JP2020152732A - 1-[2[(2,4-dimethylphenylsulfanyl)-phenyl]piperazine as compound with combined serotonin reuptake 5-ht3 and 5-ht1a activity for treatment of cognitive impairment - Google Patents

Abstract

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

Description

The present invention relates to serotonin receptor 1A (5-HT _1A ) and serotonin receptor 3 (5-H).
With respect to compounds exhibiting 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 effective, tolerant, and have a favorable safety profile than previously used compounds, namely classical tricyclic compounds. For many years, it has been the drug of choice for the treatment of certain CNS-related diseases, especially depression, anxiety and social phobia.

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

To avoid some of these shortcomings of SSRI treatment, psychiatrists sometimes utilize augmentation strategies. The enhancement of antidepressants can be achieved, for example, in combination with mood stabilizers such as lithium carbonate or triiodothyronine, or in combination with electroconvulsive therapy.

It is known that a combination of inhibition of serotonin transporter (SERT) and activity on one or more serotonin receptors can be beneficial. So far, combinations of serotonin reuptake inhibitors and compounds with 5-HT _2C antagonist or inverse agonist effects (compounds with negative efficacy at 5-HT _2C receptors) have been described.
5-HT (serotonin) in the terminal region as measured in microdialysis experiments
It has been found to result in a significant increase in levels (Patent Document 1). It is a relatively short-term expression of clinical antidepressant effects and serotonin reuptake inhibitors (SRIs).
It may have suggested an enhancement or synergistic effect of the therapeutic effect of.

Similarly, it has been reported that the combination of pindolol, which is a partial agonist of 5-HT _1A , and a serotonin reuptake inhibitor results in rapid expression of the effect (Non-Patent Document 1).

CNS-related disorders such as depression, anxiety and schizophrenia often co-exist with other disorders or dysfunctions such as cognitive or cognitive dysfunction (Non-Patent Documents 2 and 3).

International Publication No. 01/41701 Pamphlet

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

It is speculated that several neurotransmitters are involved in the neurological events that regulate this cognitive ability. In particular, the cholinergic system plays an important role in cognition and therefore
Compounds that affect the cholinergic system are potentially useful in the treatment of cognitive dysfunction. 5-H
Compounds that affect the T _1A and / or 5-HT ₃ receptors are known to affect the cholinergic system, and as such, they are used in the treatment of cognitive dysfunction. Can be useful.

For this reason, compounds that function 5-HT _1A and / or 5-HT ₃ receptor activity can be expected to be useful in the treatment of cognitive dysfunction. SER on it
Compounds that also function T-activity will be particularly useful in the treatment of cognitive dysfunction in depressed patients, as such compounds are believed to also result in rapid onset of therapeutic effects in the treatment of depression.

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

Surprisingly, we found that 1- [2- (2,4-dimethylphenylsulfanil) phenyl] piperazin inhibits SERT, 5-HT ₃ antagonism and 5-HT _1A.
We have found that it exerts a combination of partial agonism. Therefore, in one embodiment, the invention is 1- [2- (2,4-dimethylphenylsulfanil) -phenyl].
Provided are compound I, which is a piperazine, and a pharmaceutically acceptable salt of the compound, provided that the aforementioned compounds are not free bases in non-crystalline form.

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

In one embodiment, the invention provides a pharmaceutical composition comprising Compound I.

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

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

XRPD of crystalline base. Alpha-type hydrobromic acid XRPD. Beta-type hydrobromic acid XRPD. Gamma-type hydrobromic acid XRPD. XRPD of hydrobromic acid in the form of hemihydrate. XRPD of a mixture of ethyl acetate solvate and alpha hydrobromic acid salt. XRPD of hydrochloride. XRPD of hydrochloride in the form of monohydrate. XRPD of mesylate. XRPD of fumarate. XRPD of maleate. XRPD of meso-tartrate. XRPD of L- (+)-tartrate. XRPD of D- (-)-tartrate. Sulfate XRPD. Phosphate XRPD. Nitrate XRPD. Effect of the compounds of the invention in the intradermal formalin test. The X-axis shows the amount of compound administered; the Y-axis shows the amount of time (seconds) spent licking the paw. Response within a time period of 0-5 minutes. Effect of the compounds of the invention in intradermal formalin testing. The X-axis shows the amount of compound administered; the Y-axis shows 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 free-moving rats upon administration of 1- [2- (2,4-dimethylphenylsulfanil) phenyl] piperazin HBr salt. Extracellular acetylcholine levels in the ventral hippocampus of free-moving rats upon administration of 1- [2- (2,4-dimethylphenylsulfanil) phenyl] piperazin HBr salt. Effect of 1- [2- (2,4-dimethylphenylsulfanil) phenyl] piperazin HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 60 minutes prior to acquisition. Freezing behavior was scored (pre-shock acquisition) (white bar) during the 58-second habituation period prior to the foot shock US. Freezing behavior was measured 24 hours after training (retention test) (black bar). Effect of 1- [2- (2,4-dimethylphenylsulfanil) phenyl] piperazine HBr salt on contextual fear conditioning in Sprague-Dawley rats when given 1 hour prior to retention test. Freezing behavior was scored (acquired) (white bar) for 58 seconds prior to Footshock US. Freezing behavior was measured 24 hours after training (retention test) (black bar). Effect of AA21004 on contextual fear conditioning in Sprague-Dawley rats when given shortly after acquisition. Prior to the foot shock US, freezing behavior was scored for 58 seconds (pre-shock acquisition) (white bar). Freezing behavior was measured 24 hours after training (memory retention test) (black bar).

The structure of the present invention is

With respect to compound I, 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine and a pharmaceutically acceptable salt thereof, where compound I is a free base in non-crystalline form. Make it not exist.

In one embodiment, the pharmaceutically acceptable salt described above is an acid addition salt of a non-toxic acid. Such salts are salts produced 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. , Tartrate acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, silicic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamate,
Includes salts produced from benzenesulfonic acid, theophylline acetic acid, and 8-halotheophylline, such as 8-bromotheophylline. In addition, such salts may be produced from inorganic salts, for example, from hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like. As special ones, methanesulfonic acid, maleic acid, fumaric acid,
Salts produced from meso-tartaric acid, (+)-tartaric acid, (-)-tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorous acid and nitric acid can be mentioned. Hydrobromic acid can be mentioned as a special one.

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

In one embodiment, the crystals of the invention are solvates, i.e., crystals in which solvent molecules form part of their crystal structure. The solvates 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 non-solvate crystals.

Some compounds are hygroscopic, i.e., they absorb moisture when exposed to moisture. Hygroscopicity is generally considered to be an undesirable property for compounds that should be present in drug formulations, especially in dry formulations, such as in tablets. In one embodiment, the present invention provides crystals with low hygroscopicity. In the case of oral dosage forms with crystalline active ingredients, it is also beneficial that those crystals are well defined.
In this context, the term "clearly defined" specifically means that its stoichiometry is well-defined, i.e., between the ions forming its salt. It means that the ratio is a ratio between small integers, for example 1: 1, 1: 2, 2: 1, 1: 1: 1. In one embodiment, the compounds of the invention are well-defined crystals.

The crystalline compounds of the invention may be present in more than one form, i.e., they may be present in polymorphic form. Polymorphic forms exist when a compound can crystallize in more than one form. The present invention is intended to include all such polymorphic forms, whether in the case of pure compounds or mixtures of those compounds.

In one embodiment, the compounds of the invention are in purified form. The term "purified form" is intended to indicate that a compound is, in some cases, essentially free of other compounds or compounds identical to those of other forms.

In one embodiment, the invention provides a crystalline salt of a compound of the invention having XRDP as shown in FIGS. 1-17, in particular FIGS. 2, 3, 4 and 5.

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

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

For example, as evidenced by FIGS. 2-5, the compounds of the invention, in this case hydrobromic acid, can be present in several forms, i.e., polymorphic. .. Their polymorphic forms have different properties, as shown in Example 4d. Beta hydrobromic acid has high stability, as indicated by the higher DSC melting point and lower solubility. Moreover, the beta form described above has an attractive composite property of low hygroscopicity and solubility, which makes the compound particularly suitable for making tablets. Therefore, in one embodiment, the present invention is about 6.89, 9.73.
1- [2- (2,4-dimethylphenylsulfanil)-with XRDP reflections at 13.78 and 14.62 (° 2θ), especially XRPD as shown in FIG.
Phenyl] provides hydrobromic acid salt of piperazine.

The solubility of the active ingredient is also important in selecting the dosage form, as it can have a direct effect on bioavailability. In the case of oral dosage forms, the higher solubility of the active ingredient is generally considered beneficial as it enhances bioavailability.

Cortical and hippocampal cholinergic neurotransmission is very important for cognition, and numerous preclinical observations point to the importance of serotonin receptor 1A (5-HT _1A ) for this system. T. Koyama is a member of Neurosci. Lett. , 265, 33-3
6, 1999 reported that the 5- _HT1A agonist BAYX3702 increases acetylcholine outflow from rat cortex and hippocampus. Interestingly
The 5-HT _1A antagonist WAY-100635 can eliminate the effect of BAYX3702, indicating that the effect of BAYX3702 is 5-HT _1A mediated.

A number of studies have reported on the effect of modulators of 5-HT _1A on cognitive impairment. A. Menus is described in Neurobiol. Learn. Memory,
In 71, 207-218, 1999, it is a partial 5- _HT1A agonist (±).
-8-Hydroxy-2- (di-n-propylamino) -tetralin, HCl (8-OH-
DPAT) has been reported to promote consolidation of learning in normal rats and to normalize cognitive function in cognitively impaired rats.

These preclinical observations appear to be reflected clinically. T. Sumiy
oshi is Am. J. Psych. Reported on studies in 158, 1722-1725, 2001, in which patients were given typical antipsychotics such as haloperidol, sulpiride and pimozide in combination with placebo or the 5- _HT1A agonist tandospirone ( All lacked 5-HT _1A activity) were administered. Patients who received tandospirone in addition to antipsychotics showed improved cognitive ability,
On the other hand, patients receiving placebo showed no improvement. Similarly, also 5-HT _1A
Agonists such as atypical antipsychotics, such as clozapine, also enhance cognition in schizophrenic patients, while typical antipsychotics, such as haloperidol, which do not have 5-HT _1A activity, do not. (Y. Chung, Brain Res., 1023,
54-63, 2004).

As mentioned above, the cholinergic system is thought to be involved in the neurological events that regulate cognition, and the cholinergic system is also serotonin receptor 3 (5-HT _3).
) Is likely to be affected by suppression control by [Giovannini et al., J. Mol.
Pharmacol. Exp. The. , 1998, 285: 1219-1225; C
Ostall and Naylor, Current Drug Targets-CNS
& Neurobiol. Disord. 2004, 3: 27-37].

In a habituation test in mice, a T-maze forced alternation test (T-maze r) in rats
In the einforced alternation task), as well as in the marmoset (obje)
In ct discrimination) and reversal learning tasks, ondansetron reduced dysfunction caused by the muscarinic antagonist scopolamine or lesions of the cholinergic pathway emerging from the basal ganglia (Barnes et al., Pharmacol. Bioc).
hem. Behave. 1990, 35: 955-962; Carey et al., Pharmac
ol. Biochem. Behave. 1992, 42: 75-83). Boast et al. (N
eurobiol. Learn. Mem. 1999, 71: 259-271) is NMD
MK-801, a non-competitive antagonist of the A receptor, was used to disrupt the cognitive abilities of rats trained in the delayed sample non-matching radial maze task. Ondansetron has been shown to block cognitive dysfunction. Moreover, in a study of the amnesiac effect of ethanol in a passive avoidance task in mice, this amnestic effect of ethanol was partially restored to normal by ondansetron (Napiorkowska-Paw).
lake et al., Fundam. Clin. farmacol. 2000, 14: 125-1
31). Therefore, before the promotion of cholinergic transmission by 5-HT ₃ antagonism after impairment of the cholinergic system in the clinical model (Diez-Ariza et al, Psychophar
macollogy, 2003, 169: 35-41; Gil-Bea et al., Neuroph
armcol. 2004, 47: 225-232) suggests evidence for the use of this treatment in the treatment of cognitive impairment.

In healthy assessment of persistent storage as well as attention conducted words and spaces in a randomized double-blind cross-over study in subjects male, 5-HT ₃ antagonist is alosetron storage of words and spaces It has been shown to reduce scopolamine-induced disorders (Preston, Recent Advances in the t).
reactent of Neurodegenerative disorders
and cognitive function, 1994, (eds.) Ragagn
i and Ranger, Basel Karger, p. 89-93).

In conclusion, compounds that exhibit 5-HT _1A partial agonist activity in combination with 5-HT ₃ antagonist activity are considered to be particularly useful in the treatment of cognitive dysfunction. In addition, compounds that exert serotonin reuptake inhibition have cognitive dysfunction associated with depression, as serotonin reuptake inhibition combined with 5-HT _1A partial agonism results in a more rapid therapeutic effect on depression. It will be exceptionally useful for treatment.

