CN106831559A - PTP1B inhibitor containing nicotinamide structure, and preparation method and application thereof - Google Patents

PTP1B inhibitor containing nicotinamide structure, and preparation method and application thereof Download PDF

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CN106831559A
CN106831559A CN201710074729.7A CN201710074729A CN106831559A CN 106831559 A CN106831559 A CN 106831559A CN 201710074729 A CN201710074729 A CN 201710074729A CN 106831559 A CN106831559 A CN 106831559A
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compound
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preparation method
inhibitor containing
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蔡子洋
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佛山市赛维斯医药科技有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Abstract

The invention relates to the field of medicines related to type II diabetes. Specifically, the invention relates to a PTP1B inhibitor containing a nicotinamide structure, and a preparation method and application thereof in preparation of medicines for type II diabetes. The formula is shown in the specification.

Description

一种含烟酸酰胺结构的PTP1B抑制剂、制备方法及其用途 PTP1B inhibitor containing nicotinic acid amide structure, preparation and use thereof

技术领域 FIELD

[0001] 本发明涉及II型糖尿病治疗的药物领域。 [0001] The present invention relates to the field of pharmaceutical treatment of type II diabetes. 更具体地讲,本发明涉及对II型糖尿病具有治疗作用的一种含烟酸酰胺结构的PTPlB抑制剂、其制备方法,以及在制药上的用途。 More particularly, the present invention relates to a PTPlB inhibitor having a therapeutic effect on type II diabetes containing nicotinic acid amide structure, their preparation, and their use in the pharmaceutical.

背景技术 Background technique

[0002] II型糖尿病是一种常见的代谢紊乱疾病,其特征是外周对膜岛素产生抵抗作用, 在分子水平表现为胰岛素与胰岛素受体结合后信号转导缺失。 [0002] Type II diabetes mellitus is a common metabolic disorder that is characterized by an outer periphery of the membrane Insulin resistance effect produced at the molecular level showed absence of binding the signal transduction of insulin to the insulin receptor. 蛋白酶氨酸的磷酸化水平是细胞内信号转导的重要调节因素,它由蛋白酶氨酸激酶(protein tyrosine kinase,PTK) 和蛋白酶氨酸磷酸酶(protein tyrosine phosphatase,PTP)共同调控。 Phosphorylation levels of acid protease is an important regulator of intracellular signal transduction of tyrosine kinases consisting of a protease (protein tyrosine kinase, PTK) acid phosphatase and protease (protein tyrosine phosphatase, PTP) co-regulation. 近年研究发现,蛋白酶氨酸磷酸酶IB可以去磷酸化蛋白酶氨酸,在胰岛素信号转导通路中起着重要的负调控作用。 Recent studies have found that proteases can threonine phosphatases dephosphorylate IB acid protease, plays an important role in the negative regulation of insulin signal transduction pathway. 敲除PTPIB基因,或运用反义核昔酸(ASO)抑制体内PTPlB蛋白及mRNA的表达,不仅可以显著提高受试小鼠对胰岛素的敏感性,而且能明显降低肥胖症的患病几率。 PTPIB gene knockout, or the use of antisense nucleic acid Xi (ASO) PTPlB inhibition of in vivo expression of protein and mRNA, not only can significantly improve the insulin sensitivity of the test mice, and significantly reduced disease risk of obesity. 这些研究表明,PTPlB有可能成为治疗II型糖尿病的新靶点。 These studies show that, PTPlB may become a new target for the treatment of type II diabetes.

[0003] 本发明公开了一种结构新颖的含烟酸酰胺结构的PTPlB抑制剂,这些化合物可用于制备治疗II型糖尿病的药物。 [0003] The present invention discloses a novel structure PTPlB inhibitor containing nicotinic acid amide structure, these compounds may be used medicament for the treatment of type II diabetes.

发明内容 SUMMARY

[0004] 本发明的一个目的是提供一种具有式I的良好活性的PTPlB抑制剂。 [0004] An object of the present invention is to provide a good activity having Formula I PTPlB inhibitors.

[0005] 本发明的另一个目的是提供制备具有式I的化合物的方法。 [0005] Another object of the present invention is to provide a compound of formula I prepared by the process.

[0006] 本发明的再一个目的是提供含有式I的化合物作为有效成分在治疗II型糖尿病方面的应用。 [0006] A further object of the present invention is the use to provide a compound of formula I as an active ingredient in the treatment of Type II diabetes.

[0007] 现结合本发明的目的对本发明内容进行具体描述。 [0007] The object of the present invention are combined with the content of the present invention will be specifically described.

[0008] 本发明具有式I的化合物具有下述结构式: [0008] The compounds of formula I of the present invention has the following structural formula:

Figure CN106831559AD00031

[0010] 本发明所述式I化合物通过以下路线合成: [0010] The compounds of formula I of the present invention is synthesized by the following scheme:

Figure CN106831559AD00041

[0012] 化合物II在碱存在下与化合物III发生取代反应,得到化合物IV;化合物IV在DCC (N,N二环己基碳化二亚胺)存在下与化合物V反应,得到VI;化合物VI被氧化剂氧化,得到化合物I。 [0012] Compound II with a compound in the presence of a base substitution reaction III, to give compound IV occurs; Compound IV in DCC (N, N-dicyclohexyl carbodiimide) reaction of compound V with the presence, to give VI; oxidizing agent is Compound VI oxidized, to give compound I. 化合物Π可以按照文献方法制备(Leon Katz; et al, Journal of Organic Chemistry,1954,19,711)。 Π compounds may be prepared (Leon Katz; et al, Journal of Organic Chemistry, 1954,19,711) according to literature methods.

