CN104803972A - Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof - Google Patents

Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof Download PDF

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CN104803972A
CN104803972A CN 201510034007 CN201510034007A CN104803972A CN 104803972 A CN104803972 A CN 104803972A CN 201510034007 CN201510034007 CN 201510034007 CN 201510034007 A CN201510034007 A CN 201510034007A CN 104803972 A CN104803972 A CN 104803972A
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yl
oxo
benzoate
piperidin
compound
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谭颂德
谢福胜
蔡泽绵
植建琼
陈淑君
王为波
李同双
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深圳信立泰药业股份有限公司
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04Monocyclic monocarboxylic acids
    • C07C63/06Benzoic acid
    • C07C63/08Salts thereof
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses a benzoate of a 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and a preparation method and a pharmaceutical composition thereof. Structural formula of the benzoate of the 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative is represented by formula II. The benzoate of the 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative is suitable for development of an excellent medicine used for treating type-2 diabetes, and is applied to clinical practice; product quality is ensured effectively; and excellent guarantee is provided for drug application safety and effectiveness. The preparation method is simple in technology; cost is relatively low; yield and purity are both high; and the preparation method is suitable for large-scale industrial production.

Description

3- (3-氨基哌啶-1 -基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐、其制备方法及其药物组合物 3- (3-piperidin -1-- yl) -5-oxo-1,2, 4- benzoate triazine derivatives, their preparation and pharmaceutical compositions thereof

技术领域 FIELD

[0001] 本发明属于医药发明领域,具体涉及一种能抑制二肽基肽酶-IV活性的3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐、其制备方法及其药物组合物。 [0001] Field of the Invention The present invention pertains to medicine, particularly relates to 3- (3-piperidin-1-yl) one can inhibit dipeptidyl peptidase activity -IV-5-oxo-1,2,4- benzoate triazine derivatives, their preparation and pharmaceutical compositions thereof.

背景技术 Background technique

[0002] 糖尿病影响全世界数百万人,被认为是21世纪人类死亡的主要威胁之一。 [0002] Diabetes affects millions of people worldwide, is considered to be one of the major threats to human deaths in the 21st century. 随着时间推移,不被控制的糖尿病能损坏身体系统,包括心脏、血管、眼、肾和神经。 Over time, diabetes can not be controlled damage to body systems, including the heart, blood vessels, eyes, kidneys and nerves. 在全世界范围, 糖尿病的社会经济负担很沉重。 Worldwide, social and economic burden of diabetes is very heavy.

[0003] 有两种主要类型的糖尿病,命名为I型和II型,其中II型糖尿病占全世界所有糖尿病的超过90%。 [0003] There are two main types of diabetes, type I and II named type, where type II diabetes accounts for over 90% of all diabetes worldwide. I型糖尿病特征为胰岛素缺乏,主要由自身免疫介导的胰岛β细胞破坏引起,II型糖尿病特征为胰岛素分泌异常和随之而来的胰岛素耐受。 Type I diabetes mellitus characterized by insulin deficiency, mainly caused by the autoimmune destruction of islet β cell-mediated, Type II diabetes wherein insulin secretion and consequent abnormal insulin resistance. 为预防引起酮酸中毒, 患有I型糖尿病的患者必须摄取外源胰岛素以存活。 To prevent causing ketoacidosis, patients with Type I diabetes must uptake of exogenous insulin to survive. 尽管II型糖尿病患者不像I型糖尿病患者那样依赖于外源胰岛素,他们可能需要外源胰岛素以控制血糖水平。 Although Type II diabetes, unlike Type I diabetes patients that depend on exogenous insulin, they may need exogenous insulin to control blood sugar levels.

[0004] 二肽基肽酶IV(Dipeptidyl peptidase IV,DPP_IV)是丝氨酸蛋白酶,能特异性水解多肽或蛋白质N末端的Xaa-Pro或Xaa-Ala二肽。 [0004] Dipeptidyl peptidase IV (Dipeptidyl peptidase IV, DPP_IV) is a serine protease, capable of specifically hydrolyzing the N-terminus of the polypeptide or protein Xaa-Pro or Xaa-Ala dipeptides. DPP-IV是非典型丝氨酸蛋白酶,其C 末端区域的Ser-Asp-His催化三联体与典型丝氨酸蛋白酶不同,为逆序排列。 DPP-IV is an atypical serine protease catalytic Ser-Asp-His C-terminal region of the serine protease triad typical different, is in reverse order. DPP-IV为II 型膜整合蛋白,广泛分布于哺乳动物各组织。 DPP-IV is a type II integral membrane protein, it is widely distributed in various mammalian tissues. DPP-IV在分化上皮细胞表面表达,如肠、肝脏、 肾近端小管、前列腺、黄体和白细胞亚型如淋巴细胞和巨噬细胞。 DPP-IV expression on the surface of differentiated epithelial cells, such as intestinal, liver, kidney proximal tubules, prostate, corpus luteum, and subtypes of leukocytes such as lymphocytes and macrophages. 血清中存在DPP-IV的可溶性蛋白形式,其结构和功能与膜结合蛋白形式相同但缺少疏水跨膜结构域。 In the form of soluble protein present in the serum of DPP-IV, the same structural and functional membrane-bound form of the protein but lacks the hydrophobic transmembrane domain.

[0005] DPP-IV有多种生理学相关底物,如炎症趋化因子类、正常T细胞表达和分泌因子(regulated on activation normal T-cell expressed and secreted,RANTES)、嗜酸细胞活化趋化因子和巨噬细胞衍生趋化因子、神经肽类如神经肽Y(neurop印tide Y,NPY)和P5 物质、血管活性肽、肠降血糖素如胰高糖素样肽(glucagon-like peptide-l,GLP-l)和葡萄糖依赖性促膜岛素多肽(glucose-dependent insulinotropic polypeptide,GIP)。 [0005] DPP-IV has a more physiologically relevant substrates, such as inflammatory chemokines, normal T cell expressed and secreted factors (regulated on activation normal T-cell expressed and secreted, RANTES), chemokine eotaxin and macrophage-derived chemokine, neuropeptides such as neuropeptide Y (neurop printing tide Y, NPY) and P5 substances, vasoactive peptides, incretins such as glucagon-like peptide (glucagon-like peptide-l , GLP-l) and glucose-dependent polypeptides promoting film islands (glucose-dependent insulinotropic polypeptide, GIP).

[0006] 抑制体内DPP-IV可使内源性GLP-I (7-36)水平上升,减少其拮抗物GLP-I (9-36) 的生成。 [0006] DPP-IV in vivo can inhibit the endogenous GLP-I (7-36) levels rise, which reduce the production antagonist GLP-I (9-36) a. 因此,DPP-IV抑制剂可能对与DPP-IV活性相关的疾病有效,例如2型糖尿病,糖尿病血脂异常,糖耐量降低(impaired glucose tolerance, IGT),空腹血糖受损(impaired fasting plasma glucose, IFG),代谢性酸中毒,酮病,食欲调节和肥胖。 Thus, DPP-IV inhibitors may be effective for the activity of DPP-IV related diseases, such as type 2 diabetes, diabetic dyslipidemia, impaired glucose tolerance (impaired glucose tolerance, IGT), impaired fasting glucose (impaired fasting plasma glucose, IFG ), metabolic acidosis, ketosis, appetite regulation and obesity.

[0007] 因此,抑制DPP-IV被认为是新的治疗II型糖尿病的治疗途径。 [0007] Thus, inhibiting DPP-IV is considered a new therapeutic approach to treating Type II diabetes.