As shown in Example 1, the compounds of the invention are potent inhibitors of the human serotonin transporter, i.e., they inhibit serotonin reuptake. Moreover, those compounds are potent antagonists in mouse, rat, guinea pig and dog 5-HT ₃ receptors. In human 5-HT ₃ receptor, cloned into oocytes, their compounds are antagonists at low concentrations (IC 50 ₌ about 30 nM), whereas at higher concentrations, the compounds agonist properties Shown (ED ₅₀ = 2.
It turned out to be 1 μM). Subsequent application of the compounds of the invention at high concentrations did not show any agonistic response, which is a rapid desensitization in vitro.
Or it could have been due to direct antagonism. Thus, at low concentrations, the compounds of the invention, similar to that observed with 5-HT ₃ receptor from other species, shows significant antagonism in humans 5-HT ₃ receptor.

5-HT _1A in compound, brain homogenate of both rats and mice of the present invention
It binds to the receptor with low affinity. However, the compounds of the present invention is human in _{K i} of 40 nM 5-
It binds to the HT _1A receptor. Moreover, functional data show that the compounds of the invention are partial agonists at the human 5- _HT1A receptor, resulting in 85% efficacy.

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

As shown in Example 26, the compounds of the present invention result in increased extracellular acetylcholine levels in the frontal cortex and ventral hippocampus in rats. These preclinical findings are expected to translate into clinical effects in the treatment of cognitive dysfunction, such as the treatment of Alzheimer's disease, compared to the use of acetylcholinesterase inhibitors in the treatment of cognitive dysfunction. Further support for this view can be found in Example 27, where the data show that the compounds of the invention enhance contextual memory in rats. After all, the pharmacological profile of the compounds of the invention in combination with their effects on acetylcholine levels and memory in rats strongly suggests that the compounds of the invention are useful in the treatment of cognitive dysfunction. There is.

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

Cognitive or cognitive dysfunction includes cognitive or cognitive decline, such as work memory, attention and arousal, linguistic learning and memory, visual learning and memory, logical thinking and problem solving, such as executive functioning. Includes reduced processing speed and / or social cognition. In particular, cognitive or cognitive dysfunction is a lack of attention, dismantled thinking, slow thinking.
ing), difficulty in understanding, poor concentration
, Impairment of problem solving, poor memory
Difficulties in expressing thoughts, feelings and behavio, and / or difficults in integrating thoughts, feelings and behavio
ur), or difficulties in extinction of irrelevant t
houghts) can be represented. The terms "cognitive impairment" and "cognitive impairment" are intended to refer to the same thing and are used interchangeably.

In one embodiment, the patient comprises another CNS disorder, such as an emotional disorder, such as depression; generalized depression; major dementia disorder; general anxiety disorder and panic disorder. Anxiety disorder; obsessive-compulsive disorder; schizophrenia; panic disorder; dementia;
Diagnosis of AIDS-induced dementia; ADHD; age-related memory impairment; or Alzheimer's disease has also been made at the same time.

Cognitive dysfunction is one of the typical features of depression, such as major depressive disorder. Cognitive impairment, to some extent, means that improvement in depression also results in improvement in cognitive dysfunction.
Can be secondary to depression. However, there is also clear evidence that cognitive impairment is actually independent of depression. For example, several studies have shown cognitive dysfunction that persists upon recovery from depression [J. Nervous Mental Disease
, 185, 748-754, 197]. Moreover, further support for the idea that the differential effects of antidepressants on depression and cognitive dysfunction are independent of depression and cognitive dysfunction, even if they are often co-existing. Giving. Although serotonin and noradrenaline medications provide comparable improvement in depressive symptoms, some studies have shown that regulation of the noradrenalinergic system did not improve cognitive function as much as serotonin regulation [Brain Res. Bull. , 58, 345-350, 2002; Hum P
sychpharmacol. , 8, 41-47, 1993].

Treatment of cognitive dysfunction in depressed patients by administration of the compounds of the present invention is considered to be particularly advantageous. Multifaceted pharmacology of the compounds of the present invention, especially SERT, 5-HT
₃ and 5-HT _1A activity is expected to result in improved cognitive function combined with the rapid onset of therapeutic effects in depression.

Cognitive dysfunction is a particularly important consideration in the elderly. Cognitive dysfunction progresses normally with aging, but it also progresses with depression. Therefore, in one embodiment, the patient treated for cognitive dysfunction is the elderly, especially those with depression.

Cognitive function is often impaired in patients with schizophrenia, as mentioned above. In addition, some studies have found that cognitive function is a vocational functio in schizophrenia.
He also concludes that it is related to [Scizophrenia Res. , 45
, 175-184, 2000]. In one embodiment, the patient treated for cognitive dysfunction is a schizophrenic patient.

5-HT ₃ receptor antagonist is further for the treatment of various diseases, for example emesis, chemotherapy-induced vomiting, craving, substance abuse, pain, irritable bowel syndrome (IBS), schizophrenia and eating disorders such as It has also been suggested for the treatment of [Eur. J. Pharmacol. , 56
0, 1-8, 2007; Pharmacol. Therapist. , 111, 855
876, 2006; Alimentary Pharmacol. The. , 24, 1
83-205, 2006].

One clinical study found that mirtazapine and SSRIs were better combined with SSRIs to treat depressed patients with inadequate clinical responses (treatment-resistant depression (TRD) or refractory depression). Has been shown to be superior to when used 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 in the treatment of TRD.

Hot flushes are a symptom associated with menopause. In some women, this hot flush can interfere with sleep or general activity to the extent that treatment is needed. Hormone-compensated therapy with estrogen has been the default treatment for decades, but recently there have been concerns about side effects such as breast cancer and cardiac events. Clinical trials using SSRIs have shown that these compounds are effective for hot flushes, if not as much as for estrogen [J. Am. Med. Ass. , 295, 2057-2071, 2006]. However, treatments for hot flushes with compounds that inhibit serotonin reuptake, such as the compounds of the invention, are alternative treatments for women who cannot or do not accept estrogen.

Sleep apnea or obstructive sleep apnea-hypopnea syndrome or obstructive sleep apnea is a disorder in which effective drug therapy remains in a state where it should be identified. However, some studies in animals have suggested that 5-HT ₃ antagonists, such as compounds of the invention, may be effective in treating these diseases [Sleep, 21, 131-136].
, 1998; Sleep, 8, 871, 878, 2001].

In one embodiment, the invention relates to emotional disorders; depression; major depressive disorders; postpartum depression; bipolar disorders, Alzheimer's disease, psychiatric disorders, cancer, age or depression associated with Parkinson's disease. Anxiety; Generalized Anxiety Disorder; Social Anxiety Disorder; Compulsive Disorder; Panic Disorder; Panic Attack; Fear; Social Fear; Square Fear; Stress Urine Incontinence; Vomiting; IBS; Eating Disorder; Chronic Pain; Partial Partial responders; Treatment-resistant depression; Alzheimer's disease; Cognitive dysfunction; ADHD; Melancholy; PTSD; Facial red tide; Sleep aspiration; Alcohol, nicotine or carbohydrate craving; Substance abuse; and Alcohol or drug abuse In connection with a method of treating a disease selected from, the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the invention. In one embodiment, the aforementioned patient treated for any of the diseases listed above is first diagnosed with that disease.

It is well known that treatment with antidepressants in general, especially with SSRIs, is associated with sexual dysfunction and often results in discontinuation of treatment. 30 of patients treated with SSRIs
As many as 70% of patients complain of sexual dysfunction [J. Clin. Psych. , 6
6,844-848,2005], those disorders include diminished libido, delayed orgasm, reduced or absent, reduced sexual arousal and erectile dysfunction. In clinical trials, a total of 114 subjects received the compounds of the invention; only one of these 114 subjects complained of sexual dysfunction. These data suggest that clinical interventions with the compounds of the invention involve a surprisingly small number of sexual dysfunctions.

As mentioned above, the compounds of the present invention are particularly well suited for the treatment of chronic pain. Chronic pain includes phantom limb pain, neuropathy pain, diabetic neuropathy, postherpetic neuralgia (PHN), carpal tunnel syndrome (CTS), HIV neuropathy, complex local pain syndrome (CPRS), trigeminal neuralgia / trigeminal neuralgia. Neuralgia / painful tics, surgical interventions (eg postoperative analgesics), diabetic angiopathy, capillary resistance or diabetic symptoms with pancreatitis, angina-related pain, menstrual-related pain, cancer-related Pain, toothache, headache, migraine, tension pain, trigeminal neuralgia, jaw joint syndrome, myofascial pain muscular inj
ury), fibromyalgia syndrome, osteoarthritis (osteoarthritis), rheumatoid arthritis, chronic rheumatoid arthritis and edema resulting from trauma with burns, osteoarthritis, osteoarthritis, metastasis to bone or unknown reasons Bone pain due to contusion or fracture, gout, osteoarthritis, myofascial pain, thoracic exit syndrome, upper back pain or lower back pain (where this back pain is systematic, local or major spinal disease (nerve) Root disorder), pelvic pain, cardiac chest pain, non-cardiac chest pain, spinal cord injury (SCI) related pain, central post-stroke pain, cancer neuropathy, AIDS pain,
Includes indications such as sickle cell pain or geriatric pain.

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

As used herein, the term "therapeutically effective amount" of a compound cures the clinical signs of a given disease and its complications in a therapeutic intervention involving administration of the compounds described above. Means enough to relax or partially stop. The appropriate amount to achieve this is defined as the "therapeutically effective amount". The effective dose for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. Appropriate dose determination is routine by constructing a matrix of numbers and testing at various different points in the matrix (all of which are within the normal technical competence of a trained physician). It will be understood that it can be achieved by using various experiments.

As used herein, the terms "treat" and "treat" mean the management and care of a patient with the aim of combating a condition, such as a disease or disorder. The term refers to the entire spectrum of treatment for a given condition that a patient is suffering from, eg, those symptoms and complications to alleviate those symptoms or complications, to slow the progression of the disease, disorder or condition. To alleviate or alleviate the condition and / or to cure or eliminate the disease, disorder or condition, and to prevent the condition.
It is intended to include administration of active compounds, etc., where prevention should be understood to mean the management and care of patients with the aim of combating the disease, condition or disorder, and their symptoms. Alternatively, it involves administration of an active compound to prevent the development of complications. Although,
Prophylactic treatment (treatment aimed at prevention) and therapeutic treatment (treatment aimed at curing) are two distinct embodiments of the present invention. The patient to be treated is preferably a mammal, especially a human.

Typically, the treatment of the present invention will involve daily administration of the compounds of the present invention. This can include administration once daily, or twice daily or even more frequently.

In one embodiment, the invention relates to emotional disorders; depression; major depressive disorder; postpartum depression; bipolar disorder, Alzheimer's disease, psychiatric disorders, cancer, age-related or Parkinson's disease; anxiety; Generalized Anxiety Disorder; Social Anxiety Disorder; Obsessive-Compulsive Disorder; Panic Disorder; Panic Attack; Fear; Social Fear; Square Fear; Stress Urinary Incontinence; Vomiting; IBS; Eating Disorder; Chronic Pain; Partial Respondent Treatment-resistant depression; Alzheimer's disease; Cognitive dysfunction; ADHD;
Melancholy; PTSD; flushing; sleep apnea; alcohol, nicotine or carbohydrate craving; substance abuse; or the use of compounds of the invention to produce agents for treating alcohol or substance abuse.

In one embodiment, the invention relates to emotional disorder, depression, major depressive disorder, postpartum depression, bipolar disorder, Alzheimer's disease, psychiatric disorder, cancer, age-related or Parkinson's disorder, anxiety, Generalized Anxiety Disorder, Social Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorder, Panic Attack, Fear, Social Fear, Square Fear, Stress Urinary Incontinence, Vomiting, IBS, Eating Disorder, Chronic Pain, Partial Respondent , Treatment-resistant depression, Alzheimer's disease, cognitive dysfunction, ADHD,
The present invention relates to compounds of the invention for use in the treatment of diseases selected from melancholy, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse, or alcohol or substance abuse.

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

The drug formulation of the present invention can be produced by conventional methods in the art. With particular reference to tablets, tablets can be produced by mixing the active ingredient with a conventional supplement and / or diluent and then compressing the mixture with a conventional tableting machine. Examples of supplements or diluents are: anhydrous calcium hydrogen phosphate, PVP, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, corn starch, mannitol, potato starch, talcum, magnesium stealth, gelatin, lactose, rubber. And so on. Any other supplement or additive commonly used for such purposes,
For example, colorants, flavoring agents, preservatives and the like can also be used provided they are compatible with the active ingredient.

