4-[2- (4-甲基苯硫基）-苯基]脈啶的盐的液体制剂 Liquid preparations pulse piperidine salt - 4- [phenyl-2- (4-methyl-phenylthio)]

技术领域 Technical Field

[0001 ] 本发明涉及液体药物组合物。 [0001] The present invention relates to liquid pharmaceutical compositions. 技术背景 BACKGROUND

[0002] 作为WO 2003/029232出版的国际专利申请公开了如化合物4-[2_(4_甲基苯硫基）苯基]哌啶（化合物I)作为游离碱和相应HCl加成盐。 [0002] As published International Patent Application WO 2003/029232 discloses the compound 4- [2_ (4_ methylthiophenyl) phenyl] piperidine (Compound I) as the free base and the corresponding HCl addition salt. 该化合物据说是5-羟色胺传输剂和5-羟色胺受体2C(5-HT2。）的抑制剂，和据说可用于治疗情感病症，如抑郁和焦虑。 The compound is said to be serotonin transport agent and a serotonin receptor 2C (5-HT2.) Inhibitor, and is said to be used for the treatment of mood disorders, such as depression and anxiety.

[0003] 已经发现，化合物I也是5-羟色胺受体3 (5-HT3)和5_羟色胺受体2A (5_HT2A)的有效的拮抗剂，其中化合物I可用于治疗较宽范围的症状，包括疼痛和认知损害。 [0003] It has been found, the compounds I are also serotonin receptor 3 (5-HT3) and 5_ serotonin receptor 2A (5_HT2A) effective antagonist, wherein the compound I can be used to treat a wide range of symptoms, including pain and cognitive impairment. 该药理性能还公开于WO 2007/144006。 The pharmacological properties are also disclosed in WO 2007/144006.

[0004] 对于许多药物化合物，预期用于吞咽的片剂，胶囊，丸剂或类似物的口服给药是优选的给药形式。 [0004] For many pharmaceutical compounds oral administration intended for swallowing tablets, capsules, pills or the like are preferred administration form. 但一些患者，如年老患者可能难于吞咽，和液体溶液可以是合适的选择，避免对吞咽片剂，胶囊，丸剂，等的需求。 However, some patients, such as elderly patients may have difficulty swallowing, and liquid solutions may be a suitable choice, avoid swallowing tablets, capsules, pills, and other needs. 液体溶液进一步提供柔性加药方式的可能性。 Liquid solution further provides the possibility of a flexible dosing methods. 为了限制液体溶液的体积，需要在溶液中具有高浓度的活性成分，同样需要高溶解度的活性成分。 In order to limit the volume of liquid solution, is required to have a high concentration of active ingredient in the solution, also requires a high solubility of the active ingredient.

[0005] 本发明是涉及化合物I的液体制剂。 [0005] The present invention relates to liquid formulations of compound I.

[0006] 发明综述 [0006] SUMMARY OF THE INVENTION

[0007] 本发明人已经意外发现，4-[244_甲基苯硫基）苯基]哌啶的DL-乳酸加成盐（= DL-乳酸盐），戊二酸加成盐（=戊二酸盐），L-天冬氨酸加成盐（=L-天冬氨酸盐）和谷氨酸加成盐（=谷氨酸盐）是优异可溶。 [0007] The present inventors have unexpectedly found that 4- [244_ methyl) phenyl] piperidine DL- lactic acid addition salt (= DL- lactate), glutaric acid addition salt (= glutarate), L- aspartic acid addition salt (= L- aspartate) and glutamic acid addition salt (= glutamate) are excellent soluble. 因此，本发明涉及包含4-[2-(4_甲基苯硫基）苯基]哌啶的DL-乳酸加成盐，戊二酸加成盐，L-天冬氨酸加成盐或谷氨酸加成盐的液体制剂。 Accordingly, the present invention relates to compositions comprising 4- [2- (4_ methylthiophenyl) phenyl] piperidine DL- lactic acid addition salt, glutaric acid addition salt, L- aspartic acid addition salt or glutamic acid-addition salt of a liquid formulation.

[0008] 在一个实施方案中，本发明涉及一种治疗方法，所述方法包括向需要治疗的病人供给本发明液体制剂。 [0008] In one embodiment, the present invention relates to a method of treatment, said method comprising administering to a patient in need of treatment a liquid formulation of the present invention is supplied.

[0009] 在一个实施方案中，本发明涉及本发明盐在制造用于治疗某些疾病的液体药物组合物中的用途。 [0009] In one embodiment, the present invention relates to liquid pharmaceutical compositions of the present invention in the manufacture of the salt used in the treatment of certain diseases in use.

[0010] 在一个实施方案中，本发明涉及用于治疗某些疾病的本发明盐，其中所述盐在液体制剂中。 [0010] In one embodiment, the present invention relates to the treatment of certain diseases of the present invention salt, wherein the salt in a liquid formulation.

[0011] 在一个实施方案中，本发明涉及包含本发明液体制剂的容器，其中所述容器配有滴加组件。 [0011] In one embodiment, the present invention relates to a container comprising a liquid formulation of the present invention, wherein the container is equipped with components added dropwise.

[0012] 附图 [0012] FIG.

[0013] 图1 ：在给药化合物I时在前额皮层和腹海马中的乙酰胆碱水平。 [0013] FIG. 1: In the administration of Compound I when the levels of acetylcholine in the prefrontal cortex and ventral hippocampus.

[0014] 图2 ：在给药化合物I时在前额皮层中的多巴胺水平。 [0014] Figure 2: the level of dopamine in the prefrontal cortex in the administration of Compound I when.

[0015] 发明详述 [0015] DETAILED DESCRIPTION

[0016] 本发明所涉及的制剂都是药物制剂。 Formulation [0016] The present invention is a pharmaceutical formulation.

[0017] 实施例中的表2显示4-[2-(4-甲基苯硫基）苯基]哌啶的各种盐的溶解度。 [0017] Examples of Table 2 shows the embodiment of 4- [2- (4-methyl) phenyl] piperidine solubility of various salts. 从数据显然看出，DL-乳酸，L-天冬氨酸，谷氨酸，和戊二酸加成盐具有特别高的溶解度。 As apparent from the data, DL- lactic acid, L- aspartic acid, glutamic acid, and glutaric acid addition salts have exceptionally high solubility. 简便起见，这些盐被称作本发明盐。 Brevity, these salts are salts of the present invention is referred to.

[0018] DL乳酸还称作DL-2-羟基丙酸，它与用于本发明的4-[2-(4_甲基苯硫基）苯基] 哌啶形成1 ： 1酸加成盐。 [0018] DL-lactic acid is also known as DL-2- hydroxy propionic acid, it is used in the present invention with a 4- [2- (4_ methylthiophenyl) phenyl] piperidine formed: an acid addition salt thereof .

[0019] 戊二酸还是称作1，5-戊烷二酸，它与用于本发明的4- [2- (4-甲基苯硫基）苯基] 哌啶形成1 ： 1酸加成盐。 [0019] glutaric acid or acid called 1,5-pentane, which the present invention is 4- [2- (4-methyl) phenyl] piperidine to form a 1: 1 acid addition salt.

[0020] L-天冬氨酸与用于本发明的4-[2-(4_甲基苯硫基）苯基]哌啶形成1 ： 1酸加成盐。 [0020] L- aspartic acid and 4- [2- (4 _ methyl) phenyl] piperidine of the present invention is used to form a 1: 1 acid addition salt.

[0021] 谷氨酸与用于本发明的4-[2-(4_甲基苯硫基）苯基]哌啶形成1 ： 1酸加成盐。 [0021] glutamic acid and 4- [2- (4 _ methyl) phenyl] piperidine used in the present invention is the formation of a 1: 1 acid addition salt.

[0022] 甲基苯硫基）苯基]哌啶可如WO 2003/029232所公开而制备。 [0022] methyl) phenyl] piperidine may be prepared as disclosed by WO 2003/029232. 另外， 4-[2-(4_甲基苯硫基）苯基]哌啶可按照实施例所述而制备。 Further, 4- [2- (4_ methylthiophenyl) phenyl] piperidine may be prepared as described in Example. 本发明盐可通过添加适当酸，随后析出沉淀来制备。 Salts of the present invention may be by adding a suitable acid, and then precipitated prepared. 沉淀可以通过诸如冷却，脱除溶剂，添加另一种溶剂或其混合物进行。 Such as precipitation by cooling, solvent removal, addition of another solvent or a mixture thereof. 实施例公开了用于得到盐的具体路径。 Embodiment discloses a specific path for obtaining salt.

[0023] 液体制剂可预期用于口服或不经肠道给药。 [0023] Liquid formulations may be intended for oral or parenteral administration. 包括浸泡溶液的用于不经肠道给药的液体制剂在许多方面类似于其他液体制剂，但另外以无菌和等渗为特征。 Including soaking solution for parenteral administration a liquid formulation similar to other liquid formulations in many ways, but the other is characterized by sterile and isotonic.

[0024] 本发明的液体口服制剂可被制成糖浆，酏剂，口服溶液，悬浮液，或浓缩口服制剂。 Liquid oral formulation [0024] of the present invention may be made syrups, elixirs, oral solutions, suspensions, or concentrated oral formulation. 这些给药形式的一个优点是，患者无需困难地吞咽固体形式，尤其是对于年老的患者或在口或喉中有创伤的患者。 One advantage of these administration forms, patients without difficulty swallowing solid form, especially for elderly patients or in the mouth or throat trauma patients.

[0025] 糖浆和酏剂通常是包含活性药物成分的增甜的，加香液体。 [0025] Syrups and elixirs typically contain active pharmaceutical ingredients sweetened, flavored liquids. 糖浆通常具有较高糖含量，和酏剂通常还包含醇。 Syrups typically have a higher sugar content, and elixirs typically also contain alcohol. 口服溶液是活性成分的溶液。 Oral solution is a solution of the active ingredient. 悬浮液是包含分散在液体中的固体颗粒的两相体系。 The suspension is dispersed in a liquid containing solid particles of a two-phase system. 糖浆，酏剂，口服溶液和悬浮液的给药通常包括摄入相对大量的液体， 即10-50ml。 Administration syrups, elixirs, oral solutions and suspensions typically include a relatively large amount of liquid intake, namely 10-50ml.

[0026] 相反，本发明的浓缩口服制剂通过从合适的分配器中测出预定体积的所述制剂， 将所得体积加入一杯液体（饮料，如水，果汁或类似物），然后患者饮掉该液体而向病人给药。 [0026] In contrast, concentrated oral formulations of the present invention from a suitable dispenser by measuring predetermined volumes of the formulation, the resulting volume added to a glass of liquid (beverage, water, fruit juice, or the like), and the patient to drink out of the liquid and administered to the patient. 方便起见，所配给的体积小，如低于anl，如低于lml，如低于0. 5ml。 Convenience, the volume dispensed is small, such as below anl, such as less than lml, such as less than 0. 5ml. 在一个特定的实施方案中，本发明的浓缩口服制剂通过从合适的分配器，如具有滴加组件的容器中配给预定数的所述制剂液滴，将这些液滴加入一杯液体（水，果汁或类似物），然后患者饮掉该液体而向病人给药。 In a particular embodiment, the concentrated oral formulations of the invention by the suitable dispenser container as having the formulation droplet dropping assembly in a predetermined number of rationing, these droplets by adding a cup of liquid (water, juice or the like), then the patient can drink out of the liquid and administered to the patient. 在此，滴加组件是配在容器上的组件，使得所述容器内的液体可从所述容器一离散液滴被分配出。 Here, the component is added dropwise to the container with the assembly, such that the liquid in the container can be dispensed from the container a discrete droplet.

[0027] 本发明盐在浓缩口服制剂中的浓度由需要收集的液滴（或体积）的数目和需要给药的盐的量而确定。 Salt [0027] The present invention concentration in concentrated oral formulations is determined by the number and amount of salt needed for administration need to collect droplets (or volume). 一般认为，配给约10-20滴是治疗的安全/效力和方便性两者之间的最佳平衡。 It is generally believed that about 10 to 20 drops of rationing is the best balance between security / ease and effectiveness of both treatments between. 如果本发明盐的浓度太高，即如果仅配给少量的液滴，可能会危害治疗的安全或效力。 If the concentration of the present invention, the salt is too high, that is, if only a small amount of drip rationing might jeopardize the safety or efficacy of the treatment. 在少量液滴的情况下，避所需超出或不足1或2滴会明显增加所提供的剂量的不确定性。 In the case of a small amount of liquid droplets, avoid over or less than the required one or two drops significantly increase the dose provided by uncertainty. 另一方面，如果本发明盐的浓度太低，所配给的液滴数高，不方便患者或护理者。 On the other hand, if the concentration of the salt of the present invention is too low, the high number of dispensed droplets, inconvenience patients or caregivers.

