温度が約８０℃から約１２０℃までの間である、請求項１８～３４のいずれかに記
載の方法。
［３６］
以下のステップ：
ａ．１～１．５当量の化合物Ｉ、ＩＩおよびＩＩＩをトルエン中に溶解または分散させ
て混合物Ａを得るステップ；
ｂ．１～２モル％のＰｄｄｂａ_２および１～２モル％のｒａｃ－ＢＩＮＡＰを２～３当
量のＮａＯ（ｔ－Ｂｕ）とともに混合物Ａに加えて混合物Ｂを得るステップであって、こ
こで、化合物ＩＩおよびＩＩＩが完全に変換されるまで前記混合物Ｂが約１００℃に加熱
されるステップ；
ｃ．ステップｂで得られた混合物の温度を、化合物ＩＶが完全に変換されるまで、約１
２０℃に高めるステップ；および
ｄ．場合によって、化合物ＩＶが保護型ピペラジンであるときに、酸水溶液を加えるこ
とによって前記保護基を取り除くステップ；
を含む、請求項２０に記載の方法。
［３７］
１～１．５当量の２，４－ジメチル－チオール、１－ブロモ－１－ヨード－ベンゼン（
または１，２－ジブロモ－ベンゼン）およびピペラジンをトルエン中に分散し、続いて、
トルエン中に分散された２～５当量のＮａＯ（ｔ－Ｂｕ）および１～２モル％のＰｄ_２ｄ
ｂａ_３およびｒａｃ－ＢＩＮＡＰを加えて混合物を得、前記混合物を１００～１３０℃に
２～１０時間加熱して生成物１－［２－（２，４－ジメチル－フェニルスルファニル）－
フェニル］－ピペラジンを得る、請求項２０に記載の方法。
［３８］
前記混合物が３～５時間加熱還流され、そして、後続のステップであって、得られた生
成物が対応する臭化水素酸付加塩を得るべく、更にＨＢｒ水溶液と反応させられるステッ
プがそれに続く、請求項３７に記載の方法。
［３９］
２～５当量のＮａＯ（ｔ－Ｂｕ）、２～５当量のピペラジン、０．２～０．６モル％の
Ｐｄｄｂａ_２および０．６～１モル％のｒａｃ－ＢＩＮＡＰをトルエン中に分散して混合
物Ａ’を得、前記混合物Ａ’に約１当量の２－ブロモ－ヨードベンゼンを加えて混合物Ｂ
’を得、前記混合物Ｂ’に１当量の２，４－ジメチルチオフェノールを加え、得られた混
合物を３～７時間加熱還流して１－［２－（２，４－ジメチル－フェニルスルファニル）
－フェニル］－ピペラジンを得る、請求項２０に記載の方法。
［４０］
前記の得られた混合物が４～６時間加熱還流され、そして、後続のステップであって、
得られた生成物が対応する臭化水素酸付加塩を得るべく、更にＨＢｒ水溶液と反応させら
れるステップがそれに続く、請求項３９に記載の方法。
［４１］
対応する臭化水素酸塩を得るために、ＨＢｒ水溶液を生成物