Injectable solutions are prepared by dissolving the active ingredient and possible additives in an injectable solvent, preferably part of distilled water, adjusting the solution to the desired volume, sterilizing the resulting solution and sterilizing an appropriate ampoule. Alternatively, it can be produced 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 compositions of the invention or pharmaceutical compositions produced according to the invention can be administered by any suitable route, even when administered orally in the form of tablets, capsules, powders, syrups and the like. It may be administered parenterally in the form of an injectable solution. Various methods well known in the art may be used to produce such compositions.
Also, any pharmaceutically acceptable carrier, diluent, excipient or other additive commonly used in the art can be used.

Conveniently, the compounds of the invention are administered in a unit dosage form containing the compound in an amount of about 1 mg to 50 mg. The upper limit is believed to be set by the concentration dependency of the 5-HT ₃ activity. The total daily dose is typically in the range of about 1-20 mg of the compounds of the invention, eg, up to about 1 mg to 10 mg, about 5-10 mg, about 10-20 mg or about 10-15 mg of the compounds of the invention. is there. 5 mg as a special daily dose
10 mg, 15 mg or 20 mg can be mentioned.

Tablets containing the compound of the present invention can be conveniently produced by a wet granulation method. When using this method, dry solids (active ingredients, bulking agents, binders, etc.) are blended and moistened with water or other wetting agents (eg alcohol) to form agglomerates or granules in those moist solids. Will be built. Wet agglomeration formation is continued until the desired uniform particle size is achieved, after which the granulated product is dried. The compounds of the present invention are typically mixed with water in a high shear mixer with lactose monohydrate, corn starch and copovidone. After forming the granules, these granules may be sifted through a sieve having an appropriate sheave size and dried. The resulting dried granules are then mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stealth, after which the tablets are compressed. Alternatively, wet granulation of the compounds of the invention uses mannitol, corn starch and copovidone and mixes the granules with microcrystalline cellulose, sodium starch glycolate and magnesium stealth before compressing the tablets. It may be achieved by. Alternatively, wet granulation of the compounds of the invention uses anhydrous calcium hydrogen phosphate, corn starch and copovidone, and the granules of the granules are microcrystalline cellulose, sodium starch glycolate (type A) prior to compaction of the tablets. , Tark and magnesium stealth may be achieved by mixing. Copovidone is a PVP-VA copolymer.

In one embodiment, the compounds of the invention are, for example, beta hydrobromic acid salts.
Suitable tablets may consist of the following (percentages shown are w / w%):
HBr salt: 2-20%
Lactose monohydrate: 30-50%
Starch: 15-30%
Copovidon: 3-5%
Microcrystalline Cellulose: 15-25%
Croscarmellose sodium: 2-5%
Mg steer alert: 0.5-5%.

In particular, the tablets may consist of:
HBr salt: 3-4%
Lactose monohydrate: 44-46%
Starch: 22-23%
Copovidon: 3-4%
Microcrystalline Cellulose: 20-22%
Sodium croscarmellose: 3-3.5%
Mg steer alert: 0.5 to 1%
Or HBr salt: 15-16%
Lactose monohydrate: 35-38%
Starch: 18-20%
Copovidon: 3-4%
Microcrystalline Cellulose: 20-22%
Sodium croscarmellose: 3-3.5%
Mg steer alert: 0.5 to 1%
Or HBr salt: 1-2%
Lactose monohydrate: 44-46%
Starch: 20-24%
Copovidon: 3-4%
Microcrystalline Cellulose: 22-24%
Croscarmellose sodium: 3-4%
Mg steer alert: 0.5 to 1%.

In one embodiment, the compounds of the invention are, for example, beta hydrobromic acid salts.
Suitable tablets 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 steer alert: 0.25 to 5%, for example 0.25 to 2%.

In particular, the tablets 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 stealth: 0.25 to 1%
Or HBr salt: 12-13%
Mannitol: 36-37%
Corn starch: 18-19%
Copovidon: 3-4%
Microcrystalline Cellulose: 24-25%
Sodium starch glycolate: 3-4%
Mg stealth: 0.25 to 1%
Or HBr salt: 25-27%
Mannitol: 27-29%
Corn starch: 13-15%
Copovidon: 3-4%
Microcrystalline Cellulose: 24-25%
Sodium starch glycolate: 3-5%
Mg stealth: 0.25 to 1%
Or HBr salt: 3-4%
Mannitol: 40-42%
Corn starch: 20-22%
Copovidon: 3-4%
Microcrystalline Cellulose: 26-28%
Sodium starch glycolate: 3-5%
Mg steer alert: 0.5%.

In one embodiment, the compound of the invention is hydrobromic acid, 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 stealth: 0.5-2%.

In particular, the tablets may consist of:
HBr salt: about 5%
Anhydrous Calcium Hydrogen Phosphate: Approximately 39%
Corn starch: about 20%
Copovidon: about 3%
Microcrystalline Cellulose: Approximately 25%
Sodium starch glycolate: about 3%
Talc: about 4%
Magnesium stealth: Approximately 1%.

Tablets with various different amounts of active compound, eg 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 of free base can be obtained by selecting the correct amount of the compound of the present invention in combination with an appropriate size 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 can stick to the plunger of the tablet machine. On the other hand, those crystals should not be too large. The rate of dissolution in the intestine decreases with increasing crystal size. Therefore, if the crystals are too large, the bioavailability of the compound may be impaired. Quantiles, such as D5%, D10%, D50%, D90%, D95% and D98%, can be used to represent the particle size distribution. As used herein, the term "particle size distribution" is used as Sy.
It means the cumulative volume size distribution of the diameters of equivalent spherical particles as determined by laser diffraction at a dispersion pressure of 1 bar in a pentec Heros apparatus.

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

The free base of the present invention can be produced as disclosed in International Publication No. 2003/029232. The salts of the present invention can be prepared by dissolving the free base in a suitable solvent, adding the relevant acid and then precipitating. Precipitation
It can be accomplished by either the 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.

The formation of aromatic carbon-heteroatom bonds can be achieved by aromatic nucleophilic substitution or copper-mediated Ullman reactions. More recently, palladium has formed such bonds,
In particular, it has been shown to be a potent catalyst in the formation of CN and CS bonds (see, eg, US Pat. No. 5,573,460).

In one embodiment, the invention

Provided a method for producing the compound II.

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

Compounds of [where X ₁ and X ₂ independently represent halogens], and formula IV.

In the formula, R represents a hydrogen or a protecting group].

In one embodiment, the method is divided into sub-processes, in which compound II and compound III are reacted in the first reaction and the following formula

Brings the compound of. The compound is then optionally purified to the appropriate degree and then reacted with compound IV to give 4- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine.

One-pot synthesis, i.e. synthesis in which all the reactants are mixed together at the beginning of the reaction or method, is particularly useful because of their inherent simplicity. On the other hand, the number of undesired side reactions that can occur has increased dramatically, which again increases the number and / or amount of undesired by-products, correspondingly to the desired product yield. It means that it can be reduced. Specifically, in the case of the method of the present application, it can be observed that piperazine has two nitrogens, and each nitrogen is potentially involved in the formation of CN bond. Surprisingly, it has been found that the method of the present application can be carried out as a one-pot synthesis, i.e., a method 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 corresponding thiolate. Judging from an occupational health point of view, thiolates such as Li ⁺ , Na to avoid the problem of odor associated with thiols.
^It may be beneficial to use ⁺ or K ⁺ thiolate and the like. However, in one embodiment, R'is hydrogen.

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

The solvent used in the method of the present invention may be selected from within the reaction temperature range, i.e., an aprotic organic solvent having a boiling point of 60-130 ° C. or a mixture 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 the solvent.

At the core of the method is the use of palladium catalysts, which would otherwise not react. This palladium catalyst consists of a palladium source and a phosphine ligand. Useful palladium sources include a variety of different oxidation states, such as palladium such as 0 and II. Examples of palladium sources that can be used in the methods of the invention are Pd ₂ dba ₃ , Pddba.
₂ and Pd (OAc) ₂ . dba is an abbreviation for dibenzylideneacetone. In particular, the names Pddba ₂ and Pd ₂ dba ₃ can be mentioned. This palladium source is
Typically, it is applied in an amount of 0.1 to 10 mol%, such as 1-10 mol%, for example 1-5 mol%. Throughout this application, mol% is calculated for limiting microorganisms.

Numerous phosphine ligands are known for both monodentate and bidentate. Useful phosphine ligands are racemic 2,2'-bis-diphenylphosphanyl- [1,1'] binaftalenyl (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- Il) -dimethyl-amine, [2'-(di-)
It contains t-butyl-phosphanyl) -biphenyl-2-yl] -dimethyl-amine, and dicyclohexyl- (2', 4', 6'-tri-propyl-biphenyl-2-yl) -phosphan. In addition, carbene ligands such as 1,3-bis- (2,6-di-isopropyl-phenyl) -3H-imidazol-1-ium; chloride can be used in place of the phosphine ligand. In one embodiment, the phosphine ligand is rac
-BINAP, DPPF or DPEphos, especially rac-BINAP. This phosphine ligand is typically applied between 0.1 mol% and 10 mol%, for example between 1 mol% and 5 mol%, typically in an amount of about 1-2 mol%. Applies in.

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

Compound IV is a piperazine compound. Piperazine has two nitrogens, only one of which is involved in the formation of CN bonds. In one embodiment, the formation of a bond to the second nitrogen is avoided by using a mono-protected piperazine, i.e. by using an embodiment in which R in the formula 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.
oc. Bn is an abbreviation for benzyl; boc is an abbreviation for t-butyloxycarbonyl; cbz is an abbreviation for benzyloxycarbonyl. If protected piperazines are used in those reactions, the protecting groups must be removed in subsequent steps, typically by adding an aqueous acid solution. If methyl is used as a protecting group, it may be removed by reaction with carbamate and subsequent removal of this group.

Surprisingly, it has been found that unprotected piperazine 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; for example.
Piperazine is virtually insoluble in toluene, while boc-protected piperazine is highly soluble in toluene. In general, it would be expected that easy dissolution of all reactants in the applied solvent would be a prerequisite for successful reaction. Nevertheless, the method of the present invention uses toluene as the solvent and is a non-protected piperazine, ie
It was found to be carried out in high yield using the piperazine of the embodiment in which R in the formula is hydrogen. Thus, in one embodiment, the solvent is toluene and compound IV is piperazine. In one further embodiment, this combination of conditions is used in 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-phenylsulfanil)
Phenyl] -Piperazine is produced by a method that includes the following steps:
a. Steps of dissolving or dispersing 1 to 1.5 equivalents of compounds II, III and IV in toluene to give mixture A;
b. Mixture B is added to Mixture A with 1-2 mol% Pddba ₂ and 1-2 mol% rac-BINAP, optionally dispersed or dissolved or dispersed in toluene, with 2-3 equivalents of NaOt-Bu. Obtain, until compounds II and III are completely converted
The step of heating this mixture B to about 100 ° C., typically for 5-10 hours;
c. Steps of raising the temperature of the mixture obtained in step b to about 120 ° C., typically for 16-32 hours, until compound IV is completely converted; and d. In some cases, when compound III is a protected piperazine, the step of removing the protecting group by adding an aqueous acid solution.

In some cases, the above series 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 2 to 5 equivalents dispersed in toluene, for example N such as 3 equivalents.
Add aOt-Bu and 1-2 mol% Pd ₂ dba ₃ and rac-BINAP to obtain a mixture and reflux the mixture for 2-10 hours, typically 3-5 hours 1- [2-(
2,4-Dimethyl-phenylsulfanil) -phenyl] -piperazin is obtained. In some cases, the product can be further reacted with an aqueous HBr solution to obtain 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% Pddba ₂ and 0.6-1 mol% rac-BINAP are dispersed in toluene to give mixture A', and about 1 equivalent of 2-bromo-iodobenzene is added to the mixture. To give mixture B', 1 equivalent of 2,4-dimethylthiophenol was added to the mixture, and the resulting mixture was heated for 3-7 hours, eg 4-6 hours, to reflux and 1-
[2- (2,4-Dimethyl-phenylsulfanil) -phenyl] -piperazine is obtained.
In some cases, the product can be further reacted with an aqueous HBr solution to obtain the corresponding hydrobromic acid addition salt.

In some situations, 1- [2- (2,4-dimethyl-) rather than as a free base.
It may be desirable to obtain an acid addition salt of phenylsulfanil) -phenyl] -piperazine. The acid addition salt may be obtained in a further process step in which the resulting free base is reacted with a suitable acid such as fumaric acid, sulfuric acid, hydrochloric acid or hydrobromic acid. The acid may be added directly to the reaction mixture or, optionally, the free base may first be purified to some appropriate degree prior to such a step. If the free base has been isolated as a dry compound, it may be necessary to use a solvent to make the free base a solution prior to reaction with the acid. In one embodiment, aqueous hydrobromic acid solution is added directly to the reaction mixture without any initial purification of the free base.