[0008] PCT/CN2010/080370 描述了一系列3- (3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物,这类化合物在动物体内表现出对DPP-IV具有良好的抑制活性。 [0008] PCT / CN2010 / 080370 described a series of 3- (3-piperidin-1-yl) -5-oxo-1,2,4-triazine derivatives, such compounds exhibit in vivo good inhibitory activity against DPP-IV. 与其他DPP-IV抑制剂相比,该3- (3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物具有有效性更高、选择性更高的优点。 Compared to other DPP-IV inhibitor, the 3- (3-piperidin-1-yl) -5-oxo-1,2,4-triazine derivatives having a higher effectiveness and higher selectivity The advantages. 其公开了化合物(R) 2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代_1,2, 4-三嗪-4 (5H)-基)甲基)-4-氟苄腈(以下简称化合物A),结构式如式I所示: Which discloses compound (R) 2 - ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo _1,2, 4-triazin -4 (5H) - yl ) methyl) -4-fluorobenzonitrile (hereinafter referred to as compound A), the structural formula as shown in formula I:

[0009] [0009]

Figure CN104803972AD00041

[0010] 然而,在对化合物A的研宄过程中,发现其不稳定,并且容易氧化。 [0010] However, in the study based on the process of compound A, which was found unstable and easily oxidized. 因此,迫切需要开发化合物A的新形式,以解决其稳定性差的问题,制备得到更为理想的治疗II型糖尿病药物。 Accordingly, an urgent need to develop new forms of Compound A, to solve the problem of poor stability, prepared by the treatment of type II diabetes drugs more desirable.

发明内容 SUMMARY

[0011] 本发明的目的在于提供一种抑制二肽基肽酶IV活性的3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物化合物A的新形式---化合物A苯甲酸盐,该化合物A的新形式具有良好的稳定性,并且不易氧化,有效地保证了产品的质量,从而对用药安全性和有效性具有重要意义。 [0011] The object of the present invention is to provide a method for inhibiting dipeptidyl peptidase IV activity of 3- (3-piperidin-1-yl) -5-oxo-1,2,4-triazine derivative compounds the new form a of compound a --- benzoate, a new form of the compound a has good stability, and is not easily oxidized, effectively guarantee the quality of the product, so that the effectiveness is important for safety and medication.

[0012] 本发明的目的通过以下技术方案实现: [0012] The object of the present invention is achieved by the following technical solution:

[0013] 一种如下式II所述的3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐, [0013] A according to the formula II 3- (3-piperidin-1-yl) -5-oxo-benzoate 1,2,4-triazine derivative,

[0014] [0014]

Figure CN104803972AD00042

[0015] 式II所述的3-(3-氨基哌啶-1-基)-5_氧代-1,2, 4-三嗪衍生物的苯甲酸盐的化学名称为:(R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基) 甲基)-4_氟苄腈苯甲酸盐(即化合物A苯甲酸盐),分子式为:C17H19FN 6O · C7H6O2,分子量为:464.49。 [0015] according to formula II 3- (3- amino-piperidin-1-yl) -5_ oxo-1,2, 4-benzoate chemical name triazine derivative is: (R) 2- ((3- (3-piperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin -4 (5H) - yl) methyl) -4_ fluorobenzonitrile benzoate (i.e. benzoate compound A), of the formula: C17H19FN 6O · C7H6O2, molecular weight: 464.49.

[0016] 所述的3-(3-氨基哌啶-1-基)-5_氧代-1,2, 4-三嗪衍生物的苯甲酸盐的熔点为:95°C -115Ό。 [0016] The 3- (3-amino-piperidin-1-yl) -5_ oxo-1,2, 4-benzoate m.p. triazine derivative is: 95 ° C -115Ό.

[0017] 本发明的另一目的在于提供化合物A苯甲酸盐的制备方法。 [0017] Another object of the present invention to provide a method of preparing compound A benzoate.

[0018] -种制备上述3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐方法,其特征在于该制备方法包含如下步骤:将3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物进行精制,以有机溶剂或有机溶剂与水的混合溶液作为溶剂,分别溶解苯甲酸和和精制后的3- (3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物,内温保持在10°C~35°C 下向3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物溶液中滴加等摩尔的苯甲酸溶液,所得反应液洗涤过滤,浓缩干燥,即得3- (3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐。 [0018] - preparation of the above types of 3- (3-piperidin-1-yl) -5-oxo-1,2, benzoate triazine derivatives Method 4, characterized in that the method comprises preparing the steps of: 3- (3-piperidin-1-yl) -5-oxo-1,2,4-triazine derivative purified, an organic solvent or a mixed solution of an organic solvent and water as a solvent, benzoic acid were dissolved and the purified 3- (3-piperidin-1-yl) -5-oxo-1,2,4-triazine derivatives, the inner temperature was maintained at 10 ° C ~ 35 ° C the solution of 3- (3-amino-piperidin-1-yl) -5-oxo-1,2,4-triazine derivative is added dropwise an equimolar benzoic acid solution, the resulting reaction solution was washed filtered, dried and concentrated , i.e., to give 3- (3-piperidin-1-yl) -5-oxo-1,2, 4- benzoate triazine derivative.

[0019] 所述的有机溶剂为乙醇、四氢呋喃等或其两种任意比例的混合物。 [0019] The organic solvent is ethanol, tetrahydrofuran, etc., or a mixture of both in any proportions.

[0020] 所述的内温优选15 °C~25 °C。 [0020] The internal temperature of preferably 15 ° C ~ 25 ° C.

[0021] 其中,化合物A可根据PCT/CN2010/080370公开的方法制备,具体合成路线及主要的反应条件如下: [0021] wherein the compound A may be prepared PCT / CN2010 / 080370 disclosed method, specific synthesis routes and primary reaction conditions are as follows:

Figure CN104803972AD00051

[0023] 主要包含以下三个步骤: [0023] consists of three main steps:

[0024] (1)以1-溴-2-(溴甲基)-4_氟苯(1)为起始原料,异硫氰酸根取代以及与水合肼反应得到硫脲,硫脲与丙酮酸甲酯发生缩合反应,在碱性条件下环合后得硫代三嗪酮(5); [0024] (1) 1-bromo-2- (bromomethyl) fluorobenzene -4_ (1) as a starting material, isothiocyanato, and hydrazine hydrate is reacted with a substituted thiourea, thiourea pyruvate ester condensation reaction, to give thio-triazin-one (5) after the cyclization under basic conditions;

[0025] (2)硫代三嗪酮(5)经硫甲基化、(R)-3-Boc-氨基哌啶取代反应以及钯催化氰基化后得关键中间体(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4, 5-二氢-1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(9); To give the key intermediate [0025] (2) thio-triazin-one (5) of the sulfur-methyl, (R) -3-Boc- amino substituted piperidine palladium catalyzed cyanation reactions, and (R) - tert-butyl l- (4- (2-cyano-5-fluoro-benzyl) -6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl) piperidine -3-carbamate (9);

[0026] (3)中间体(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4, 5-二氢-1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(9)在酸性环境中脱Boc后得到3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的游离碱(10),即化合物A。 [0026] (3) Intermediate (R) - tert-butyl-1- (4- (2-cyano-5-fluoro-benzyl) -6-methyl-5-oxo-4,5-dihydro - 1,2,4-triazin-3-yl) piperidin-3-carbamate (9) in an acidic environment after deprotection of Boc group to give 3- (3-piperidin-1-yl) -5-oxo Generation -1,2, 4- triazine derivative of the free base of (10), i.e. the compound A.

[0027] 本发明的又一目的在于提供一种含有化合物A苯甲酸盐的药物组合物。 [0027] A further object of the present invention is to provide a pharmaceutical composition containing compound A benzoate.

[0028] -种药物组合物,包含本发明的3- (3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物苯甲酸盐和一种以上可药用辅料组成。 [0028] - pharmaceutical compositions comprising the present invention 3- (3-piperidin-1-yl) -5-oxo-1,2,4-triazine derivative and one or more benzoate pharmaceutically acceptable adjuvant composition.

[0029] 所述的可药用辅料包含粘合剂、填充剂、崩解剂、润滑剂、增塑剂、防腐剂、矫味剂、 增溶剂、着色剂、分散剂、释放速度调节剂等中的一种或两种以上上述物质的混合物。 [0029] The pharmaceutically acceptable excipients comprise binders, fillers, disintegrants, lubricants, plasticizers, preservatives, flavoring agents, solubilizers, coloring agents, dispersing agents, release rate modifiers, etc. one or two or more mixtures thereof.