[0028] 在5mg的本发明盐每日剂量下，具有5mg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0028] In the present invention 5mg daily dose of salt, with the active ingredient 5mg / ml concentration concentrated oral formulations may be appropriate. 5mg/ml的浓度和20滴/ml的滴数使得可给药20滴（对于5mg剂量）。 The concentration of 5mg / ml and 20 drops / ml makes the number of drops can be administered 20 drops (for the 5mg dose).

[0029] 在5mg的本发明盐每日剂量下，具有IOmg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0029] In the present invention 5mg daily dose of salt, with IOmg active ingredient / ml concentration concentrated oral formulations may be appropriate. 10mg/ml的浓度和20滴/ml的滴数使得可给药10滴（对于5mg的剂量）。 10mg / ml and a concentration of 20 drops / ml can be administered such that the number of drops 10 drops (for 5mg dose).

[0030] 在IOmg的本发明化合物的每日剂量下，具有20mg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0030] In IOmg daily dose of the compounds of the present invention, the active ingredient with a 20mg / ml concentration concentrated oral formulations may be appropriate. 20mg/ml的浓度和20滴/ml的滴数使得可给药10滴（对于IOmg的剂量）。 The concentration of 20mg / ml and 20 drops / ml makes the number of drops can be administered 10 drops (for IOmg dose).

[0031] 在20mg的本发明化合物每日剂量下，具有40mg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0031] In the compounds of the present invention the daily dose of 20mg, with 40mg of active ingredient / ml concentration concentrated oral formulations may be appropriate. 40mg/ml的浓度和20滴/ml的滴数使得可给药10滴（对于20mg的剂 The concentration of 40mg / ml and 20 drops / ml makes the number of drops can be administered 10 drops (for 20mg of agent

量)O Amount) O

[0032] 在30mg的本发明化合物每日剂量下，具有60mg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0032] 30mg of the compound at a daily dose of the present invention, the active ingredient having 60mg / ml concentration of the concentrated oral formulations may be suitable. 60mg/ml的浓度和20滴/ml的滴数使得可给药10滴（对于30mg的剂 The concentration of 60mg / ml and 20 drops / ml makes the number of drops can be administered 10 drops (for 30mg of agent

量)O Amount) O

[0033] 在40mg的本发明化合物每日剂量下，具有80mg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0033] In the 40mg daily dose of the compounds of the present invention, the active ingredient having 80mg / ml concentration concentrated oral formulations may be appropriate. 80mg/ml的浓度和20滴/ml的滴数使得可给药10滴（对于40mg的剂 The concentration of 80mg / ml and 20 drops / ml makes the number of drops can be administered 10 drops (for 40mg of agent

量)O Amount) O

[0034] 在50mg的本发明化合物每日剂量下，具有的IOOmg活性成分/ml浓度的浓缩口服制剂可以是合适的。 [0034] In the compounds of the present invention, a daily dose of 50mg of the active ingredient with the IOOmg / ml concentration of the concentrated oral formulations may be suitable. 100mg/ml的浓度和20滴/ml的滴数使得可给药10滴（对于的剂量)50mg。 100mg / ml concentration and 20 drops / ml can be administered such that the number of drops 10 drops (for dose) 50mg.

[0035] 在一个实施方案中，浓缩口服滴剂制剂从具有笔或注射器类加药设备的装置给药。 [0035] In one embodiment, the concentrated oral drop formulation administered dosing device means from having pen or syringes. 这些给药装置的例子在如WO 03/061508，US2004/0186431，US 2003-089743中提供。 Examples of these devices in the administration, such as WO 03/061508, US2004 / 0186431, US 2003-089743 provided. 这些装置在密封腔，如墨盒中包含本发明浓缩口服制剂和它们具有用于提供计量量的浓缩口服溶液的装置。 These devices in a sealed chamber, such as the ink cartridge contains concentrated oral formulations of the present invention, and they have a means for providing a metered amount of the concentrated oral solution. 为了限制该设备的尺寸，浓缩口服溶液的体积小（0. Ol-Iml)，而且要求盐是高度可溶的。 In order to limit the size of the apparatus, the concentrated oral solution is small (0. Ol-Iml), and require the salt is highly soluble. 这些笔或注射器类加药设备方便病人使用，因为它们可如在胸袋中携带，和合适设计的设备可用于隐藏它是药物分配器的事实。 These pens or syringes convenient dosing device patients to use because they can be carried as in a breast pocket, and proper design of equipment can be used to hide the fact that it is the drug dispenser.

[0036] 在5至IOmg的本发明盐每日剂量下，具有IOOmg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0036] In the present invention the daily dose of salt 5 to IOmg having IOOmg active ingredient / ml concentration concentrated oral formulations may be appropriate. 这意味着，0. 05ml被传送（对于5mg的剂量）和0. Iml被传送（对于IOmg的剂量)。 This means, 0. 05ml is transmitted (for 5mg dose) and 0. Iml transmitted (for IOmg dose).

[0037] 在20_50mg的本发明化合物每日剂量下，具有200mg活性成分/ml的浓度的浓缩口服制剂可以是合适的。 [0037] In the compounds of the present invention 20_50mg daily dose, with 200mg of active ingredient / ml concentration concentrated oral formulations may be appropriate. 这意味着，0. Iml被传送（对于20mg的剂量）和0. 25ml被传送(对于50mg的剂量)。 This means, 0. Iml be transferred (for 20mg dose) and 0. 25ml transmitted (for 50mg dose).

[0038] 因此，本发明的浓缩口服制剂包含约5-250mg/ml本发明盐。 [0038] Accordingly, concentrated oral formulations of the present invention comprises a salt about 5-250mg / ml of the present invention. 特殊例子包括约10-100mg/ml,约20_200mg/ml，约150_200mg/ml，约20_80mg/ml，约30_70mg/ml，和约10， 20,30,40,50,60,70,80,90或100mg/ml.在一个实施方案中，本发明口服滴剂制剂包含至少5mg/ml本发明盐。 Specific examples include about 10-100mg / ml, about 20_200mg / ml, about 150_200mg / ml, about 20_80mg / ml, about 30_70mg / ml, about 10, 20,30,40,50,60,70,80,90 or 100mg / ml. In one embodiment, the oral drop formulation of the present invention comprises a salt of at least 5mg / ml of the present invention. 在一个实施方案中，本发明口服滴剂制剂包含至少10mg/ml本发明盐。 In one embodiment, the oral drop formulation of the present invention comprises a salt of at least 10mg / ml of the present invention. 在一个实施方案中，本发明口服滴剂制剂包含至少20mg/ml本发明盐。 In one embodiment, the oral drop formulation of the present invention comprises a salt of at least 20mg / ml of the present invention. 在一个实施方案中， 本发明口服滴剂制剂包含至少30mg/ml本发明盐。 In one embodiment, the oral drop formulation of the present invention comprises a salt of at least 30mg / ml of the present invention. 在一个实施方案中，本发明口服滴剂制剂包含至少50mg/ml本发明盐。 In one embodiment, the oral drop formulation of the present invention comprises a salt of at least 50mg / ml of the present invention. 在一个实施方案中，本发明口服滴剂制剂包含至少80mg/ml 本发明盐。 In one embodiment, the oral drop formulation of the present invention comprises a salt of at least 80mg / ml of the present invention.

[0039] 除了本申请的盐，本申请的口服溶液，和尤其是浓缩口服制剂可包含溶剂，缓冲剂，表面活性剂，表面紧张改性剂，粘度改性剂，防腐剂，抗氧化剂，着色剂，味道遮盖剂，香料等。 [0039] In addition to the salt of the present application, the oral solutions of the present application, and in particular concentrated oral formulations may comprise solvents, buffers, surfactants, surface tension modifiers, viscosity modifiers, preservatives, antioxidants, coloring agents, flavor cover agents, perfumes and the like.

[0040] 溶剂的例子包括水和其他溶剂，可与水混溶或是增溶剂，和适用于口服用途。 [0040] Examples of the solvent include water and other solvents, miscible with water or solubilizing agents, and suitable for oral use. 合适的溶剂的例子是乙醇，丙二醇，甘油，聚乙二醇，泊洛沙姆，山梨醇，苯甲醇。 Examples of suitable solvents are ethanol, propylene glycol, glycerin, polyethylene glycol, poloxamers, sorbitol, benzyl alcohol. 活性成分的水溶解度可通过向溶液中加入药物可接受共溶剂，环糊精或其衍生物而进一步增加。 Water solubility of the active ingredient can be prepared by adding to the solution a pharmaceutically acceptable co-solvent, a cyclodextrin or a derivative thereof further increases. [0041] 缓冲剂体系可用于保持制剂的pH在最佳pH范围内。 PH [0041] buffer systems can be used to maintain the formulation within the optimum pH range. 缓冲剂体系是合适量的弱酸如乙酸，磷酸，琥珀酸，酒石酸，乳酸或柠檬酸和其配合物碱的混合物。 Buffer system is a mixture of a suitable amount of a weak acid such as acetic acid, phosphoric acid, succinic acid, tartaric acid, citric acid and lactic acid or base complexes. 理想地，缓冲剂体系足以在用中性，稍微酸性或稍微碱性饮料稀释时保持在预期PH范围内。 Ideally, the buffer system sufficient time, slightly acidic or slightly alkaline drink diluted with neutral PH remain within the expected range.

[0042] 表面活性剂是增溶活性化合物，不足地溶解在水介质中（通常伴随胶束的形成） 的物质。 [0042] Surfactant solubilization of the active compound is insufficient to dissolve (usually accompanied by the formation of micelles) substance in an aqueous medium. 优选所用的表面活性剂应该是非离子的，因为毒性较低。 The surfactant is preferably used should be non-ionic, because of the lower toxicity. 可以使用高浓度的表面活性剂，使得在给药时稀释而不沉淀。 Can use high concentrations of surfactant, such that when administered diluted without precipitation. 表面活性剂的例子包括吐温，司盘和甘油单-和二酯。 Examples of surfactants include Tweens, Spans and glycerol mono - and diglycerides. 可以包括表面紧张改性剂以调节口服滴剂制剂的滴数。 Surface tension modifiers may include oral drop formulations to regulate the number of drops. 表面紧张改性剂的一个例子是乙醇，它能够降低表面紧张和增加滴数。 An example of surface tension modifier is ethanol, which can reduce the surface tension and increase the number of drops.

[0043] 可以包括粘度改性剂以调节浓缩口服制剂的滴加速度。 [0043] may include a viscosity modifier for adjusting the dropping rate concentrated oral formulation. 方便起见，以离散液滴从配有滴加组件的容器中配给的制剂的滴加应该不超过2滴/秒。 Convenience, dropping discrete droplets dispensed from a container with a solution of the components in the formulation should not exceed 2 drops / sec. 粘度改性剂的例子包括乙醇，羟基乙基纤维素，羧甲纤维素钠，甲基纤维素，聚乙烯醇，聚乙烯基吡咯烷酮，聚乙二醇和甘油。 Examples of viscosity modifiers include ethanol, hydroxyethylcellulose, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol and glycerine.

[0044] 可以加入防腐剂以防微有机体如细菌，酵母和真菌在往往要重复使用的液体制剂中的生长。 [0044] may be added preservative to prevent the growth of micro-organisms such as bacteria, yeasts and fungi in liquid formulations to be repeated often used by. 合适的防腐剂应该在所需PH范围内是药物可接受，物理化学稳定和有效的。 Suitable preservatives should be within the desired range of PH is pharmaceutically acceptable, physicochemical stable and effective. 防腐剂的例子包括乙醇，苯甲酸，山梨酸，对羟基苯甲酸甲酯，对羟基苯甲酸丙酯和苯甲醇。 Examples of preservatives include ethanol, benzoic acid, sorbic acid, methyl paraben, propyl paraben and benzyl alcohol.

[0045] 因为溶解形式的药物物质比固体形式对化学降解更敏感，可能需要在液体制剂中包括抗氧化剂。 [0045] Because the ratio of the drug substance in dissolved form to a solid form are more susceptible to chemical degradation and may need to include an antioxidant in the liquid formulation. 抗氧化剂的例子包括丙基没食子酸盐，棕榈酸抗坏血酸基酯，抗坏血酸，亚硫酸钠，柠檬酸和EDTA。 Examples of antioxidants include propyl gallate, ascorbyl palmitate ester, ascorbic acid, sodium sulfite, citric acid and EDTA.

