TW200817329A - Compounds with combined serotonin and norepinephrine reuptake inhibition - Google Patents

Abstract

Crystalline forms of4-[2-(4-methylphenylsulfanyl)-phenyl]piperidine and salts thereof are provided e.g. for the treatment of neuropathic pain.

Description

200817329 IX. DESCRIPTION OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to the use of a compound j for the treatment of Compound j. , including the pharmaceutical composition of Compound I, and Compound I in the manufacture of a medicament [Prior Art] The feeling of pain is transmitted directly to a specific receptor in the brain than the signal from the injured part of the body', Pain is proportional to injury. More specifically, the surrounding tissue is injured and harms God and menstruation, which may cause changes in the central nervous system involved in pain perception, affecting subsequent pain sensitivity. The neural plasticity can cause the towel to reflect a longer lasting harmful stimuli, and may be manifested by, for example, chronic pain, that is, the feeling of pain, even after the harmful stimuli have stopped, or manifested by hyperalgesia, ie, plus Stimulating reaction, which is normal and painful. Among the more mysterious and dramatic examples are the phantom limbs, that is, the limbs that have been previously amputated, and the pain of performance. A recent review of central nervous system plasticity and pain, see MelZaCk et al., Ann. Ν·Υ Acad Sci., 933, 157-174, 2001. Fe pain, such as neuropathic pain, manifests in a manner different from other types of pain, such as physical or visceral pain. The pain is often described as shooting, burning, nailing and acupuncture, numbness or tingling. Common causes of neuropathic pain include alcoholism, amputation, back, leg and hip problems, chemotherapy, diabetes, HIV, multiple sclerosis, spinal surgery, and herpes zoster infection. 200817329 A central component of chronic pain can explain why chronic pain, such as, for example, God, work: atypical pain often responds poorly to typical analgesics, such as non-steroidal anti-inflammatory (NSAIDS) and opioid analgesics. The tricyclic antidepressant (tca), represented by amitryhne, has become a standard for the treatment of neuropathic pain and is "mediated by the inhibition of the binding of serotonin and norepinephrine transporter. The effect [(: 1 vs. Th^., 26, % 979, 2004]. In order to treat neuropathic pain clinically, a so-called dual-acting antidepressant has been used, which resorbs both serotonin and norepinephrine. There are inhibitory effects [Human Psych〇pharm·, 19, s2i_s25, 2004]. Examples of dual-acting antidepressants are venlafaxine and duloxetine, and such antidepressants are often referred to as SNRI. There is a lack of information on the use of selective serotonin reuptake inhibitors (SSRIs) for neuropathic pain, but usually implies limited effects ci^· PharmacoL, 96, 399_4〇9, 2〇〇5]. In fact, it has been hypothesized Ssri, s 匕 itself is slightly anti-nociceptive, but the inhibition of serotonin transporter increases the antinociceptive effect of norepinephrine reuptake inhibition. The idea was reviewed in 22 animals and 5 human studies Support, the study showed that SNRI, s has superior antinociceptive effects compared to norepinephrine reuptake inhibitors, which once again outperformed SSRI [Pain Med· 4, 31〇_ 316, 2000] 〇Recently on 5- The data for the HT3 antagonist ondansetron (〇dansetr〇n) suggests that 5-HT3 antagonists may have analgesic effects and can therefore be used to treat neuropathic pain [Anesth· Analg·, 97, 1474-1478, 2003] 〇200817329 However, the use of tricyclic antidepressants is associated with known anticholinergic side effects such as drowsiness, anxiety, insomnia, and cognitive and memory difficulties. Therefore, this technique requires finding another treatment for neuropathic pain. The International Patent Application, which is hereby incorporated by reference in its entirety by reference in its entirety, the disclosure of the disclosure of the the the the the the the the the the the the the the It is an inhibitor of serotonin transport, protein and serotonin receptor 2C (5-HT2C), and it can be used to treat mood disorders such as depression and anxiety. SUMMARY OF THE INVENTION The present inventors have unexpectedly discovered that In addition to the well-understood pharmacological profile, 4-[2-(4-tolylsulfanyl)-phenyl]piperidine is a potent inhibitor of serotonin reuptake and norepinephrine reuptake, serotonin receptor An antagonist of 3(5_HT3), an antagonist of serotonin receptor 2Α(5·ΗΤ2Α), and an inhibitor of q 1 adrenergic receptor, and thus the compound itself can be used to treat, for example, chronic pain. Accordingly, the present invention relates to a compound which is 4-[2-(4-methylphenyl-sulfanyl)phenyl]piperidine in crystalline form, and a pharmaceutically acceptable salt thereof, as long as the The compound is not a '[2_(4-methylphenyl-sulfanyl)phenyl]-piperidine hydrochloride addition salt. In a specific fact, the invention relates to a compound for use in therapy. In a specific aspect, the invention relates to a method of treatment comprising administering to a patient in need thereof a therapeutically effective amount of Compound I. In a specific fact, the invention relates to a pharmaceutical composition comprising a compound of the formula 2008 17329. In the specific facts, the present invention relates to compounds

Use on. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to Compound I, which is a crystalline form of 4 [2 4 thiol-alkyl)phenyl]anthracene, and As long as the compound is not a hydrochloric acid addition salt, the structure of 4"?M m ^ ^ L2-(4-methylphenylsulfanyl)-phenyl]piperidine is

The pharmacological rounds of the compounds of the present invention are described in the Examples as outlined below. The compound is an inhibitor of serotonin and norepinephrine reuptake; they inhibit serotonin from 胄2A, 2C*3; and they inhibit "adrenergic receptors. In a particular fact, the pharmaceutically acceptable salt An acid addition salt of a non-toxic acid. The salt includes salts made of organic acids, such as maleic acid, fumaric acid, stupid acid, ascorbic acid, albino acid, oxalic acid, Bis-arylene salicylic acid, decanesulfonic acid, ethane disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, 8 200817329 malonic acid, almond acid, Cinnamic acid ^ ^ ^ ^ ^ ^ 彳T Kangxi aspartic acid, stearic acid, chlorination I Yikang 3, glycolic acid, cake face lean m ^ ^ basal formic acid, glutamic acid, benzene Sulfonic acid, base acid acetic acid, and 8# and 8_Nalan base, for example, 8-bromine tea can be made of inorganic acid, such as hydrobromide, xyl base t 7Γ ^ t λΑ , -, 丨LI, amine sulfonic acid , phosphoric acid and nitronium. In the table of κ application Id (Table υ) r rate other useful salts. In a specific fact _, this & addition salt. θ The chemical substance, i.e., the formula "is in a specific fact, the present invention and especially the 1:1 salt. The compound of the formula is a DL_lactic acid addition salt. In a specific fact, a salt, and particularly a 1: sulfonium salt. In a specific fact, and especially a 1:1 salt. The compound of the present invention is L•aspartic acid addition The compound of the present invention is a valine acid addition salt, and the compound of the present invention is a glutaric acid addition salt in a specific fact and particularly a 1:1 salt. In a specific fact, the compound of the present invention is a malonic acid addition salt, and in particular it is found to exist in the form of two polymorphic modifications. 'Based on a lower solubility, it is believed that the 6 form is the most stable. . ...in the specific fact, the compounds of the invention are in purified form. The term "deformation" is intended to mean that the compound is substantially free of other forms of other compounds, i.e., polymorphic beta oral dosage forms of the compound, and especially lozenges and capsules, usually The patient and the physician's rut are more compliant because of the easy administration of the drug. For the key agent and capsule 200817329, the active ingredient is preferably crystalline. The crystal of the present invention may exist in the form of a solvate, that is, in the crystal. The bath molecule forms part of the crystal structure. The solvate can be formed from water, and in the case of the case, the solvate is often referred to as a hydrate. Alternatively, other glutamine can be used to form a solvate, such as For example, the exact amount of ethanol, acetone or acetonitrile/capacitor composition will generally depend on the situation. For example, hydrates will generally release moisture as temperature increases or relative humidity decreases. It is generally considered that when conditions such as, for example, When the humidity changes, there is no change or only a slight change (the compound is more suitable for pharmaceutical formulations. Note that when precipitated from water, the HBr addition salt does not form hydration) And such as succinic acid, malic acid and tartaric acid addition salts. Some compounds are hygroscopic, that is, they absorb moisture when they are exposed to moisture. It is generally considered that hygroscopicity is not expected to appear in pharmaceutical formulations. In particular, dry formulations, such as the properties of the compounds in tablets and capsules. In a particular aspect, the invention provides crystals having low hygroscopicity. M is in the form of an oral dosage form using a crystalline active ingredient if the crystal is Ming I is indeed arrogant and profitable. In the context of the text, the definition of the word, the word, especially the syllabus is clearly defined, that is, the ratio between the ions forming the salt is The ratio in a small range, such as 1:1, 1:2, 2:1, 1:1:1, etc. In the specific fact, the compound of the present invention is a well-defined crystal. The solubility of the active ingredient, for the dosage form The choice is also important as it may have a direct impact on bioavailability. For oral dosage forms, higher solubility active ingredients are generally believed to benefit from increased bioavailability. Some patients, such as older ones Patient swallow Can have difficulties, 200817329 2: Service = solution may be a suitable alternative, to avoid the swallowing agent in order to limit the volume of oral droplet solution, there must be high / minute active ingredients in the solution, which again requires ancient A compound with a degree of resolution. As shown in Table _3, DL-lactic acid, L-aspartic acid, glutamic acid, glutaric acid and a propionic acid addition salts have extremely high solubility. The acicular crystals have a tendency to be difficult to handle in the production environment, such as over-cracking, because it becomes more difficult and time consuming. The precise crystal form of a particular salt can be visualized, for example, under the basin. According to the conditions of the salt, the HBr acid of the present invention is added to the ruthenium, and the ruthenium addition salt is grown into a needle-like, medium-matched crystal when it is precipitated from ethanol, acetic acid and propanol, but when HBr is added When the salt emerges from the water, the non-hydrated form of the crystal is not needle-like, which provides better filtration characteristics. ^ Table 3 also describes the pH obtained, that is, the pH in a saturated solution of the salt. . Hite is extremely important 'because moisture may not be completely avoided during storage' and the accumulation of wet milk will result in a decrease in pH in or on the mirror containing low salt & pH salts, which may reduce shelf life. In addition, if the tablet is produced by wet granulation, a salt having a low pH value may cause corrosion of the process e. The data in Table 3 suggests that tear, (10) and adipic acid addition salts may be dominant in this regard. In a specific fact, the compound of the invention is a HBr addition salt in crystalline form, especially in purified form. In a further specific case, the bismuth salt is in the X-ray powder diffraction pattern (XRPD) at about 6, 〇δ I4·81, 19.26. There is a peak at 25 and 38 °2, especially the HBr salt has XRPD as described in Figure 1. 11 200817329 In a specific fact, the compound of the invention is a crystalline form of dl_lactic acid addition salt (1:1), especially in purified form. In a further specific case, the DL-lactic acid addition salt is in the XRPD at about 5.30. , 8, 81 9.44 and 17·24 ° 2 have a peak, especially the DL lactic acid addition salt has xrpd as described in FIG. In a specific fact, the compound of the invention is a crystalline form of the W-glycolic acid addition salt (1:1), especially in purified form. In a further specific fact, the L-aspartate addition salt is non-complexed and is in the range of about n.〇5 in XR^PD. 2〇 16. 2〇6〇. There is one peak at 25 〇〇〇 2 ’', especially the L-aspartic acid addition salt of Yanhai, and the XRPD as described in Fig. 17 when mixed with Xiao L-aspartic acid. In a specific fact, the L-aspartic acid addition salt is a hydrate, especially in a purified form. In the specific case of further progress, Xiao L-aspartate addition brine II has a peak at about 7.8 〇〇, 13.8 〇〇, 14 1 〇〇, ΐ 9 63 〇 2θ in XRPD, especially The L-aspartic acid addition salt hydrate, when mixed with the 1 amine acid, has as described in Figure 18. In a specific fact, the compound of the present invention is a valeric acid addition salt (1:1) in the form of a crystalline form, in particular a purified form, ^ _ in a further specific case, the 縠The amine acid addition salt is at about 7.71 at XRPD φ, +丄', T'. , 14_01. 19.26. There is a peak at 22.572 牯, 牯 η 4 , and the methionine addition salt, when mixed with glutamic acid monohydrate, and /, XRPD as described in Fig. 19. T Double In a specific fact, the compound of the present invention is a ginary acid addition salt (1:1) in the form of π, day-day, especially in a purified form. In the case of the body, the malonic acid addition salt is in the α-form and is in the XRPD at about 10.77. 16.70. , 19·93°, 24.01. 2 (9 has a peak, or the malonic acid addition salt is not-formed, and in XRPD, at about 6.08°, 10.11., 18.25., 20.26.20) The peak, especially the malonic acid addition salt, has an XRPD as described in Figure 9 or 10.