に加える付加的なステップを伴い、前記生成物が場合によっては精製された形態である、
請求項１８～３７のいずれかに記載の方法。
［４２］
１－［２－（２，４－ジメチル－フェニルスルファニル）－フェニル］－ピペラジン臭
化水素酸付加塩を製造するための方法であって、１～１．５当量の２，４－ジメチル－チ
オール、１－ブロモ－１－ヨード－ベンゼン（または１，２－ジブロモ－ベンゼン）およ
びピペラジンをトルエン中に分散し、続いて、トルエン中に分散された２～５当量のＮａ
Ｏ（ｔ－Ｂｕ）および１～２モル％のＰｄ_２ｄｂａ_３およびｒａｃ－ＢＩＮＡＰを加えて
混合物を得、前記混合物を３～５時間加熱還流して生成物１－［２－（２，４－ジメチル
－フェニルスルファニル）－フェニル］－ピペラジンを得、前記ピペラジンを更に臭化水
素酸水溶液と反応させる、前記の方法。
［４３］
１－［２－（２，４－ジメチル－フェニルスルファニル）－フェニル］－ピペラジン臭
化水素酸付加塩を製造するための方法であって、２～５当量のＮａＯ（ｔ－Ｂｕ）、２～
５当量のピペラジン、０．２～０．６モル％のＰｄｄｂａ_２および０．６～１モル％のｒ
ａｃ－ＢＩＮＡＰをトルエン中に分散して混合物Ａ’を得、前記混合物Ａ’に約１当量の
２－ブロモ－ヨードベンゼンを加えて混合物Ｂ’を得、前記混合物Ｂ’に１当量の２，４
－ジメチルチオフェノールを加え、結果として得られた混合物を４～６時間加熱還流して
１－［２－（２，４－ジメチル－フェニルスルファニル）－フェニル］－ピペラジンを得
、前記ピペラジンを更に臭化水素酸水溶液と反応させる、前記の方法。

The compound is not anxiogenic but has the potential to enhance cognition (pro-cognitive).
5 mg/kg after the acquisition session to reinforce
The compound was administered at doses of , 10 mg/kg and 20 mg/kg. As a result, in this set of experiments, the compound remained on-board both during acquisition and throughout the retention study.
board). Here, the compound at a dose of 5 mg/kg was observed to significantly increase the time spent freezing during a retention test performed 24 hours after the acquisition session (45.58±4.50% , n=8, vs. 2 in vehicle-treated animals
5.26±3.57%, n=19, p<0.05). The percentage of time spent freezing during re-exposure to the situation has been described as a measure of fear-related memory [Pavlov
J. Biol. Sci. 15, 177-182, 1980], which is increased in compound-treated rats when compared to vehicle-treated animals (Figures 20 and 21). Taken together, these data indicate that the compounds enhance contextual memory.

The present invention can include the following aspects.
[1]
1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine and its pharmaceutically acceptable salts, provided that the compound is not the free base in amorphous form.
[2]
The compound is hydrobromide, hydrochloride, mesylate, fumarate, maleate, meso-tartrate, L-(+)-tartrate, D-(-)-tartrate, sulfate, phosphorus 2. The compound of claim 1, which is an acid salt or a nitrate.
[3]
3. The compound of claim 1 or 2, wherein the compound is crystalline.
[4]
Claim 3, wherein the compound has an XRDP as shown in any of Figures 1-17
The compound described in .
[5]
2. The compound of claim 1, which is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide in crystalline form.
[6]
The compounds have XR
6. A compound according to claim 5, having a PD reflex.
[7]
6. The compound of claim 5, wherein the compound has an XRDP as shown in FIG.
[8]
The compound is:
D98%: 650-680 μm; D50%: 230-250 μm; and D5%: 40
~60 μm;
D98%: 370-390; d50%: 100-120 μm; D5%: 5-15 μm;
D98%: 100-125 μm; D50%: 15-25 μm; and D5%: 1-3 μm
m; or D98%: 50-70 μm; D50%: 3-7 μm; and D5%: 0.5-2,
7. The compound of claim 6, having a particle size distribution corresponding to .
[9]