[0046] 着色剂可用于一些制剂以向产品引入一致性的外观。 [0046] The colorant may be used in some formulations to introduce a uniformity of appearance to the product. 一些活性成分可进一步对光非常敏感和可能需要向滴剂制剂中加入着色剂以保护它们避光和用于稳定。 Some active ingredients may further very sensitive to light and may need to add a coloring agent formulation drops to protect them from light and for stability. 合适的着色剂包括例如酒石黄和日落黄。 Suitable colorants include, for example tartrazine and sunset yellow.

[0047] 增甜剂可遮盖与一些制剂有关的未愉悦的味道或实现所需味道。 [0047] sweeteners may be covered with some preparations not related to the pleasure of taste or achieve the desired taste. 增甜剂的例子是糖精，糖精的钠盐，葡萄糖，山梨醇，甘油，乙酰舒泛钾和新桔皮苷二氢查耳酮。 Examples of sweeteners are aspartame, saccharin sodium, glucose, sorbitol, glycerol, acesulfame potassium and new hesperidin dihydrochalcone. 味道可通过加入一种或多种调味物质而进一步优化。 Taste by the addition of one or more flavoring substances and further optimized. 合适的调香物质是水果香料如樱桃，红莓，红醋栗，柠檬香或草莓香或其他香料如美味料，anis，薄荷，饴糖等。 Suitable flavoring substances are fruit flavors such as cherry, raspberry, red currant, lemon or strawberry incense or other spices such as delicious material, anis, mint, caramel and so on.

[0048] 可用滴加组件给药的浓缩口服制剂的具体例子是甲基苯硫基）-苯基] 哌啶=化合物I) [0048] Available dropwise concentrated oral formulation for administration component Specific examples are methyl phenylthio) - phenyl] piperidine = Compound I)

[0049] 0. 73%化合物I戊二酸盐，对应于0. 5%化合物I游离碱 [0049] 0.73% Compound I glutarate corresponding compound I free base in 0.5%

[0050] 水，足量，加至100% [0050] water, adequate, up to 100%

[0051] 1. 58%化合物I谷氨酸盐，对应于化合物I游离碱 [0051] 1.58% Compound I glutamate corresponding to the free base of compound I

[0052] 0. 08%对羟基苯甲酸甲酯 [0052] 0.08% methyl paraben

[0053] 0.02%对羟基苯甲酸丙酯 [0053] 0.02% propyl paraben

[0054] 水，足量，加至100% [0054] water, adequate, up to 100%

[0055] 2. 94%化合物IL-天冬氨酸盐，对应于2%化合物I游离碱 [0055] 2.94% compound IL- aspartate, Compound I free base corresponds to 2%

[0056] 0. 08%对羟基苯甲酸甲酯 [0056] 0.08% methyl paraben

[0057] 0.02%对羟基苯甲酸丙酯 [0057] 0.02% propyl paraben

[0058] 7% 乙醇 [0058] 7% ethanol

[0059] 水，足量，加至100% [0059] water, adequate, up to 100%

[0060] 10. 化合物IDL-乳酸盐，对应于8%化合物I游离碱[0061] 0.08%对羟基苯甲酸甲酯 [0060] 10. A compound IDL- lactate, corresponding to 8% Compound I free base [0061] Methylparaben 0.08%

[0062] 0.02%对羟基苯甲酸丙酯 [0062] 0.02% propyl paraben

[0063] 水，足量，加至100% [0063] water, adequate, up to 100%

[0064] 可用笔或注射器类设备给药的浓缩口服制剂的具体例子是 [0064] Available pen or concentrated oral formulation of specific examples of a syringe-type device administration is

[0065] 26. 36%化合物IDL-乳酸盐，对应于20%化合物I游离碱 [0065] Compound IDL- lactate 26.36%, corresponding to 20% Compound I free base

[0066] 0. 08%对羟基苯甲酸甲酯 [0066] 0.08% methyl paraben

[0067] 0.02%对羟基苯甲酸丙酯 [0067] 0.02% propyl paraben

[0068] 水，足量，加至100% [0068] water, adequate, up to 100%

[0069] 本发明盐的药物性能公开于实施例。 [0069] Drug performance salt of this invention disclosed in the embodiments. 总之，本发明盐是5-羟色胺传输剂和5-羟色胺受体2C (5-HT2C)的抑制剂和5-羟色胺受体3 (5-HT3)，5-羟色胺受体2A (5_HT2A)和α 1 肾上腺能受体的拮抗剂和它们似乎带来乙酰胆碱在前额皮层和腹海马中的细胞外水平和在前额皮层中的多巴胺水平的增加。 In short, the salts of the invention are serotonin transport agent and a serotonin receptor 2C (5-HT2C) inhibitors and serotonin receptor 3 (5-HT3), 5- serotonin receptor 2A (5_HT2A) and α 1 adrenergic receptor antagonists and they seem to bring and increase in dopamine levels in the prefrontal cortex of acetylcholine in the prefrontal cortex and ventral hippocampus extracellular level. 另外，本发明盐有效地治疗实施例所给出的疼痛。 Further, salts of the present invention is effective in the treatment of pain given embodiment. 药理性能与预临床数据的组合预期被反映在本发明盐的临床用途上。 Pharmacological properties in combination with pre-clinical data are expected to be reflected in the clinical use of the present invention is a salt. 因此，本发明盐据信可用于治疗疾病，包括心情病症，重性抑郁病症，一般焦虑病症，非典型抑郁，双极抑郁，社会焦虑病症，强迫性强制病症，恐慌病症，创后压迫病症，滥用，饮食病症，睡眠病症，阿耳茨海默氏疾病，痴呆，慢性疼痛，与认知损害相关的抑郁，与精神病相关的抑郁，精神分裂症中的认知损害，与疼痛有关的抑郁或焦虑，老年人的行为障碍，ADHD，忧郁症治疗反抗性抑郁和具有残留症状的抑郁。 Thus, salts of the present invention are believed to be useful in the treatment of diseases, including mood disorders, major depressive disorder, general anxiety disorder, atypical depression, bipolar depression, social anxiety disorder, obsessive compulsory disorder, panic disorder, post-condition creating compression, abuse, eating disorders, sleep disorders, Alzheimer's disease, dementia, chronic pain, depression associated with cognitive impairment, and psychosis related to depression, schizophrenia, cognitive impairment, depression associated with pain or anxiety, behavioral disorders of the elderly, ADHD, depression treatment against depression and has residual symptoms of depression.

[0070] 5-HT2C受体位于诸如多巴胺能神经元上，在此，活化对多巴胺释放产生强化的抑制影响，而且5-HT2C拮抗药将影响多巴胺水平的提高。 [0070] 5-HT2C receptors are located, such as dopaminergic neurons, in this, activated by generating enhanced inhibition of dopamine, and 5-HT2C antagonist will affect raise dopamine levels. 实施例中提供的数据显示，化合物I的确会在大脑中带来胞外多巴胺水平的提高。 Data provided in the examples show that compound I certainly will bring increase extracellular dopamine levels in the brain. 在这种背景下，可以预期，5-HT2。 In this context, it can be expected, 5-HT2. 拮抗药特别适用于治疗难以用选择性血清素再摄取抑制剂治疗的抑郁症。 Antagonists especially useful in the treatment difficult selective serotonin reuptake inhibitors for the treatment of depression. 这个预期在若干临床研究中得到支持，这些研究显示，米氮平与SSRI的组合优于SSRI单独用于治疗没有足够临床反应的抑郁症患者（抗治疗抑郁症，TRD，或顽固性抑郁症）[Psychother.I^sychosom.，75， 139-153,2006]。 This is expected to get support in several clinical studies, these studies show that a combination of mirtazapine and SSRI is superior to SSRI alone for patients with depression do not have enough clinical response to treatment (treatment-resistant depression, TRD, or refractory depression) [Psychother.I ^ sychosom., 75, 139-153,2006]. 米氮平也是一种5-HT2和5_HT3拮抗药，这表明，兼备血清素再摄取抑制使用以及5-HT2和5-HT3拮抗作用的化合物，例如化合物I，可用于治疗TRD，即会提高患有抗治疗抑郁症的患者的缓解速率。 Mirtazapine is also a 5-HT2 antagonist and 5_HT3, which indicates that both compounds as well as serotonin 5-HT2 and 5-HT3 antagonism reuptake inhibition, for example the compounds I, for the treatment of TRD, i.e. will increase the risk of anti-remission rate of depression patients.

[0071] 实施例中提供的数据显示，化合物I能提高脑中乙酰胆碱的胞外水平。 [0071] Data provided in the embodiment example shows that Compound I can enhance brain extracellular levels of acetylcholine. 长期存在的临床症据表明，提高大脑中乙酰胆碱水平是治疗阿尔茨海默病和一般认识缺损的一种途径，参照乙酰胆碱酯酶在阿尔茨海默病治疗中的用途。 Long-term data indicate the presence of clinical disease, improve brain levels of acetylcholine in the treatment of Alzheimer's disease and a defect in the way the general understanding, reference acetylcholinesterase in Alzheimer's disease treatment purposes. 在这种背景下，相信化合物I可用于治疗阿尔茨海默病和认识缺损以及情绪异常，例如与阿尔茨海默病和认识缺损相联系的抑郁症。 In this context, I believe that the compounds are useful in treating Alzheimer's disease and understanding of defects and mood disorders, such as Alzheimer's disease and understanding of defects linked to depression.

[0072] 部分抑郁症患者在如下意义上会对用诸如SSRI的治疗作出反应：它们会在临床相关抑郁尺度例如MADRD和HAMD上有所改善，但在这种情况下其他症状例如睡眠紊乱和认识缺损依然如故。 [0072] section with depression in the sense that would be used to respond to SSRI treatment such as: they are clinically relevant depression scales such as improvements in the MADRD and HAMD, but in this case other symptoms such as sleep disorders and cognition defects remains the same. 在本发明范畴内，这些患者称为部分反应者和患有具有残余症状的抑郁症。 In the context of the present invention, called a partial response in these patients suffer from depression and have residual symptoms. 由于以上讨论的对乙酰胆碱水平的影响，化合物I，除抑郁症外，还可望可用于治疗认识缺损。 Discussed above due to acetylcholine levels, compound I, in addition to depression, but also expected to be useful for treating cognition defects. 临床研究已经显示，哌唑嗪化合物-即一种α-l肾上腺素能受体拮抗药-减少了睡眠紊舌L [Raskind, Biol. Psychiatry, 2006出版]。 Clinical studies have shown that the compound prazosin - i.e. an α-l-adrenergic receptor antagonist - reduced sleep disordered tongue L [Raskind, Biol Psychiatry, 2006 publication.]. 进而，本发明化合物的5-HT2a和5_HT2C 拮抗作用相信也有镇静，睡眠改善效果[Neuroparmacol 1. 33，467-471，1994]，因此，本发明化合物可用于治疗部分反应者（具有残留症状的抑郁症），或换言的，用化合物I对抑郁症患者的治疗将使部分反应者的部分减少。 Furthermore, 5-HT2a and 5_HT2C antagonism of the present compounds I believe there are sedative, sleep-improving effect [Neuroparmacol 1. 33,467-471,1994], therefore, the compounds of the present invention can be used in treatment of partial responders (having a residual depressive symptoms disease), or in other words, with the compound I for the treatment of patients with depression will partially reduce some responders.

[0073] 在一个实施方案中，本发明涉及一种治疗以下疾病的方法：心情病症，重性抑郁病症，一般焦虑病症，非典型抑郁，双极抑郁，社会焦虑病症，强迫性强制病症，恐慌病症，创后压迫病症，滥用，饮食病症，睡眠病症，阿耳茨海默氏疾病，痴呆，慢性疼痛，与认知损害相关的抑郁，与精神病相关的抑郁，精神分裂症中的认知损害，与疼痛有关的抑郁或焦虑，老年人的行为障碍，ADHD，忧郁症治疗反抗性抑郁和具有残留症状的抑郁，所述方法包括向需要治疗的病人给药治疗有效量的本发明液体制剂。 [0073] In one embodiment, the present invention relates to a method for treating the following disorders: mood disorders, major depressive disorder, general anxiety disorder, atypical depression, bipolar depression, social anxiety disorder, obsessive compulsory disorder, panic disease, oppression after invasive disease, abuse, eating disorders, sleep disorders, Alzheimer's disease, dementia, chronic pain, depression associated with cognitive impairment, depression associated with psychosis, cognitive impairment in schizophrenia depression, pain associated with depression or anxiety, behavioral disorders in the elderly, ADHD, melancholia treatment resistant depression and having resistance residual symptoms, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a liquid formulation of the present invention.

[0074] 在一个实施方案中，所述液体制剂是浓缩口服制剂。 [0074] In one embodiment, said liquid formulation is a concentrated oral formulation.