In a specific fact, the compound of the invention is a crystalline form of a glutaric acid addition salt (1:1), especially in a purified form. In still further specific facts, the glutaric acid addition salt is in the XRPD at about 9.39. , 11.70. There are peaks at 14.05° and 14.58. 20, especially the glutaric acid addition salt has XRPD as described in Fig. 8. As mentioned above, the compounds of the invention are particularly suitable for the treatment of chronic pain. Chronic pain includes, for example, phantom limb pain, neuropathic pain, diabetic neuropathy, banded cancer post-neopathic neuralgia (PHN), wrist-associated sign syndrome (CTS), HIV neuropathy, and complex regional pain syndrome (CRps) , three nerve pain / three and neuralgia / three and neuralgia, surgery (such as post-analgesic), diabetic angiopathy, diabetes resistance related to capillary resistance, pain associated with angina p: Pain, toothache, headache, migraine, pain, bipolar neuralgia, temporomandibular joint syndrome meat damage, fibromyalgia syndrome, bone, painful muscle arthritis, cause of burn-related wounds = bone 2 Joint inflammation), sprained or fractured bone pain caused by wind; inflammation and monthly metastasis or unknown cause, gout, scutellaria, sputum exit syndrome, upper back pain or τ back pain (where; second fascia Pain, chest pain, caused by systemic 13 200817329 regional or primary spinal disease (spinal radiculopathy), pelvic pain, cardiac chest pain, non-cardiac chest pain, pain associated with spinal cord injury (SCI),Indications for central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain, or old-age pain. The compounds of the genus and sigma are useful for the treatment of mood disorders such as depression associated with the chronic pain indications listed above. International Association for Pain Research (Internati〇nal Ass〇ciati〇n the

Study 〇f Pain) (lASP) defines the pain, the uncomfortable feelings and emotional experiences associated with actual or possible tissue damage, or the deficiencies of the category of injury, (IASP's Chronic Pain Classification (1 tear)仙(五)(10)〇f chr〇nic

Pam), 2nd edition, IASP Press (2〇〇2), 21〇). Even if the pain is always subjective, + can classify its cause or syndrome. "Neuropathic pain, a subtype that is derogatory as a pain caused or caused by a primary lesion or dysfunction in the nervous system." Different subtypes of neuropathic pain are recognized by the IASP, and examples are • allodynia, which is defined as “pain that results from a stimulus that does not cause pain normally”. • Burning pain defines it as a syndrome of persistent burning pain, allodynia and hyperalgesia after traumatic neuropathy, often mixed with vasomotor and sweating dysfunction, and later nutritionally The change.” f 3 kmin derogatoryly means “in addition to feeling, increase sensitivity to stimulation”. "Nerve pain, which is defined as "pain in the nerves or nerves.", 200817329 • Neuritis, shame it i,,, ι & I am the inflammatory response of arsenic or nerves. • Neuropathy, which will be 1 佘 ★ 疋 ” ” ” ” 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 功能 在一 在一 在一 在一 在一 在一 rr rr rr rr rr rr rr rr rr rr rr rr rr rr rr Na and bilateral, it is multi-neuropathy. Neuropathy can be related to, for example, diabetes, in this case called diabetic neuropathy. Hyperalgesia, which is defined as, to increase the stimulation of normal pain. The response, • hyperalgesia, is defined as, the pain syndrome, characterized by an abnormal pain response to stimuli, especially repeated stimuli, and an increased threshold”. Stimulations that induce neuropathic pain may be mechanical or thermal. The unique pharmacological profile of the compounds of the invention makes them suitable for the treatment of other conditions not directly related to chronic pain. The 5_HT^ receptor is located, for example, on dopaminergic neurons, where activation exerts an enhanced inhibitory effect on dopamine release, while S-HLc antagonists result in an increase in dopamine content. The data provided in Example 2E shows that the compounds of the invention do cause a dose-dependent increase in extracellular dopamine content in the brain. In this context, it may be assumed that 5-HT2c antagonists are particularly suitable for the treatment of refractory treatments with selective serotonin reuptake inhibitors [Psychopharmacol· Bull., 39, 147-166, 2006]. This hypothesis is supported in several clinical studies that show that mirtazapine (combination of sir > sir] is an inhibitor of treatment for patients with inadequate clinical response (treatment for depression, TRD or refractory depression), It is better than using mri alone [Psychother· Psychosom·, 75, 139-153, 2006]. Miqiping is also 15 200817329 5-HT2 and 5-ΗΤ3 antagonists, this # _ with the combination of SHI and 5-HT3 antagonism The effect of serotonin reuptake inhibits 1 compound, such as the compound of the present invention, can be used to treat TRD, that is, the rate of deafness of the thumb, the reduction rate of the sputum, and the treatment of resistance depression In Examples 2F and 2G, the λα is now referred to as ">, showing that the compound of the present invention can cause an increase in the amount of forehead in the forehead, and in the pelt and ventral hippocampus. Extracellular content of choline. There is a long-term 矽戍% 务% = 仏 转 转 转 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 , , , , , , , , , , Usually refers to acetylcholinesterase inhibitors in the treatment of Alzheimer's disease Uses. In this context, it is believed that the compounds of the present invention can be used to treat Alzheimer's disease and cognitive impairment, and also to lie on the right side of the body. Mourn's disease is associated with cognitive impairment. Some depressed patients respond to treatments such as SSRI, in the sense that they have improved clinically relevant levels of depression, such as MADRD and HAMD, but still retain Other signs, such as sleep disorders and cognitive impairment. These patients are referred to hereinafter as partial responders before the present invention. Due to the effect of the above discussion on the acetylcholine content, the compounds of the present invention are expected to be in addition to depression. It can also be used to treat cognitive impairment. Clinical studies have shown that the compound prazrazin, which is an α-丨 adrenergic receptor antagonist, reduces sleep disorders [Bi〇l. Psychiatry, 61, 928-934 , 2007]. Moreover, it is also believed that the 5-Ht2a and 5-ΗΤκ antagonism of the compound of the present invention has a sedative, sleep-improving effect [Nenropharmacol, 33, 467-471, 1994], so the compound of the present invention It is used to treat partial responders, or to treat a compound with a compound of the invention. 16 200817329 Patients will reduce a fraction of partial responders. Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder. ADHD is characterized by the appearance Social trials and communication damage, and there are restrictions, repetitions or fixed behaviors. ADHD usually begins in children or adolescence, but the symptoms can be sustained to adulthood. Atosin, ding (at〇inoxetine) is currently only FDA Approved non-stimulants for the treatment of ADHD [Drugs, 64, 205-222, 2004]. Atoxetine is a norepinephrine reuptake inhibitor, and this suggests that the compounds of the invention are useful in the treatment of ADHD. In addition, the compounds of the present invention also have a sedative effect due to the alpha adrenergic receptors and 5-HT2 antagonism discussed above, which are beneficial for the treatment of adhD. Depression is a special subtype of depression and is often associated with severe depression; this type of depression is also known as depression. Depression is associated with anxiety, anxiety about the future, insomnia, and loss of appetite. Compounds that inhibit the reuptake of both serotonin and norepinephrine, such as, for example, venlafaxine, have been shown to be particularly costly in the treatment of patients with severe depression and sorrows [(10)(1)·