[0030] 所述的药物组合物可以制备成适合口服给药的剂型,如:片剂(包括普通片剂、包衣片剂),□含片,润喉剂,水性或油性混悬剂,分散粉剂或颗粒剂,乳剂,硬胶囊或软胶囊, 糖浆剂、丸剂、冻干粉或酊剂。 [0030] The pharmaceutical composition can be prepared into a dosage form suitable for oral administration, such as: tablets (including ordinary tablets, coated tablets), □ troches, throat, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, pills, lyophilized powder or tincture. 也可以制备成注射剂及适合局部给药的乳膏剂,凝胶剂,软膏剂,乳剂,溶液剂,洗剂,悬液,酊剂,糊剂,泡沫剂,气雾剂,灌肠剂,喷雾剂,栓剂等。 Injection and may be prepared for topical administration of creams, gels, ointments, emulsions, solutions, lotions, suspensions, tinctures, pastes, foams, aerosols, enemas, sprays, suppository.

[0031] 本发明所述的3-(3-氨基哌啶-1-基)-5_氧代-1,2, 4-三嗪衍生物的苯甲酸盐, 相对于现有技术具有如下的优点及有益效果: [0031] The present invention is 3- (3-piperidin-1-yl) -5_ oxo-1,2,4-triazin-benzoate derivative, with respect to the prior art has the following advantages and beneficial effects:

[0032] (1)本发明的化合物A苯甲酸盐相对于化合物A、化合物A盐酸盐及化合物A甲磺酸盐均具有更好的稳定性,更适用于制剂使用。 Compound [0032] (1) of the present invention with respect to A benzoate Compound A, Compound A hydrochloride and mesylate salt of Compound A has a better stability, the formulation more suitable for use.

[0033] (2)本发明的化合物A苯甲酸盐在动物体内证明具有良好的生物利用度。 [0033] benzoate Compound A (2) of the present invention proved to have good in vivo bioavailability.

[0034] 因此,本发明化合物更适合开发成为一种优良的治疗II型糖尿病药物,从而应用于临床,有效地保证了产品的质量,对用药安全性和有效性提供了良好的保障。 [0034] Thus, the compounds of the present invention is suitable for development into a more superior treatment of type II diabetes drugs, used clinically so, effectively ensure the product quality, safety and efficacy of the drug provides a good protection.

附图说明 BRIEF DESCRIPTION

[0035] 图1本发明实施例9 (R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4(5H)_基)甲基)-4-氟苄腈苯甲酸盐的高效液相色谱图 [0035] Example 9 (R) 2- ((3- (3- amino-piperidin-1-yl) 1 of the present invention methyl-5-oxo-1,2,4-triazin - 4 (5H) _ yl) methyl) -4-fluorobenzonitrile benzoate by HPLC FIG.

[0036] 图2本发明实施例9 (R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4(5H)_基)甲基)-4-氟苄腈苯甲酸盐的红外光谱图 Example [0036] The present invention FIG. 2 9 (R) 2- ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin - 4 (5H) _ yl) methyl) -4-fluorobenzonitrile benzoate IR spectrum

具体实施方式 detailed description

[0037] 下面结合实施例和附图对本发明作进一步详细的描述,但发明的实施方式不限于此。 [0037] The following Examples and the accompanying drawings of the present invention will be described in further detail, but the invention is not limited to this embodiment.

[0038] 实施例1 1-溴-4-氟-2-(异硫氰酸甲基)苯⑵的制备 Preparation of bromo-4-fluoro-2- (methyl iso thiocyanate) in benzene ⑵ [0038] Example 11-

[0039] 向1-溴-2-(溴甲基)-4-氟苯(1,5. 36g,20.0 mmol)的DMF 溶液(20ml)中,加入碘化钠(1.20g, 8. OOmmol)和硫氰酸钾(3. 88g, 40.0 mmol)。 [0039] l-bromo-2- (bromomethyl) -4-fluorobenzene (1,5. 36g, 20.0 mmol) in DMF (20ml) was added sodium iodide (1.20g, 8. OOmmol) and potassium thiocyanate (3. 88g, 40.0 mmol). 该混合物在氮气氛围下加热到80°C反应12h后,冷却到室温,向其中加入100mL水,并用乙酸乙酯萃取(50mLX2),合并有机层用饱和食盐水洗涤,无水硫酸镁干燥,抽滤浓缩得粗品,残余物用硅胶柱色谱纯化(洗脱剂:石油醚)得1-溴-4-氟-2-(异硫氰酸甲基)苯(2)。 The mixture was heated under nitrogen atmosphere to 80 ° C the reaction after 12h, cooled to room temperature, and thereto was added 100mL of water, and extracted with ethyl acetate (50 mL x 2), the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtered and concentrated to give crude residue was purified by silica gel column chromatography: to give 1-bromo-4-fluoro-2- (methyl iso thiocyanate) benzene (2) (eluent petroleum ether).

[0040] 实施例2 N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3)的制备 [0040] Example 2 N- group hydrazine-carbothioamide (3) of (2- bromo-5-fluorobenzyl)

[0041] 将水合肼(80%,2. 22g,35. 5mmol)的1,4-二氧六环溶液(20ml)冷却到0°C,向其中加入1-溴-4-氟-2-(异硫氰酸甲基)苯(2, 3. 16g, 12. 8mmol)的1,4-二氧六环溶液(5ml)。 [0041] Hydrazine hydrate (80%, 2. 22g, 35. 5mmol) in 1,4-dioxane (20ml) was cooled to 0 ° C, to which was added 1-bromo-4-fluoro-2- (methyl iso thiocyanate) benzene (2, 3. 16g, 12. 8mmol) in 1,4-dioxane (5ml). 该混合物在室温搅拌2h,向其中加入100mL冰水,有固体析出,抽滤,水洗,五氧化二磷干燥过夜,得N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3)。 The mixture was stirred at room temperature for 2h, and thereto was added 100mL of ice water, solid was precipitated, filtered off with suction, washed with water, dried over phosphorus pentoxide overnight to give N- (2- bromo-5-fluorobenzyl) thio-hydrazino A amide (3). MS:m/z,278(100%,M+1),2 80(100% ), 300(10% ,M+23), 302(10% ) 〇 MS: m / z, 278 (100%, M + 1), 2 80 (100%), 300 (10%, M + 23), 302 (10%) square

[0042] 实施例3甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4)的制备 Preparation of 2- (2- (2-bromo-5-fluorophenyl carbothioamide methylamino) hydrazino) propionate (4) [0042] Example 3 methyl

[0043] 向丙酮酸(352mg, 4. OOmmol)的甲醇溶液(15mL)中先后加入N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3, I. 112g,4. OOmmol),以及浓硫酸5滴,将该混合物加热到回流7h,蒸除大部分溶剂,残余物用乙酸乙酯萃取(150ml),有机层先后分别用水,饱和碳酸氢钠溶液,饱和食盐水洗绦,无水硫酸镁干燥,抽滤浓缩得甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4)。 [0043] to pyruvate (352mg, 4. OOmmol) in methanol (15mL) were added successively N- (2- bromo-5-fluorobenzyl) hydrazino carbothioamide (3, I. 112g, 4 . OOmmol), and 5 drops of concentrated sulfuric acid, and the mixture was heated to reflux 7H, most of the solvent was distilled off, the residue was extracted with ethyl acetate (150ml) and the organic layer was successively washed with water, saturated sodium bicarbonate solution, saturated brine sash, dried over anhydrous magnesium sulfate, filtered and concentrated to give methyl 2- (2- (2-bromo-5-fluoro-carbothioamide methylamino) hydrazino) propionate (4). MS:m/z,362(100 %,M+1),364(100% ),384(60% ,M+23), 386(60% ) 〇 MS: m / z, 362 (100%, M + 1), 364 (100%), 384 (60%, M + 23), 386 (60%) square

[0044] 实施例4 4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3, 4-二氢-1,2, 4-三嗪-5 (2H)-酮(5)的制备 [0044] Example 4 4- (2-bromo-5-fluorophenyl) -6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin -5 (2H -one (5) -)