[0075] 在一个实施方案中，所要治疗的患者已被诊断为患有该病人所要治疗的疾病。 [0075] In one embodiment, the patient to be treated has been diagnosed as having the disease of the patient to be treated.

[0076] 在实施方案，本发明化合物的给药量是约0. 001至约100mg/kg体重/天。 [0076] In embodiments, the compounds of the present invention is administered in an amount from about 0.001 to about 100mg / kg body weight / day.

[0077] 典型口服剂量是约0. 001至约100mg/kg体重/天，优选约0. 01至约50mg/kg体重/天，以一个或多个剂量如1至3个剂量给药。 [0077] A typical oral dosage is about 0.001 to about 100mg / kg body weight / day, preferably from about 0.01 to about 50mg / kg body weight / day, in one or more doses such as 1-3 doses. 确切剂量取决于给药频率和方式，治疗对象的性别，年龄，体重和总体状况，治疗病症的性质和严重性，任何要治疗的伴行疾病以及业内技术人员显而易见的其他因素。 The exact dose depends on the frequency and mode of administration, the treatment of gender, age, weight and general condition of the subject, the nature and severity of the condition of the treatment, other factors accompanying any disease to be treated and apparent to those skilled in the industry.

[0078] 成人的典型口服剂量范围是1〜IOOmg/日本发明化合物，例如1〜30mg/日，或5〜25mg/日。 [0078] A typical adult oral dose ranges are 1~IOOmg / Japan of a compound, such as 1~30mg / day, or 5~25mg / day. 典型地，一日一次或两次给药0. 1〜50mg，例如1〜25mg，如1，5，10，15，20， 25，30，40，50或60mg本发明化合物，就可以做到这一点。 Typically, once or twice a day dosing 0. 1~50mg, for example 1~25mg, such as compound 1,5,10,15,20, 25,30,40,50 or 60mg of the present invention, it can be done at this point.

[0079] 本文中使用的化合物的“治疗有效量”系指在一种包含所述化合物给药的治疗干预中足以治愈，缓解或部分终止某一给定疾病及其并发症的临床表现的数量。 Therapeutic interventions [0079] "therapeutically effective amount" as used herein means a compound comprising the compound administered is sufficient to cure, alleviate or partially terminated for a given number of clinical manifestations of the disease and its complications . 足以实现这一点的数量就定义为“治疗有效量”。 Quantity sufficient to achieve this is defined as "therapeutically effective amount." 这一术语也包括在一种包含所述化合物给药的治疗中足以治愈，缓解或部分终止某一给定疾病及其并发症的临床表现的数量。 The term also includes the administration of compounds comprising treatment sufficient to cure, alleviate or partially terminate a given number of clinical manifestations of the disease and its complications. 每一个目的有效量都取决于该疾病或受伤的严重性，以及该对象的体重和总体状态。 Each object of an effective amount depends on the severity of the illness or injury, as well as the weight and general state of the object. 要理解的是，适当剂量的确定可以实现如下：利用常规实验，构建数值点阵，和测试该点阵中不同的点，这些都在训练有素的医生的普通技能范围内。 To understand that, you can determine the proper dosage to achieve the following: the use of routine experimentation, numerical lattice build, and test the different lattice points, which are within the ordinary skill of a trained physician.

[0080] 本文中使用的“治疗”这一术语系指患者的管理和护理，以达到克服某一病症例如疾病或异常的目的。 [0080] As used herein, "treating" the term refers to the management and care of patients, in order to achieve the purpose of overcoming certain illnesses such as disease or abnormal. 这一术语意图包括该患者所患的某一给定病症的全治疗谱，例如该活性化合物给药以缓解症状或并发症，以延缓该疾病，异常或病症的进展，以缓解或减轻症状和并发症，和/或以治愈或消除该疾病，异常或病症以及以预防该病症，其中预防要理解为患者的管理和护理以达到克服该疾病，病症，或异常的目的，而且包括活性化合物给药以预防该症状或并发症发作。 The term is intended to include the patient is suffering from a given condition the whole treatment spectrum, such as the active compound is administered to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or reduce symptoms and complications, and / or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of patients in order to achieve overcome the disease, condition, or the purpose of the exception, but also to the active compound drugs to prevent the onset of the symptoms or complications. 不过，预防性（预防）和治疗性（治愈）治疗是本发明的两个独立方面。 However, prophylactic (preventive) and therapeutic (cure) treatment are two separate aspects of the invention. 要治疗的患者较好是哺乳动物，尤其人类。 The patient to be treated is preferably a mammal, especially humans.

[0081] 在一个实施方案中，本发明涉及本发明盐用于下列疾病治疗用液体制剂的制造中的用途：心情病症，重性抑郁病症，一般焦虑病症，非典型抑郁，双极抑郁，社会焦虑病症，强迫性强制病症，恐慌病症，创后压迫病症，滥用，饮食病症，睡眠病症，阿耳茨海默氏疾病，痴呆，慢性疼痛，与认知损害相关的抑郁，与精神病相关的抑郁，精神分裂症中的认知损害，与疼痛有关的抑郁或焦虑，老年人的行为障碍，ADHD，忧郁症治疗反抗性抑郁和具有残留症状的抑郁。 [0081] In one embodiment, the present invention relates to salts of the present invention is used for the treatment of the following diseases in the manufacture of a liquid formulation uses: mood disorders, major depressive disorder, general anxiety disorder, atypical depression, bipolar depression, social anxiety disorders, obsessive compulsory disorder, panic disorder, post-create conditions of oppression, abuse, eating disorders, sleep disorders, Alzheimer's disease, dementia, chronic pain, depression associated with cognitive impairment, depression associated with psychosis , schizophrenia, cognitive impairment, and pain-related depression or anxiety, behavioral disorders of the elderly, ADHD, depression treatment against depression and has residual symptoms of depression. 在一个实施方案中，所述液体制剂是浓缩口服制剂。 In one embodiment, said liquid formulation is a concentrated oral formulation.

[0082] 在一个实施方案中，本发明涉及用于治疗下列疾病的本发明盐：心情病症，重性抑郁病症，一般焦虑病症，非典型抑郁，双极抑郁，社会焦虑病症，强迫性强制病症，恐慌病症， 创后压迫病症，滥用，饮食病症，睡眠病症，阿耳茨海默氏疾病，痴呆，慢性疼痛，与认知损害相关的抑郁，与精神病相关的抑郁，精神分裂症中的认知损害，与疼痛有关的抑郁或焦虑， 老年人的行为障碍，ADHD，忧郁症治疗反抗性抑郁和具有残留症状的抑郁，其中所述盐在液体制剂中。 [0082] In one embodiment, the present invention relates to the treatment of the following diseases salts of the present invention: mood disorders, major depressive disorder, general anxiety disorder, atypical depression, bipolar depression, social anxiety disorder, obsessive compulsory disorder , panic disorder, post-create conditions of oppression, abuse, eating disorders, sleep disorders, Alzheimer's disease, dementia, chronic pain, depression associated with cognitive impairment, and psychosis related to depression, schizophrenia recognition known damage, pain associated with depression or anxiety, behavioral disorders in the elderly, ADHD, melancholia treatment resistant depression and having a residual resistance depressive symptoms, wherein said salt in a liquid formulation. 在一个实施方案中，所述液体制剂是浓缩口服滴剂制剂。 In one embodiment, said liquid formulation is a concentrated oral drop formulation.

[0083] 本发明盐可单独或与另一治疗活性化合物结合给药，其中两种化合物可同时或顺序给药。 [0083] salts of the present invention may be used alone or in combination with another therapeutically active compound is administered, wherein the two compounds may be administered simultaneously or sequentially. 可有利地与化合物I结合的治疗活性化合物的例子包括镇静剂或安眠剂，如苯并地西泮；抗惊厥剂，如拉莫三嗪，丙戊酸，托吡酯，加巴喷丁，卡马西平；心情稳定剂如锂；多巴胺能药物，如多巴胺激动剂和L-多巴；用于治疗ADHD的药物，如托莫西汀；精神刺激剂， 如莫达非尼，氯胺酮，哌甲酯和苯丙胺；其他抗抑郁药，如米氮平，米安色林和安非他酮；荷尔蒙，如T3，雌激素，DHEA和睾酮；非典型抗精神病，如奥氮平和阿立哌唑；典型抗精神病， 如氟哌啶醇；用于治疗阿耳茨海默氏疾病的药物，如胆碱脂酶抑制剂和美金刚，叶酸；S-腺苷基_蛋氨酸；免疫调节剂，如干扰素；鸦片剂，如丁丙诺非；血管紧张素II受体1拮抗剂(ATI拮抗剂）；ACE抑制剂；抑胃酶氨酸；和α 1肾上腺能拮抗剂，如哌唑嗪。 Examples of treatment can be advantageously combined with active compound I include sedatives or sleep binding agents, such as benzo diazepam; anticonvulsants, such as lamotrigine, valproate, topiramate, gabapentin, carbamazepine; stabilize mood agents such as lithium; dopaminergic drugs, such as dopamine agonists and L- dopa; drugs used to treat ADHD, such as atomoxetine; psychostimulants, such as modafinil, ketamine, methylphenidate and amphetamine; other antidepressants, such as mirtazapine, mianserin and bupropion; hormones, such as T3, estrogen, DHEA and testosterone; atypical antipsychotics, such as olanzapine and aripiprazole; typical anti-psychotics, such as droperidol piperidinol; for the treatment of Alzheimer's disease drugs, such as cholinesterase inhibitors and memantine, folate; S- adenosyl methionine _; immunomodulatory agents, such as interferon; opiates, such as buprenorphine Connaught non; angiotensin II receptor antagonist (ATI antagonist); ACE inhibitors; gastric inhibitory enzyme acid; and α 1 adrenergic antagonists such as prazosin.

[0084] 本文中引用的所有参考文献，包括出版物，专利申请，和专利都以其全文列为本文参考文献，并达到这样的程度：个别，具体地指出要列为参考文献和全文列入本文中（在法律允许的最大程度上）的每篇参考文献，无论本文中其他地方所做的，任何单独提供的特定文件引用如何。 [0084] All references cited herein, including publications, patent applications, and patents are incorporated herein by reference in their entirety, and to such an extent: Individual, specifically incorporated herein by reference and to point out in full in the paper (to the maximum extent permitted by law) of each reference, whether made elsewhere herein, any reference to a specific file separately how.

[0085] 在描述本发明的范畴内，“一个”，“一种”和“该”这些术语和类似参照物的使用，要理解为同时涵盖单数和复数，除非本文中另有指出或上下文明显相矛盾。 [0085] within the scope of the invention described, "a", "an" and "the" and similar use of such terms of reference, to be understood as to cover both the singular and the plural, unless otherwise indicated herein or the context clearly contradict. 例如，“化合物”这一短语要理解为系指本发明的各种“化合物”或具体描述的方面，除非另有指出。 For example, "compound" is to be understood that aspects of the various phrase "compound" or specifically described the present invention means, unless otherwise indicated.

[0086] 除非另有指出，否则本文中提供的所有确切数值都是相应近似值的代表（例如， 所提供的，关于某一特定因子或测定的所有确切例示性数值，都可以理解为也提供适当时用“约”修饰的相应近似测定）。 [0086] Unless otherwise indicated, all exact values ​​provided herein are representative of corresponding approximate values ​​(e.g., provided, all exact exemplary values ​​with respect to a particular factor or measurement, can also be understood to provide adequate "Testament" modified corresponding approximate measurement) is used.

[0087] 本文中参照一种或多种要素使用“包含”，“有”，“包括”，或“含有”这样的术语对本发明任何一个或多个方面的描述，意图提供对“组成为”，“基本组成为”，或“实质上包含” 该一种或多种要素的本发明一个或多个类似方面的支持，除非上下文另有说明或明显矛盾(例如，本文中描述为包含某一特定要素的组合物应当理解为也描述一种由该要素组成的组合物，除非上下文另有说明或明显矛盾）。 [0087] As used herein with reference to one or more of the elements use "contains", "have", "include" or "contain" terms to describe the present invention, any one or more aspects, intended to provide for "composition" "consisting essentially of" or "consists essentially of" one or more support similar aspects of the one or more elements of the present invention, unless otherwise stated or clearly contradicted by context (for example, described herein as comprising a The composition of a particular element should be understood as also describes a composition consisting of that element composition, unless otherwise stated or clearly contradicted by context).