Anxiety, 12, 50-54, 2000]. As discussed above, compounds that exert 5_ht^ antagonism increase dopamine content, so such compounds are expected to be effective in treating depression [psychpharm· BuU·, 39, i47-166, 2006]. Furthermore, it is also expected that the adrenergic receptor 5-HT2 antagonism of the compound of the present invention can help normalize sleep, and thus the compound can be used for the treatment of depression. The FDA has recently approved sertraline and paroxetine, two SSRl, s, for the treatment of post-traumatic stress disorder (PTSD). Moreover, compounds having 5_cho 2-8 antagonistic activity are useful, 17 200817329 because they are expected to control disorders, insomnia, and temper in PTSD patients [Curr opinion Invest DrUg, 4, 37-41, 2003]. Thus, the compounds of the invention are expected to be useful in the treatment of pTSD. Hot flashes are signs associated with the transition period of menopause. Some women are affected by the hot red, to the extent of sleep or general activity, and need treatment. Hormone replacement therapy using estrogen has been established over the past decade, but concerns about side effects such as breast cancer and cardiac events have recently been expressed. Clinical trials of SSRI and SNRI have shown that these compounds have an effect on hot flashes, albeit worse than estrogen [j. Am Med ASS., 295, 2057-2071, 2006]. However, compounds that inhibit serotonin and/or norepinephrine reuptake, such as the compounds of the present invention, for treating hot flashes may be another treatment for women who are unable or unwilling to receive estrogen. Sleep apnea or obstructive sleep apnea hypopnea syndrome or obstructive sleep-respiratory disorder is a condition and its effective pharmaceutical treatment remains to be determined. However, several studies on animals suggest that 5_ht3 antagonists, such as the compounds of the invention, may be effective in therapeutic intervention [Sleep, 21, 131-136, 1998, Sleep, 8, 871, 2001]. It has recently been shown that the 5-HT3 antagonist ondansetron is effective in treating cravings and alcohol redness and drug abuse [Drug Ale. Depend., 84, 256-263, 2〇〇6; Pharmacol Therapeut, 111, 855-876, 2006]. This appears to support 5-HT3 antagonists, e.g., the compounds of the invention can be used to treat cravings such as sputum, sputum or carbohydrate cravings; and the idea of alcohol and drug abuse. Suggested uses for other 5-HT3 antagonists, including. Area vomiting, especially 200817329 Treatment caused by vomiting, eating disorders, such as binge eating disorder and irritable bowel syndrome (iBs) [Exp· 〇ριη· Ther· Targets, 11, 527-540, 2007]. It is also contemplated that the compounds of the present invention having a unique pharmacological profile can be used to treat affective disorders, depression, severe anxiety, postpartum anxiety, depression associated with bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease. Symptoms, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, panic attack, phobia, social phobia, wild phobia and stress urinary incontinence. In a specific fact, the present invention relates to the treatment of chronic pain, partial responders, treatment of depression, Alzheimer's disease, cognitive impairment, HD depression, PTSD, hot flashes, sleep apnea, alcohol, tobacco Alkali or carbohydrate cravings, substance abuse, alcohol or substance abuse, vomiting, eating disorders, IBS, affective disorder, depression, severe depression, postpartum depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis or pa A method of treatment for patients with need, such as patients with sinus, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, panic attack, phobia, social phobia, wild phobia or stress urinary incontinence Administration of a therapeutically effective amount of the compound. In a specific case, the patient who is to be treated for any of the diseases listed above has been diagnosed with the disease at the outset. In a specific aspect, the invention relates to a method of treating chronic pain, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound I. In a specific case, the chronic pain is selected from the group consisting of phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), wrist follow-up syndrome (CTS), HIV neuropathy, complexity Regional pain syndrome 19 200817329 (CRPS), two neuropathic pain / three as analgesic after surgery), diabetes, and neuralgia, surgical intervention (for example, with islet inflammation related to hair tube resistance or diabetes) Symptoms, pain associated with the heart, sputum, sputum, pain, pain associated with the rain, toothache, vine, worry ^ a tension headache, three nerve pain, temporomandibular joint syndrome, Pain, painful muscle injury, fibromyalgia syndrome, hunger gluteal rheumatoid arthritis, caused by fresh wounds right Guan "guana pain (osteoarthritis), phlegm and edema, bone joints... 4 related trauma Rheumatoid arthritis is caused by a sprain or fracture bone metastasis or an unknown sputum caused by fire. ^ Yue Bei ^ Zheng, original mouth, gout, fibrositis, exudation sign group, upper back palpebral pain, chest F ^ ^ Monthly pain or lower back pain (where Back pain is caused by systemic, & domain or primary spinal wide chest pain, non-cardiac chest pain, gynecological β-plate pain, heart central t-wind (4) r (4) (4) (10)) (4) pain, cell pain or pain in the elderly 々 嫌 = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ , neuritis, neuropathic sensation, allergies, burning pain and allodynia. In a specific fact, ν - kg 曰 4, mother's day about 〇.0〇1 to about 100 mg / kg body weight read and the present invention The typical oral agent | — 疋 in the range of about 0.001 to about 100 mg / kg body weight on the mother's day — ancient 乂 乂 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土 土One or more doses, such as 1 to 3. The exact dose will depend on the frequency of administration of the sheep and sputum, the sex of the individual to be treated, the age of 20, 2008, 329 years of age, weight and general health, the nature of the condition to be treated And severity, and any treatment to be treated With the disease, and any factors that are obvious to those skilled in the art. A typical oral dose suitable for adults is a compound of the formula ^00 mg/day, such as i-30 mg/day, or 5-25 mg/day. This is usually By administering one or two times a day (U-50 mg, such as 丨25 mg, such as 1, 5, 10, 15, 20 or 25 mg of the compound of the invention). When used herein, A therapeutically effective amount of a compound means an amount of a clinical symptom that cures, alleviates or partially arrests a particular disease and its complications in a therapeutic agent comprising the administration of the compound. Derogatory meaning is ''therapeutic effective amount,,. The term also encompasses an amount sufficient to cure, alleviate or partially arrest a clinical condition of a particular disease and its complications in a treatment comprising administration of the emollient. The effective amount for each purpose will depend on the severity of the disease or injury, as well as the individual's weight and general health. It should be understood that routine experiments can be used, by constructing a matrix of values, and testing different points in the matrix, which are within the general skill of the skilled practitioner and determine the appropriate dose. As used herein, treatment, or, treatment ... (10) squeaking, as the term, means managing and caring for a patient in order to combat a condition, > disease or condition. The term attempts to include the full range of treatments for a particular condition, from the patient suffering from, such as administration of an active compound to alleviate a symptom or complication, to delaying the progression of the disease, condition or condition, to alleviating or relieving symptoms or complications, and / or cure or rule out diseases, conditions or conditions, and prevent diseases, it should be understood that prevention is to fight against diseases, conditions or conditions and to treat patients and patients, including patients with active compounds to prevent signs or concurrency The occurrence of the disease. Nonetheless, prophylactic (preventive) and therapeutic (therapeutic) treatments are two different aspects of the invention. The patient to be treated is preferably a mammal, especially a human. In a specific aspect, the invention relates to the use of the invention in the manufacture of a medicament for treating chronic pain, partial response, treatment of resistance depression, Alzheimer's disease, cognitive impairment, adhd, depression Symptoms, PTSD, hot flashes, sleep apnea, alcohol, test or carbohydrate thirst, use of alcohol, substance abuse, alpha vomiting, eating disorders, IB s, affective disorder, depression, severe anxiety • postpartum Depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, panic attack, phobia, social phobia , wilderness phobia or stress urinary incontinence. In one particular aspect, the invention relates to the use of the invention in the manufacture of a medicament for the treatment of spastic pain, such as neuropathic pain. In a specific aspect, the invention relates to the use of a compound of the invention as a medicament for the treatment of chronic pain, partial response, treatment of depression, Alzheimer's disease, cognitive impairment, ADHD, depression Symptoms, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance abuse, alcohol or substance abuse, vomiting, eating disorders, IBS, affective disorder, barbarism, severe sorrow, postpartum sorrow, Depression associated with bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, panic attack, phobia, social phobia, wilderness fear Symptoms or stress urinary loss 22 200817329 ' Forbidden. In particular, the invention relates to the use of a compound of the invention as a medicament for the treatment of chronic pain, such as neuropathic pain. The compound of the present invention, which is administered as a pure compound alone or in admixture with: a carrier or excipient which is acceptable for administration, is administered in single or multiple doses. Can be based on traditional techniques, such as in Remington _: Pharmaceutical Science and Practice (R_ngt〇n: The Science and Practice 〇f pharmacy),

Edition, Gennaro Editor, Mack publishing c〇, Ε_η, % (9) $ those described in 'utilizing pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, to be formulated according to this The pharmaceutical composition of the invention. The pharmaceutical composition can be specially formulated to be administered by any appropriate route, such as oral, rectal, nasal, transpulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, transvaginal and Oral routes are preferred for parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes. It is clear that the preferred route will depend on the general health and age of the patient to be treated, the nature of the condition to be treated, and the active ingredient chosen. Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, granules, sugar-coated linkages, pills, troches, powders and granules. Where appropriate, they can be prepared using coatings. Liquid dosage forms for oral administration include: gluten, emulsions, suspensions, syrups, and ugly agents. Pharmaceutical compositions for parenteral administration include sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders, which are reconstituted in a sterile injectable solution or dispersion prior to use. Other forms of administration include Strain, Spray, Ointment Gel, Inhalation, Transdermal Patch, Implant, and the like. Pore phase, for convenience, the compound of the invention is administered in unit dosage form, containing the compound in an amount of from about 0.1 to 50 mg, such as i mg, 5 mg, 15 g of hair, 2 mg or 25 mg. Inventive compound. Γ As far as the parenteral route is concerned, such as intravenous, intrathecal, intramuscular, and the like, the dose is usually about half of the dose used for oral administration. For parenteral administration, solutions of the compounds of the invention in sterile aqueous solutions, aqueous propylene glycol, a water-sustained f E sesame or peanut oil may be employed. If you need to [locally buffer this type of aqueous solution, i first make the liquid diluent into isotonic with enough physiological saline or glucose. The aqueous solution is particularly suitable for intra-pulmonary, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media used can be readily obtained by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, (iv), gum arabic, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, eucalyptus oil, phospholipids, fatty acids, fatty acids, and women's epoxides. The pharmaceutical composition is formed by mixing the compound of the present invention with a pharmaceutically acceptable carrier, and then rapidly administered in a variety of dosage forms suitable for the above-mentioned routes of administration. Formulations of the invention suitable for oral administration can be provided in separate units, such as capsules or lozenges, each containing a predetermined amount of active ingredient, and may contain the appropriate excipients. In addition, the orally administrable formulation can be in the form of an early or winter granule, in the form of an aqueous or non-aqueous liquid eucalyptus oil or a water-in-oil liquid emulsion. ...suspension, or water pack = use of a solid carrier for administration] The preparation may be a tablet, for example, in the form of a powder or pellet in a gelatin capsule, or in the form of a tablet. The amount of solid carrier can be changed to about ......