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

For all reactions and reaction mixtures described herein, the idea that purging them with an inert gas or running them under a blanket of an inert gas may be advantageous. Nitrogen is an example of an inexpensive and readily available inert gas.

All references cited herein, including publications, patent applications and patents, are hereby made by reference in their entirety, and elsewhere herein. Regardless of the inclusion of any particular document given separately, to the extent that each reference is individually and specifically instructed to be incorporated by reference, and in its entirety, the present specification. It is incorporated herein to the same extent as described herein (to the maximum extent permitted by law).

The use of the terms "a", "an" and "the" and similar referents in the context of describing the present invention is expressly denied unless otherwise indicated herein or by context. Unless otherwise stated, it should be interpreted as covering both the singular and the plural. For example, the phrase "the compound" should be understood to refer to the various compounds of the present invention or certain stated embodiments, unless otherwise indicated.

Unless otherwise indicated, all exact values given herein are representative of the corresponding approximate values (eg, all exact values given for a particular factor or survey). Illustrative values can be considered to be changed to "about" where appropriate and also give the corresponding approximate survey).

"Comprising", "ha" for one component or multiple components
Descriptions herein of any aspect or aspect of the invention using terms such as "ving", "including" or "containing" are not otherwise stated. , Or, unless explicitly denied by the context, "consisting of", "essentially (such a component)" of that particular component or multiple specific components.
It is intended to provide support for similar aspects or aspects of the invention that "consist of" or "substantially include (such components)" (eg, as those comprising a particular component). The composition described in is to be understood as also describing the composition of its components, unless otherwise stated or explicitly denied by the context. is there).

Analysis method
¹ Bruker Avance at 100.13 MHz NMR spectrum
Recorded on the DRX500 device. Dimethyl sulfoxide (99.8% D) is used as the solvent and tetramethylsilane (TMS) is used as the internal reference standard.

The melting point is measured using differential scanning calorimetry (DSC). The instrument is a TA-Instruments DSC-Q10 calibrated at 5 ° / min to give a melting point as a starting value.
It is 00. Approximately 2 mg of sample is heated at 5 ° / min in a loosely closed pan under nitrogen flow.

The thermogravimetric analysis (TGA) used to estimate the solvent / water content of the dried material is performed using the TA-Instruments TGA-Q500. 1-10 mg
Samples are heated at 10 ° / min in an open pan under nitrogen flow.

The powder X-ray diffraction pattern is a PANalytical X'Per using CuK _α1 radiation.
It was measured by t PRO X-Ray Diffractometer. The sample is X
It was measured 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 (blocking 5-HT uptake)
Human serotonin transporter: IC ₅₀ 40 nM (blocking 5-HT uptake)
Human _{5-HT 1A} receptor: a partial _agonism, K i 40nM (85% potency)
Rat 5-HT _{3 receptor:} IC 50 0.2 nM (antagonism in functional assay)
Human _{5-HT 3A} receptor: _{IC 50} around 20 nM (antagonism in functional assay).
At higher concentrations, the compound exhibits agonistic activity with 2.1 μM ED ₅₀ . The compounds of the present invention also showed high affinity for human 5HT3 receptors in in vitro binding assays (Ki 4.5 nM).

Example 2: Cognitive Action As discussed above, the compounds of the invention interact with the cholinergic system and are effective in one or more of the following items in an in vivo model: Will be expected.

5-Selective reaction time test (5-CSRT) (useful for demonstrating effect on continuous attention)
Spatial Y-shaped maze test (useful for demonstrating effects on short-term memory, long-term memory and working memory)
-Attentional set shifting model (useful for demonstrating executive function, that is, its effect on logical thinking and problem solving).

Example 3a: Preparation of compound I of free base 10 grams of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine hydrobromide in a stirred mixture of 100 ml of 3M NaOH and 100 ml of ethyl acetate. Treated for 10 minutes. The organic phase is separated and 100 ml of 15% wt N
Washed with aCl (aq), dried over sulfonyl ₄ , filtered and concentrated under vacuum to give 7.7 grams (98%) of compound I base as a clear colorless oil. ..
NMR is compatible with the structure.

Example 3b: Preparation of Compound I of Crystalline Base 3.0 grams of a colorless oil of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine is treated with 70 ml of acetonitrile and heated. And refluxed. 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. The crystalline base was isolated as a 2.7 gram (90%) white solid. NMR is compatible with the structure. Elemental analysis: 72.4
0% C, 9.28% N, 7.58% H (theoretical value: 72.26% C, 9.36% N, 7.42% H).

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

Example 4a: Preparation of alpha hydrobromic acid of Compound I 2.0 grams of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazin dissolved 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 allow proper agitation. 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 is compatible with the structure. Elemental analysis: 57
.. 05% C, 7.18% N, 6.16% H (theoretical value for 1: 1 salt: 56.9)
9% C, 7.39% N, 6.11% H).

Example 4b: Characteristic Depiction of Alpha-type Hydrobromid of Compound I This alpha-type hydrobromid produced as in Example 4a is crystalline ().
XRPD) -See Figure 2. This crystalline hydrobromide has a melting point of about 226 ° C. In addition, this hydrobromid absorbs about 0.3% of water when exposed to high relative humidity and has a solubility of 2 mg / ml in water.

Example 4c: Preparation of beta-type hydrobromic acid of Compound I 49.5 grams of 1- [2- (2,4-dimethylphenylsulfanil) -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 at room temperature overnight. Filtration and drying under vacuum (50 ° C.) overnight gave 29.6 grams of product as a white solid (47%).
NMR is compatible with the structure. Elemental analysis: 56.86% C, 7.35% N, 6.24% H (theoretical value for 1: 1 salt: 56.99% C, 7.39% N, 6.11) % H)
..

Example 4d: Characteristic Depiction of Beta Hydrobromid of Compound I This beta hydrobromid produced as in Example 4c is crystalline (X).
RPD) -See Figure 3. This crystalline hydrobromide has a melting point of about 231 ° C. In addition, this hydrobromid absorbs about 0.6% of water when exposed to high relative humidity and has a solubility of 1.2 mg / ml in water.

Example 4e: Production of gamma-type hydrobromic acid salt of Compound I 1 g of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazin hydrobromid produced as in Example 4a. It was added to 20 ml of water and heated to 85 ° C. The solution was almost clear. The solution became clear by adding a drop of HBr. HBr was added until a cloudy spot was observed. The solution was cooled to room temperature and dried. NMR is compatible with the structure. Elemental analysis: 56.63% C, 7.18% N, 6
.. 21% H (theoretical value for 1: 1 salt: 56.99% C, 7.39% N, 6.1
1% H).

Example 4f: Characteristic Depiction of Gamma-Type Hydrobromid of Compound I This hydrobromid produced as in Example 6e is crystalline (XRPD)-.
See FIG. This DSC curve shows some thermal events at about 100 ° C., probably changes in crystal form. The hydrobromid is then melted at about 220 ° C. This crystalline hydrobromide absorbs about 4.5% water when exposed to high relative humidity and about 2% water when exposed to 30% RH at room temperature.

Example 4g: Preparation of Hydrobromid Hydrate of Compound I Add 1.4 grams of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine oil to 20 ml of water and bring to 60 ° C. It was heated. P with 48% HBr
H was adjusted to 1. The solution was cooled to room temperature and dried. NMR is compatible with the structure. Elemental analysis: 55.21% C, 7.16% N, 6.34% H (theoretical value for 1: 1 salt hemihydrate: 55.68% C, 7.21% N , 6.23% H).

Example 4h: Characteristic Depiction of Hemihydrate of Hydrobromid of Compound I This hydrate produced as in Example 4g is crystalline (XRPD) -see Figure 5. Moisture content is strongly dependent on relative humidity. At room temperature with 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 hydrobromic acid of Compound I 0.9 g of 1- [2- (2,4-dimethylphenylsulfanyl) -phenyl] piperazine oil in 35 ml. It was dissolved in ethyl acetate and 0.5 ml of 48% wt HBr (aq) was added. This addition resulted in the formation of a thick slurry, which was stirred at room temperature overnight. Filter, wash with 30 ml diethyl ether, then under vacuum (50 ° C.)
) Overnight to give 1.0 grams (65%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine HBr EtOAc solvate. NMR is compatible with the structure. Elemental analysis: 56.19% C, 6.60% N, 6.56%
H (Theoretical value 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: Characteristic description of the ethyl acetate solvate of the hydrobromide of Compound I This ethyl acetate solvate produced as in Example 4i is crystalline (X).
RPD) -See Figure 6. The batch contains a mixture of the solvate of Compound I and the alpha form, probably because drying caused partial desolvation. This desolvation is 10 °
When heated at / min, it starts at about 75 ° C. After desolvation, the alpha form is formed. When exposed to high relative humidity, ethyl acetate is replaced with water, which is then released when the humidity is lowered. The resulting solid is hygroscopic and absorbs 3.2% moisture at high relative humidity.

Example 5a: Preparation of Hydrochloride of Compound I 1.0 g of oil of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazin is 20 ml with gentle heating (30 ° C.). Dissolved in ethyl acetate. When a clear solution was obtained, a solution of 2M HCl in diethyl ether was added slowly until the pH was about 1-2. Spontaneous precipitation was observed during this addition. After the last addition, the suspension is stirred for 1 hour, then filtered and under vacuum (4).
By drying overnight at 0 ° C.), a white precipitate was isolated. 1.1 grams (99%)
) 1- [2- (2,4-Dimethylphenylsulfanil) -phenyl] piperazinehydrochloride was isolated.
NMR is compatible with the structure. Elemental analysis: 64.18% C, 8.25% N, 6.96% H (for a 1: 1 salt as corrected for 0.66% water as determined by TGA) Theoretical values: 64.13% C, 8.31% N, 6.95% H).

Example 5b: Characteristic Depiction of Hydrochloride of Compound I This hydrochloride produced as in Example 5a is crystalline (XRPD)-.
See FIG. This crystalline hydrochloride has a melting point of about 236 ° C. In addition, this hydrochloride absorbs about 1.5% of 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 1- [2- (2,4-dimethylphenylsulfanil) -phenyl]
The oily piperazine was dissolved in 100 ml of ethanol with heating. The addition of 3.5 ml of concentrated HCl (aq) made when a homogeneous solution was obtained caused an immediate precipitation of the white solid. The resulting suspension is first stirred for 5 minutes and then an additional 1 on an ice bath.
After stirring for hours, it was filtered. 100 ml of fresh cold ethanol (-
(Placed in the freezer at 18 ° C. for 2 hours), 50 ml of acetone and finally 50 ml
After washing with diethyl ether of the above, it was dried under vacuum (50 ° C.) overnight. 5.
One gram (38%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine HCl was isolated.
NMR is compatible with the structure. Elemental analysis: 61.23% C, 7.91% N, 7.16% H (theoretical value for 1: 1 salt monohydrate: 61.26% C, 7.94% N , 7.14
% H).

Example 5d: Characteristic Description of Hydrochloride Monohydrate of Compound I This Hydrochloride Monohydrate produced as in Example 5c is crystalline (XR).
PD) -See Figure 8. This crystalline monohydrate begins to lose water at about 50 ° C. Further heating causes some thermal events, possibly dislocations, where this monohydrate melts at about 230 ° C, followed by recrystallization and melting at about 236 ° C. This crystalline monohydrate does not absorb additional amounts of water when exposed to high relative humidity, and the water bound to this hydrate has a relative humidity of 10% RH or less at room temperature. It will not be released until it goes down. This crystalline monohydrate has a solubility of about 2 mg / ml in water.

Example 6a: Preparation of mesylate of Compound I 1.0 grams of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazin oil is heated (70 ° C.) to 20 ml of ethyl. Dissolved in the 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 the diethyl ether was added slowly, resulting in product precipitation. The suspension was stirred on ice for 2 hours, then the resulting white precipitate was isolated by filtration and dried under vacuum (40 ° C.) overnight. 1.1 grams (85%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine mesylate was isolated. NMR is compatible with the structure. Elemental analysis: 57
.. 81% C, 6.81% N, 6.68% H (theoretical value for 1: 1 salt: 57.8)
1% C, 7.10% N, 6.64% H).

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

Example 7a: Preparation of Fumarate of Compound I 5.5 in a mixture of 50 ml methanol and 50 ml ethyl acetate
A gram of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine oil was heated and refluxed. Exothermic reaction occurred by adding 2.1 grams of fumaric acid shortly after the solution was left to cool, resulting in a white solid precipitate. The resulting suspension was stirred, during which time it was cooled to room temperature, followed by cooling in the freezer at -18 ° C. for 2 hours. The white solid was collected by filtration, washed with 20 ml cold ethyl acetate and then dried under vacuum (50 ° C.) overnight. 3.1 grams (44%) of the product was isolated.

NMR is compatible with the structure. Elemental analysis: 63.42% C, 6.64% N, 6.42%
H (Theoretical value for 1: 1 salt: 63.74% C, 6.76% N, 6.32% H
).