实施例 Example

[0088] 实施例1 ：药理性能 [0088] Example 1 Example: pharmacological properties

[0089] 实施例IA :5_羟色胺（5-ΗΤ)和降肾上腺素（NE)再吸收抑制 [0089] Example IA: 5_ serotonin (5-ΗΤ) and norepinephrine (NE) resorption inhibition

[0090] 试验化合物和鼠皮层突触体制剂的等分试样预培养10min/37°C，并随后加入[3H] NE或[3H] 5-HT (最终浓度IOnM)。 [0090] An aliquot of test compound and rat cortical synapses preparations are pre-incubated 10min / 37 ° C, and then added [3H] NE or [3H] 5-HT (final concentration IOnM). 非特定吸收在10 μ M他舒普仑或西酞普兰存在下测定和总吸收在缓冲剂存在下测定。 Non-specific absorption at 10 μ M he 舒普仑 or citalopram and the total absorption measured in the presence of a buffer measured Kaplan exist. 等分试样在37摄氏度下培养15分钟。 Aliquot incubated at 37 degrees Celsius for 15 minutes. 在培养之后，突触体所吸收的[3HjNE或[3H] 5-ΗΤ使用Tomtec Cell Harvester程序通过滤过在0. 1% PEI ψ 预浸渍30分钟的Unifilter GF/C而分离。 After incubation, synaptosomes absorbed [3HjNE or [3H] 5-ΗΤ use Tomtec Cell Harvester program by filtration through pre-soaked in 0. 1% PEI ψ 30 minutes Unifilter GF / C separated. 将滤过物质洗涤和在Wallac MicroBeta计数器中计数。 The filtered material was washed and counted in a Wallac MicroBeta counter. [0091] 在NET下，化合物I具有23nM的IC5tl值。 [0091] In NET, the compounds I have IC5tl value of 23nM. 在SERT下，化合物I具有8nM的IC5tl值。 In SERT, compound I having IC5tl value 8nM of.

[0092] 实施例IB :5-HT2A拮抗作用 5-HT2A antagonism: Example IB [0092] implementation

[0093] 测试化合物I对血清素受体的亲和性，并发现其显示出在5-HT2A受体上有亲和性(Ki 54nM)的拮抗性能。 [0093] Test Compound I serotonin receptor affinity and found to exhibit on the 5-HT2A receptor affinity (Ki 54nM) antagonist properties. 该亲和性从Y= 100/(l+10(x-log icJ)计算，式中Y表示％结合，而X表示化合物浓度。使用5个化合物浓度（1，10，30，100，IOOOnM)来计算IC5tl值。Ki是从CHeng Prusoff 方程Ki = IC50/(1+([L]/Kd))计算的。亲和性是以MDL PHarmaservices 分类号271650确定的。 The affinity = 100 / (l + 10 (x-log icJ) calculated from Y, wherein Y represents% bound, and X represents the concentration of compound. 5 using the compound concentrations (1,10,30,100, IOOOnM) .Ki IC5tl value calculated from CHeng Prusoff equation Ki = IC50 / (1 + ([L] / Kd)) calculated. affinity is determined MDL PHarmaservices words 271,650.

[0094] 在表达人5-HT2A受体的哺乳动物细胞中，化合物I显示出竞争性拮抗性能。 [0094] In expressing the human 5-HT2A receptors in mammalian cells, compound I exhibit competitive antagonism. 该化合物与5-HT2A受体结合的Ki < IOOnM,而在功能试验中，该化合物拮抗5-HT诱发的，胞内贮藏的Ca2+的释放，Kb为67nM。 The compound with the 5-HT2A receptor binding Ki <IOOnM, and in the functional assay, the compounds antagonize 5-HT-induced, Ca2 + release of intracellular storage, Kb is 67nM. ScHild分析公开了Kb为IOOnM的竞争性拮抗作用。 ScHild analysis discloses a competitive IOOnM Kb of antagonism.

[0095] 实验进行如下：实验前2或3天，将表达250fmol/mg人5_HT2A受体的CHO细胞以足以在实验当日产生单融合层的密度涂在平皿上。 [0095] Experiments carried out as follows: 2 or 3 days before the experiment, the expression 250fmol / mg human 5_HT2A receptor in CHO cells is sufficient to produce a single fusion experiment day density layer coated on the plates. 该细胞在一台5% CO2,95%湿度，37°C恒温箱中加染料（Ca2+试剂盒，分子设备公司）60min。 The cells in a 5% CO2,95% humidity, 37 ° C incubator of dyes (Ca2 + kit, Molecular Devices Corp.) 60min. 基础荧光用一台荧光影像板读出器或分子设备公司(美国加州Sunnyvale)的FLIPR384,以488nm的激发波长和500〜560nm的发射范围监测。 Fluorescence using a fluorescence-based imaging plate reader or Molecular Devices Corp. (California, Sunnyvale) is FLIPR384, with an excitation wavelength of 488nm and an emission range 500~560nm monitoring. 激光强度设定到适当水平，以得到大约8000〜10000荧光单位的基础值。 Laser light intensity is set to an appropriate level to obtain basal values ​​of approximately 8000~10000 fluorescence units. 基础荧光的变异应当< 10% EC50值是使用涵盖至少3个数量级的试验化合物递增浓度评价的。 Variation basal fluorescence should be <10% EC50 value is used to cover at least three orders of magnitude increasing concentrations of the test compounds evaluated. 评价了PA2值，以用4个不同化合物浓度（150，400，1500和4000nM)挑战5-HT的全剂量-响应曲线。 PA2 evaluated values ​​to use four different concentrations of compound (150,400,1500 and 4000nM) challenges the full dose of 5-HT - response curve. 也评价了Kb值，以用5-HT的EC85挑战试验物质的2个数量级浓度。 Kb values ​​were also evaluated for the 5-HT EC85 by two orders of magnitude challenge concentration of the test substance. 试验物质在5-HT之前5min添加到该细胞中。 5-HT test substance is added to the cells before the 5min. Ki值是用CHeng-Prusoff方程计算的。 Ki value is calculated CHeng-Prusoff equation.

[0096] 实施例IC :5-HT3A受体拮抗作用 [0096] Example IC: 5-HT3A receptor antagonism

[0097] 在表达了人同数5-HT3A受体的卵母细胞中，5-HT以EC5tl为2600nM激活了流。 [0097] In the expression of the people with several 5-HT3A receptor oocytes, 5-HT to EC5tl as 2600nM was activated. 这种流可以用经典5-HT3拮抗药例如昂丹司琼拮抗。 This stream can be used classical 5-HT3 antagonists such as ondansetron antagonistic. 昂丹司琼在这个系统中显示出InM以下的Ki值。 Ondansetron shows Ki values ​​InM less in this system. 化合物I在低浓度（0. InM-IOOnM)时显示出强拮抗作用（IC5tl〜10nm/Kb〜2nM)， 而当以更高浓度（100〜IOOOOOnM)施用时显示出兴奋性能（EC5tl〜2600nM)，达到5-HT本身诱发的最大流的大约70〜80%的最大流。 Compound I exhibit strong antagonism (IC5tl~10nm / Kb~2nM) at low concentrations (0. InM-IOOnM) when, and when a higher concentration (100~IOOOOOnM) administration showed excitement performance (EC5tl~2600nM) , reaching 5-HT-induced maximum flow itself about 70~80% of the maximum flow. 在表达了大鼠同数5-HT3A受体的卵母细胞中， 5-HT激活了EC5tl为3.3mM的流。 In expressing the same number of receptors in rat 5-HT3A oocytes, 5-HT activates EC5tl to 3.3mM streams. 这些实验进行如下。 These experiments were performed as follows. 卵母细胞是用外科手术法从以0. 4% MS-222麻醉10〜15min的成熟雌性Xen印us Iaevis中取出的。 Oocytes are surgically method from a 0. 4% MS-222 anesthesia 10~15min mature female Xen us Iaevis India withdrawn. 然后，这些卵母细胞在0R2 缓冲剂（82. 5mNNaCl，2. OmM KCl, 1. OmM MgCl2 和5. OmM HEPES，pH 7. 6)中以0. 5mg/mL 胶原酶（1A型，Sigma-AldricH公司）在室温下消解2〜3小时选择去掉滤泡层的卵母细胞， 在改进的BartH，s 食盐水缓冲剂[88mM NaCl, ImMKCl, 15mM HEPES,2. 4mM NaHCO3,0. 41mM CaCl2,0. 82mM MgSO4,0. 3mM Ca(NO3)2]中培养24小时，该缓冲剂补充了2mM丙酮酸钠，0. IU/ L青霉素和0. lmg/L链霉素。 Then, the oocytes 0R2 buffer (82. 5mNNaCl, 2. OmM KCl, 1. OmM MgCl2 and 5. OmM HEPES, pH 7. 6) to 0. 5mg / mL collagenase (1A type, Sigma- AldricH companies) digestion select 2 or 3 hours to remove the follicular oocytes layer at room temperature, in a modified BartH, s brine buffer [88mM NaCl, ImMKCl, 15mM HEPES, 2. 4mM NaHCO3,0. 41mM CaCl2, 0. 82mM MgSO4,0. 3mM Ca (NO3) 2] were cultured for 24 hours, the buffer supplemented with 2mM sodium pyruvate, 0. IU / L penicillin and 0. lmg / L of streptomycin. 选择阶段IV-IV卵母细胞，注射12〜48nL含有14〜50pg有人5-HT3A受体编码的cRNA的无水核酸酶，在18°C培养直至它们用于电生理记录（注射后1〜7日）。 Select Stage IV-IV oocytes injected 12~48nL containing 14~50pg nuclease was dried over anhydrous 5-HT3A receptor encoding cRNA, and cultured at 18 ° C until they are used for electrophysiological recordings (injection 1~7 day). 将有人5-肌3受体表达的卵母细胞置ImL浴中，用林格氏缓冲剂（115mM NaCl, 2. 5mM KCl，IOmM HEPES, 1. 8mM CaCl2,0. ImM MgCl2, pH 7. 5)灌注。 The oocyte was placed ImL bath 5- 3 receptor expression in muscle, with Ringer buffer (115mM NaCl, 2. 5mM KCl, IOmM HEPES, 1. 8mM CaCl2,0. ImM MgCl2, pH 7. 5 ) perfusion. 细胞用含有3M KCl 的塞琼脂0. 5〜IM Ω电极和由GeneClamp500B放大器加_90mV电压进行移植。塞琼 fat cells containing 3M KCl of 0. 5~IM Ω electrode and the GeneClamp500B amplifier voltage applied _90mV transplant. 该卵母细胞不断地用林格氏缓冲剂灌注，并将药物施用于该灌注液中。 The oocytes were continuously perfused with Ringer buffer and the drugs administered to the perfusion fluid. 将5-HT兴奋剂溶液施用10〜 30秒。 The 5-HT agonist solution was administered 10~ 30 seconds. 5-肌3受体拮抗药的药效通过测定对10 μ M 5-HT刺激的浓度-响应而考察。 5- 3 receptor antagonist muscle efficacy by measuring the concentration of 10 μ M 5-HT stimulation - and study the response.

[0098] 实施例ID ： α 1A受体拮抗作用[0099] 对化合物I进行对CIia受体的亲和性试验，发现其显示出拮抗性能，对CIia受体有中等亲和性(Ki = 34nM)。 [0098] Example ID: α 1A receptor antagonism [0099] The compound I were to CIia receptor affinity test and found to exhibit antagonistic properties have moderate to CIia receptor affinity (Ki = 34nM ).

[0100] 实验当日（关于膜制备的描述见以下）将膜解冻，在缓冲剂中用一台Ultra Turrax均化，并稀释到所希望浓度（5mg/孔〜5 μ g/900 μ L，贮藏于冰上直至使用）。 [0100] Experimental day (see description of membrane preparation or less) the film is thawed in buffer with an Ultra Turrax homogenizer, and diluted to the desired concentration (5mg / hole ~5 μ g / 900 μ L, storage on ice until use).