If a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule or a non-reading injectable liquid such as an aqueous or non-aqueous liquid or solution. The lozenge can be prepared by mixing the active ingredient with a conventional adjuvant and/or diluent, followed by compacting the mixture with a conventional tablet machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives commonly used for such purposes, such as coloring agents, perfumes, preservatives and the like, may be used as long as they are compatible with the active ingredients. A capsule comprising a compound of the present invention can be prepared by mixing a powder comprising the compound with microcrystalline cellulose and magnesium stearate and placing the powder in a hard gelatin capsule. The capsule may be colored with a suitable pigment as desired. The system "gel morning" will comprise from 0.25 to 20% of a compound of the invention, such as 3·0-4 · 〇 %, 14.0-16.0% of the compound of the invention. These strengths can be conveniently used to deliver 1, 5, 10, 15, 20 and 25 mg of the compound of the invention in unit dosage form. The solution can be sterilized and filled into appropriate ampoules or vials by dissolving the active ingredient and possible additives in a portion of the injected solvent, preferably sterile water, to the desired volume. In the preparation of an injection solution. Any suitable additives conventionally used in the art, such as tensioning agents, preservatives, antioxidants, and the like, may be added. Compounds can be prepared as outlined in WO2003/029232. The salt of compound i can be prepared by adding an appropriate acid followed by precipitation. The sink can be caused by, for example, cooling, removing the solvent, adding other solvents, or a mixture thereof. All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference in their entirety as if It is described in this article (to the maximum extent permitted by law): Does not consider any separate documents provided separately in this document. Before the present invention is described, the terms singular and plural are used to mean both the singular and the plural, unless otherwise specified herein or otherwise explicitly recited. For example, a compound ", unless otherwise specified," means a compound of the invention or the particular aspect. The exact value provided in this article, the approximate value corresponding to the table (for example, the exact value for a particular cause can be regarded as an approximate measurement corresponding to the 攸h of the relative r, 丨里楗仏, , about "modification" 〇 W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W , a noun of the class x, means an element or component that attempts to provide support for a similar aspect or aspect of the invention, which consists of, consists essentially of, or consists essentially of. Including, a particular element or element, unless otherwise stated or explicitly refuted (for example, a composition comprising a particular element as described herein is also understood to be a component of the composition, unless Unless otherwise stated or explicitly refuted). Example Analysis Method At? Eight him 171^&1\,? State? On the ruler 0-ray diffractometer, use the (::1^ α 1 round shot 'metry X-ray powder diffraction pattern (XRPD). In the reflection mode in the range of 2 0 _ 5-40 °, use ' (^161^〇1^ detector, measuring sample. Elemental composition (CHN) was measured on Elementar Vario EL instrument from Elementar. Approximately 4 mg of sample was used for each measurement and averaged twice. Values provide the results. f Example 1 a HBr salt of compound τ in 442 g of 4-(2-p-tolylsulfanyl-phenyl)-piperidine as an oil which was stirred and heated slightly (about 45 ° C) To the ethyl carboxylate, 545 ml of 33 wt% HBr (5.7 M, 2.5 equiv.) in AcOH was added. This mixture gave an exotherm of 1 ° C. After the last addition, the reaction mixture was heated to 80. °C, and allowed to stand for 18 hours. The sample was taken back and analyzed by HPLC. If it was not completed, more 33% by weight of HB r in AcOH had to be added. On the other hand, the mixture was cooled to 25 °C. The product 4-(2-p-tolylsulfanyl-phenyl)-piperidine hydrobromide precipitated. After 1 hour at 25 ° C, 800 ml of the thick suspension was added. Ether. Stirring was continued for an additional 1 27 200817329 hours, then the product was isolated by filtration, washed with 400 mL of diethyl ether and dehydrated overnight at 40 ° C. The isolated hydrobromide salt of Compound I was a white solid. Lb compound T. of HBr salt 2-(4-tolylsulfanyl)-phenyl bromide in a stirred nitrogen blanketed reactor, flushing N_methyl-pyrrolidone with nitrogen, ΝΜΡ (4·5 liters) 20 Min. Add 4-methylthiophenol (9 g, 7.25 mol), then add 1,2-dibromobenzene (1709 g, 7.25 mol). Finally add potassium third potassium butoxide ( 8 13 g, 7.25 mol), the final reactant. The reaction is exothermic, raising the temperature of the reaction mixture to 70 ° C. The reaction mixture is then heated to 12 0 ° C for 2 - 3 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (4 liters) and aqueous sodium sulphate (1 5 % ' 2 · 5 liters) were added. The mixture was stirred for 20 minutes. The liquid phase was separated and taken in another part. Extraction of acetic acid B (2 liters). Separation of the liquid phase, mixing of the organic phase, followed by gasification of sodium (1 5 %, 2 · 5 liters) rinse. The organic phase is separated, dehydrated with sodium sulfate, and evaporated under reduced pressure to become a red oil containing 20-30% NMP. The oil is diluted to two with methanol. a volume of vol., and refluxing the mixture. Add more sterol until a clear solution is obtained. Slowly cool the solution to room temperature while sealing. The product crystallizes into an off-white crystal 'separate them by filtration, It was rinsed with decyl alcohol and then dehydrated in a vacuum oven at 40 ° C until constant weight. 4-Hydroxy- 4-(2-(4-tolylsulfanyl)phenyl)-Blu-u-butyl phthalate is designed to be stirred in a reactor under nitrogen blanket. 4_methylphenylthioalkyl)-phenyl bromide (600 g, 2.15 mol) was suspended in heptane (4.5 liter) 28 200817329. At room temperature, 1 〇M of BuLi (235 liters < 2.36 moles) in hexane was added over 10 minutes. Just notice a little exotherm. The suspension was stirred at ambient temperature for 1 hour and then cooled to -4 () c > c. The 1-ethoxycarbonyl(carbeth〇xy)-4-pyridinone (368 g, 2.15 mol) dissolved in THF (1.5 liters) was added at a rate not faster than maintaining the reaction temperature at -40 C. . When the reaction was complete, it was warmed to and 1 M HCl (1 liter) was added to keep the temperature below 丨〇. The acidic liquid phase was separated and extracted with ethyl acetate (1 liter). The organic phases were combined and extracted with a sodium chloride solution (丨, 1 liter). The organic phase was dehydrated with sodium sulfate and evaporated to a semi-crystalline mass. It was slurried in ethyl scale (250 ml) and filtered. Dehydrated in a 4 (rc vacuum oven until constant weight. 4-(2-(4-tolylthiol)-phenyl) 0 丨 丨 竣 竣 竣 将 二 II II 2.8 2.8 24.9 mol) and triethyldecane (362 g '3.1 mol) were charged into a reactor equipped with an efficient stirrer. 4-hydroxy-4-(2-(4-曱) was added in portions via a powder funnel. Ethyl phenylsulfanyl)phenyl)-piperidine-1-carboxylate (462 g, 1.24 mol). The reaction is somewhat exothermic. The temperature is allowed to rise to 50 ° C. After the addition is stopped, The reaction mixture was added to 60 C for 8 hours. The reaction mixture was cooled to room temperature. Toluene (750 liters) and water (750 ml) were added. The organic phase was separated and extracted with toluene (750 ml) In the liquid phase, the organic phase is mixed and washed with sodium chloride solution (15%, 500 ml) and then dehydrated with sodium sulfate. The sodium sulphate is filtered off and the filtrate is evaporated under reduced pressure to become a red oil in the next step. Further treatment in. 4-(2-(4-Tolylsulfenyl)phenyldine hydrogen oxalate 29 200817329 In a stirred reactor, Example 3, crude 4-(2-(4-tolylsulfanyl)phenyl)-red oil in the form of a red oil, and ethyl hydrobromide in acetic acid (40%, 545 ml, 3·η moles were mixed. The mixture was heated to 80 ° C for 18 hours. The reaction mixture was cooled to room temperature. The product crystallized during cooling. After 1 hour at room temperature, in the reaction mixture Diethyl ether (800 ml) was added and the mixture was stirred for another hour. The product was filtered, washed with diethyl ether and dried in a vacuum oven at 50 ° C until constant weight. f Example 1 c HBr salt of compound I Crystallization of ruthenium in 100 ml of H20, heating a mixture of HBr salt of ruthenium compound I (for example as prepared above) to reflux. The mixture became clear and completely dissolved at 8 〇 -9 。. To the solution, 1 g of activated carbon was added and reflux was continued for 15 minutes, then filtered and left to cool automatically to room temperature. During cooling, a white solid precipitated and the suspension was stirred at room temperature for 1 hour. Dehydrated overnight in a vacuum at 40 ° C, yielding 6.9 grams (6 9%) HBr acid addition salt of compound I. See XRpD of Figure 1. Elemental analysis · 3.92% Ν, 59.36% C, 6.16% Η (theoretical value: 3.85% Ν 59.43% C, 6·09% Η). Example 1 d Preparation of a free base mother liquor A mixture of 500 ml of ethyl acetate and 200 ml of H 2 hydrazine was added to 50 g of the compound HH salt to produce a two-phase polymer. The crucible was added to about 25 ml of concentrated NaOH which caused the formation of a clear two-phase solution (measuring the pH to 13-14). The solution was vigorously stirred for 5 minutes and the organic phase was separated. The organic phase was washed with 200 mL of hydrazine, dried over Na 2 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s 10 g of oil was dissolved in ethyl acetate, and the volume was adjusted to 15 ml to give a mother liquor of 0.235 Torr in ethyl acetate, using a 15 ml aliquot from it (100 mg free test). 10 g of oil was dissolved using 96% by volume of Et〇H, and the volume was adjusted to 100 ml to give a mother liquor of 0.353 M in EtOH, using a 1.0 ml aliquot (1 mg of free base) therefrom. fAl1] le is formed using a free base mother liquor. The specified aliquots are placed in a test tube while stirring, and an appropriate amount of acid is added as indicated in Table 1. If the acid is a liquid, add it directly, otherwise dissolve it in the specified solvent before adding it. Stirring was continued overnight after mixing and sinking, and the precipitate was collected by filtration. Prior to dehydration in 3 (rc vacuum), a small amount of reference sample was taken and dehydrated at room temperature but without vacuum. The procedure was included to test the solvate. The results are presented in Table 1. XRPD is shown in Figure 1-22. The diffraction pattern is plotted and the selected peak positions are tabulated in Table 2. Table 3 shows the /glutinability of the compounds of the invention in water along with the pH in the resulting saturated solution. Whether the precipitate separated after the solubility is determined is the same as the dissolved compound, which represents the formation of the hydrate. 31 200817329 Table 1