[0045] 将由钠(273mg,11. 88mmol)和干燥甲醇(30ml)新鲜制备的甲醇钠(0. 4M)溶于甲醇30ml,向其中加入甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4, I. 434g,3. 96mmol),将该混合物加热回流22h,蒸除大部分溶剂,残余物用水100mL稀释,用2N浓盐酸调节pH为1~2,乙酸乙酯萃取(50mLX 2),合并萃取层用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品,经硅胶柱色谱纯化(洗脱剂:乙酸乙酯/石油醚=20 %~30% ),得4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3,4-二氢-1,2,4_三嗪-5 (2H)-酮(5),MS: m/z, 330 (65 %,M+1),332 (60 %,M+23)。 [0045] The sodium by sodium methoxide (273mg, 11. 88mmol) and dry methanol (30ml) freshly prepared (0. 4M) was dissolved in methanol 30ml, to which was added methyl 2- (2- (2-bromo-5- carbothioamide methylamino-fluorophenyl) hydrazono) propanoate (4, I. 434g, 3. 96mmol), and the mixture was heated at reflux for 22h, most of the solvent, the residue was diluted with 100mL distilled water, with 2N hydrochloric acid conc. pH was adjusted to 1-2, extracted with ethyl acetate (50mLX 2), combined extract layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20% to 30%) to give 4- (2-bromo-5-fluorophenyl) -6-methyl-3-thioxo-3,4-dihydro--1,2,4_ triazin -5 (2H) - one (5), MS: m / z, 330 (65%, m + 1), 332 (60%, m + 23).

[0046] 实施例5 4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4_三嗪-5 (4H)-酮(6)的制备 [0046] Example 5 4- (2-bromo-5-fluorophenyl) -6-methyl-3- (methylthio) -1,2,4_ triazin -5 (4H) - one ( 6) preparation of

[0047] 将4- (2-溴-5-氟苯甲基)-6-甲基-3-硫代-3, 4-二氢-1,2, 4-三嗪-5 (2H)-酮(5, 914mg, 2. 77mmol)悬浮于乙醇15ml中,先后加入氢氧化钠(lllmg, 2. 77mmol)和碘甲烧(787mg,5. 54_〇1)。 [0047] 4- (2-bromo-5-fluorophenyl) -6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin -5 (2H) - ketone (5, 914mg, 2. 77mmol) was suspended in 15ml of ethanol, was added followed by sodium hydroxide (lllmg, 2. 77mmol) and methyl iodide burning (787mg, 5. 54_〇1). 将该混合物于室温搅拌10分钟得澄清黄色溶液,反应用水100mL稀释,乙酸乙酯萃取(30mLX 2),合并萃取层用饱和食盐水洗涤,无水硫酸镁干燥,抽滤浓缩, 残余物用硅胶柱色谱纯化(洗脱剂:乙酸乙酯/石油醚=20~25% )得4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4-三嗪-5 (4H)-酮(6)。 The mixture was stirred at room temperature for 10 minutes to give a clear yellow solution, reaction was diluted with 100mL water and extracted with ethyl acetate (30mLX 2), combined extract layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by silica gel purification by column chromatography (eluent: ethyl acetate / petroleum ether = 20-25%) to give 4- (2-bromo-5-fluorophenyl) -6-methyl-3- (methylthio) -1 , 2,4-triazine -5 (4H) - one (6). 1H NMR(400MHz, DMSO, ppm ):5 7.73 (m, 1H), 7. 16 (br, 1H), 7. 05 (d, 1H), 5. 09 (s, 2H), 2. 56 (s, 3H), 2. 32 (s, 3H). MS: m/ z, 344(100% ,M+1), 346(100% ) 〇 1H NMR (400MHz, DMSO, ppm): 5 7.73 (m, 1H), 7. 16 (br, 1H), 7. 05 (d, 1H), 5. 09 (s, 2H), 2. 56 (s , 3H), 2. 32 (s, 3H) MS:. m / z, 344 (100%, m + 1), 346 (100%) square

[0048] 实施例6 (R)-叔丁基I-(4-(2-溴-5-氟苯甲基)-6-甲基-5-氧代-4, 5-二氢-1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(8)的制备 [0048] Example 6 (R) - tert-butyl-I- (4- (2- bromo-5-fluorophenyl) -6-methyl-5-oxo -4,5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-carbamate (8)

[0049] 将4- (2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2, 4-三嗪-5 (4H)-酮(6, 180mg, 0· 523mmol)与(R)-叔丁基哌啶-3-氨基甲酸醋(7, 208mg, I. 04mmol)研磨5 分钟,在氮气氛围下加热到135°C反应13h,反应混合物用硅胶柱色谱纯化(洗脱剂:乙酸乙酯/石油醚=10~50 % )得(R)-叔丁基1- (4- (2-溴-5-氟苯甲基)-6-甲基-5-氧代-4, 5-二氢-1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(8)。 [0049] 4- (2-bromo-5-fluorophenyl) -6-methyl-3- (methylthio) 1,2,4-triazine -5 (4H) - one (6, 180mg, 0 · 523mmol) and (R) - reaction of tert-butyl piperidin-3-ylcarbamate acetate (7, 208mg, I. 04mmol) ground for 5 minutes, heated to 135 ° C under a nitrogen atmosphere 13H, the reaction mixture was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 10 to 50%) to give (R) - tert-butyl-1- (4- (2-bromo-5-fluorobenzyl) -6- -5-oxo-4,5-dihydro-1,2,4-triazin-3-yl) piperidin-3-carbamate (8). MS: m/z,496 (100 %,M+1),498 (100 % )。 MS: m / z, 496 (100%, M + 1), 498 (100%).

[0050] 实施例7 (R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4, 5-二氢-1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(9)的制备 [0050] Example 7 (R) - tert-butyl-1- (4- (2-cyano-5-fluoro-benzyl) -6-methyl-5-oxo-4,5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-carbamate (9)

[0051] 向碳酸钠(53mg, 0. 50mmol)、醋酸钯(3mg, 0. 013mmol)和N-甲基吡咯烷酮0. 5ml 的混合物中加入异丙醇3滴和水2滴,该混合物室温搅拌5分钟,向其中加入(R)-叔丁基1- (4- (2-溴-5-氟苯甲基)-6-甲基-5-氧代-4, 5-二氢-1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(8, 246mg,0· 496mmol)的NMP 溶液(1.0 mL),并加热到140°C,再加入K4[Fe(CN )6].3!120(20911^,0.496臟〇1),在140°〇加热1211,冷却到室温,加入水101111,乙酸乙酯萃取(20mLX 2),合并有机层用饱和食盐水洗涤,无水硫酸镁干燥,抽滤浓缩得粗品,经硅胶柱色谱纯化(洗脱剂:乙酸乙酯/石油醚=20~35% )得(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4, 5-二氢_1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(9). MS: m/ z,418 (20 % ),443 (100 %,M+1),465 (95 %,M+23)。 [0051] To a solution of sodium carbonate (53mg, 0. 50mmol), palladium acetate (3mg, 0. 013mmol) and N- methylpyrrolidone was added 0. 5ml of 3 drops of isopropanol and 2 drops of water, and the mixture was stirred at room temperature 5 minutes, to which was added (R) - tert-butyl-1- (4- (2-bromo-5-fluorophenyl) -6-methyl-5-oxo -4,5-dihydro-1, 2, 4-triazin-3-yl) piperidin-3-carbamate (8, 246mg, 0 · 496mmol) in NMP (1.0 mL), and heated to 140 ° C, then add K4 [Fe ( CN) 6] .3! 120 (20911 ^, 0.496 dirty 〇1), heated at 140 ° 1211 square, cooled to room temperature, water was added 101111, extracted with ethyl acetate (20mLX 2), the organic layers were washed with saturated brine , dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20 to 35%) to give (R) - tert-butyl-1- (4- (2 - cyano-5-fluoro-benzyl) -6-methyl-5-oxo-4,5-dihydro _1,2, 4-triazin-3-yl) piperidin-3-carbamate (9) MS:. m / z, 418 (20%), 443 (100%, m + 1), 465 (95%, m + 23).