[0101] 实验始于50 μ L试验化合物，50 μ L[3H]_哌唑嗪和900 μ L膜的混合，该混合物在25°C培养20min。 [0101] Experimental test compound begins 50 μ L, 50 μ L [3H] _ mixed prazosin and membrane 900 μ L, and the mixture was cultured at 25 ° C 20min. 非专性结合是在ΙΟμΜ WB-4101的存在下确定的，而总结合是在缓冲剂的存在下确定的。 Non-specifically binding under ΙΟμΜ WB-4101 to determine the presence of, and total binding was determined in the presence of a buffer. 培养之后，使用Tomtec Cel IHavester程序（D4. 2. 4)，通过经由预先在0. 1% PEI中浸渍30min的UnifiIterGF/B过滤，使结合的配体与未结合的配体分离。 After incubation, using Tomtec Cel IHavester program (D4. 2. 4), via a pre-impregnated 30min in 0. 1% PEI in UnifiIterGF / B filters, and the bound ligand is not separated from bound ligand. 96孔过滤器用ImL冰冷缓冲剂洗涤3次，在50°C干燥，向该过滤器中添加35 μ L闪烁液/孔。 96 The filters were washed 3 times ImL ice-cold buffer, dried at 50 ° C, was added to the filter 35 μ L scintillation fluid / well. 结合的放射性在一台Wallac OY 1450MicroBeta上计数。 Bound radioactivity was counted on a Wallac OY 1450MicroBeta. 亲和性从Y = 100/(l+lO0"。8 icJ) 计算，式中Y表示％结合，X表示化合物浓度。使用涵盖2个数量级的化合物浓度计算IC5tl 值。Ki 从Cheng-Prusoff 方程Ki = IC50/(1+([L]/Kd))计算。 Affinity calculated from Y = 100 / (l + lO0 ".8 icJ), wherein Y represents% combined, X is the compound concentration using covers two orders of magnitude IC5tl value .Ki compound concentration calculated from Cheng-Prusoff equation Ki = IC50 / (1 + ([L] / Kd)) calculated.

[0102] 在功能试验中，本发明化合物拮抗了肾上腺素诱发的，胞内贮藏的Ca2+的释放，功能试验公开化合物是拮抗药。 [0102] In functional assays, the compounds of the present invention antagonize epinephrine-induced intracellular Ca2 + release of storage, the test function is disclosed antagonist compounds.

[0103] 这些实验基本上像以下所述那样进行。 [0103] These experiments were as basically as described below.

[0104] 所有细胞都是在补加了10% BCS,4mM L-谷氨酰胺（或在C0S-7的情况下2mM)， 和100单位/mL青霉素+100 μ g/mL链霉素的DMEM培养基中，在37°C和5% CO2培养的。 [0104] All cells were supplemented with 10% BCS, 4mM L- glutamine (or in the case C0S-7 of 2mM), and 100 units / mL penicillin +100 μ g / mL streptomycin DMEM medium, at 37 ° C and 5% CO2 culture.

[0105] 在试验前24小时，将表达了人α 1Α_7受体的CHO细胞接种到涂有聚_D_赖氨酸的384孔黑壁微升平皿中。 [0105] In the 24 hours before the test, expressing the human receptor α 1Α_7 CHO cells were seeded into poly _D_ lysine coated 384 well black wall microliter dish. 将培养基吸入，各细胞在试验缓冲剂（50 μ L/孔）中在5% CO2中， 在37°C用1. 5μΜ Fluo-4加染料1小时，该试验缓冲剂的组成为Hank' s平衡盐溶液（138mM NaCl, 5mM KCl, 1. 3mMCaCl2,0. 5mM MgCl2,0. 4mM MgSO4,0. 3mM KH2PO4,0. 3mM Na2HPO4, 5. 6mM 葡萄糖)加20mM HEPES pH 7. 4,0. 05% BSA和2. 5mM羟苯磺丙胺。 The medium inhalation, each cell in the assay buffer (50 μ L / well) in a 5% CO2, and at 37 ° C with 1. 5μΜ Fluo-4 plus dye one hour, the assay buffer composed of Hank ' s balanced salt solution (138mM NaCl, 5mM KCl, 1. 3mMCaCl2,0. 5mM MgCl2,0. 4mM MgSO4,0. 3mM KH2PO4,0. 3mM Na2HPO4, 5. 6mM glucose) plus 20mM HEPES pH 7. 4,0. 05% BSA and 2. 5mM oxybenzone sulfonic propylamine. 弃去过剩染料之后，细胞用试验缓冲剂洗涤，分层，最终体积等于45 μ L/孔（或对拮抗药试验而言30 μ L/孔）。 After excess dye was discarded, cells were washed with assay buffer, layered, equal to a final volume of 45 μ L / well (For antagonist testing or 30 μ L / well). 在拮抗药评估的情况下，此时添加拮抗药或载剂，作为4倍于最终浓度（最终DMSO = 1%) 的含4% DMSO缓冲剂中的15 μ L等分样品，随后培养20min。 15 μ L aliquots in the case of antagonist evaluation, antagonist or vehicle at this time to add agents, as four times the final concentration (final DMSO = 1%) 4% DMSO-containing buffer, followed by culture 20min. 基础荧光用一台荧光成像板读出器或分子设备公司（Sunnyvale，CA)的FLIPR™以激发波长为488nm，发射范围为500〜 560nm监测。 Base fluorescence using a fluorescent imaging plate reader or Molecular Devices Corp. (Sunnyvale, CA) with an excitation wavelength of FLIPR ™ as 488nm, emission range of 500~ 560nm monitored. 调整激光激发能量，使得基础荧光读数为大约8000相对荧光单位（RFU)。 Adjust the laser excitation energy, so that basal fluorescence readings about 8,000 relative fluorescence units (RFU). 然后，在室温下以用试验缓冲剂（15yL)稀释的兴奋剂激发细胞，在为期2. 5min内以1.5秒间隔测量RFU。 Then, at room temperature with assay buffer (15yL) diluted stimulant stimulate cells, within a period of 2. 5min with 1.5 seconds interval measurement RFU. 计算每一孔的荧光最大变化。 Calculate the maximum change in fluorescence of each hole. 用非线性回归法（Hill方程）分析从最大荧光变化衍生的浓度响应曲线。 Analysis of the response curve derived from the maximum change in fluorescence concentration using nonlinear regression (Hill equation). 为了确定拮抗作用，在（如上所述）化合物培养20min后添加固定浓度的标准兴奋剂血清素。 In order to determine antagonism at (as described above) of the compound after 20min culture adds a fixed concentration of the standard agonist serotonin.

[0106] 实施例2A ：4-[2-(4-甲基苯硫基）苯基]哌啶，HBr盐 4- [2- (4-methyl) phenyl] piperidine, HBr salt: [0106] Example 2A

[0107] 2- (4-甲苯基硫基）-苯基溴 [0107] 2- (4-methylphenyl thio) - phenyl bromide

[0108] 在搅拌的氮覆盖的反应器中，将N-甲基-吡咯烷酮，NMP (4. 5L)用氮冲洗20分钟。 [0108] In a stirred nitrogen covered reactor, the N- methyl - pyrrolidone, NMP (4. 5L) flushed with nitrogen for 20 minutes. 加入4-甲基苯硫醇(900g，7. 25mol)并随后加入1，2_ 二溴苯（1709g，7. 25mol)。 4-methylbenzene thiol (900g, 7. 25mol) was added and then 1,2_-dibromobenzene (1709g, 7. 25mol). 叔丁醇钾(813g,7. 25mol)作为最后反应物被最后加入。 Potassium t-butoxide (813g, 7. 25mol) as the final reaction was added last. 反应放热，反应混合物的温度升至70°C .反应混合物随后加热至120°C 2-3小时。 The reaction was exothermic, the reaction mixture temperature was raised to 70 ° C. The reaction mixture was then heated to 120 ° C 2-3 hours. 反应混合物被冷却至室温。 The reaction mixture was cooled to room temperature. 加入乙酸乙酯（4L)和含水氯化钠溶液（15%，2. 5L)。 Addition of ethyl acetate (4L) and an aqueous sodium chloride solution (15%, 2. 5L). 混合物搅拌20分钟。 The mixture was stirred for 20 minutes. 将水相分离并用另一部分的乙酸乙酯（2L)提取。 The aqueous phase was separated and extracted with another portion of ethyl acetate (2L). 将水相分离并将有机相合并和用氯化钠溶液（15%，2.5L)洗涤。 The aqueous phases were separated and the organic phases were combined and (15%, 2.5L) was washed with sodium chloride solution. 将有机相分离，用硫酸钠干燥和在减压下蒸发成包含20-30% NMP的红色油。 The organic phase was separated, dried over sodium sulfate and evaporated under reduced pressure to contain 20-30% NMP red oil. 油用甲醇稀释至两倍体积并将混合物回流。 Oil was diluted to twice the volume with methanol and the mixture was refluxed. 加入更多的甲醇直至得到透明红色溶液。 More methanol was added until a clear red solution. 在接种的同时将溶液慢慢冷却至室温。 While in the inoculation solution was slowly cooled to room temperature. 产物作为米白色晶体而结晶，将它们通过过滤而分离和用甲醇洗涤和在40°C下在真空炉中干燥直至恒定重量。 The product crystallized as the off white crystals, they were isolated and washed with methanol and at 40 ° C in a vacuum oven until a constant weight by filtration and dried.

[0109] 4-羟基-4-(2-(4-甲苯基硫基）苯基）_哌啶-1-羧酸乙酯 [0109] 4-hydroxy-4- (2- (4-tolyl) phenyl) piperidine-1-carboxylate _

[0110] 在搅拌的反应器中，在氮覆盖下，将2-(4-甲苯基硫基）-苯基溴（600g，2. 15mol) 悬浮在庚烷（4. 5L)中。 [0110] In a stirred reactor under nitrogen cover 2- (4-methylphenyl thio) - phenyl bromide (. 600g, 2 15mol) was suspended in heptane (4. 5L) in. 在室温下，将在己烷（235mL，2. 36mol)中的IOM BuLi在10分钟内加入。 At room temperature in hexane (235mL, 2. 36mol) of the IOM BuLi was added over 10 minutes. 仅注意到少量发热。 Notes that only a small fever. 悬浮液在环境温度下搅拌1小时并随后冷却至-40°C.将溶解在THF(1.5L)中的I-Carb乙氧基_4_哌啶酮(368g，2. 15mol)在不快的速率下加入，使得反应温度保持低于_40°C。 The suspension was stirred at ambient temperature for 1 hour and then cooled to -40 ° C. The dissolved THF (1.5L) in the I-Carb ethoxy _4_ piperidone (368g, 2. 15mol) in offensive It was added at a rate such that the reaction temperature was kept below _40 ° C. 在反应已完成时，将它暖至0°C和加入IM HCl (IL)，保持温度低于10°C .将酸水相分离和用乙酸乙酯（IL)提取。 When the reaction was complete, it was warmed to 0 ° C and added IM HCl (IL), keeping the temperature below 10 ° C. The acidic water phase is separated and extracted with ethyl acetate (IL). 将有机相合并和用氯化钠溶液（15%， 1L)提取。 The organic phases were combined and sodium chloride solution (15%, 1L) extract. 将有机相在硫酸钠上干燥和蒸发至半结晶物质。 The organic phase was dried over sodium sulfate and evaporated to a semi-crystalline material. 将它用乙醚（250mL)制浆和过滤掉。 It with ether (250mL) pulp and filtered out. 在真空炉中在40°C下干燥直至恒定重量。 In a vacuum oven at 40 ° C in the drying until constant weight.

[0111] 4-(2-(4-甲苯基硫基）苯基）_哌啶-1-羧酸乙酯 [0111] 4- (2- (4-methylphenyl) phenyl) piperidine-1-carboxylate _

[0112] 将三氟乙酸（2. 8kg，24. 9mol)和三乙基硅烷（362g，3. lmol)装入具有有效搅拌器的反应器。 [0112] Trifluoroacetic acid (2. 8kg, 24. 9mol) and triethylsilane (362g, 3. Lmol) charged with an effective stirrer. 4-羟基-4-(2-(4-甲苯基硫基）苯基）_哌啶-1-羧酸乙酯（462g，1. 24mol)通过粉末漏斗分批加入。 4-hydroxy-4- (2- (4-tolyl) phenyl) piperidine-1-carboxylate _ (462g, 1. 24mol) was added portionwise via a powder funnel. 反应稍微发热。 The reaction is slightly warm. 温度升至50°C。 Temperature was raised to 50 ° C. 在加入完成之后，将反应混合物暖至60°C 18小时。 After the addition was complete, the reaction mixture was warmed to 60 ° C 18 hours. 反应混合物冷却至室温。 The reaction mixture was cooled to room temperature. 加入甲苯（750mL)和水（750mL)。 Toluene was added (750mL) and water (750mL). 将有机相分离并将水相用另一份甲苯（750mL)提取。 The organic phase was separated and the aqueous phase was extracted with another portion of toluene (750mL). 将有机相合并和用氯化钠溶液（15%，500mL)洗涤并在硫酸钠上干燥。 The organic phases were combined and with sodium chloride solution (15%, 500mL) and dried over sodium sulfate. 将硫酸钠过滤掉，滤液在减压下蒸发成红色油，在下一步骤中进一步处理。 The sodium sulfate was filtered off, the filtrate was evaporated under reduced pressure to a red oil, further processing in the next step.