Acid (base: acid) MW (g/mole) Acid amount (mg or microliter) Solvent CHN (experimental value) CHN (theoretical value) palmitic acid, palmitic acid 1:1 256.42 90.5 EtOAc 75.36 9.77 2.46 75.64 9.9 2.6 DL-lactic acid, DL-2-hydroxypropionic acid 1:1 90.1 31.8 EtOAc 66.88 7.26 3.52 67.53 7.29 3.75 adipic acid, 1,6-hexanedioic acid 1:1 146.14 51.6 EtOAc 66.08 7.23 2.98 67.1 7.27 3.26 Acid, 1,6-adipate 2:1 146.14 25.8 EtOAc 70.66 7.32 3.82 70.75 7.35 3.93 Fumaric acid 1:1 116.01 40.9 EtOH 65.71 6.41 3.35 66.14 6.31 3.51 glutaric acid, 1,5-glutaric acid 1 :1 132.12 46.6 EtOAc 66.09 6.97 3.2 66.48 7.03 3.37 Malonic acid 1:1 104.1 36.7 EtOAc 65.04 6.53 3.54 65.09 6.5 3.62 Oxalic acid 1:1 90.1 31.8 EtOH 64.28 6.41 3.61 64.32 6.21 3.75 Sebacoinic acid, 1,8 - 202.02 35.6 EtOAc 71.79 7.86 3.58 71.83 7.86 3.64 suberic acid 2:1 succinic acid, 1,4-succinic acid 2:1 118.1 20.8 EtOAc 65.65 6.86 3.4 65.80 6.78 3.49 (forms a 1:1 salt) L-malic acid, L-2-hydroxysuccinic acid 1:1α 134.1 47.3 EtOAc 62.87 6.20 3.22 63.29 6.52 3. 36 L-malic acid, L-2-hydroxysuccinic acid 1:1 β 134.1 47.3 EtOH 62.99 6.66 3.13 63.29 6.52 3.36 D-tartaric acid, D-2,3-dihydroxysuccinic acid 1:1 150.1 53.0 EtOH 60.67 6.4 3.07 60.95 6.28 3.23 L_aspartic acid 1:1 133.1 47.0 EtOH 59.31 6.7 7.1 (containing excess acid) 63.43 6.78 6.73 glutamic acid 1:1 165.15 58.3 EtOH 56.38 6.88 7.35 (with excess acid) 56.46 6.94 7.06 ( 1:1-salt and acid-monohydrate 1:1) Citric acid 2:1 192.13 33.9 EtOAc 65.93 6.72 3.44 66.46 6.64 3.69 HCl/Et, 0 1:1 2M 176.4 EtOH Phosphate 1:1 14.7M 24.0 EtOAc 55.79 6.47 3.43 56.68 6.34 3.67 32 200817329 Table 2: X-ray peak position (°2Θ), 2:1 means 2 bases to 1 acid. All values are + - 0.1

Palmitate 7.00 16.34 22.73 28.21 Stearate 6.70 15.52 21.81 28.91 Lactate 5.30 8.18 9.44 17.24 Lactic acid salt hydrate 11.67 16.70 18.25 21.76 Hydroxy-isobutyrate 5.09 16.60 20.38 27.37 Sebacate 7.18 12.53 21.11 24.19 Adipic acid Salt 2:1 8.03 13.52 17.90 24.60 Adipate 1:1 α 9.33 14.01 18.72 20.63 Adipate 1:1 β 15.69 21.53 25.81 31.18 glutarate 1:1 9.39 11.70 14.05 14.58 Succinate 1:1 11.74 14.33 17.75 26.84 fumarate 1:1 8.90 11.47 19.25 22.33 fumarate 2:1 8.49 12.48 17.78 23.97 maleate 1:1 12.11 15.51 17.48 22.53 maleate 1: 1 hydrate 12.81 18.76 20.53 27.31 Malonate α 10.77 16.70 19.93 24.01 Malonate β 6.08 10.11 18.25 20.26 Aspartate 11.05 20.1 20.60 25.00 Aspartate hydrate 7.80 13.80 14.10 19.63 Glutamine 7.71 14.01 19.26 22.57 Oxalate 14.68 17.45 19.50 23.90 Malate 1:1 α 8.30 12.04 17.23 20.67 Malate 1:1 β 10.91 12.87 14.14 26.16 Malate hydrate 12.30 15.56 19.56 23.30 D-tartrate (from EtOH) 5.08 17.18 19.42 22.10 Hydrochloride 12.44 16.72 19.45 25.02 Hydrobromide 6.08 14.81 19.26 25.38 Hydrobromide hydrobromide-PrOH solvate 6.57 13.12 19.07 24.77 33 200817329 Table 3 Acids (alkali : acid) Solubility (mg/ml) The resulting pH precipitate palmitic acid, hexadecanoate 1:1 0.4 ___ 8.6 = start DL-lactic acid, DL-2-hydroxypropionic acid 1:1 >150 ___ 6.1 = Start (after evaporation) adipic acid, 1,6-hexanedioic acid 1:1 2.5 —__ 4.0 Part 2:1 salt adipic acid, 1,6-hexanedioic acid 2:1 1.0 ___ 7.8 = start reverse Alkenedioic acid 1:1 0.2 ____ 3.3 = start __ glutaric acid, 1,5-glutaric acid 1:1 13 4.6 = start malonic acid 1:1 (〇〇5.2 4.0 = new form (β) _ oxalic acid 1:1 1.1 2.7 = start azelaic acid, 1,8-adipate 2:1 0.7 _ 5.5 = start succinic acid, 1,4-succinic acid 2:1 2.0 4.0 hydrate L-malic acid, L- 2-hydroxysuccinic acid 1:1,β 2.8 4.0 hydrate D-tartaric acid, D-2,3-dihydroxysuccinic acid, ι:1 1.8 3.5 hydrate L-aspartic acid 1:1 39 4.3 Hydration Glutamic acid 1:1 > 35 4.6 Citric acid 2:1 0.5 4.7 = Start · Acid 1:? 1 6.0 2.0 HC1 4.5 6.8 = Start HBr 2.4 7.0 = start i 2A serum and norepinephrine (NE) of Example resorption inhibition

An aliquot of the test compound and the rat cortical synaptosome preparation were pre-incubated for 10 minutes / 37 ° C, followed by [3H;] NE or [3H] 5-HT (final concentration 1 OnM). Non-specific absorption was determined in the presence of 1 〇μΜ taSUpram or citai 〇pram, and total absorption was determined in the presence of a buffer solution. Aliquots were incubated at 37 ° C for 15 minutes. After incubation, [3H]N]E 34 200817329 or [3Η]5-ΗΤ absorbed by the synaptosome was isolated by using the Tomtech Cell Harverter program by pre-soaking 0.1% ΡΕΙ 30 minutes of Unifilter GF/C. . The filter was rinsed and counted in a Wallae Micr(R) Beu counter. The NET compound of the present invention exhibited a 23 nMi IC5 enthalpy value. The SERT compounds of the present invention exhibit an IC5 enthalpy of 8 nM.筵2B Antagonism The affinity of the compounds of the present invention for serotonin receptors was tested and an antagonistic profile (fantasy 54 nM) showing affinity at the 5-HTm receptor was found. From