Example 7b: Characteristic Depiction of Fumarate of Compound I This fumarate produced as in Example 7a is crystalline (XRPD) − FIG.
See 0. This crystalline fumarate has a melting point of about 194 ° C. The solubility in water is 0.4 mg / ml.

Example 8a: Preparation of Maleato of Compound I 2.5 grams of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine oil is dissolved in 50 ml of ethyl acetate and at 60 ° C. After heating, 1.
1 gram of maleic acid was added. The mixture was heated again to reflux for 5 minutes and allowed to stand with stirring to cool to room temperature. 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 diethyl ether and then dried under vacuum (50 ° C.) overnight. This makes 1
.. 3 grams of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazin maleate (38%) was obtained by treating this maleate with 40 ml ethyl acetate and 5 ml methanol at reflux. Recrystallized. The clear solution is cooled to room temperature, followed by cooling in a freezer (-18 ° C) for 2 hours, then filtered to 10 ml.
It was washed twice with cold ethyl acetate and then dried under vacuum (50 ° C.) for 2 days. 0.9 grams (69%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine maleate was isolated. NMR is compatible with the structure. Elemental analysis: 63.57% C, 6.79% N, 6.39% H (theoretical value for 1: 1 salt: 6)
3.74% C, 6.76% N, 6.32% H).

Example 8b: Characteristic Depiction of Maleato of Compound I The maleate produced as in Example 8a is crystalline (XRPD) − FIG.
See 1. This crystalline fumarate has a melting point of about 152 ° C. Solubility in water is about 1 mg / ml.

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

Example 9b: Characteristic Depiction of Meso-Tartrate of Compound I This meso-tartrate produced as in Example 9a is crystalline (XRPD).
) -See Figure 12. This crystalline meso-taltolate has a melting point of about 164 ° C. Solubility in water is about 0.7 mg / ml.

Example 10a: Preparation of L- (+)-tartrate of Compound I 5 ml of 11.1 ml 0.30 M solution of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine in acetone. 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 precipitation occurred. Filtration and washing with 5 ml acetone then 3 ml diethyl ether gave the product as a white solid and the product was dried under vacuum (50 ° C.) overnight. 1.2 grams (81%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine (+)-tartaric acid was isolated. NMR is compatible with the structure. Elemental analysis: 58.86% C, 6.30% N, 6.38% H (theoretical value for 1: 1 salt: 58.91% C, 6.25% N, 6.29 % H).

Example 10b: Characteristic Depiction of L- (+)-Tartrate of Compound I This L- (+)-Tartrate produced as in Example 10a is crystalline (
XRPD) -See FIG. This crystalline L- (+)-tartrate has a melting point of about 171 ° C. Solubility in water is about 0.4 mg / ml.

Example 11a: Preparation of D- (-)-tartrate of Compound I 5 ml of 11.1 ml 0.30 M solution of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine in acetone. 0.5 dissolved in acetone
Treated with grams of D- (-)-tartaric acid. The resulting mixture was stirred at room temperature for 30 minutes during which precipitation occurred. Filtration and washing with 5 ml acetone then 3 ml diethyl ether gave the product as a white solid and the product was dried under vacuum (50 ° C.) overnight. 1.0 g (68%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine D- (-)-tartaric acid was isolated. NMR is compatible with the structure. Elemental analysis: 58.90% C, 6.26% N, 6.35% H (theoretical value for 1: 1 salt: 58.91% C, 6.25% N, 6.29 % H).

Example 11b: Characteristic Depiction of D- (-)-Tartrate of Compound I This D- (+)-tartrate produced as in Example 11a is crystalline (
XRPD) -See Figure 14. This crystalline D- (-)-tartrate has a melting point of about 175 ° C. Solubility in water is about 0.4 mg / ml.

Example 12a: Preparation of Sulfate of Compound I 11.1 ml 0.30 M solution of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine in acetone to ₂ of H ₂ SO ₄ (aq) .2 ml of 3M
Treated with solution. The resulting mixture was stirred at room temperature for 30 minutes and then on an ice bath for an additional 4 hours to cause precipitation and termination of the precipitation. Filtration and washing with 5 ml acetone then 3 ml diethyl ether gave the product as a white solid and the product was dried under vacuum (50 ° C.) overnight. 0.51 grams (39%) 1-[
2- (2,4-Dimethylphenylsulfanil) -phenyl] piperazine sulfate was isolated. NMR is compatible with the structure. Elemental analysis: 54.53% C, 7.22% N,
6.28% H (theoretical value for 1: 1 salt: 54.52% C, 7.07% N, 6.
10% H).

Example 12b: Characteristic Depiction of Sulfate of Compound I This sulphate produced as in Example 12a is crystalline (XRPD)-.
See FIG. This crystalline sulfate has a melting point of about 166 ° C. Solubility in water is about 0.1 mg / ml.

Example 13a: Preparation of Phenyl Phenyl of Compound I A solution of 11.1 ml 0.30 M of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine in acetone in 0.2 ml 65% H ₃ PO ₄ (aq)
) Was processed. The resulting mixture was stirred at room temperature for 30 minutes during which precipitation occurred. Filtration and washing with 5 ml acetone then 3 ml diethyl ether gave the product as a white solid and the product was dried under vacuum (50 ° C.) overnight. 1. 1.
Twenty-three grams (94%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine phosphate was isolated. NMR is compatible with the structure. Elemental analysis: 54.
21% C, 7.15% N, 6.43% H (theoretical value for 1: 1 salt: 54.53)
% C, 7.07% N, 6.36% H).

Example 13b: Characteristic Depiction of Phosphate of Compound I This phosphate produced as in Example 13a is crystalline (XRPD)-.
See FIG. This crystalline phosphate has a melting point of about 224 ° C. Solubility in water is about 1 mg / ml.

Example 14a: Preparation of Nitrat of Compound I A solution of 11.1 ml 0.30 M of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine in acetone to 0.2 ml 16.5 M HNO. ₃ (a
It was processed in q). The resulting mixture was stirred at room temperature for 30 minutes during which precipitation occurred. Filtration and washing with 5 ml acetone then 3 ml diethyl ether gave the product as a white solid and the product was dried under vacuum (50 ° C.) overnight. 0
.. Eighty-seven grams (73%) of 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazinnitrate was isolated. NMR is compatible with the structure. Elemental analysis: 59.
80% C, 11.67% N, 6.51% H (theoretical value for 1: 1 salt: 59.8)
1% C, 11.63% N, 6.41% H).

Example 14b: Depiction of the properties of the nitrate of Compound I The nitrate produced 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. Solubility in water is about 0.8 mg / ml.

Example 15: Tablets The following examples show typical examples of methods in which tablets containing the compounds of the present invention can be produced. Beta hydrobromic acid was used in all examples.

Example 15a
63.55 g hydrobromic acid, 923.65 g Lactoseum 350M, 46
Di 1.8 g of corn starch and 76.0 g of Kollidon VA64
Mixing was performed in an osna PP1 high shear mixer at an impeller speed of 1000 rpm for 2 minutes. The speed of the impeller was then reduced to 800 rpm and 220 g of water was added in a short period of time. Massing was performed for 7 minutes and the resulting granules were passed through a 4000 μm sized sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1383.5 g granules were combined with 400 g of Avicel PH200 and 60.
It was mixed with g Ac-Di-Sol. After lubrication of the blend by mixing with 15 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine.
In order to obtain a tablet having a target content corresponding to 5 mg of this free base, a tablet having a target core weight of 200 mg and a diameter of 8 mm was produced.

Example 15b
317.75 g of hydrobromic acid, 754.15 g of Lactoseum 350M, 3
D 77.1 g corn starch and 76.0 g Kollidon VA64
The mixture was mixed in an iosna PP1 high shear mixer at an impeller speed of 1000 rpm for 2 minutes. The speed of the impeller was then reduced to 800 rpm and 210 g of water was added in a short period of time. Agglomeration formation was performed for 7 minutes and the resulting granules were passed through a 4000 μm sized sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1386.2 g granules were combined with 400 g Avicel PH200 and 60 g Ac-.
It was mixed with Di-Sol. After lubrication of the blend by mixing with 15 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine. In order to obtain a tablet having a target content corresponding to 25 mg of this free base, a tablet having a target core weight of 200 mg and a diameter of 8 mm was produced.

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

Example 15d
540.85 g of hydrobromic acid, 953.00 g of Pearlitol 50C, 2
96.22 g of corn starch and 70.5 g of Kollidon VA64 at 1000 rpm in an Aeromatic-Fielder PMA1 high shear mixer.
Was mixed for 2 minutes at the impeller speed of. The impeller speed was then reduced to 800 rpm and 241.87 g of water was added in a short period of time. Agglomeration formation was performed for 7 minutes and the resulting granules were passed through a 4000 μm sized sieve. The granules were dried and passed through a 710 μm size sieve. The resulting 1500 g granules are combined with 531.91 g Avic
It was mixed with el PH200 and 85.11 g of Primojell. After lubrication of the blend by mixing with 10.64 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine. Tablets with a target core weight of 125 mg and a diameter of 6 mm were produced to obtain tablets with a target content corresponding to 25 mg of the free base.

Example 15e
270.45 g hydrobromic acid, 772.0 g Pearlitol 50C, 38
6.41 g of corn starch and 70.5 g of Kollidon VA64 A
The mixture was mixed in an eromatic-Fielder PMA1 high shear mixer at an impeller speed of 1000 rpm for 2 minutes. Then the impeller speed was reduced to 800 rpm
195 g of water was added in a short period of time. Agglomeration formation was performed 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 granules are combined with 425.5 g Avice
l PH200 and 68.09 g of Primogel were mixed. After lubrication of the blend by mixing with 8.8 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine. Tablets with a target core weight of 100 and a diameter of 6 mm were produced to obtain tablets with a target content corresponding to 10 mg of this free base.

Example 15f
504.85 g of this free base, 552.95 g of Pearlitol 50C, 276
.. 53g corn starch and 65.7g Kollidon VA64 Ae
Mixing was performed in a romantic-Fielder PMA1 high shear mixer at an impeller speed of 1000 rpm for 2 minutes. The impeller speed was then reduced to 800 rpm and 182 g of water was added in a short period of time. Agglomeration formation was performed 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 granules were combined with 443.31 g of Avice.
l PH200 and 70.8 g of Primogel were mixed. After lubrication of the blend by mixing with 8.92 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine. In order to obtain a tablet having a target content corresponding to 50 mg of this free base, a tablet having a target core weight of 250 mg and a diameter of 8 mm was produced.

Example 15g
135.23 g of hydrobromic acid, 863.2 g of Pearlitol 50C, 43
2.69 g of corn starch and 70.66 g of Kollidon VA64 in an Aeromatic-Fielder PMA1 high shear mixer at 1000 rpm
Was mixed for 2 minutes at the 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 formation was performed 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 granules are 425.28 g Avice
l PH200 and 68.2 g of Primogel were mixed. After lubrication of the blend by mixing with 8.58 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine. In order to obtain a tablet having a target content corresponding to 5 mg of this free base, a tablet having a target core weight of 100 mg and a diameter of 6 mm was produced.

Example 15h
67.6 g of hydrobromic acid, 908.0 g of Pearlitol 50C, 453.
Dio with 9g of corn starch and 70.51g of Kollidon VA64.
Mixing was carried out in a sna PP1 high shear mixer at an impeller speed of 1000 rpm for 2 minutes. The impeller speed was then reduced to 800 rpm and 195 g of water was added in a short period of time. Agglomeration formation was performed 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 granules were combined with 531.91 g Avicel PH200 and 85.11.
It was mixed with g Primogel. After lubrication of the blend by mixing with 10.64 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine. 207.8 mg to obtain tablets with a target content corresponding to 5 mg of this free base
Tablets with a target core weight of 7 mm and a diameter of 7 mm were produced.

Example 15i
2290.1 g hydrobromic acid salt, 17568 g anhydrous calcium hydride phosphate and 8783 g corn starch and 1510 g copovidone in Aeroma
Mixing was performed in a tic-Fielder PMA100 high shear mixer at an impeller speed of 200 rpm for 3 minutes. Then 5130 g of water was added during 2 minutes at an impeller speed of 150 rpm. The agglomeration formation 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 525 mm sized screen. Approximately 15 with dried granules and a screen with a size of 2.388 mm
It was passed through a conical mill operating at 00 rpm. 1 of the resulting 28747 g of granules
It was mixed with 1250 g of microcrystalline cellulose, 1350 g of sodium starch glycolate (type A) and 1800 g of talc. After lubrication of the blend by mixing with 450 g of magnesium stealth, the resulting powder blend was transferred to a tablet molding machine. In order to obtain a tablet having a target content of hydrobromic acid salt corresponding to 5 mg of the free base, a tablet having a target core weight of 125 mg and a diameter of 6 mm was produced. Further, in order to obtain a tablet having a target content of hydrobromic acid salt corresponding to 10 mg of the free base, a tablet having a target core weight of 250 mg and a diameter of 8 mm was produced.