[0113] 4-(2-(4-甲苯基硫基)苯基）_哌啶氢溴化物 [0113] 4- (2- (4-methylphenyl) phenyl) piperidine hydrobromide _

[0114] 将来自实施例3的作为红色油的粗乙基4-(2-(4_甲苯基硫基）苯基）_哌啶-1-羧酸盐在搅拌反应器中与在乙酸中的氢溴酸（40%，545mL，3. Ilmol)混合。 [0114] from Example 3 as a red oil crude ethyl 4- (2- (4_ toluene-ylthio) phenyl) piperidine-1-carboxylate _ in the reactor with stirring in acetic acid hydrobromic acid (40%, 545mL, 3. Ilmol) mixing. 混合物在80°C下加热18小时。 The mixture was heated at 80 ° C for 18 hours. 反应混合物冷却至室温。 The reaction mixture was cooled to room temperature. 在冷却过程中，产物结晶出。 During cooling, the product crystallized. 在室温下1 小时之后，将乙醚（SOOmL)加入反应混合物，和混合物搅拌另一小时。 After 1 hour at room temperature, diethyl ether (SOOmL) added to the reaction mixture, and the mixture was stirred for another hour. 将产物过滤掉，用乙醚洗涤和在真空炉中在50°C下干燥直至恒定重量。 The product was filtered off, washed with ether and vacuum oven dried at 50 ° C until constant weight.

[0115] 实施例2B ：4[2-(4-甲基苯基硫基）苯基]哌啶，HBr盐 4 [2- (4-methylphenyl) phenyl] piperidine, HBr salt: [0115] Example 2B

[0116] 向442克作为油的搅拌的和稍微加热（约45摄氏度）的4_(2_p_甲苯基磺氨基-苯基）-哌啶-1-羧酸乙酯中加入545ml在AcOH中的33wt_% HBr (5. 7M, 2. 5eqv.)。 [0116] To 442 g as oil and slightly heated with stirring (approximately 45 ° C) 4_ (2_p_ toluene sulfonic amino - phenyl) - piperidine-1-carboxylate was added 545ml of 33wt_ in AcOH % HBr (5. 7M, 2. 5eqv.). 该混合产生10摄氏度放热。 The hybrid produces 10 degrees Celsius heat. 在最终加入之后，将反应混合物加热至80摄氏度和放置18小时。 After the final addition, the reaction mixture was heated to 80 degrees Celsius and 18 hours. 取样和通过HPLC而分析，和如果没有完成，必须加入更多的在AcOH中的33wt-% HBr0 否则，将混合物冷却至25摄氏度，使产物4- (2-p-甲苯基磺氨基-苯基）-哌啶氢溴化物沉淀。 The sampling and analysis by HPLC and if not completed, AcOH must be added in the more 33wt-% HBr0 Otherwise, the mixture was cooled to 25 ° C, the product 4- (2-p- toluene sulfonyl amino - phenyl ) - piperidine hydrobromide precipitate. 在25摄氏度下1小时之后，向稠悬浮液中加入800ml 二乙醚。 After 1 hour at 25 ° C, the thick suspension was added 800ml diethylether. 继续搅拌另一小时，然后将产物通过过滤而分离，用400ml 二乙基醚洗涤和在真空中在40摄氏度下干燥过夜。 Stirring was continued for another hour, then the product was isolated by filtration, washed with 400ml diethyl ether and vacuum dried at 40 ° C overnight. 化合物I的氢溴化物作为白色固体而被分离。 Hydrobromide of compound I was isolated as a white solid.

[0117] 实施例2C ：4-[2-(4-甲基苯基硫基)苯基]哌唆，HBr盐的重结晶 4- [2- (4-methylphenyl) phenyl] piperazine instigate, HBr salt was recrystallized from: [0117] Example 2C

[0118] 将10. 0克如上制备的HBr盐的混合物在100ml H2O中加热回流。 [01] The HBr salt mixture prepared above 10.0 g was heated to reflux in 100ml H2O. 混合物变得透明和在80-90摄氏度下完全溶解。 The mixture became clear and fully dissolved at 80-90 degrees Celsius. 向该透明溶液中加入1克木炭和继续回流15分钟，然后过滤和自然冷却至室温。 To this clear solution was added 1 gram of charcoal and reflux was continued for 15 minutes, then cooled to room temperature and filtered. 在冷却过程中，白色固体发生沉淀并将悬浮液在室温下搅拌1小时。 During cooling, a white solid precipitated and the suspension was stirred at room temperature for 1 hour. 过滤和在真空中在40摄氏度下干燥过夜，得到6. 9克（69% )4-[2-(4-甲基苯基硫基）苯基]-哌啶的HBr酸加成盐。 Filtered and dried in a vacuum overnight at 40 ° C to give 6.9 g (69%) of 4- [2- (4-methyl) phenyl] - piperidine HBr acid addition salt.

[0119] 实施例3 ：4-[2-(4-甲基苯基硫基)苯基]哌啶，其他盐 [0119] Example 3: 4- [2- (4-methylphenyl) phenyl] piperidine, other salts

[0120] 游离碱的原料_溶液的制备 Preparation of the free base of the feed solution _ [0120]

[0121] 将500ml乙酸乙酯和200ml H2O的混合物加入50克HBr盐，得到两相淤浆。 [0121] The 500ml 200ml H2O mixture of ethyl acetate and 50 g HBr salt to give a two-phase slurry. 向该淤浆中加入约25ml cone. NaOH，形成透明两相溶液（pH被测定为13-14)。 To this slurry was added approximately 25ml cone. NaOH, to form a transparent two-phase solution (pH was measured to 13-14). 将溶液剧烈搅拌15分钟并分离有机相。 The solution was stirred vigorously for 15 minutes and the organic phase was separated. 将有机相用200ml H2O洗涤，在Na2SO4上干燥，过滤和在60摄氏度下真空蒸发，得到38克产量（99% )作为几乎无色油的游离碱。 The organic phase was washed with 200ml H2O, dried over Na2SO4, filtered and evaporated at 60 ° C under vacuum to give 38 g yield (99%) as the free base almost colorless oil.

[0122] 溶解10克油和使用乙酸乙酯调节体积至150ml，得到在乙酸乙酯中的0. 235M原料_溶液，使用1. 5ml (IOOmg游离碱)的等分试样。 [0122] 10 g of oil was dissolved with ethyl acetate and the volume was adjusted to 150ml, in ethyl acetate to give the material _ 0. 235M solution, using 1. 5ml (IOOmg free base) aliquots.

[0123] 溶解10克油和使用96-vol% EtOH调节体积至100ml，得到在EtOH中的0. 353M 原料_溶液，使用1. Oml (IOOmg游离碱)的等分试样。 [0123] dissolving 10 grams of oil and use the 96-vol% EtOH volume was adjusted to 100ml, get in EtOH 0. 353M raw material _ solution, use 1. Oml (IOOmg free base) aliquots.

[0124] 使用游离碱的原料_溶液形成盐 [0124] The free base form a salt solution of a raw material _

[0125] 将给定等分试样放在试验管中和在搅拌下加入表1所示的合适量的酸。 [0125] given aliquot placed in a test tube and stirring the appropriate amount of acid added to the table shown in Figure 1. 如果酸是液体，它被净加入，否则在加入之前将它溶解在给定溶剂中。 If the acid is a liquid, it is added to the net, otherwise it was dissolved prior to the addition in a given solvent. 在混合和沉淀之后，继续搅拌过夜和通过过滤而收集沉淀物。 After mixing and precipitation stirring was continued overnight and the precipitate was collected by filtration. 表2给出了4-[2-(4-甲基苯基硫基）-苯基]哌啶的盐的溶解度。 Table 2 gives the 4- [2- (4-methylphenyl thio) - phenyl] piperidine salt solubility.

[0126]表 1 [0126] Table 1

[0127] [0127]

酸（碱：酸） 丽(g/mol) 酸的量(mg 或μ 1) 溶剂 CHN(exp.) CHN (理论）棕榈酸，十六酸酸1 ： 1 256. 42 90. 5 EtOAc 75. 36 9. 77 2. 46 75. 64 9. 9 2. 6DL-乳酸，DL-2- 羟基丙酸1 ： 1 90. 1 31. 8 EtOAc 66. 88 7. 26 3. 52 67. 53 7. 29 3. 75己二酸，1，6-己烷二酸酸1 ： 1 146. 14 51. 6 EtOAc 66. 08 7. 23 2. 98 67. 1 7. 27 3. 26己二酸，1，6-己烷二酸酸2 ： 1 146. 14 25. 8 EtOAc 70. 66 7. 32 3. 82 70. 75 7. 35 3. 93富马酸1：1 116.01 40. 9 EtOH 65. 71 6. 41 3. 35 66. 14 6. 31 3. 51戊二酸，1，5-戊烷二酸1 ： 1 132. 12 46. 6 EtOAc 66.09 6. 97 3.2 66.48 7. 03 3. 37丙二酸1 ： 1 104. 1 36. 7 EtOAc 65. 04 6. 53 3. 54 65. 09 6. 5 3. 62草酸1 ： 1 90. 1 31. 8 EtOH 64.28 6.41 3.61 64. 32 6. 21 3. 75 Acid (base: acid) (. Exp) Li (g / mol) the amount of acid (mg or μ 1) Solvent CHN CHN (theory) palmitic acid, palmitic acid 1: 1 256. 42 90. 5 EtOAc 75. 36 9. 77 2. 46 75. 64 9. 9 2. 6DL- lactic acid, DL-2- hydroxy acid 1: 1 90. 1 31. 8 EtOAc 66. 88 7. 26 3. 52 67. 53 7. 29 3.75 adipic acid, 1,6-hexane two Acid 1: 1 146. 14 51. 6 EtOAc 66. 08 7. 23 2. 98 67. 1 7. 27 3. 26 adipic acid, 1 , 6-hexane two Acid 2: 1 146. 14 25. 8 EtOAc 70. 66 7. 32 3. 82 70. 75 7. 35 3. 93 fumarate 1: 1 116.01 40. 9 EtOH 65. 71 6.41 3.35 66.14 6.31 3.51 glutaric acid, 1,5-pentane acid 1: 1 132. 12 46. 6 EtOAc 66.09 6. 97 3.2 66.48 7. 03 3. 37 prop Acid 1: 1 104. 1 36. 7 EtOAc 65. 04 6. 53 3. 54 65. 09 6. 5 3. 62 acid 1: 1 90. 1 31. 8 EtOH 64.28 6.41 3.61 64. 32 6. 21 3.75

[0130]表 2 [0130] Table 2

[0131] [0131]

[0132] [0132]

[0133] 实施例4 ：对乙酰胆碱水平的影响 [0133] Example 4: effect on levels of acetylcholine

[0134] 实验设计得能评估本发明化合物对自由活动大鼠的前额皮层和腹海马中乙酰胆碱胞外水平的影响。 [0134] experiments designed to assess the compounds of the present invention, the prefrontal cortex of rats on the freedom of movement and ventral hippocampal extracellular acetylcholine levels of influence.

[0135] 使用初始重量275〜300g的雄性Sprague-Dawley大鼠。 [0135] using the initial weight 275~300g Male Sprague-Dawley rats. 这些动物在规定室内温度（21 士2°C )和湿度（55士5% )的受控条件下以12小时亮/暗周期隔离，且可以任意获取饵料和水。 These animals indoors at a predetermined temperature (21 persons 2 ° C) and humidity (55 ± 5%) of the controlled conditions in 12-hour light / dark cycle of isolation, and can get any food and water. [0136] 外科手术和微渗析实验 [0136] Surgery and microdialysis experiments

[0137] 大鼠用芬太尼/多美康（2mL/kg)麻醉，并将脑内导管（CMA/12)用空间定位法植入海马中，旨在将渗析探针尖端定位于腹海马中（坐标：前囟后5. 6mm，侧向-5. 0mm，腹部到硬膜7. Omm)或定位于前额皮层中（坐标：前囟前3. 2mm，侧向0. 8mm，腹部到硬膜4. Omm)。 [0137] in rats with fentanyl / multiple US health (2mL / kg) anesthesia and brain catheter (CMA / 12) space hippocampus implant positioning method, aimed at positioning the dialysis probe tip in the ventral hippocampus (the coordinates: after anterior fontanelle 5. 6mm, lateral -5 0mm, the abdomen to the dura 7. Omm.) or located in the prefrontal cortex (coordinates: Front fontanelle 3. 2mm, lateral 0. 8mm, belly to subdural 4. Omm). 使用锚固螺钉和丙烯酸类粘固剂固定该导管。 Use anchor screws and acrylic cement to secure the catheter. 该动物的体温用直肠探针监测并保持在37°C。 The animal's body temperature monitored and maintained at 37 ° C with a rectal probe. 让大鼠在手术后康复2天，单独关在笼中。 The rats recovered two days after the operation, in solitary confinement in a cage. 实验当日，将微渗析探针（CMA/12，0.5mm直径， 3mm长度）经由导管插入。 Day experiment, the microdialysis probe (CMA / 12,0.5mm diameter, 3mm length) is inserted via a catheter.