[0052] 实施例8化合物A (R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代_1,2, 4-三嗪-4(5H)_基)甲基)-4-氟苄腈(10)的制备 Example 8 Compound A (R) [0052] Embodiment 2 - ((3- (3-piperidin-1-yl) -6-methyl-5-oxo _1,2, 4-triazin-4 ) preparation of (5H) _ yl) methyl-4-fluoro-benzonitrile (10)

[0053] 向(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6_甲基-5-氧代-4, 5-二氢-1,2, 4-三嗪-3-基)哌啶-3-氨基甲酸酯(9, 37mg)的二氯甲烷溶液lml,加入三氟醋酸0. 5ml,室温搅拌lh,用饱和碳酸氢钠溶液中和,二氯甲烷萃取(10ml X 3),合并有机层用无水硫酸钠干燥,抽滤浓缩得粗品,经硅胶柱色谱纯化(洗脱剂:二氯甲烷/甲醇/氨水= 92:6:2)得(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5!1)-基) 甲基)-4_ 氟苄腈(10),即化合物A。 [0053] to (R) - tert-butyl-1- (4- (2-cyano-5-fluorobenzyl) -6_-5-oxo-4,5-dihydro-1,2, dichloromethane was lml 4- triazin-3-yl) piperidin-3-carbamate (9, 37mg) and trifluoroacetic acid was added 0. 5ml, LH stirring at room temperature, neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane (10ml X 3), the organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol / aqueous ammonia = 92: 6: 2 ) to give (R) -2 - ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin-4 (51)! ​​- yl) methyl) -4_ fluorobenzonitrile (10), i.e. the compound A. 1H NMR(400MHz, DMSO, ppm) : δ 7. 96 (m, 1H), 7. 36 (br,1 Η),7· 29 (d,1H),5· 23 (s,2H),3· 15 (m,3H),2· 72 (m,2H),2· 23 (s,3H),I. 78 (d,1H),I. 64 (d,I Η), I. 47(m,1H), I. 12(m,lH).MS:m/z,343(100%,M+1)。 1H NMR (400MHz, DMSO, ppm): δ 7. 96 (m, 1H), 7. 36 (br, 1 Η), 7 · 29 (d, 1H), 5 · 23 (s, 2H), 3 · 15 (m, 3H), 2 · 72 (m, 2H), 2 · 23 (s, 3H), I. 78 (d, 1H), I. 64 (d, I Η), I. 47 (m, 1H), I. 12 (m, lH) .MS: m / z, 343 (100%, m + 1).

[0054] 实施例9 (R) 2- ((3- (3-氨基哌啶-I-基)-6-甲基-5-氧代-1,2, 4-三嗪-4(5H)_基)甲基)-4-氟苄腈苯甲酸盐(化合物A苯甲酸盐)的制备 [0054] Example 9 (R) 2- ((3- (3- amino-piperidin -I--yl) -6-methyl-5-oxo-1,2,4-triazin -4 (5H) -4-fluorobenzonitrile benzoate (compound a benzoate) of _-yl) methyl)

[0055] 配置95%乙醇溶液:50〇1^烧杯中加入2281^乙醇,加入1211^水,搅拌均匀,备用。 [0055] Configuration 95% ethanol solution: 50〇1 ^ 2281 ^ beaker of ethanol, water was added 1211 ^ uniformly stirred, spare.

[0056] 取2. 14g苯甲酸,室温下加入10mL95%乙醇搅拌溶解,备用;向500mL反应瓶中加入化合物A精制品60g,95 %乙醇120mL,搅拌,溶清,过滤,用95 %乙醇18ml洗涤;使内温保持在15°C下滴加苯甲酸的乙醇溶液。 [0056] 2. 14g take acid, was added 10 mL of 95% ethanol and dissolved with stirring at room temperature, the standby; A purified product Compound 60g was added to 500mL reaction flask, 120 mL of 95% ethanol, with stirring, a clear solution, filtered, washed with 18ml 95% ethanol washed; maintaining the internal temperature was added dropwise a solution of benzoic acid in ethanol at 15 ° C. 滴加完毕,95 %乙醇洗涤,减压干燥至恒重, 得42. 4g (R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基)甲基)-4_氟苄腈苯甲酸盐(本品)。 Upon completion, washed with 95% ethanol, and dried under reduced pressure to constant weight to give 42. 4g (R) 2- ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo 1,2,4-triazin -4 (5H) - yl) methyl) benzoate -4_ fluorobenzonitrile (the product).

[0057] 熔点测定:测定仪器:天津大学精密仪器厂YRT-3熔点仪。 [0057] Melting point determination: Instrument: Tianjin University Precision Instrument Factory YRT-3 melting point apparatus. 检测方法:取本品适量,研细,60°C减压干燥2小时,按照中国药典2010年版二部附录VI C测定本品熔点为95°C -115Ό。 Detection method: take the appropriate, small study, 60 ° C for 2 hours under reduced pressure, the product was measured melting point 95 ° C -115Ό according to China Pharmacopoeia 2010 Appendix VI C.

[0058] 苯甲酸鉴别:取(R) 2-( (3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4(5H)_基)甲基)-4-氟苄腈苯甲酸盐0. lg,照中国药典2010年版二部附录ΙΙΓ一般鉴别试验"下"苯甲酸盐"试验方法进行试验,置IOml量瓶中,加水溶剂并稀释至刻度,摇匀, 精密量取5ml至IOml烧杯中,调节溶液对酚酞呈中性,滴加三氯化铁溶液,观察均有赭色沉淀产生。同时做空白对照试验,结果:多批样品的苯甲酸鉴别检测结果均呈阳性反应,试剂空白不干扰测定,专属性强。 [0058] -benzoic acid Identification: Take (R) 2- ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin-4 ( "lower" 5H) _ yl) methyl) -4-fluorobenzonitrile benzoate 0. lg, according to China Pharmacopoeia 2010 edition Appendix ΙΙΓ Usually benzoate identification test "test method test set amount IOml flask, add aqueous solvent and dilute to volume, shake, the precise amount of 5ml to IOml beaker, the solution was adjusted to neutral phenolphthalein was added dropwise a solution of ferric chloride, ocher precipitate were observed. At the same time as a blank test results: benzoic discrimination detection result of multiple batches of samples were positive, the reagent blank did not interfere, and specific.

[0059] 高效液相色谱法鉴别:色谱条件:采用Agilent Eclipse Plus C18色谱柱(5 μm, 4. 6 x 250mm),检测波长为229nm,流动相为乙腈:0. 1%磷酸=7 :3,流速1.0 ml/min,进样量20 μ 1〇 [0059] Identification HPLC: Chromatographic conditions: column using Agilent Eclipse Plus C18 (5 μm, 4. 6 x 250mm), detection wavelength of 229nm, mobile phase of acetonitrile: 01% phosphoric acid = 7: 3 flow rate 1.0 ml / min, the injection volume was 20 μ 1〇

[0060] 取实施例8的化合物A 7. 5mg于50mL容量瓶中,用体积比70 %的乙腈水溶液溶解并稀释至刻度,摇匀,作为化合物A对照品溶液;以及12. 5mg苯甲酸于25mL容量瓶中, 用体积比70 %的乙腈水溶液溶解并稀释至刻度,取ImL于25mL容量瓶中,用体积比70 %的乙腈水溶液溶解并稀释至刻度,摇匀,作为苯甲酸对照品溶液;取本品IOmg于50mL容量瓶中,用体积比70%的乙腈水溶液溶解并稀释至刻度,摇匀,作为本品化合物A苯甲酸盐的供试品溶液。 [0060] A compound of embodiments taken 7. 5mg Example 8 in 50mL volumetric flask, dissolved by volume of 70% acetonitrile in water and dilute to volume, shake, as the reference solution of Compound A; and benzoic acid in 12. 5mg 25mL volumetric flask, dissolved by volume of 70% acetonitrile in water and dilute to volume, taken in ImL 25mL volumetric flask, dissolved by volume of 70% acetonitrile in water and dilute to volume, shake, benzoic acid as reference solution ; this product IOmg in 50mL volumetric flask, dissolved by volume of 70% acetonitrile in water and dilute to volume, shake, the product as the benzoate salt of compound a test solution. 分别精密量取对照品溶液和供试品溶液各20 μ 1,按照高效液相色谱法(中国药典2010年版二部附录VD),按上述色谱条件进样,色谱图如图1所示,按外标法计算。 Precise amount of the reference solution and the test solution 20 μ 1, according to high performance liquid chromatography (China Pharmacopoeia 2010 Appendix VD), the above-described injection chromatographic conditions, the chromatogram shown in Figure 1, press external standard method.