Example 16: Pain effects in an intradermal formalin test in mice
In this model, mice receive formalin (4.5%, 20 μl) infusion on their left hind paw. The irritation caused by this formalin injection elicits a characteristic biphasic behavioral response, which is quantified by the amount of time spent licking the injured foot. The first phase (about 0-10 minutes) represents direct chemical stimulation and nociception, while the second phase (about 20-3)
0 minutes) is considered to represent pain of neuropathic origin. These two phases are separated by a sedative phase, during which behavior returns to normal. The effectiveness of the test compound for reducing painful irritation is assessed by measuring the amount of time spent licking the injured foot in these two phases.

The compounds of the present invention showed a significant reduction in pain score in Phase 2 (FIG. 18b), indicating efficacy for pain of neuropathic origin. Moreover, the compounds of the present invention also showed a significant reduction in score in Phase 1 (FIG. 18a), indicating that they have a higher analgesic effect at the highest doses. In summary, these results indicate that the compounds of the invention are likely to be effective in the treatment of 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 of Pd ₂ dba ₃ (0.35 mmol; 1 mol%) and 381 mg of DPEPHos (
Before 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 of KOB
u ^t (78 mmol) was added, immediately heterogeneous mixture was formed. The suspension was heated to 100 ° C. under nitrogen. After 1 hour, the mixture was cooled to 0 ° C., stirred for 2 hours and then filtered through a pad of Celite. 2 x 50 of the obtained filtered cake
Washing with ml of toluene and evaporating the combined filtrate gave 21 g of an orange-reddish oil (99% yield), which was HPLC and GC.
-MS revealed a purity of> 96%.

Example 18

Put 500 ml of toluene in a 1 L three-necked round bottle with a mechanical stirrer.
203 mg Pddba ₂ (0.35 mmol; 0.1 mol%) and 760 mg D
PEPhos (1.5 mmol; 0.4 mol%) was added. After purging the dark red solution with nitrogen for 5 minutes, 100 g of 2-bromoiodobenzene (353 mmol) and 4
8.9 g of 2,4-dimethylthiophenol (353 mmol) was added. 43
.. The addition of 6g of KOBu ^t (389 mmol) causes an exothermic reaction, the temperature was increased to 36 ° C. from 20 ° C., at the same time, it resulted in the formation of a heterogeneous mixture. The suspension was heated to 100 ° C. under nitrogen. After 7 hours, the mixture was cooled to 0 ° C., stirred for 2 hours and then filtered through a pad of Celite. 2 x 200 of the obtained filtered cake
Washing with ml of toluene and evaporating the combined filtrate yields 104 g of an orange oil (105% yield), which can be 97% pure by HPLC. It was found, and it was confirmed by NMR that it had a desirable structure. The oil solidified while standing at room temperature.

Example 19

To a solution of 10 grams of 1- (2-bromo-phenylsulfanil) -2,4-dimethyl-benzene (34 mmol) in 50 ml of dry toluene, add 7 grams of boc-piperazine (38 mmol) and remove with nitrogen for 5 minutes. Feeling, 312 mg of Pd ₂ dba ₃ (2)
mol%) and 637mg rac-BINAP (3mol%) was added and further was degassed for 5 minutes, 3.9 grams of ^Bu t ONa (41mmol) was added and heated to 80 ° C. 15 hours. The reaction mixture was cooled to room temperature and extracted twice with 20 ml of 15% brine.
14.2 grams of brownish oil with 95% purity as determined by NMR by drying on Na ₂ SO ₄ , adding activated charcoal, refluxing for 15 minutes, filtering through Celite and evaporating. The product (4- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -BOC-piperazine) was obtained. After dissolving this crude oil in 200 ml of MeOH and 20 ml of 6M HCl (aq.) And refluxing for 1 hour, HPLC showed complete deprotection. After cooling to room temperature, the methanol was removed by vacuum in a rotary evaporator.
20 ml of concentrated NaOH (pH was 13-14) was added and the resulting mixture was then stirred with 100 ml of EtOAc for 15 minutes. Collect the organic phase and collect 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 uniform solution is formed during heating and reflux, and during either further heating or cooling, a rapid precipitation occurs from that solution. The precipitate is collected, washed with 20 ml EtOAc and 20 ml acetone and dried under vacuum to give a total yield of 66%, 9.3 grams 1- as a white powder.
[2- (2,4-Dimethyl-phenylsulfanil) -phenyl] -piperazine fumarate (22 mmol) was obtained, which had 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 of Pddba ₂ (8 mmol; 2 mol%) and 13.1 g of rac-BINAP
Prior to (21 mmol; 5 mol%), the solution is purged with nitrogen. 5 reaction mixtures
Stir for minutes, during which the color changes from dark red to orange. 61g of NaOBu ^t (6
36 mmol) and 200 ml of toluene were added and an immediately heterogeneous mixture was formed. The suspension was heated to 80 ° C. under nitrogen. After 10 hours, the mixture is cooled to 60 ° C.
After cooling to 102.6 g of boc-piperazin (5) in 500 ml of toluene.
Add 51mmol) and another 61g of NaOBu ^t (636mmol). After purging the reaction mixture with nitrogen, another portion of 4.6 g of Pddba ₂ (8 mmol; 2 mol).
%) And 13.1 g of rac-BINAP (21 mmol; 5 mol%) were added. This time, the mixture was heated to reflux (110 ° C.) for an additional 6 hours or until HPLC showed complete conversion. The resulting reaction mixture was cooled on ice for 2 hours and then the mixture was filtered through a pad of Celite. The resulting filtered cake is washed with 2 x 200 ml of toluene and the combined filtrate is evaporated to give 242 g of red oil.
This oil was dissolved in 1000 ml of MeOH and 115 ml of 48 wt% HBr (a).
q. ) Was added slowly, followed by heating and refluxing for 2 hours, after which 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 continued stirring for hours, the slurry was left in the freezer overnight (-18 ° C.). Filter and 2
Wash twice with 00 ml Et ₂ O and dry under vacuum at 40 ° C. 17
2 g of a brownish solid was obtained. 1500 ml of boiling H from the brownish solid
After treating with ₂ O for 1 hour, it was cooled to room temperature for another 2 hours. Filtration and drying at 40 ° C. under vacuum overnight gave 98 g of 4- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine hydrobromid (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. 81 g of BOC-piperazine (434 mmol) was added to this solution, followed by 2.08 g of P.
ddba ₂ (1 mol%) and 4.51 g of rac-BINAP (2 mol%) were added. The mixture was purged with nitrogen for 5 minutes, it was added a slurry of NaOBu ^t in 87g of toluene in 300ml (905mmol). The resulting suspension was heated to 100 ° C. overnight under nitrogen. GCMS analysis showed complete conversion to the intermediate product (1- (2-bromo-phenylsulfanil) -2,4-dimethyl-benzene), the temperature was raised and refluxed for an additional 24 hours (120 ° C.). .. HPLC analysis was performed on the intermediate (1-BOC-4- [2]
It showed complete conversion to-(2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine). The reaction mixture was cooled on ice for 1 hour and then the mixture was filtered. The resulting filtered cake was washed with 2 x 200 ml of toluene and 80 ml in a combined filtrate.
48 wt% of HBr (aq.) Was added, followed by heating and refluxing for 18 hours before HP.
Complete deprotection was detected by LC. The resulting mixture was cooled on ice for 2 hours and filtered. 1000 ml of boiling H ₂ O with activated carbon (25 g) of the brownish solid
It was dissolved in it for 1 hour, filtered while it was hot, and left to cool. The resulting precipitate was collected by filtration and dried at 40 ° C. under vacuum overnight to give 49 g of 4 as a white solid.
-[2- (2,4-Dimethyl-phenylsulfanil) -phenyl] -piperazine hydrobromide (36%) was obtained.

Example 22

Put 500 ml of toluene in a 1 L three-necked round bottle with a mechanical stirrer.
809 mg of Pd ₂ dba ₃ (0.88 mmol; 0.5 mol%) and 952 mg of DPEPHos (1.77 mmol; 0.5 mol%) were added. After purging the dark red solution with nitrogen for 5 minutes, 100 g of 2-bromoiodobenzene (353 mmol) and 48.9 g of 2,4-dimethylthiophenol (353 mmol) were added.
The addition of 43.6g of KOBu ^t (389 mmol) causes an exothermic reaction, the temperature 20
It was raised from ° C to 42 ° C, resulting in the formation of a heterogeneous mixture, and its color changed from dark red to orange / brownish. Place the suspension under nitrogen 10
It was heated to 0 ° C. After only 20 minutes, the HPLC was 1- (2-bromo-phenylsulfanil)
It showed a 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 2 x 100 ml of toluene. The combined organic phase was washed with 100 ml of 2M HCl (aq.), 100 ml of 15 wt% NaCl, dried over Na ₂ SO ₄ , refluxed with activated carbon (10 g) for 15 minutes and filtered twice. By evaporation, 107.3 g of an orange-red oil was obtained (103%), which was an HPL.
C proved to be 98% pure.

90 grams of the orange-red oil mentioned above in 500 ml of dry toluene (
57 grams of boc-piperazine (307 mmol) was added to a solution of 307 mmol).
Degassed with nitrogen for 5 minutes and 1.4 g of Pd ₂ dba ₃ (1.53 mmol; 0.5 mol%)
And 2.9g of rac-BINAP; a (4.6 mmol 1.5 mol%) was added and after degassing for an additional 2 minutes 35.4 grams of ^Bu t ONa the (368 mmol) was added and heated to 80 ° C. 18 hours .. HPLC showed complete conversion, the reaction mixture was cooled to room temperature, filtered and the resulting filtered cake was washed with 2 x 100 ml of toluene. The combined filtrate was extracted twice with 2 x 150 ml 15 wt% NaCl, dried over Na ₂ SO ₄ , added activated carbon, refluxed for 30 minutes, filtered twice and evaporated to 140. 7
Grams of brownish oil (4- [2- (2,4-dimethyl-phenylsulfanil))
-Phenyl] -BOC-piperazine) was obtained. 300 ml of MeO with this crude oil
Dissolved in H and 200 ml of 6M HCl (aq.), refluxed for 1 hour, then HPL
C showed complete deprotection. After cooling to room temperature, methanol was removed by vacuum in a rotary evaporator, 200 ml of concentrated NaOH (pH was 13-14) was added, and the resulting mixture was then stirred with 1000 ml of EtOAc for 15 minutes. .. Collect that organic phase,
Extracted with 300 ml 15 wt% brine, dried over Na ₂ SO ₄ and added to a solution of 46.3 g fumaric acid (399 mmol) in 300 ml 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 EtOAc and 100 ml acetone and dried under vacuum (50 ° C.) to give a total yield of 81% as a white powder.
03.2 g of 1- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine fumarate (249 mmol) was obtained, which fumarate had 99% purity by LC-MS. .. The fumarates, using EtOAc _{/ H} 2 O _/ conc. NaOH, the free base (1- [2- (2,4-dimethyl - phenylsulfanyl) - phenyl] -
Conversion to piperazine), the organic phase washed with brine, dried over Na ₂ SO ₄ , filtered and precipitated by adding 34 ml of 48 wt% HBr (aq.) To the filtrate. Was caused. The solid was collected, treated with boiling of H _{2 O} 1000 ml, which was formed slurry and cooled to room temperature. This final product (1- [2- (
2,4-Dimethyl-Phenylsulfanil) -Phenyl] -Piperazine Hydrobromid)
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 (measured value) 57.11; 6.15; 7.35].

Example 23

815g of NaOBu ^t (8.48mol), piperazine of 844g (9.8mol)
, 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 and continued stirring for 30 minutes, and finally 390.8 g of 2,4-dimethylthiophenol (390.8 g).
2.83 mmol) was added with 1.5 L of toluene. The suspension was heated to reflux and continued to reflux for 5 hours. The reaction mixture was cooled overnight. After adding 2 L of water and stirring for 1 hour, the mixture was filtered through a filtration aid. Then, the obtained filtrate was washed with 3 × 1 L brine. After this, the combined aqueous phase was extracted with 600 ml of toluene.
After this, the combined toluene phase was 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-phenylsulfanil) -phenyl] -piperazine hydrobromid) was collected by filtration and under vacuum (60 ° C.).
) To give 895 g (84% yield) of product.