[0138] 这些探针经由双通道旋转接头连接到一台微注射泵上。 [0138] The probe is connected to a micro-injection pump via dual-channel rotary joint. 含有0. 5 μ M新斯的明的过滤林格氏溶液（145mM NaCl, 3mM KCl, ImM MgCl2,1. 2mM CaCl2)对微渗析探针的灌注始于该探针临插入大脑中前，并以lyL/min的恒定流量率继续于整个实验期间。 Containing 0. 5 μ M neostigmine filtered Ringer solution (145mM NaCl, 3mM KCl, ImM MgCl2,1. 2mM CaCl2) perfusion microdialysis probes began the probe inserted into the brain before clinical and at a constant flow rate lyL / min continued throughout the duration of the experiment. 稳定ISOmin 后，启动实验。 After stabilizing ISOmin, launch the experiment. 每20min收集渗析物。 Each was dialyzed 20min collected. 实验后将动物宰杀，取出其大脑，冷冻，切片，以验证探针配置。 After animal slaughtered, their brains removed, frozen, sliced, to verify the probe configuration.

[0139] 渗析物乙酰胆碱的分析 Analysis [0139] dialysate acetylcholine

[0140] 渗析物中乙酰胆碱（ACH)的浓度是借助于有电化学检测的HPLC分析的，所使用的移动相组成为IOOmM磷酸氢二钠，2. OmM辛磺酸，0. 5mM氯化四甲铵，和0. 005% MB(ESA)，pH 8.0。 [0140] dialysate acetylcholine (ACH) electrochemical concentration is detected by means of HPLC analysis, the mobile phase composition used for the IOOmM disodium hydrogen phosphate, 2. OmM octyl sulfonate, 0. 5mM tetrakis carbamate, and 0. 005% MB (ESA), pH 8.0. 含有包埋胆碱氧化酶的柱前酶反应器消除了分析柱（ESA ACH-250)上ACh分离前注射样品（IOyL)中的胆碱；流量率0. 35mL/min，温度35°C。 Anterior column enzyme reactor containing entrapped choline oxidase eliminated choline analytical column (ESA ACH-250) before injection on ACh samples isolated (IOyL) in; flow rate 0. 35mL / min, temperature 35 ° C. 分析柱后，样品通过了一个含有包埋乙酰胆碱酯酶和胆碱氧化酶的柱后固相反应器（ESA)。 After the analytical column, after a sample containing entrapped by acetylcholinesterase and choline oxidase column solid phase reactor (ESA). 后一个反应器使ACh转化成胆碱，随后又使胆碱转化成甜菜碱和H202。 ACh after a reactor to be converted to choline and subsequently converted to betaine and choline make H202. 后者使用钼电极进行电化学检测（分析池：ESA，型号5040)。 Which uses molybdenum electrode electrochemical detection (analysis of cell: ESA, model 5040).

[0141] 数据表述 [0141] data representation

[0142] 在单一注射实验中，用化合物临给药前3个相继ACh样品的平均值作为每个实验的基础水平，将数据换算成基础值的百分率（平均基础注射前值归一化为100% )。 [0142] In single injection experiments, pre-clinical compound administered three consecutive ACh samples as the average value of the basal level for each experiment, the conversion percentage of baseline data prior to the (average value normalized based injection 100 %). 数据表述于图Ia和Ibo Data representation in Fig. Ia and Ibo

[0143] 图Ia和Ib中表述的数据显示大脑中胞外乙酰胆碱水平的剂量依赖型提高。 [0143] Figure Ia and Ib the data expressed in brain extracellular levels of acetylcholine in a dose-dependent increase. 这个临床前发现可望解读为可用于诸如治疗以认识缺损为特征的疾病例如阿尔茨海默病患者， 部分反应者，认识缺损的临床安排中认识的改善。 The clinical findings are expected to interpret the front that can be used to recognize, such as the treatment of diseases characterized by defects such as Alzheimer's disease, a partial response who recognize defects in clinical arrange awareness improvement.

[0144] 实施例5 ：对多巴胺水平的影响 Effect of dopamine levels: 5 [0144] Example

[0145] 化合物I的单一注射剂量依赖地提高了大鼠前额皮层中的胞外多巴胺（DA)水平。 [0145] Compound I single dose-dependent increase in the rat prefrontal cortex extracellular dopamine (DA) levels. 8. 9mg/kg和18mg/kg皮下注射的本发明化合物，相对于图2中所示基线而言，使DA水平分别提高了约100%和150%。 8. 9mg / kg and 18mg / kg subcutaneously compound of the invention, relative to baseline shown in Figure 2, the so DA levels were increased by about 100% and 150%. 数量是作为游离碱计算的。 The number is calculated as the free base.

[0146]方法。 [0146] method.

[0147] 使用初始重量275〜300g的雄性Sprague-Dawley大鼠。 [0147] using the initial weight 275~300g Male Sprague-Dawley rats. 这些动物在规定室内温度（21 士2°C )和湿度（55士5% )的受控条件下以12小时亮/暗周期隔离，饵料和自来水可任意取用。 These animals indoors at a predetermined temperature (21 persons 2 ° C) and humidity (55 ± 5%) of the controlled conditions in 12-hour light / dark cycle of isolation, food and water can be freely accessible. 三天治疗实验使用的是渗透小型泵（Alzet，2MLl)。 Three days treatment experiment using a small osmotic pump (Alzet, 2MLl). 这些泵在无菌条件下灌装，并在七氟烷麻醉下植入皮下。 These pumps are filled under aseptic conditions and implanted subcutaneously in the sevoflurane anesthesia. 实验用植入的小型泵进行。 Experiments conducted with a small implanted pump. 实验结束时采集血样，用于测定3天治疗后试验化合物的血浆水平。 Blood samples were taken at the end of the experiment for determination of plasma levels of the test compound after 3 days of treatment.

[0148] 外科手术和微渗析实验 [0148] Surgery and microdialysis experiments

[0149] 试验动物用芬太尼/多美康（2mL/kg)麻醉，脑内导管（CMA/12)用立体定位法植入海马中，将渗析探针尖定位于腹海马中（坐标：前囟前5. 6mm，侧向-5. 0mm，腹部到硬膜7. Omm)；或定位于前额皮层中（坐标：前囟前3. 2mm，侧向3. 0mm，腹部到硬膜4. Omm)。 [0149] Test animals fentanyl / multiple US health (2mL / kg) anesthesia, intracerebral catheter (CMA / 12) by stereotactic implantation method in the hippocampus, positioning the dialysis probe tip in the ventral hippocampus (coordinates: before the anterior fontanelle 5. 6mm, lateral -5 0mm, the abdomen to the dura 7. Omm); or located in the prefrontal cortex (coordinates: Front skull 3. 2mm, lateral 3. 0mm, belly to the dura mater 4 . Omm). 使用锚固螺钉和丙烯酸类粘固粉固定该导管。 Use anchor screws and acrylic cement to secure the catheter. 动物体温。 Animal body temperature. 动物体温用直肠探针监测并保持在37°C。 Animal rectal probes to monitor temperature and maintained at 37 ° C. 让动物用2天时间从外科手术中康复，单独关在笼中。 Let the animals spend two days recovering from the surgery, in solitary confinement in a cage. 实验当日，将微渗析探针(CMA/12,0. 5mm直径，3mm长）经由导管插入。 Day experiment, the microdialysis probe (CMA / 12,0. 5mm in diameter, 3mm long) via a catheter inserted. 这些探针经由一种双通道旋转接头连接到一台微注射泵上。 These probes are connected to the rotary joint on a micro-injection pump via a dual channel. 过滤的林格氏溶液（145mM NaCl, 3mM KCl，lmM MgCl2,1. 2mM CaCl2)对微渗析探针的灌注始于该探针临插入大脑中之前，而且以1 (1. 3) μ L/min的恒定流量率继续于整个实验期间。 Filtered Ringer solution (145mM NaCl, 3mM KCl, lmM MgCl2,1. 2mM CaCl2) perfusion microdialysis probe began in the brain before insertion of the probe face, and with 1 (1. 3) μ L / min constant flow rate continues throughout the duration of the experiment. 稳定180min之后，启动实验。 After the stabilization 180min, launch the experiment. 每20 (30)min收集渗析物。 Every 20 (30) min was collected dialyzed.

[0150] 实验之后，用斩首法宰杀大鼠，将其大脑取出，冷冻，切片，以验证探针放置。 [0150] After the experiment, rats sacrificed by decapitation method, remove the brain, frozen, sliced, to verify the probe placement.

[0151] 渗析物分析 [0151] Analysis of dialysate

[0152] 渗析物中多巴胺的浓度是借助于HPLC以电化学检测分析的。 [0152] dialysate dopamine concentration by means of HPLC with electrochemical detection analysis. 一胺类是用逆相液体色谱法（0DS 150 X 3mm, 3 μ M)分离的。 Amines with a reversed-phase liquid chromatography (0DS 150 X 3mm, 3 μ M) separation. 多巴胺：移动相组成为90mM NaH2PO4, 50mM柠檬酸钠，367mg/L 1-辛磺酸钠，50 μ MEDTA和8%乙腈（pH 4. 0)，流量率为0. 5mL/min。 Dopamine: Mobile phase consisting of 90mM NaH2PO4, 50mM sodium citrate, 367mg / L 1- octyl sulfonate, 50 μ MEDTA and 8% acetonitrile (pH 4. 0), the flow rate of 0. 5mL / min. 电化学检测使用库仑检测器完成，电位设定于250mV(保护电池设定于350mV) (CoulocHemII, ESA)。 Electrochemical detection Coulomb detector is completed, the potential is set to 250mV (to protect the battery set to 350mV) (CoulocHemII, ESA).

[0153] 实施例6 ：对神经疼痛的影响 Effect of nerve pain: 6 [0153] Example

[0154] 为了示范对神经病痛的疗效，本发明化合物用福尔马林神经病痛模型进行试验[Neuropharm.，48，252-263，2005 ；Pain, 51,5-17,1992]。 [0154] In order to demonstrate the efficacy of nerve pain, the compounds of the present invention, nerve pain model with formalin test [Neuropharm, 48,252-263,2005;. Pain, 51,5-17,1992]. 在这种模型中，小鼠接受福尔马林(4.5%,20uL)对左后爪跖表面的注射，随后放进单个玻璃烧杯（2L容量）中观察。 In this model, mice received formalin (4.5%, 20uL) of the plantar surface of the left hind paw injection, and then into individual glass beakers (2L capacity) was observed. 福尔马林引起的刺激诱发特征性两阶段行为反应，用受伤爪舔食所花费的时间量予以量化。 Formalin stimulation induced behavioral response characteristic of a two-stage, the amount of time spent licking the injured paw to quantify with. 第一阶段（〜0〜IOmin)代表直接化学刺激和感受伤害，而第二阶段（〜20〜30min)被认为代表神经病源的疼痛。 The first phase (~0~IOmin) represents a direct chemical irritation and feelings of hurt, and the second phase (~20~30min) is considered the representative of neuropathic pain source. 这两个阶段由一个行为回归正常的静止期分开。 It consists of a two-stage behavior return to normal quiescent separately. 这两个阶段中受伤爪舔食所花费的时间量的测定评价了试验化合物减少疼痛刺激的有效性。 Determination of both phases were injured paw licking the amount of time spent on the evaluation of the effectiveness of the test compounds to reduce the painful stimulus.

[0155] 每组试验8只C57/B6小鼠（约25g)。 [0155] in each test eight C57 / B6 mice (approximately 25g). 以下表3显示两个阶段即福尔马林注射后0〜5min和20〜30min中受伤爪舔食所花费的时间量。 The following Table 3 shows the amount of time that is two stages after the formalin injection 0~5min and 20~30min injured paw lick spent. 化合物给药量是作为游离碱计算的。 The dose of the compound is calculated as the free base.

[0156]表 3 [0156] Table 3

[0157] [0157]

[0158] 表3中数据显示，化合物I在代表直接化学刺激和感受伤害的第一阶段有一点效果。 [0158] The data in Table 3 show that the compounds I have little effect in the first stage represents a direct chemical irritation and nociceptive. 更显著地，该数据也显示第二阶段中爪舔食所花费的时间明显且剂量依赖型减少，表明化合物I在神经痛治疗方面的效果。 More significantly, the data also show that the second phase of the time spent licking the paw and significant dose-dependent decrease in the effect of Compound I indicate that treatment of neuropathic pain.