[0061] 结果显示,主峰保留时间和对照品保留时间一致,并通过峰面积计算化合物A和苯甲酸的含量,本品中化合物A和苯甲酸的摩尔比为1 :1。 [0061] The results showed that the peak retention time and the retention time consistent reference, and the content of the compound A and the peak area is calculated by the benzoic acid, the molar ratio of compound A and the product acid is 1: 1.

[0062] 红外吸收光谱鉴别:采用美国NICOLET AVATAR 330FT-IR红外光谱仪,按照中国药典2010年版二部附录IV C校正,取本品适量,用KBr压片法进行测定,本品的红外衍射图(如图2 所示)中以波数CnT1 表示,在3419. 75〇11'2936· 46〇11'2230· 38〇11'1683· 28CHT1、 1609. 47〇11'1511· 65〇11'1419· 44〇11'829· 18〇11'722· 67CHT1有特征吸收峰,误差为±0. 2cm、 [0062] Infrared Absorption Spectroscopy: American NICOLET AVATAR 330FT-IR infrared spectrometer according to China Pharmacopoeia 2010 Appendix IV C correction, the proper amount, was measured by KBr tablet method, the infrared diffraction pattern of this product ( As shown) in FIG. 2 represents a wave number CnT1, in 3419. 75〇11'2936 46〇11'2230 · · 38〇11'1683 · 28CHT1, 1609. 47〇11'1511 65〇11'1419 · 44 · · · 18〇11'722 〇11'829 67CHT1 characteristic absorption peak has an error of ± 0. 2cm,

[0063] 核磁数据鉴别:1!1匪1?(01^0-(16,400皿取,口口111)6 7.96-7.88(111,3!1),7.45-7· 26 (m, 5H), 6. 80 (brs, 3H), 5. 21 (q, 2H), 3. 41 (d, 1H), 3. 11-3. 08 (m, 2H), 2. 91-2. 79 ( m, 2H), 2. 23(s, 3H), I. 95-1. 91 (m, 1H), I. 78-1. 74(m, 1H), I. 57-1. 42 (m, 2H). MS:m/ z, 341(100% ,M-1), 343(100% ,M+1). [0063] NMR data discrimination:!?! Bandit 1 1 1 (01 ^ 0- (16,400 take dish, mouth 111) 6 7.96-7.88 (111,3 1), 7.45-7 · 26 (m, 5H), 6. 80 (brs, 3H), 5. 21 (q, 2H), 3. 41 (d, 1H), 3. 11-3. 08 (m, 2H), 2. 91-2. 79 (m, 2H), 2. 23 (s, 3H), I. 95-1. 91 (m, 1H), I. 78-1. 74 (m, 1H), I. 57-1. 42 (m, 2H) . MS: m / z, 341 (100%, m-1), 343 (100%, m + 1).

[0064] 实施例10 (R) 2- ((3- (3-氨基哌啶-I-基)-6-甲基-5-氧代-1,2, 4-三嗪-4(5H)_基)甲基)-4-氟苄腈苯甲酸盐(化合物A苯甲酸盐)的制备 [0064] 1,2,4-triazin-4 Example 10 (R) 2- ((3- (3- amino-piperidin -I--yl) -6-methyl-5-oxo (5H) -4-fluorobenzonitrile benzoate (compound a benzoate) of _-yl) methyl)

[0065] 取2. 14g苯甲酸,室温下加入20mL四氢呋喃搅拌溶解,备用;向500mL反应瓶中加入化合物A精制品60g,四氢呋喃120mL,搅拌,溶清,过滤,用18ml四氢呋喃洗涤;使内温保持在25°C下滴加苯甲酸的四氢呋喃溶液。 [0065] 2. 14g take acid, 20mL of tetrahydrofuran was added and dissolved with stirring at room temperature, the standby; A purified product Compound 60g was added to 500mL reaction flask, 120 mL of tetrahydrofuran, with stirring, a clear solution, filtered, washed with tetrahydrofuran 18ml; internal temperature benzoic acid was added dropwise a tetrahydrofuran solution holding at 25 ° C. 滴加完毕,四氢呋喃洗涤,减压干燥至恒重, 得42. 8g (R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基)甲基)-4_氟苄腈苯甲酸盐。 Upon completion, washed with tetrahydrofuran, and dried under reduced pressure to constant weight to give 42. 8g (R) 2- ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo-1 , 2, 4-triazin -4 (5H) - yl) methyl) benzoate -4_ fluorobenzonitrile.

[0066] 按照实施例9的鉴别方法,分别进行熔点测定、苯甲酸鉴别、高效液相色谱鉴另IJ、红外吸收光谱鉴别以及核磁数据鉴别,结果与实施例9的结果基本一致,确定其为(R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基)甲基)-4-氟苄腈苯甲酸盐,且其中化合物A和苯甲酸的摩尔比为1 :1。 [0066] The authentication method according to Example 9, were measured melting point, benzoic discrimination, another discrimination IJ HPLC, and NMR Spectroscopy Infrared absorption authentication data, results with the results of Example 9 are basically the same, which is determined (R) 2- ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin -4 (5H) - yl) methyl) -4-fluoro-benzonitrile benzoate, and wherein the molar ratio of compound a and benzoic acid is 1: 1.

[0067] 实施例11 (R) 2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代_1,2, 4-三嗪-4 (5H)-基)甲基)-4-氟苄腈盐酸盐(化合物A盐酸盐)的制备 [0067] Example 11 (R) 2 - ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo _1,2, 4-triazin -4 (5H) - preparation yl) methyl) -4-fluoro-benzonitrile hydrochloride (compound a hydrochloride)

[0068] 称取IOg的化合物A精制品,加入50ml甲醇室温溶解,降温,控制温度0-10°C,滴加2. 3ml盐酸/IOml甲醇;滴加后,反应4h,浓缩,干燥至恒重,得8g (R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基)甲基)-4-氟苄腈盐酸盐。 [0068] A compound was weighed IOg purified product was dissolved 50ml of methanol was added at room temperature, cooling to control the temperature 0-10 ° C, hydrochloric acid was added dropwise 2. 3ml / IOml methanol; After the addition, the reaction 4h, concentrated, and dried to constant weight to give 8g (R) 2- ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin -4 (5H) - yl ) methyl) -4-fluorobenzonitrile hydrochloride.

[0069] 核磁数据鉴别,HNMlUDMSO-dj^OOMHzjpm) δ7·98-7·94(πι,4Η),7·39 -7· 30 (m,2Η),5· 20 (q,2Η),3· 53-3. 49 (m,1Η),3· 30-3. 26 (m,1Η),3· 07-3. 02 (m,2 Η), 2. 85-2. 80 (m, 1H), 2. 23 (s, 3H), I. 98 (m, 1H), I. 79 (m, 1H), I. 54 (m, 2H). MS : m/ z, 341(100% ,M-1), 343(100% ,M+1). [0069] NMR data authentication, HNMlUDMSO-dj ^ OOMHzjpm) δ7 · 98-7 · 94 (πι, 4Η), 7 · 39 -7 · 30 (m, 2Η), 5 · 20 (q, 2Η), 3 · 53-3. 49 (m, 1Η), 3 · 30-3. 26 (m, 1Η), 3 · 07-3. 02 (m, 2 Η), 2. 85-2. 80 (m, 1H) , 2. 23 (s, 3H), I. 98 (m, 1H), I. 79 (m, 1H), I. 54 (m, 2H) MS:. m / z, 341 (100%, M- 1), 343 (100%, M + 1).

[0070] 其中,盐的个数通过离子色谱确定盐的个数为1(即化合物A盐酸盐中化合物A和盐酸的摩尔比为I :1)。 [0070] wherein the number of the salt by ion chromatography to determine the salt is the number 1 (i.e., molar ratio of the compound A Compound A hydrochloride and hydrochloric acid is I: 1). 离子色谱检测仪器:Dionex ICS-5000离子色谱仪,检测依据:JY/T 020-1996尚子色谱分析方法通则,氯尚子含量:93. Omg/g。 Ion Chromatography Instrument: Dionex ICS-5000 ion chromatography, based on detection: JY / T 020-1996 Naoko General chromatographic methods, Naoko chlorine content:. 93 Omg / g.