γ = 100 / (1 + 10 (χ · logarithm 丨 C5 〇)) to calculate the affinity, where Y represents the % binding, and X represents the concentration of the compound. Five concentrations of the compound (1, 1 〇, 30, 100, l〇〇〇nM) were used to calculate the ic5() value. Ki was calculated from Cheng Prus〇ff equation Ki = (IC5Q/(l + ([L]/Kd)). Affinity was determined at MDL Pharmaserices catalog No. 271650. Mammalian cells expressing human-HTm receptors In the present invention, the compound of the present invention exhibits competitive antagonistic properties. The compound binds to 5-HT2a in a phantom of <1〇〇nM, and in a functional assay, the compound antagonizes 5-HT-induced Kb Ca2+ was released from the intracellular storage. Schlld analysis showed that the competitive antagonism was Kb of ΙΟΟηΜ. The experiment was carried out as follows. 2 or 3 days before the experiment, the density of the single confluent layer was generated on the day of the experiment, and the expression was 25 CHO cells with a nanomolar/mg human 5-HT2a receptor. The cells were loaded with dye for 60 minutes at 37 ° C in a 95% humidity 5% C 2 incubator (Ca2+ from Molecular Devices) - Set). Fluorescence analysis of the developed plate readout or FLIPR3 84 from Molecular Devices (Sunnyvale, CA) with an excitation wavelength of 488 nm and an emission range of 5 to 5 60 nm, 35 200817329 Monitor basic fluorescence. Set the laser intensity to suit Level to obtain a base value of approximately 8〇〇〇-1〇〇〇0 fluorescent units. The amount of phosphorescence on the base fluorescence should be less than 1%. Use an increasing concentration covering at least 3 decimals. The test compound was evaluated for EC5 values. The pA2 values were evaluated at four different concentrations of compounds (15 〇, 4 〇〇, 1500, and 4000 nM) to challenge the 5-HT full-dose response curve. The ECU challenged the test substance of two decimal concentrations and evaluated the Kb value. The test substance was added to the cells 5 minutes before 5-HT. The Ki value was calculated using the Cheng-Prusoff equation. fife Example 2C 5-HT^ Receptor antagonism In an egg cell expressing the human heptopeptide (h〇m〇meric) 5-HT3A receptor, the 5-HT activation current has an ECS of 26〇〇nM. A typical 5_HA antagonist can be utilized. For example, ondansetron antagonizes this current. In this system, ondansetron shows a Ki value lower than InM. The compounds of the invention show potent antagonism at low concentrations (O.lnM-lOOnM) (IC5 〇 about 1〇nM/Kb about 2nM), and when used at a higher concentration ^(8)-丨(8)(8)叱]^), the agonist characteristic (EC" is about 2600nM), the maximum is reached. The current is about 70-80% of the maximum current induced by 5_ht itself. In the egg cells expressing the rat_homopeptide kHTsA receptor, the 5-ΗΤ activation current has an EC50 of 3·3 μΜ. The experiment was carried out as follows. The cells were surgically removed from mature female Xenepus laevis anesthetized with 0.4% MS-222 for 10-15 minutes. The egg cells were then digested with collagenase (type IA-Sigma) in 0.5 mg/ml in OR2 buffer (82.5 mN NaCl, 2.0 mM KC1, 1.0 MmM MgCl2 and 5.0 mM HEPES, ΡΗ7·6) at room temperature. 2-3 hours. Egg cells without follicular layer were selected and modified Barth,s physiological saline buffer solution [88 mM NaCl, 1 mM KC1, supplemented with 2 mM sodium pyruvate, 0el units/cm 36 200817329 liter of penicillin and 0.1 μg/liter streptomycin. 15 mM HEPES, 2.4 mM NaHC03® 41.41 mM CaCl25 0.82 mM MgS045 3.3 mM Ca(N03)2] was cultured for 24 hours. The IV-XV phase of the egg cells was confirmed, and the nuclease containing 12-50 micrograms of cRNA encoding human 5-HT3A receptor was injected at 12-48 liters, and cultured at 18 , until Electrophysiology δ has been recorded (1-7 days after injection) until they are used. Egg cells expressing human 5_hT3 receptor were placed in a 丨ml bath and perfused with Ringer's buffer solution (115 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1.8 mM CaCl2, O.lmM MgCl2, ΡΗ7·5). The cell was inserted into the cell with a 0.5-1 million ohm electrode plug containing 3M KC and locked to _90 millivolts by a GeneClamp 5〇〇Β amplifier. The cells were continuously infused with Ringer's buffer solution and the drug was applied to the perfusate. The 5_Ητ agonist solution was applied for 10-30 seconds. The potency of the 5-HT3 receptor antagonist was examined by measuring the concentration-response to 1 〇uM5_HT stimulation. ^ΛΜ^2Ό_^αα receptor binding effect The affinity of the compound of the present invention for the α ια receptor was tested, and it was found that the «1Α style exhibited an antagonistic profile of medium affinity (Ki = 34 nM). On the day of the test alone, the membrane (see below for membrane preparation) was thawed and homogenized, using a disperser (ultra Unax) and diluted to the desired concentration (5 μg/well approximately 5 μg/ 9 〇〇 microliters, stored on ice until use). The experiment was started by mixing 50 microliters of the test compound, 5 liters of [3H]-prazosin and 9 liter microliters of membrane, and the mixture was incubated at 25 Torr for 2 minutes. 37 200817329 Non-specific binding was determined in the presence of 10 μΜ WB-4101 and total binding was determined in the presence of buffer solution. After incubation, the Tomtec Cell Harvester program (D4.2..4) 96 wells were used to separate the unbound ones by filtration through Unifilter GF/B soaked in 0.1% hydrazine for 30 minutes. body. The filter was rinsed 3 times with 1 ml of ice-cold buffer solution, dehydrated at 50 °c and 35 μl of scintillation fluid/well was added to the filtrate. The bound radioactivity was counted in Wallac® 1450 MicroBeta. Affinity is calculated from γ = 1 〇〇 / (1 + 1 〇 (χ· , log 1C5 〇)), where Υ represents % of binding and X represents the concentration of the compound. IC5〇 values were calculated using compound concentrations covering 2 decimals. Ki was calculated from Cheng Prusoff's equation Ki = (IC5〇/(l-([L]/Kd)). In functional assays, the compounds of the invention antagonize adrenaline-induced release of Ca2+ from intracellular stores, And this functional assay showed the compound to be an antagonist. These experiments were carried out essentially as follows.

All cells were cultured at 37 ° C, 5% CO 2 supplemented with [ 10% BCS, 4 mM L-melamine amide (or 2 mM in the case of COS-7) and 100 units/ml penicillin plus 1 〇 〇μg/ml streptomycin in DMEM medium. CHO cells expressing the human α 1Α·7 receptor were seeded in a 384-well black well microtiter plate coated with poly-aspartic acid 24 hours before the assay. Aspirate the medium at 37 ° C, 5 ° / 〇 C02, in a solution of Hank's balanced salt solution (138 mM NaCl, 5 mM KC1, 1.3 mM CaCl2, 0.5 mM MgCl2, 〇. 4 mM MgS04, 〇. 3 mM KH2P04, 0.3 mM Na2HP04, 5.6 mM glucose) plus 20 mM HEPES ρΗ7·4, 0.05% BSA and 2.5 mM propyl sulphate 38 200817329 (probenicid) (50 μl/well) in assay buffer solution 15^M Fluo-4 The cells were loaded with the dye for 1 hour. After discarding the excess dye, the cells were washed with the assay buffer solution and layered at a final volume equal to 45 microliters/well (or 30 microliters/well as determined by the antagonist). In the case of antagonist evaluation, an antagonist or vehicle was added to the final concentration of 4x (final DMSO = 1%) in a buffer solution containing 4% DMS in 15 microliters at this time, followed by incubation. 20 minutes. Fluorescence analysis of a developing plate reader or FUpR384 from Molecular Devices (SunnyVale, USA) with an excitation wavelength of 488 nm and an emission range of 500 to 560 nm monitors the base fluorescence. Adjust the laser excitation energy so that the base fluorescence range is approximately 8, 相对 relative fluorescence units (RFU). The cells were then stimulated with an agonist diluted with assay buffer solution (15 microliters) at room temperature and RFU was measured at intervals of 1.5 seconds over a period of 2.5 minutes. Calculate the maximum fluorescence change per well. The concentration-response curve derived from the maximum fluorescence change was analyzed by nonlinear regression (Hill equation). As for the determination of the antagonist, a fixed concentration of the standard agonist serotonin was added after 2 minutes of compound culture (as above). A single injection of the compound of the present invention in the rat frontal cortex was added to dopaquinone. The extracellular DA content was increased in a cap-dependent manner. The compounds of the present invention were injected subcutaneously at 9 oz/kg and 18 mg/kg, respectively, increasing the da content by about 10% and 150%, respectively, in Figure 23. The above baseline content is described. The content is calculated as free base. The method uses a male Sprague-Dawley large 39 200817329 rat weighing 275-300 g at the beginning, under a 12-hour light/dark cycle, and adjusting the room temperature (21 ±2 It and the degree of (55 ± 5%) control animals, freely supply food and tap water. For the 3 day treatment experiment, use the infiltration mini pump (4) zd 2ML i ). Fill under sterile conditions Pu, and implanted under the anesthesia under seven (four) w) anesthesia. The experiment was completed using a mini-loader. At 3 A after the treatment, blood samples were collected at the end of the experiment, and the plasma content of the test compound was measured. Oral surgery and microdialysis

The animals were anesthetized with hyPn〇rm/d〇rmicum (2 ml/kg), and the brain was guided into the set of f (CMA/12R into the hippocampus to make the dialysis probe tip In the ventral hippocampus (coordinates · 5.6 mm before the anterior iliac crest, lateral _5 · 〇 $ m '7 〇 mm ventral to the dura mater), or in the frontal cortex (coordinates: before the front pack 3.2 Mm; side 3 () mm; 4 () mm ventral to dura mater). Fix the guide cannula with a set screw and acrylic cement. Monitor the animal's body temperature with a rectal probe and maintain it in the grip. Allow the rat to The surgery was resumed for 2 days and housed in a cage alone. On the day of the experiment, a microdialysis probe (CMA/12, 〇·5 mm diameter, 3 mm long) was inserted through the guide cannula. The probe was connected via a two-way turntable to Microinjection of the pump. Immediately after inserting the probe into the brain, 'filtered Ringer's solution (145 mM)

The microdialysis probe was perfused with NaCl, 3 mM KC1, 1 can of MgCl2, 1.2 mM CaCl 2 ) and continued to flow at a constant flow rate of 1 (1, 3) microliters per minute during the experiment/main after 180 minutes of stabilization. , start the experiment. The dialysate was collected every 2 〇 (3 〇) minutes. After the test, the rats were sacrificed by decapitation, their brains were removed, and 200817329 was frozen and sectioned to confirm the position of the probe. Analysis of dialysate The concentration of dopamine in the dialysate was analyzed by HPLC using electrochemical detection. The monoamine was isolated by reverse phase liquid chromatography (〇DS 150 x 3 mm, 3 μΜ). Dopamine: a mobile phase containing NaHJO4, 50 mM sodium citrate, 367 mg/liter sodium oxalate sulfonate, 50 uM EDTA and 8% acetonitrile (ρΗ4·0) at a flow rate of 毫升·5 ml/min. Use a gas detector; set the potential at 250 millivolts (protective battery at 35 〇 millivolts) (Coixl〇chem®, ES Α) to complete the electrochemical test. Example 2: Enhancement of acetamidine design This experiment was conducted to evaluate the effect of the compound of the present invention on the extracellular content of acetaminophen in the uranium cephalic cortex of a freely moving rat. Male Wistar rats (280-350 g; Harlan, Zeist, The Netherlands) were used in this experiment. The rats were individually housed in plastic cages (3〇χ3〇χ4〇) and were freely accessible to food and water. Rats were anesthetized with isoflurane (2%, 400 ml/min N20, 400 house liters per minute 〇 2). Local anesthesia was performed with lidycaine (1〇0/〇 weight/volume). Each animal was placed on a directional rack (K〇pf instrument, USA) and a self-made I-shaped probe (Hospal AN 69 membrane, 4 mm contact surface) was used using a rat brain map of Paxinos and Watson (1982). ) inserted into the central prefrontal cortex (mPFC). The coordinates of the probe tip are mPpctAPy / mm, L = -0.8 mm ' V == 5.0 mm]. The probe is then secured to the skull using dental cement and screws. Flunixin (1 mg/kg subcutaneous) was administered as an analgesic after surgery. 41 200817329 Experiments were performed 24-48 hours after surgery. On the day of the experiment, the rat and micro-perfusion pump (CMA102) were connected with a flexible PEEK tube and at a flow rate of 1.5 μl/min to Ringer's containing 147 mM NaCl, 3_0 mM KCl, 1.2 mM CaCl2 #1·2ηιΜ MgCl2. The buffer solution is perfused with a dialysis probe. The microdialysis sample was collected into a mini-vial containing 55 μl of 0.02 M hyperthyroidism at intervals of 3 minutes to determine acetylcholine. Samples were collected by autodissolved collectors (C:MA 142) and stored at -80 °C until analysis. After completing the experiment, the rats were sacrificed. Remove the brain and store in a solution of secondary formaldehyde (4 / 〇 heavy / volume). By making a coronal slice of the brain, according to