Example 24

40.76g of _{^{NaOBu t (424.1mol), Pddba 2}} (0 of 0.33g.
57 mmol) and 0.68 g of rac-BINAP (1.09 mmol) in 200 m.
Stirred with l of toluene. Then 42 g of 2-bromo-iodobenzene (362)
mmol) and 19.54 g of 2,4-dimethylthiophenol (362 mmol) were added with 50 ml of toluene. The suspension was heated to reflux and continued to reflux overnight. HPLC analysis showed intermediate products (1- (2-bromo-phenylsulfanil) -2,4-
It showed a complete conversion to dimethyl-benzene). The reaction mixture was cooled to room temperature and filtered through a filtration aid. NaOBu ^t (424.1mmol of 40.76g The filtrate
), 42.2 g of piperazine (489.9 mmol), 0.33 g of Pddba ₂ (0.
It was added to a mixture of 57 mmol) and 0.68 g of rac-BINAP (1.09 mmol), heated and refluxed for 2 hours. The reaction mixture was cooled overnight. 100 ml of water was added and the aqueous phase was separated and removed. The organic phase is filtered through a filtration aid and then
The resulting filtrate was washed with 3 x 80 ml brine. After this, 5 aqueous phases that combine them
Extracted with 0 ml of toluene. Then, the toluene phase in which they are combined is 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-phenylsulfanil) -phenyl] -piperazine hydrobromid) was collected by filtration and dried under vacuum (60 ° C.) to give 40.18 g. An off-white powder was obtained (75% yield).

Example 25

40.76g of _{^{NaOBu t (424.1mmol), Pddba 2}} (0 of 0.33g
.. 57 mmol) and 0.68 g of rac-BINAP (1.09 mmol) 200
Stir 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 with 50 ml of toluene. The suspension was heated to reflux and continued to reflux overnight. HPLC analysis shows the intermediate product (1- (2-bromo-phenylsulfanil))
It showed a complete conversion to −2,4-dimethyl-benzene). The reaction was cooled to 50 ° C. and 42
.. 2 g of piperazine (489.9 mmol) was added with 100 ml of 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 a filtration aid. The resulting filtered cake was then washed with 50 ml of toluene.

After the aqueous phase is separated and removed, the organic phase is removed with 3 x 25 ml brine and 25.
Washed with ml of water. After this, the combined aqueous phase was extracted with 30 ml of toluene.
The combined toluene phase is then heated to 70 ° C., followed by 16.46 ml of 48.
wt% HBr (aq.) And 8.23 ml of water were added. The resulting mixture was cooled to room temperature overnight. The final product (1- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine hydrobromid) was collected by filtration under vacuum (60 ° C.).
By drying in, 46.8 g (87% yield) of product was obtained.

Example 26: Effect of acetylcholine on extracellular levels in the brain of free-moving rats Method 1- [2- (2,4-dimethylphenylsulfanil) phenyl] piperazin,
HBr salt was administered.

Animals We used male Sprague-Dawley rats weighing 275-300 g when first weighed. These animals have free access to food and tap water under conditions controlled to obtain regular room temperature (21 ± 2 ° C) and humidity (55 ± 5%). , Breeding under a 12 hour light / dark cycle.

Surgery and microdialysis experiments Rats were anesthetized with Hypnolm / Dormicum (2 ml / kg) and ventral hippocampus (coordinates: 5.6 mm posterior to Bregma, -5.0 mm lateral, 7.0 mm ventral to dura mater) or Intracerebral guide cannula (CMA / 12) for the purpose of positioning the dialysis probe tip in the frontal cortex (coordinates: 3.2 mm anterior to Bregma; lateral, 0.8 mm; 4.0 mm ventral to the dura)
Was stereotactically embedded in the brain. The guide cannula was secured with an anchor screw and acrylic cement. Animal body temperature is monitored by a rectal probe, 37
It was maintained at ° C. The rats were allowed to recover from surgery for 2 days and were kept in cages one by one. On the day of the experiment, the microdialysis probe (CM) through the guide cannula mentioned above.
A / 12, diameter 0.5 mm, length 3 mm) was inserted.

The probes were connected to the microinjection pump via a dual channel swivel. Filtered Ringer's solution (containing 0.5 μM neostigmine, 1)
45 mm NaCl, 3 mM KCl, 1 mM MgCl ₂ , 1.2 mM CaCl ₂ )
Perfusion of the microdialysis probe in the brain is started shortly before the probe is inserted into the brain, 1 μl /
It was continued for the duration of the experiment at a constant flow rate of minutes. After 180 minutes of stabilization, the experiment was started. The dialysate was collected every 20 minutes. After the experiment, these animals were sacrificed, their brains were removed, frozen and sliced to confirm probe placement.

The compound was dissolved in 10% HPbetaCD and injected subcutaneously (2.5-10 mg /).
kg). Dose is expressed as mg / kg body weight of salt. The compound was administered in an amount of 2.5 ml / kg.

Analysis of dialysate acetylcholine Concentrations of acetylcholine (ACh) in dialysate are 100 mM disodium hydrogen phosphate, 2.0 mM octane sulfonic acid, 0.5 mM tetramethylammonium chloride and 0.005% MB (ESA). Analyzed by HPLC with electrochemical detection using a mobile phase of pH 8.0 consisting of. The pre-column enzyme reactor (ESA) containing immobilized choline oxidase is the analytical column (ESA ACH-250); flow rate 0.
Infused sample (10 μl) prior to separation of ACh at 35 ml / min, temperature: 35 ° C.
) Excluded 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, then choline to betaine and H ₂
Converted to O ₂ . The latter H ₂ O ₂ was electrochemically detected by using a platinum electrode (analytical cell: ESA, model 5040).

Representation of data In single infusion experiments, the mean of the three consecutive ACh samples immediately prior to compound administration was used as the basal level in each experiment, and the data were basal (100% normalized mean basal infusion). Converted to a percentage of the previous value).

Results The compound significantly increased extracellular levels of ACh in the frontal 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-dimethylphenylsulfanil).
It was a phenyl] piperazine HBr salt.

We investigated the effect 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). Upon re-exposure 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 has been well studied, and several studies have shown 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; Behave. Neurosci. , 106, 274-285, 1992
].

Animals and Drugs Charle, 2 animals per cage under a 12 hour light / dark cycle
Adult male Sprague-, obtained from s River Laboratories
Dawley rats (training weight, 250-300 g) were used. Food and water were free to consume. The rats were used one week after arrival. The compound was dissolved in 10% HPbetaCD and injected subcutaneously. The drug is 2.
It was administered in an amount of 5 ml / kg.

Equipment training and testing were performed in a soundproof chamber (30 x 20 x 40 cm) housed in an isolated room and connected to a ventilation system. Lighting 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 before training and testing
It was cleaned with an ethanol solution of. Video cameras have enabled observation and recording of training session behavior in offline analysis.

Acquisition and Retention Test During acquisition, animals are allowed to freely explore the new environment during a 1 minute acclimation period, which 1 minute acclimation period is given through a chargeable lattice floor 1 It ended at the same time as the inevitable foot shock (unconditional stimulation, US). The footshock had a duration of 2 seconds and an intensity of 0.75 mA. Animals were kept in the conditioning chamber for an additional 60 seconds after US. Freezing behavior was scored during the first 58 seconds (pre-shock acquisition; experimenters were not informed of group information) to determine the baseline-freezing behavior response to this situation. At the end of the acquisition, the animal was gently removed and placed in its original cage. Twenty-four hours later, the same animal was re-entered into the training situation described above (fear conditioning chamber) and a 2-minute retention test was performed. No foot shock was applied during this period. Experimenters who were not informed about the group scored freezing behavior during the entire study period and presented it as a percentage of the total study period.

Results and Examination The Effect of Compounds on Contextual Fear Conditioning in Rats The effects of compounds on Contextual Fear Conditioning in Rats are: (i) Acquisition (drug application prior to acquisition, FIG. Drug application prior to testing, Figure 21) and (ii)
i) Fixed (drug application immediately after acquisition, FIG. 22) was investigated. 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. FIG. 20 shows the training period (58 before the food shock).
It depicts the acquisition of freezing behavior in retention tests during (seconds) and after 24 hours. The following findings were found:
• The compound does not affect baseline freezing behavior prior to foot shock at any dose tested.

The compound at a dose of 5 mg / kg tends to increase the time spent on freezing behavior during memory retention studies performed 24 hours after acquisition (39.24 ± 13.76%).
, N = 6, vs. 24.30 ± 4.40% in animals treated with excipients, n = 16).

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

As described in FIG. 20, this fear conditioning model is a standard procedure described in the literature for learning and memory studies. To further elucidate the acute effect of this drug on memory recall, compounds (5 mg / kg, 10 mg / kg and 20 mg / kg) were applied 1 hour prior to the retention test. The compound was observed to suppress the development of freezing behavior during memory studies at a dose of 5 mg / kg (12.86 ± 3.57%, n = 9, vs, in animals treated with excipients. 33.61 ± 4.29%, n = 13, p <0.05) (Fig. 21).

As mentioned above, the compound itself does not affect baseline freezing behavior prior to the start of the US (Figure 20), so the seemingly most plausible hypothesis is:
It is hypothesized that the effect observed in FIG. 21 is due to the anxiolytic effect. Conditioned memory is assessed by freezing behavior, a response reduced by compounds with potential anxiolytic effects. This experiment showed that the compound given immediately before memory recall had an anxiolytic effect, and therefore the increase in freezing behavior shown in FIG. 20 was due to the anxiolytic effect of the compound. It is unlikely that it is a thing.

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。

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

The present invention may include the following aspects.
[1]
1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazin and a pharmaceutically acceptable salt thereof, provided that the compound is not a free base in non-crystalline form.
[2]
Compounds are hydrobromide, hydrochloride, mesylate, fumarate, maleate, meso-tartrate, L- (+)-tartrate, D- (-)-tartrate, sulfate, phosphorus The compound according to claim 1, which is a hydrochloride or nitrate.
[3]
The compound according to claim 1 or 2, wherein the compound is crystalline.
[4]
3. Claim that the compound has an XRDP as shown in any of FIGS. 1-17.
The compound described in.
[5]
The compound according to claim 1, which is 1- [2- (2,4-dimethylphenylsulfanil) -phenyl] piperazine hydrobromic acid in crystalline form.
[6]
XR at compound at about 6.89, 9.73, 13.78 and 14.64 (° 2θ)
The compound according to claim 5, which has PD reflection.
[7]
The compound according to 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,
The compound according to claim 6, which has a particle size distribution corresponding to the above.
[9]
The compound according to any one of claims 1 to 8, for use in treatment.
[10]
A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, together with a pharmaceutically acceptable excipient.
[11]
The composition according to claim 10, which comprises the compound according to claim 5 or 6.
[12]
Tablets produced by the wet granulation method, and anhydrous calcium hydride phosphate,
The composition according to claim 10, which comprises corn starch, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, talc and magnesium stealth.
[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 stealth: 0.5-2%
12. The composition according to claim 12.
[14]
HBr salt: about 5%
Anhydrous Calcium Hydrogen Phosphate: Approximately 39%
Corn starch: about 20%
PVP-VA copolymer: about 3%
Microcrystalline Cellulose: Approximately 25%
Sodium starch glycolate: about 3%
Talc: about 4%
Magnesium stealth: about 1%
12. The composition according to claim 12.
[15]
Emotional Disorder, Depression, Major Depressive Disorder, Postpartum Depression, Bipolar Disorder, Alzheimer's Disease, Psychiatric Disorder, Cancer, Aging or Parkinson's Depression, Anxiety, Generalized Anxiety Disorder, Social Anxiety Disorder, Compulsive Disorders, Panic Disorders, Panic Attacks, Fear, Social Anxiety, Square Fear, Stress Urinary Incontinence, Vomiting, IBS, Eating Disorders, Chronic Pain, Partial Respondents, Treatment Resistant Depression, Alzheimer's Disease, Cognition A method of treating disorders selected from dysfunction, ADHD, melancholy, PTSD, facial depression, sleep aspiration, alcohol, nicotine or carbohydrate craving, substance abuse, and alcohol or drug abuse in need of treatment. A method of treatment comprising administering to a patient a therapeutically effective amount of the compound according to any of claims 1-8.
[16]
Emotional Disorders, Depression, Major Depressive Disorders, Postpartum Depression, Bipolar Disorders, Alzheimer's Disease, Mental Illness, Cancer, Aging or Parkinson's Depression, Anxiety, Generalized Anxiety Disorder, Social Anxiety Disorder, Compulsiveness Disorders, Panic Disorders, Panic Attacks, Fear, Social Anxiety, Square Fear, Stress Urinary Incontinence, Vomiting, IBS, Eating Disorders, Chronic Pain, Partial Respondents, Treatment-Resistant Depression, Alzheimer's Disease, Cognition Any of claims 1-8 for producing a drug for treating dysfunction, ADHD, melancholy, PTSD, facial depression, sleep aspiration, alcohol, nicotine or carbohydrate craving, substance abuse, or alcohol or drug abuse. Use of the compounds listed in Crab.
[17]
Emotional Disorders, Depression, Major Depressive Disorders, Postpartum Depression, Bipolar Disorders, Alzheimer's Disease, Mental Illness, Cancer, Aging or Parkinson's Depression, Anxiety, Generalized Anxiety Disorder, Social Anxiety Disorder, Compulsiveness Disorders, Panic Disorders, Panic Attacks, Fear, Social Anxiety, Square Fear, Stress Urinary Incontinence, Vomiting, IBS, Eating Disorders, Chronic Pain, Partial Respondents, Treatment Resistant Depression, Alzheimer's Disease, Cognition Claims 1-8 for use in the treatment of disorders selected from dysfunction, ADHD, melancholy, PTSD, facial depression, sleep aspiration, alcohol, nicotine or carbohydrate craving, substance abuse, and alcohol or drug abuse. The compound according to any.
[18]
Less than:

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.
Compound II

[In the formula, R'represents hydrogen or a monovalent metal ion], formula III

Compounds of [where X ₁ and X ₂ independently represent halogens] and formula IV

The method described above comprising reacting with a compound of [where R represents hydrogen or protecting group].
[19]
Compound II and Compound III are reacted in the first reaction and, in some cases, the reaction product of the first reaction.