A compound according to any one of claims 1 to 8 for use in therapy.
[10]
A pharmaceutical composition comprising a compound according to any of claims 1-8 together with a pharmaceutically acceptable excipient.
[11]
11. A composition according to claim 10, comprising a compound according to claim 5 or 6.
[12]
A tablet manufactured by a wet granulation method, and comprising anhydrous calcium hydrogen phosphate,
11. The composition of claim 10, comprising corn starch, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, talc and magnesium stearate.
[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: about 5%
Anhydrous calcium hydrogen phosphate: about 39%
Corn starch: about 20%
PVP-VA copolymer: about 3%
Microcrystalline cellulose: about 25%
Sodium starch glycolate: about 3%
Talc: about 4%
Magnesium stearate: about 1%
13. The composition of claim 12, comprising:
[15]
Affective disorder, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis, cancer, depression associated with aging or Parkinson's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder Disorder, panic disorder, panic attack, phobia, social phobia, agoraphobia, stress urinary incontinence, vomiting, IBS, eating disorder, chronic pain, partial responder, treatment-resistant depression, Alzheimer's disease, cognition A method of treating a disorder selected from dysfunction, ADHD, melancholy, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, and alcohol or drug abuse, wherein the disorder is in need of treatment. A method of treatment comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1-8.
[16]
Affective disorder, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis, cancer, depression associated with aging or Parkinson's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder Disorder, panic disorder, panic attack, phobia, social phobia, agoraphobia, stress urinary incontinence, vomiting, IBS, eating disorder, chronic pain, partial responder, treatment-resistant depression, Alzheimer's disease, cognition any of claims 1-8 for the manufacture of a medicament for treating functional disorders, ADHD, melancholy, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, or alcohol or drug abuse Use of a compound according to
[17]
Affective disorder, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychosis, cancer, depression associated with aging or Parkinson's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder Disorder, panic disorder, panic attack, phobia, social phobia, agoraphobia, stress urinary incontinence, vomiting, IBS, eating disorder, chronic pain, partial responder, treatment-resistant depression, Alzheimer's disease, cognition of claims 1-8 for use in the treatment of disorders selected from functional disorders, ADHD, melancholy, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, and alcohol or drug abuse. A compound according to any one of the above.
[18]
Less than:

at a temperature between 60° C. and 130° C. in the presence of a solvent, a base, and a palladium catalyst consisting of a palladium source and a phosphine ligand,
Compound II

[wherein R′ represents hydrogen or a monovalent metal ion] is represented by formula III

[wherein X ₁ and X ₂ independently represent halogen] and formula IV

[wherein R represents hydrogen or a protecting group].
[19]
Compound II and Compound III are reacted in a first reaction, optionally the reaction product of said first reaction

is isolated and purified, followed by subsequent reaction with said compound IV.
8. The method according to 8.
[20]
Compound II, Compound III and Compound IV are mixed together at the beginning of said method;
19. The method of claim 18.
[21]
A method according to any of claims 18-20, wherein X ₁ and X ₂ independently represent Br or I.
[22]
22. _The method of claim 21, wherein X1 represents Br and X2 represents _I.
[23]
A method according to any of claims 18-22, wherein said solvent is an aprotic solvent.
[24]
A process according to any of claims 18-23, wherein said solvent is selected from toluene, xylene, triethylamine, tributylamine, dioxin or N-methylpyrrolidone.
[25]
25. The method of claim 24, wherein said solvent is toluene.
[26]
A method according to any of claims 18-25, wherein said palladium source is selected from Pddba ₂ , Pd(OAc) ₂ or Pd ₂ dba ₃ .
[27]
27. The method of claim 26 _, wherein the palladium source is _Pddba2 or _Pd2dba3 .
[28]
The phosphine ligand is 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-amine; and dicyclohexyl-(2′,4′,6′-tri-propyl-biphenyl-2-yl)-
Phosphane;
The method of any of claims 18-27, selected from
[29]
29. The method of claim 28, wherein said phosphine ligand is rac-BINAP.
[30]
the base is NaO(t-Bu), KO(t-Bu), Cs ₂ CO ₃ , DBU or DA
A method according to any of claims 18-28, selected from BCO.
[31]
31. The method of claim 30, wherein said base is NaO(t-Bu).
[32]
A method according to any one of claims 18 to 31, wherein R represents hydrogen.
[33]
A method according to any of claims 18-31, wherein R represents a protecting group selected from Boc, Bn, Cbz, C(=O)Oet or Me.
[34]
34. The method of any of claims 18-33, wherein R' is hydrogen.
[35]
The method of any of claims 18-34, wherein the temperature is between about 80°C and about 120°C.
[36]
Steps below:
a. dissolving or dispersing 1-1.5 equivalents of compounds I, II and III in toluene to obtain a mixture A;
b. adding 1-2 mol% of Pddba ₂ and 1-2 mol% of rac-BINAP with 2-3 equivalents of NaO(t-Bu) to mixture A to obtain mixture B, wherein compound II heating said mixture B to about 100° C. until complete conversion of and III;
c. Raise the temperature of the mixture obtained in step b to about 1
increasing to 20°C; and d. optionally removing said protecting group by adding an aqueous acid solution when compound IV is a protected piperazine;
21. The method of claim 20, comprising:
[37]
1-1.5 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 % Pd ₂ d dispersed in toluene
ba ₃ and rac-BINAP are added to give a mixture and the mixture is heated to 100-130° C. for 2-10 hours to give the product 1-[2-(2,4-dimethyl-phenylsulfanyl)-
21. The method of claim 20, wherein phenyl]-piperazine is obtained.
[38]
The mixture is heated to reflux for 3-5 hours, followed by a subsequent step in which the resulting product is further reacted with aqueous HBr to obtain the corresponding hydrobromic acid addition salt, 38. The method of claim 37.
[39]
2-5 equivalents of NaO(t-Bu), 2-5 equivalents of piperazine, 0.2-0.6 mol% of Pddba ₂ and 0.6-1 mol% of rac-BINAP dispersed in toluene. A mixture A' is obtained and about 1 equivalent of 2-bromo-iodobenzene is added to said mixture A' to obtain a mixture B
1-[2-(2,4-dimethyl-phenylsulfanyl) is obtained by adding 1 equivalent of 2,4-dimethylthiophenol to said mixture B′ and heating the resulting mixture to reflux for 3-7 hours to give 1-[2-(2,4-dimethyl-phenylsulfanyl).
-Phenyl]-piperazine is obtained.
[40]
The resulting mixture is heated to reflux for 4-6 hours, and the subsequent step of
40. The method of claim 39, followed by a step in which the obtained product is further reacted with aqueous HBr to obtain the corresponding hydrobromic acid addition salt.
[41]
To obtain the corresponding hydrobromide, an aqueous solution of HBr is added to the product

wherein the product is optionally in purified form, with the additional step of adding
A method according to any of claims 18-37.
[42]
Process for preparing 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide addition salt comprising 1-1.5 equivalents of 2,4-dimethyl-thiol , 1-bromo-1-iodo-benzene (or 1,2-dibromo-benzene) and piperazine were dispersed in toluene followed by 2-5 equivalents of Na
O(t-Bu) and 1-2 mol % of Pd ₂ dba ₃ and rac-BINAP are added to give a mixture which is heated to reflux for 3-5 hours to give the product 1-[2-(2,4 -Dimethyl-phenylsulfanyl)-phenyl]-piperazine and further reacting said piperazine with aqueous hydrobromic acid.
[43]
A process for preparing 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide addition salts comprising 2-5 equivalents of NaO(t-Bu), 2-
5 eq piperazine, 0.2-0.6 mol % Pddba ₂ and 0.6-1 mol % r
ac-BINAP was dispersed in toluene to obtain a mixture A', to said mixture A' was added about 1 equivalent of 2-bromo-iodobenzene to obtain a mixture B', to said mixture B' was added 1 equivalent of 2, 4
-Dimethylthiophenol is added and the resulting mixture is heated to reflux for 4-6 hours to give 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further oxidized. The above method, wherein the reaction is performed with an aqueous solution of hydrochloric acid.

Claims (2)

1-[ Crystals of 2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt . A pharmaceutical composition comprising the crystal of claim 1 together with a pharmaceutically acceptable excipient.

Images