Paxmos and Wats〇n (1982) confirmed the position of each probe histologically. The X test compound was dissolved in 1〇0/. In 2_〇H_propyl cold-cyclodextrin, subcutaneous injection of 5 ml/kg volume was administered at different doses. The concentration of the acetaminophen was determined by HPLC with tandem mass spectrometry (MS/MS) detection. An aliquot (25 microliters) was injected into the HPLC column using an I automated sample syringe (perkinElmer Instruments, Series 200). Layers were performed on a reverse phase 150x2.00 mm (4 micron) analytical column (Phenomenex Synergy MAX-RP, Bester) protected by a 4x2.0 house protection column (Phenomenex Synergy MAX-RP AJO-6073, Bester) The separation was carried out and both columns were maintained at a temperature of 30 °C. The mobile phase (equal gradient) consists of ultrapure water (UP), acetonitrile (ACN) and trifluoroacetic acid (TFA) (UP..ACN: TFA 2 95·0:0·5:1·vol/vol/vol% )composition. Throughout the system, the mobile phase was run by a HPLC pump (PerkinElmer Instruments, Series 200 Micro Pump) at a flow rate of 42 200817329 0-300 ml/min. Use an API 4〇〇〇Ms/MS system consisting of an API 4000 MS/MS detector and a thirsty ion spray (τ_〇I〇n Spray) interface (both from Applied Bi〇syst, such as Nethedands) Perform lc/ms analysis. Probing in a positive ionization mode with an ionization injection voltage set at 5·5 kV and an atomizer gas pressure of 50 psi (at the sciek scale Ορο) with a probe temperature of 6 〇〇 C. The instrument was operated in a multi-reaction-monitoring (mrm) mode to detect acetylcholine (precursor 1461 Da, product 86.8 Da). The collision energy is 21.0 eV and the collision gas (nitrogen) pressure is maintained at 7 (on the scmx scale 0-12). Quanzheng data was quantified using the AnalystTM data system (AppHed Biosystem, version 1.2). Take two consecutive microdialysis samples with a variation of no more than 50%, as a baseline with 1 and set to 1 〇〇0/. . The change in the concentration of acetylcholine is expressed as a percentage of the baseline in the same individual. The data is shown in Fig. 24. Inhibition of the increase in the 2G rabbit base This experiment was conducted to evaluate the effect of the compound of the present invention on the extracellular content of acetylcholine in the prefrontal cortex and ventral hippocampus of freely moving rats. Male Sprague-Dawley rats weighing 275.300 grams at the beginning were used. Animals were kept under free-charged food and tap water under a 12-hour light/dark cycle and under controlled conditions of room temperature (21 ± 2 〇 c) and house (5 5 ± 5%). Surgical and microdialysis complex ^ 43 200817329 Anesthetized rats with sub-Tini / guide sleep (2 ml / kg), and directed the intracerebral guide cannula (CMA / 12) into the hippocampus + # The position of the dialysis needle tip is aimed at the ventral hippocampus (coordinates: 5.6 mm before the pre-crisis, side _5 〇 not 7.0 mm ventral to the dura mater), or in the frontal cortex (coordinate: in the front) 3.2 mm; side 0.8 mm; 4 mm ventral to dura mater). The guide I tube was fixed with a set screw and acrylic cement. Looking at the rectum: monitor the animal's body temperature' and maintain it at 3rc. Rats allowed: During surgery: 2 days in duplicate, kept in cages. On the day of the experiment, a microdialysis probe (CMA/12, 〇5 mm diameter, 3 mm long probe was connected by a two-way turntable to the microinjection sputum via the guide cannula. Shortly before inserting the probe into the brain) The microdialysis probe was perfused with the filtration, Ringer's solution ((4) Fuxi, 3 mM KC1' lmMMgCl2, 12 mM CaCl2 containing 〇5_ne〇stlgmine), and continued for 1 μl during the experiment. Constant flow perfusion at /min. After the stabilization of 18 〇 minutes, the experiment was started. The dialysate was collected every 20 minutes. After the experiment, the animals were sacrificed, their brains were vacated, frozen and sectioned to confirm the position of the probe. The analysis of hydrazine was performed by HPLC with electrochemical detection using 100 mM disodium hydrogen phosphate, 2. mM octane sulfonic acid, 5 5 mM tetramethylammonium hydride and 〇〇 〇〇 5% mb (ESA). The mobile phase consisting of ρΗ8·0 was analyzed for the concentration of acetylcholine (ACh) in the dialysate. The pre-column enzyme reactor (ESA) contained immobilized choline oxidase' in the analytical column (ESA ACH) -250) before the separation of ACh, first exclude the sample from the injection (1 〇 microliter Choline; flow rate 0.35 ml/min, temperature: 35 ° C. After analysis of the column, the sample was passed through a post-column solid phase reactor containing immobilized acetamidine 44 200817329 cholinesterase and choline oxidase ( ESA). The post reactor converts ACh to choline and then converts choline to betaine and H2〇2. The latter is electrochemically detected by using a platinum electrode (Analytical cell·ESA, model 5040). Submit f'

In a single injection experiment, the average of 3 consecutive ACh samples taken before the compound was administered was used as the baseline value for each experiment, and the data was converted to a percentage of the reference value (the average pre-injection reference value was normalized to 100). %). The data is submitted in Figures 25a and 25b. The data in Figure 24 shows an unexpected reduction in acetylcholine content (see, for example, 8 mg/kg), which is difficult to interpret and is considered experimentally unreliable. Overall, the two sets of data from Examples 2F and 2G showed the same enthalpy, a dose-dependent increase in extracellular acetylcholine content in the brain. It is contemplated that this pre-clinical finding is interpreted as a cognitive improvement in the clinical setting' to treat, for example, diseases characterized by cognitive impairment, such as, for example, Alzheimer's disease, partial responders, cognitive impairment, and the like. The Cunu syndrome is effective against neuropathic pain (five) and the compounds of the invention are tested in neuropathic pain ^ ^ [Neuropharm., 48, 252-263, 2005; Pain, 51, 5-17, =]. In this model, mice were injected with brown horse forest (4 5%, 2 〇 microliters) on the left foot surface of the left back, and then observed in a glass beaker (2 liter capacity). By using Fumalin's footsteps, a unique two-phase behavioral response is induced and quantified by the amount of time that green injury is f. [Phase (9) 〇·Η) minutes) on behalf of 45 200817329 direct chemical and sensation, and clock) represents the neurological origin of the younger brother... again (about 2 〇, the interval is separated by two stages. The column amount returns to normal at 2仃4 The amount of time in the quiescent period, the ping estimate ~ the cost of adding the injured foot to the human phase ~ sub-evaluation of the heart-shaped compound to reduce the effectiveness of the pain stimulus. The mother group tested 8 C57/B6 mice (about the cost of adding the injured foot in two stages) The time of 4, that is, the amount of the injection of fine marlin in the 〇-5 minutes and 2〇_3〇 gossip after the Fu H show. ... know the free base to calculate the investment

〇亳克/公斤 37 43 A The data in Table 4 shows that the compounds of the present invention have little effect on the first b 扪 扪 代表 代表 代表 代表 代表 代表 代表 代表 代表 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The more noteworthy 疋' data also shows that in the second phase of the time spent on the soles of the feet, there is a reduction in the dependence of the agents, agents, and agents, representing the efficacy of the compounds of the invention in the treatment of neuropathic pain. In the first step, 4-[2-(4-mercaptophenylsulfanyl)-phenyl] sulfonium hydrobromide salt was mixed with microcrystalline cellulose. In the second step, a capsule containing four strengths is prepared by mixing with the sulphuric acid S. The active ingredient is stated as a free base. 46 200817329 1 mg 5 mg 25 mg active ingredient ___12.85 g 64.25 g 321.25 g microcrystal Cellulose 2035.55 g 1684.85 g magnesium stearate ~_1 〇 · 6 g 21.2 g 21.9 g capsule content weight mg 212 mg 219 mg per batch 1 〇, capsules. [Simple diagram of the diagram] Figure 1: Compound T -

X-ray diffraction pattern of WBr HBr addition saltFig. 2 · X-ray diffraction pattern of HBr addition salt solvate cut into % " cut 1 Figure 3: Compound J Figure 4: Compound drawing 5: Compound j (〇: + /5 form) Figure 6: Compound I Figure 7 · X-ray diffraction of DL-lactic acid addition salt of X-ray diffraction pattern of palmitic acid addition salt of compound image X-ray diffraction pattern of adipic acid addition salt (1:1) of the adipic acid addition salt (2:1) X-ray diffraction pattern of fumaric acid addition salt X-ray diffraction pattern of 1:1) X-ray diffraction pattern of glutaric acid addition salt (1:1) of compound I. Figure 9. Malonate addition salt of compound I (1:1) X-ray diffraction pattern, α-formation® 10: X-ray diffraction pattern of malonate addition salt of compound I, /5 - form Figure 11 · oxalic acid addition salt of compound I (1:1) X-ray diffraction pattern Figure 12: X-ray diffraction of the azelaic acid addition salt of compound I (2:1) Figure 47 200817329 Figure 13 · Aromatic acid addition salt of compound I (2:1) X-ray diffraction pattern Figure 14: X-ray diffraction pattern of compound I L-malic acid addition salt (1:1), (2 - Form Figure 15: Compound X-ray diffraction pattern of L-malic acid addition salt (1:1) of substance I, Θ-form Figure 16: X-ray diffraction of D-tartaric acid addition salt of compound I (1:1) Figure 1 7 · L-aspartic acid addition salt of compound I (1:1), χ-ray diffraction pattern of mixture with L-aspartic acid Figure 18: L-aspartate of compound I X-ray diffraction pattern of acid addition salt hydrate (1:1), mixture with L-aspartic acid Figure 19: glutamic acid addition salt of compound I (1:1), with proline X-ray diffraction pattern of a mixture of monohydrates Figure 20: χ-ray diffraction of compound I of citric acid addition salt (2:1) Figure 21: ί of compound ί of HCi acid addition salt _Ray diffraction pattern Figure 22: χ-ray diffraction pattern of the compound phosphate addition salt (1:1) Figure 23" Figure of dopamine content in the prefrontal cortex when the compound of the invention is administered 24: Ethylcholine content in the prefrontal locus when administered to a compound of the invention. 'Figure 25a+b: Ethylquinone content in the _ and ventral hippocampus when administered to a compound of the invention. , 48 200817329 [Main component symbol description] No 49