[0071] 实施例12 (R) 2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代_1,2, 4-三嗪-4(5H)_基)甲基)-4-氟苄腈甲磺酸盐(化合物A甲磺酸盐)的制备 [0071] Example 12 (R) 2 - ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo _1,2, 4-triazin -4 (5H) preparation _-yl) methyl) -4-fluorobenzonitrile methanesulfonate (mesylate salt of compound a) of

[0072] 称取IOg的化合物A精制品,加入50ml甲醇室温溶解,降温,控制温度O-KTC, 滴加2. 7g甲磺酸/IOml甲醇;滴加后反应16h,降温至小于0°C,过滤,干燥至恒重,得(R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基)甲基)-4-氟苄腈甲磺酸盐(8g)。 [0072] A compound was weighed IOg purified product was dissolved 50ml of methanol was added at room temperature, cooling, temperature control O-KTC, methanesulfonic acid was added dropwise 2. 7g / IOml methanol; After the addition the reaction for 16 h, cooled to less than 0 ° C , filtered, and dried to constant weight to give (R) 2- ((3- (3- amino-piperidin-1-yl) -6-methyl-5-oxo-1,2,4-triazin-4 (5H) - yl) methyl) -4-fluorobenzonitrile methanesulfonate (8g).

[0073] 核磁数据鉴别"HNMlUDMSO-dj;,400MHz, ppm) δ 7. 99-7. 94 (m, 4H),7. 39-7. 31 (m, 2H ),5· 19 (q,2Η),3· 54-3. 51 (m,1Η),3· 37 (m,1Η),3· 08-3. 03 (m,2Η),2· 82 (m,1Η),2· 36 (s,3Η) ,2. 23 (s, 3Η), 1. 97 (m, 1Η), 1. 77 (m, 1Η), 1. 54 (m, 2Η) ;MS:m/z, 343(100% ,Μ+1). [0073] NMR data discrimination "HNMlUDMSO-dj;, 400MHz, ppm) δ 7. 99-7 94 (m, 4H), 7 39-7 31 (m, 2H), 5 · 19 (q, 2Η... ), 3 · 54-3. 51 (m, 1Η), 3 · 37 (m, 1Η), 3 · 08-3. 03 (m, 2Η), 2 · 82 (m, 1Η), 2 · 36 ( s, 3Η), 2 23 (s, 3Η), 1. 97 (m, 1Η), 1. 77 (m, 1Η), 1. 54 (m, 2Η); MS:. m / z, 343 (100 %, Μ + 1).

[0074] 实施例13稳定性考察 [0074] Example 13 Stability

[0075] (一)高温实验 [0075] (a) a high temperature test

[0076] 依据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》,分别精密称取实施例9与实施例10的化合物A苯甲酸盐各25mg,裸露放入培养皿中,置于40°C的高温试验箱中,放置0天、5天、10天取样测定,结果见表1。 [0076] based on "Chinese Pharmacopoeia" 2010 the second appendix XIXc "Guidelines for stability testing of the drug in a pharmaceutical formulation", respectively accurately weighed Embodiment 9 25mg of each Example Compound A benzoate of Example 10, high temperature chamber exposed into Petri dish of 40 ° C was placed in, placed 0 days, 5 days, 10-day sample, the results are shown in Table 1.

[0077] 表1高温实验结果(40 ±2 °C ) [0077] The results in Table 1 temperature (40 ± 2 ° C)

[0078] [0078]

Figure CN104803972AD00101

[0079] 通过上述结果可以看出:化合物A苯甲酸盐在高温条件下比较稳定。 [0079] As can be seen by the above results: Compound A benzoate stable at high temperatures.

[0080] 同等条件下进行对比高温试验,结果发现,化合物A苯甲酸盐相对于化合物A、化合物A盐酸盐及化合物A甲磺酸盐均具有更好的稳定性。 Comparing the high temperature test [0080] The same conditions and found that, with respect to Compound A Compound A benzoate, Compound A hydrochloride and mesylate salt of Compound A has a better stability.

[0081] (二)高湿实验 [0081] (ii) humidity test

[0082] 依据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》,分别精密称取实施例9与实施例10的化合物A苯甲酸盐、实施例8的化合物A、实施例11的化合物A盐酸盐、实施例12的化合物A甲磺酸盐各5份,每份各100mg,裸露放入培养皿中,置于RH92. 5%的恒温恒湿箱中(温度25±2°C ),并于0天、3天、7天后取样测定, 结果见表2。 [0082] based on "Chinese Pharmacopoeia" 2010 the second appendix XIXc "Guidelines for stability testing of the drug in a pharmaceutical formulation", respectively accurately weighed Example 9 Example 10 Compound A benzoate, Example compound a 8, the embodiment of the hydrochloride salt of compound a of Example 11, Example compound a 5 parts of each of the mesylate 12, each respective 100mg, exposed into the petri dish, placed RH92. 5% of the constant temperature humidified incubator (a temperature of 25 ± 2 ° C), and 0 days, 3 days, 7 days sampling measurement results shown in Table 2.

[0083] 表2 高湿实验结果(RH92. 5%,25±2°C ) [0083] The results in Table 2 and high humidity (RH92. 5%, 25 ± 2 ° C)

Figure CN104803972AD00102

Figure CN104803972AD00111

[0085] 通过上述结果可以看出:化合物A苯甲酸盐在高湿条件下比较稳定。 [0085] As can be seen by the above results: Compound A benzoate stable under high humidity conditions.

[0086] 同等条件下进行对比高湿试验,结果发现,化合物A苯甲酸盐相对于化合物A、化合物A盐酸盐及化合物A甲磺酸盐均具有更好的稳定性。 Comparative humidity test at [0086] the same conditions, and found that, with respect to Compound A benzoate Compound A, Compound A hydrochloride and mesylate salt of Compound A has a better stability.

[0087] (三)加速实验 [0087] (c) accelerated test

[0088] 依据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》,分别精密称取实施例9与实施例10的化合物A苯甲酸盐各20mg,装入双层药用聚乙烯塑料袋中,热封,外加铝塑复合膜包装,热封。 [0088] based on "Chinese Pharmacopoeia" 2010 the second appendix XIXc "Guidelines for stability testing of the drug in a pharmaceutical formulation", respectively accurately weighed Embodiment 9 20mg of each Example Compound A benzoate of Example 10, bilayer pharmaceutical charged in polyethylene bags, heat-sealed, plus plastic composite film packaging, heat-sealed. 置加速试验箱中,于40°C,RH75±5%条件下放置〇、1、2、3、6月后取样测定,结果见表3。 Accelerated test chamber set at 40 ° C, RH75 ± 5% under conditions placed billion, 1, 2, 3, 6 months after the sample to measure the results shown in Table 3.

[0089] 表3加速实验结果(40 °C,RH75 ± 5 % ) [0089] The results in Table 3 Acceleration (40 ° C, RH75 ± 5%)

Figure CN104803972AD00112

[0091] 通过上述结果可以看出:化合物A苯甲酸盐在40°C,RH75±5%条件下加速试验6 个月,其指标与〇月基本一致,说明本品在加速40°C下比较稳定。 [0091] As can be seen by the above results: Compound A benzoate at 40 ° C, RH75 ± 5% for 6 months accelerated test conditions, consistent with the square of its index months, the product described in the accelerated 40 ° C relatively stable.

[0092] 同等条件下进行对比加速试验,结果发现,化合物A苯甲酸盐相对于化合物A、化合物A盐酸盐及化合物A甲磺酸盐均具有更好的稳定性。 Comparing the acceleration test [0092] The same conditions and found that, with respect to Compound A Compound A benzoate, Compound A hydrochloride and mesylate salt of Compound A has a better stability.