Is isolated and purified, followed by subsequent reaction with compound IV, claim 1.
8. The method according to 8.
[20]
Compound II, Compound III and Compound IV are mixed together at the beginning of the method.
18. The method of claim 18.
[21]
The method of any of claims 18-20, wherein X ₁ and X ₂ independently represent Br or I.
[22]
21. The method of claim 21, wherein X ₁ represents Br and X ₂ represents I.
[23]
The method according to any one of claims 18 to 22, wherein the solvent is an aprotic solvent.
[24]
The method according to any one of claims 18 to 23, wherein the solvent is selected from toluene, xylene, triethylamine, tributylamine, dioxin or N-methylpyrrolidone.
[25]
24. The method of claim 24, wherein the solvent is toluene.
[26]
The method according to any one of claims 18 to 25, wherein the palladium source is selected from Pdba ₂ , Pd (OAc) ₂ or Pd ₂ dba ₃ .
[27]
26. The method of claim 26, wherein the palladium source is Pddba ₂ or Pd ₂ dba ₃ .
[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)-
Phosphine;
The method according to any one of claims 18 to 27, which is selected from.
[29]
28. The method of claim 28, wherein the phosphine ligand is rac-BINAP.
[30]
The base is NaO (t-Bu), KO (t-Bu), Cs ₂ CO ₃ , DBU or DA.
The method of any of claims 18-28, selected from the BCO.
[31]
The method of claim 30, wherein the base is NaO (t-Bu).
[32]
The method according to any one of claims 18 to 31, wherein R represents hydrogen.
[33]
The method of any of claims 18-31, wherein R represents a protecting group selected from Boc, Bn, Cbz, C (= O) Oet or Me.
[34]
The method according to any one of claims 18 to 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]
The following steps:
a. Steps of dissolving or dispersing 1 to 1.5 equivalents of compounds I, II and III in toluene to give mixture A;
b. A step of adding 1-2 mol% Pddba ₂ and 1-2 mol% rac-BINAP together with 2-3 equivalents of NaO (t-Bu) to Mixture A to obtain Mixture B, wherein compound II. And the step of heating the mixture B to about 100 ° C. until complete conversion of III;
c. The temperature of the mixture obtained in step b is about 1 until compound IV is completely converted.
Steps to raise to 20 ° C; and d. In some cases, when compound IV is a protected piperazine, the step of removing the protecting group by adding an aqueous acid solution;
20. The method of claim 20.
[37]
1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-1-iodo-benzene (
Alternatively, 1,2-dibromo-benzene) and piperazine are dispersed in toluene, followed by
2-5 equivalents of NaO (t-Bu) dispersed in toluene and 1-2 mol% Pd ₂ d
Add ba ₃ and rac-BINAP to obtain a mixture and heat the mixture to 100-130 ° C. for 2-10 hours to produce product 1- [2- (2,4-dimethyl-phenylsulfanil)-.
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 an aqueous HBr solution to obtain the corresponding hydrobromic acid addition salt. The method according to claim 37.
[39]
2-5 equivalents of NaO (t-Bu), 2-5 equivalents of piperazine, 0.2-0.6 mol% Pddba ₂ and 0.6-1 mol% rac-BINAP are dispersed in toluene. Mixture A'is obtained, and about 1 equivalent of 2-bromo-iodobenzene is added to the mixture A'to mixture B.
'Is obtained, 1 equivalent of 2,4-dimethylthiophenol is added to the mixture B', and the obtained mixture is heated under reflux for 3 to 7 hours to 1- [2- (2,4-dimethyl-phenylsulfanil).
-Phenyl] -The method of claim 20, wherein piperazine is obtained.
[40]
The resulting mixture was heated to reflux for 4-6 hours and, in a subsequent step,
39. The method of claim 39, wherein the resulting product is followed by a step of further reacting with an aqueous HBr solution to obtain the corresponding hydrobromic acid addition salt.
[41]
Product HBr aqueous solution to obtain the corresponding hydrobromic acid salt

The product is in a purified form, with additional steps added to.
The method according to any one of claims 18 to 37.
[42]
A method for producing 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine hydrobromide salt, which is 1 to 1.5 equivalents of 2,4-dimethyl-thiol. , 1-bromo-1-iodo-benzene (or 1,2-dibromo-benzene) and piperazine in toluene, followed by 2-5 equivalents of Na dispersed in toluene.
O (t-Bu) and 1-2 mol% Pd ₂ dba ₃ and rac-BINAP were added to give a mixture, and the mixture was heated to reflux for 3-5 hours to produce product 1- [2- (2,4). -Dimethyl-Phenylsulfanyl) -Phenyl] -Piperazine is obtained, and the piperazine is further reacted with an aqueous hydrobromic acid solution.
[43]
A method for producing 1- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine hydrobromic acid addition salt, wherein 2 to 5 equivalents of NaO (t-Bu), 2 to
5 equivalents of piperazine, 0.2-0.6 mol% Pddba ₂ and 0.6-1 mol% r
Ac-BINAP is dispersed in toluene to obtain a mixture A', and about 1 equivalent of 2-bromo-iodobenzene is added to the mixture A'to obtain a mixture B', and 1 equivalent of 2, is added to the mixture B'. 4
-Dimethylthiophenol was added and the resulting mixture was heated to reflux for 4-6 hours to give 1- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine, which further odors the piperazine. The above method of reacting with an aqueous hydrobromic acid solution.

Claims (24)

Less than:

In the presence of a solvent, a base, and a palladium source consisting of a palladium source and a palladium catalyst consisting of 2,2'-bis-diphenylphosphanyl- [1,1'] binaphthalenyl (rac-BINAP). Compound I at temperatures between 60 ° C and 130 ° C
I

[In the formula, R'represents hydrogen or a monovalent metal ion], formula III

Compounds of [where X ₁ and X ₂ independently represent halogens] and formula IV

The method described above comprising reacting with a compound of [where R represents hydrogen or protecting group]. Less than:

In the presence of a solvent, a base, and a palladium source consisting of a palladium source and a palladium catalyst consisting of 2,2'-bis-diphenylphosphanyl- [1,1'] binaphthalenyl (rac-BINAP). Compound I at temperatures between 60 ° C and 130 ° C
I

[In the formula, R'represents hydrogen or a monovalent metal ion] and Compound III

[In the formula, X ₁ and X ₂ independently represent halogens] are reacted in the first reaction and the reaction product in the first reaction.

Is isolated, followed by the reaction product and compound IV at temperatures between 60 ° C and 130 ° C in the presence of a solvent, base, and a palladium catalyst consisting of a palladium source and rac-BINAP.

The method described above, wherein a subsequent reaction with [in the formula, R represents hydrogen or a protecting group] is carried out. Compound II, Compound III and Compound IV are mixed together at the beginning of the method.
The method according to claim 1. The method according to any one of claims 1 to 3, wherein X ₁ and X ₂ independently represent Br or I. The method of claim 4, wherein X ₁ represents Br and X ₂ represents I. The method according to any one of claims 1 to 5, wherein the solvent is an aprotic solvent. The method according to any one of claims 1 to 6, wherein the solvent is selected from toluene, xylene, triethylamine, tributylamine, dioxin or N-methylpyrrolidone. The method according to claim 7, wherein the solvent is toluene. The method according to any one of claims 1 to 8, wherein the palladium source is selected from Pddba ₂ , Pd (OAc) ₂ or Pd ₂ dba ₃ . The method of claim 9, wherein the palladium source is Pddba ₂ or Pd ₂ dba ₃ . The base is NaO (t-Bu), KO (t-Bu), Cs ₂ CO ₃ , DBU or DA.
The method according to any one of claims 1 to 10, which is selected from BCO. The method of claim 11, wherein the base is NaO (t-Bu). The method according to any one of claims 1 to 12, wherein R represents hydrogen. The method of any of claims 1-12, wherein R represents a protecting group selected from Boc, Bn, Cbz, C (= O) OEt or Me. The method according to any one of claims 1 to 14, wherein R'is hydrogen. The method according to any one of claims 1 to 15, wherein the temperature is between 80 ° C. and 120 ° C. The following steps:
a. Steps of dissolving or dispersing 1 to 1.5 equivalents of compounds II, III and IV in toluene to give mixture A;
b. A step of adding 1-2 mol% Pddba ₂ and 1-2 mol% rac-BINAP together with 2-3 equivalents of NaO (t-Bu) to Mixture A to obtain Mixture B, wherein compound II. And the step of heating the mixture B to 100 ° C. until complete conversion of III;
c. The temperature of the mixture obtained in step b is 12 until compound IV is completely converted.
Steps to raise to 0 ° C; and d. In some cases, when compound IV is a protected piperazine, the step of removing the protecting group by adding an aqueous acid solution;
3. The method according to claim 3. 1-1.5 equivalents of 2,4-dimethyl-thiophenol, 1-bromo-2-iodo-benzene (or 1,2-dibromo-benzene) and piperazine are dispersed in toluene, followed by in toluene. 2-5 equivalents of NaO (t-Bu) dispersed and 1-2 mol% P
d ₂ dba ₃ and rac-BINAP were added to give a mixture and the mixture was 100-13.
The method of claim 3, wherein the product 1- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine is obtained by heating to 0 ° C. for 2-10 hours. The mixture is heated to reflux for 3-5 hours, followed by a subsequent step in which the resulting product is further reacted with an aqueous HBr solution to obtain the corresponding hydrobromic acid addition salt. The method according to claim 18. 2-5 equivalents of NaO (t-Bu), 2-5 equivalents of piperazine, 0.2-0.6 mol% Pddba ₂ and 0.6-1 mol% rac-BINAP are dispersed in toluene. Mixture A'is obtained, and 1 equivalent of 2-bromo-iodobenzene is added to the mixture A'to mixture B'.
1 equivalent of 2,4-dimethylthiophenol was added to the mixture B', and the obtained mixture was heated under reflux for 3 to 7 hours to 1- [2- (2,4-dimethyl-phenylsulfanil)-.
The method of claim 3, wherein phenyl] -piperazine is obtained. The resulting mixture was heated to reflux for 4-6 hours and, in a subsequent step,
20. The method of claim 20, wherein the resulting product is followed by a step of further reacting with an aqueous HBr solution to obtain the corresponding hydrobromic acid addition salt. Product HBr aqueous solution to obtain the corresponding hydrobromic acid salt

The product is in a purified form, with additional steps added to.
The method according to any one of claims 1-18. A method for producing 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine hydrobromide salt, which is 1 to 1.5 equivalents of 2,4-dimethyl-thio. Phenol, 1-bromo-2-iodo-benzene (or 1,2-dibromo-benzene) and piperazin were dispersed in toluene, followed by 2-5 equivalents of NaO (t-Bu) dispersed in toluene. And 1-2 mol% Pd ₂ dba ₃ and rac-BINAP were added to obtain a mixture, and the mixture was heated under reflux for 3-5 hours to produce product 1- [2- (2,4-dimethyl-phenylsulfanyl). -Phenyl] -Phenylpiperazine is obtained, and the piperazine is further reacted with an aqueous hydrobromic acid solution, as described above. A method for producing 1- [2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine hydrobromic acid addition salt, wherein 2 to 5 equivalents of NaO (t-Bu), 2 to
5 equivalents of piperazine, 0.2-0.6 mol% Pddba ₂ and 0.6-1 mol% r
Ac-BINAP is dispersed in toluene to obtain a mixture A', and 1 equivalent of 2 is added to the mixture A'.
-Bromo-iodobenzene was added to give mixture B', and 1 equivalent of 2,4- to the mixture B'.
Dimethylthiophenol was added and the resulting mixture was heated to reflux for 4-6 hours 1
-[2- (2,4-dimethyl-phenylsulfanil) -phenyl] -piperazine,
The method of further reacting the piperazine with an aqueous hydrobromic acid solution.

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