Claims (1)

200817329 X. Patent application garden: 1. A compound I, which is a crystalline form of the private [2_(4•methylphenyl sulfanyl)phenyl] And a pharmaceutically acceptable salt thereof, the restriction condition is that the compound is not a 4-[2-(4-methylphenyl-thioalkyl)phenyl]-D-dihydrochloride addition salt (4_[2_ (4-methylphenylsulfanyl)phenyl]-piperidine hydrochloride addition salt) The compound of claim 1, wherein the compound is an HBr addition salt. 3. A compound as claimed in claim 2, wherein the compound is characterized by a peak in XRPD at about 6 08, 14.81, 19.26 and 25.3802 0. 4. A compound as claimed in claim 2, wherein the compound is characterized by having an XRPD as described in Figure 1. 5. A compound as claimed in claim 1, wherein the compound is a D L -lactic acid addition salt. 6. A compound as claimed in claim 5, wherein the compound is characterized by a peak in 乂1^〇 at about 5.30, 8.18, 9.44 and 17.24 〇; 2 β. 50. The compound of claim 5, wherein the compound is characterized by having an XRPD as described in Figure 4. 8. The compound of claim 1, wherein the compound is a glutaric acid addition salt (1:1). 9. A compound as claimed in claim 8 wherein the compound is characterized by a peak in XRPD at about 9.39, 11.70, 14·5 and 14.58.26». The compound of claim 8, wherein the compound is characterized by having XRPD as described in Fig. 8. 11. A compound as claimed in claim 1 wherein the compound is a propionic acid addition salt (1:1). 12. A compound as claimed in claim 11, wherein the compound is characterized by a peak in XRPD at 10.77. 16.70. , 19.930 and 24·〇1°20, or at 6.08. 10.11. 18.25. And 2〇.26.20. 13. The compound of claim 11, wherein the compound is characterized by having xrpd as described in Figure 9 or 10. 14. The compound of claim 3, wherein the compound is L•aspartic acid addition salt (1:1) or L-aspartic acid addition salt hydrate (1:1). 15. The compound of claim 3, wherein the compound is a proline addition salt (1:1) or a glutamic acid addition salt monohydrate. 16. If the patent application is in the range of 15 to 15, the compound is used for treatment.丨 7. A pharmaceutical composition comprising a compound of any of the items in the scope of the patent application, together with a pharmaceutically acceptable excipient. 51 200817329 \ 18·-A method for treating diseases, the disease (4) ϋ ❹ m / knife responders, treatment of resistance depression, Alzheimer's disease, cognition: ADHD, depression, PTSD, craze, #朝,,工, sleep apnea, alcohol, test or carbohydrate cravings, substance abuse, alcohol or drug abuse disorder, emotional disorders, barbarism, severe ", production: two::, depression associated with bipolar disorder, Az Haimo's disease, psychosis or Monlin's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, illness, panic attack, phobia, social phobia, and urinary incontinence A compound according to any one of the claims of the patent application is intended to be administered to a patient in need thereof. 19. The method of claim 18, wherein the disease is chronic pain. 20. The method of claim 19, wherein the chronic disease is extended from phantom limb pain, neuropathic pain, diabetic neuropathy, post-therapy neuropathic pain (PHN), and wrist-associated syndrome (cts) , hiv## lesions, complex regional pain syndrome (CRPS), Z and neuralgia (8) Na (five) η (10) lgia) / trigeminal neuralgia (8) geminus snoring (4) / trigeminal neuralgia (douloureux) surgical intervention (eg postoperative analgesic) , diabetic angiopathy, capillary resistance or diabetes associated with island inflammation, pain associated with angina pectoris, pain associated with menstruation, pain associated with cancer, toothache, headache, migraine, tension headache, three again Neuropathic pain, mandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatism and sexual joints caused by burn-related trauma Inflammation and edema, osteoarthritis cited 52200817329 sprain or fracture bone pain genus, osteoporosis, bone metastasis or unknown original 1, gout, fibrositis, myofascial Pain, chest, sputum syndrome, upper back pain or lower back pain (in the basin, rain, u, gamma pain caused by systemic, regional or primary spinal disease (spinal radiculopathy)), pelvis Pain, heart chest pain, non-cardiac chest pain, pain associated with spinal cord injury, central post-stroke pain, cancer neuropathy, fine, sickle cell pain, and old man pain. 1. The method of claim 2, wherein the chronic pain is neuropathic pain. △ For example, the method of claim 21, wherein the neuropathic pain is selected from the group consisting of hyperpathia, hyperalgesia, yp gesia, pathological changes, diabetic neuropathy, neuritis, neuralgia, Allergies, burning and allodynia. , 23·- such as the scope of the patent scope of the 丨i 15 item - the use of the compound is used to treat the treatment selected from chronic pain, partial response, treatment of resistance depression, Alzheimer Disease, cognitive impairment, ADHD, depression, PTSD, hot flashes, sleep apnea, alcohol, test or carbohydrate cravings, substance abuse, alcohol or substance abuse, vomiting, eating disorders, (four), dysfunction, Depression, severe depression, postpartum depression ^ Depression associated with _ illness, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, = episode, A remedy for a disease of phobia, W1 (4) or stress urinary incontinence. 24. For the purpose of the 23rd patent case (4), which is the pain. 53 200817329 25 . The use of claim 24, wherein the chronic pain is selected from the group consisting of phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), and carpal tunnel syndrome (CTS) ), HIV neuropathy, complex regional pain syndrome (CRps), trigeminal neuralgia / trigeminus neuralgia / tic douloureux, surgical intervention (eg postoperative analgesics) ), diabetic angiopathy, capillary resistance or diabetes associated with isletitis, pain associated with angina pectoris, pain associated with menstruation, pain associated with cancer, toothache, headache, migraine, tension headache, three Neuropathic pain, temporomandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, osteogenesis and joint pain (osteoarthritis), rheumatoid arthritis, rheumatoid joints resulting from burn-related trauma Inflammation and edema, sprain or fracture bone pain caused by osteoarthritis, osteoporosis, bone metastasis or unknown cause 匕, gout, fiber Weizhiyan, myofascial pain, thoracic outlet sign, upper or lower back pain (where back pain results from systemic, regional or primary spinal disease (radial radiculopathy)), pelvic pain, heart, Dirty chest pain, non-cardiac chest pain # spinal cord injury (SCI) _ related pain, central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain and old man pain. ^ If the scope of the patent application is 25, the slowness is neuropathic pain.朋27·If you apply for the patent scope, the painful grandchildren, s occupies the production of the shellfish, the neuropathy, rain system & self-hyperalgesia (hyp Μ (hyperalgesia), silk shoulder see broken, work disease k; Diabetic neuropathy, neuropathic pain, hyperesthesia, burning pain, and allodynia. Fire, 54 200817329 28 · For example, in the scope of the patent application 丨i 15 item, the compound: in the treatment selected from chronic pain , partial responders, treatment for resistance depression, Alzheimer's disease, cognitive impairment, ADHD, depression, PTSD, hot flashes, sleep apnea, alcohol, nicotine or carbohydrate cravings, substance-alcohol or substance abuse , vomiting, eating disorders, (4), depression, depression, severe depression, postpartum depression, depression related to bipolar disorder, Alzheimer's disease, psychosis or Parkinson's disease, anxiety, generalized anxiety disorder, Father's anxiety, obsessive-compulsive disorder, panic disorder, panic attack, phobia, social phobia, wild phobia or stress urinary incontinence. 29. Compounds as claimed in Article 28 It is used in the treatment of chronic pain. < 3〇·The compound of claim 29, for treating phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), Wrist tunnel syndrome (CTS), HIV neuropathy, complex regional pain syndrome (CRPS), trigeminal neuraigia / trigeminus neuralgia / trigeminal neuralgia (Uc d〇 = 〇ureux), Surgical intervention (eg analgesic after surgery), diabetic rickets, capillary resistance or diabetes associated with island inflammation, pain associated with angina pectoris, pain associated with cerebral menstruation, pain associated with cancer, gums, Head lice, migraine, tension headache, trigeminal neuralgia, temporomandibular joint syndrome, myofascial pain muscle injury, fibromyalgia syndrome, bone and joint pain (osteoarthritis), rheumatoid arthritis, cause Rheumatoid arthritis and edema associated with burns, sprains or monthly pain caused by osteoarthritis, osteoporosis, bone metastases or unknown origin , 55 200817329 Gout, iron worm inflammation, or lower back pain (its t back pain::: pain, thoracic export syndrome, upper back pain (rock radiculopathy), bone * 疚 / systemic, regional Or primary spinal disease and spinal cord injury (SCI) - have: painful skin, chest pain, non-cardiac chest pain, ▲ related pain, central post-stroke pain, #, 广红红病 3C, AIDS Pain, sickle cell pain, or pain in the elderly. Ί 31. For the treatment of neuropathic pain, as in the compound of the scope of patent application. 32. The compound according to claim 31, wherein the neuropathic pain is selected from the group consisting of hyperpathia, hyperalgesia, neuropathy, diabetic neuropathy, neuritis, neuralgia, hyperesthesia, burning Pain and allodynia. Eleven, circle: as the next page 56