[0093] 实施例14生物利用度研宄 [0093] The bioavailability study based on 14 EXAMPLE

[0094] 选取健康Beagle犬6只,雌雄各半,体重9. 5~11kg,禁食12h后将称量好的(R) 2- ((3- (3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基)甲基)-4-氟节腈苯甲酸盐按5mg/kg犬体重,并用50mL水灌服,给药前空白血,于给药后0. 25、0. 5、1. 0、 2. 0、3. 0、4. 0、6. 0、8. 0、12及24h经小隐静脉取血0. 5ml,置加有肝素的试管中,将血样以4000r/min离心5min,分取血浆,-75± 10°C保存供测试。 [0094] Select 6 healthy Beagle dogs, male and female, weighing 9. 5 ~ 11kg, after a 12h fasting weighed (R) 2- ((3- (3- amino-piperidin-1-yl) 6-methyl-5-oxo-1,2,4-triazin -4 (5H) - yl) methyl) -4-fluoro-carbonitrile benzoate press section 5mg / kg body weight of the dog, and washed with 50mL of water fed, white blood before administration, after administration 0. 25,0. 5,1. 0, 2. 0,3. 0,4. 0,6. 0,8. 0,12 and 24h via low saphenous vein blood 0. 5ml, placed tubes plus heparin, the blood samples 4000r / min centrifugal 5min, fractionated plasma, -75 ± 10 ° C storage for testing. 将血药浓度-时间数据以3P87程序经计算机拟合,AUC值为梯形面积法计算所得。 The plasma concentration - time data was computer fitted to 3P87 program, the calculated AUC value trapezoidal area method.

[0095] 结果显示,Beagle犬口服给予(R) 2-((3-(3-氨基哌啶-1-基)-6_甲基-5-氧代-1,2, 4-三嗪-4 (5H)-基)甲基)-4-氟苄腈苯甲酸盐后吸收迅速,达峰时间Tmax在1-1. 5h,平均口服生物利用度在80%以上。 [0095] The results show, the Beagle dogs orally administered (R) 2 - ((3- (3- amino-piperidin-1-yl) -6_-5-oxo-1,2,4-triazin - 4 (5H) - yl) methyl) -4-fluorobenzonitrile post benzoates rapidly absorbed, peak time Tmax at 1-1 5h, the mean oral bioavailability more than 80%.

[0096] 相同剂量和实验方法下,化合物A苯甲酸盐以化合物A计的生物暴露量为阿格列汀的1. 5-2倍,表明化合物A苯甲酸盐有更高的体内贮留的量。 [0096] Under the same experimental methods and doses, Compound A Compound A biologically benzoate exposure meter to 1. 5-2 times alogliptin, compound A showed a higher body benzoate reservoir the amount of the reservation.

[0097] 实施例15药物组合物的制备 Preparation of the pharmaceutical composition of Example 15 [0097] Embodiment

[0098] 化合物A苯甲酸盐6. 78g [0098] Compound A benzoate 6. 78g

[0099] 糊精84. OOg [0099] dextrin 84. OOg

[0100] 按常规方法,将上述物质混合均匀后,分1000等份分别装入普通明胶胶囊,得到1000颗胶囊。 [0100] by a conventional method, the above materials mixed, are charged 1000 parts sub ordinary gelatin capsule to give 1,000 capsules.

[0101] 上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化, 均应为等效的置换方式,都包含在本发明的保护范围之内。 [0101] The preferred embodiment of the present invention embodiment, but the embodiment of the present invention is not limited to the above embodiments, changes made to any other without departing from the spirit and principle of the present invention, modifications, substitutions , combined, simplified, should be equivalent replacement method, it is included within the scope of the present invention.

Claims (7)

  1. 1. 3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐,其结构式如下式II所示: 1. 3- (3-piperidin-1-yl) -5-oxo-1,2, 4- triazine benzoate derivatives having the formula the following formula II:
    Figure CN104803972AC00021
  2. 2. 如权利要求1所述的3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐,其特征在于,其熔点为95°C _115°C。 2. 3- (3-piperidin-1-yl) according to claim 1 5-oxo-1,2, 4- benzoate triazine derivatives, characterized in that the melting point to 95 ° C _115 ° C.
  3. 3. -种制备如权利要求1-2任一权利要求所述的3- (3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐的方法,其特征在于,该制备方法包含以下步骤:将3_ (3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物进行精制,以有机溶剂或有机溶剂与水的混合溶液作为溶剂,分别溶解苯甲酸和和精制后的3-(3-氨基哌啶-1-基)-5-氧代-1,2,4-三嗪衍生物,内温保持在10°C~35°C下向3-(3_氨基哌啶-1-基)-5_氧代-1,2, 4-三嗪衍生物溶液中滴加等摩尔的苯甲酸溶液,所得反应液洗涤过滤,浓缩干燥, 即得3-(3-氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物的苯甲酸盐。 3. - 1,2,4-triazine derivative of claims 1-2 3- (3-piperidin-1-yl) claim a 5-oxo-prepared seed claim benzoic the method of salt, wherein the preparation process comprises the steps of: 3_ (3-amino-piperidin-1-yl) -5-oxo-1,2,4-triazine derivative was purified organic 3- (3-piperidin-1-yl) solvent or a mixed solution of the organic solvent and water as a solvent, and benzoic acid were dissolved and purified 5-oxo-1,2,4-triazine derivative , the temperature was maintained at 10 ° C ~ 35 ° C -5_ oxo-1,2,4-triazine derivative was added dropwise a solution of 3- (3_-amino-piperidin-1-yl) equimolar the benzoic acid solution, washing the resulting reaction solution was filtered, concentrated and dried to obtain 3- (3-piperidin-1-yl) -5-oxo-1,2, 4- benzoate triazine derivative.
  4. 4. 如权利要求3所述的制备方法,其中所述的有机溶剂为乙醇、四氢呋喃等或其两种任意比例的混合物。 4. The method as recited in claim 3, wherein said organic solvent is ethanol, tetrahydrofuran, etc. or a mixture thereof in any ratio two.
  5. 5. 如权利要求3所述的制备方法,其中所述的内温为15°C~25°C。 5. The method as recited in claim 3, wherein said inner temperature of 15 ° C ~ 25 ° C.
  6. 6. 如权利要求4所述的制备方法,其中所述的内温为15°C~25°C。 6. The method as claimed in claim 4, wherein the inner temperature of 15 ° C ~ 25 ° C.
  7. 7. -种药物组合物,包含权利要求1-2任一权利要求所述的3-(3_氨基哌啶-1-基)-5-氧代-1,2, 4-三嗪衍生物苯甲酸盐和一种以上可药用辅料。 7. - 1,2 pharmaceutical compositions, comprising any of claims 1-23- (piperidin-1-yl-amino-3_) according to claim-5-oxo, 4-triazine derivatives benzoate and one or more pharmaceutically acceptable excipients.
CN 201510034007 2014-01-24 2015-01-23 Benzoate of 3-(3-aminopiperidine-1-yl)-5-oxo-1,2,4-triazine derivative, and preparation method and pharmaceutical composition thereof CN104803972A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101360735A (en) * 2005-09-16 2009-02-04 武田药品工业株式会社 Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
CN102791701A (en) * 2009-12-30 2012-11-21 上海复尚慧创医药研究有限公司 3-(3-aminopiperidin-1-yl)-5-oxo-1,2,4-triazine derivates as dipeptidyl peptidase IV(DPP-IV) inhibitors
CN103068392A (en) * 2010-05-12 2013-04-24 Mapi医药公司 Polymorphs of alogliptin benzoate
CN103172615A (en) * 2013-03-29 2013-06-26 山东罗欣药业股份有限公司 Benzoic acid alogliptin crystal form compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101360735A (en) * 2005-09-16 2009-02-04 武田药品工业株式会社 Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
CN102791701A (en) * 2009-12-30 2012-11-21 上海复尚慧创医药研究有限公司 3-(3-aminopiperidin-1-yl)-5-oxo-1,2,4-triazine derivates as dipeptidyl peptidase IV(DPP-IV) inhibitors
CN103068392A (en) * 2010-05-12 2013-04-24 Mapi医药公司 Polymorphs of alogliptin benzoate
CN103172615A (en) * 2013-03-29 2013-06-26 山东罗欣药业股份有限公司 Benzoic acid alogliptin crystal form compound

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