[0013] 本发明所述式I化合物具有PTPlB的抑制作用,可作为有效成分用于制备II型糖尿病治疗药物。 [0013] The inhibitory effects of compounds of Formula I of the present invention has PTPlB, Type II diabetes can be used to prepare the therapeutic agent as an active ingredient. 本发明所述式I化合物的活性是通过受体结合试验来验证的。 Activity of the compounds of formula I of the present invention is verified by the receptor binding assay.

[0014] 本发明的式I化合物在相当宽的剂量范围内是有效的。 [0014] The compounds of formula I of the present invention over a wide dosage range is effective. 例如每天服用的剂量约在Img-IOOOmg/人范围内,分为一次或数次给药。 For example, administered in a daily dose of about Img-IOOOmg / person range, once or several times divided doses. 实际服用本发明式I化合物的剂量可由医生根据有关的情况来决定。 The actual administration of the compound of the present invention of formula I dose determined by a physician under the relevant circumstances.

具体实施方式 Detailed ways

[0015] 下面结合实施例对本发明作进一步的说明。 [0015] The following embodiments in conjunction with embodiments of the present invention will be further described. 需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。 Incidentally, the following examples are only for illustration, and are not intended to limit the present invention. 本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。 Skilled in the art that various changes in accordance with the teachings of the present invention shall be made within the scope of the claims in the present application claims.

[0016] 实施例1化合物I的合成 Synthesis of compound of Example 1 I [0016] Embodiment

Figure CN106831559AD00042

[0018] A.化合物IV-I的合成 [0018] A. Synthesis of Compound IV-I

[0019] 化合物11 (1 · 55g,IOmmol)、化合物111-I (1 · 96g,1 Ommol)和固体K2CO3 (5 · 53g, 40mmol)加入30mL干燥的DMF中,室温下搅拌过夜,TLC跟踪发现反应完成。 [0019] Compound 11 (1 · 55g, IOmmol), compound 111-I (1 · 96g, 1 Ommol) and solid K2CO3 (5 · 53g, 40mmol) was added 30mL of dry DMF, stirred at room temperature overnight, TLC tracking found The reaction was complete. 反应混合物倾倒入200mL冰水中,搅拌,用浓盐酸调节pH=4-5,用CH2Cl2 (60mL X 3)萃取,合并萃取相,用盐水洗涤,无水硫酸钠干燥。 The reaction mixture was poured into 200mL of ice water, stirred, adjusted with concentrated hydrochloric acid, pH = 4-5, and extracted with CH2Cl2 (60mL X 3), combined extracts were washed with brine, dried over anhydrous sodium sulfate. 抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,得到的残余物使用柱层析纯化,得到化合物IV-I,白色固体。 Filtered to remove the drying agent, the filtrate was evaporated to dryness on a rotary evaporator, the resulting residue was purified by column to afford Compound IV-I, as a white solid. ESI-MS,m/z = 269 ([MH]-)。 ESI-MS, m / z = 269 ([MH] -).

[0020] B ·化合物VI-I的合成 [0020] B · Synthesis of Compound VI-I

[0021] 化合物IV-I (1.35g,5mmol)、化合物VI (0.43g,5mmol)、DCC(1.24g,6mmolWP4-: 甲氨基吡啶(DMAP,0.3g)溶于干燥的20mL THF中,室温下搅拌过夜,TLC跟踪发现反应完成。 反应混合物倾倒入200mL冰水中,搅拌,用CH2Cl2 (60mL X 3)萃取,合并萃取相,依次用2%稀盐酸和盐水洗涤,无水硫酸钠干燥。抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,得到的残余物使用柱层析纯化,得到化合物VI-I,白色固体。ESI-MS,m/z = 338 ([M+H] +)。 [0021] Compound IV-I (1.35g, 5mmol), compound VI (0.43g, 5mmol), DCC (1.24g, 6mmolWP4-: dimethylaminopyridine (DMAP, 0.3g) was dissolved in dry 20mL THF at room temperature was stirred overnight, TLC tracking reaction was complete. the reaction mixture was poured into 200mL of ice water, stirred, and extracted with CH2Cl2 (60mL X 3), combined extract phase, then washed with 2% hydrochloric acid and brine, dried over anhydrous sodium sulfate. filtered off with suction the desiccant was removed, the filtrate was evaporated to dryness on a rotary evaporator, the resulting residue was purified by column to give compound VI-I, as a white solid .ESI-MS, m / z = 338 ([m + H] +).

[0022] C.化合物I的合成 [0022] C. Synthesis of Compound I

[0023] 化合物VI-I (0.67g,2mmol)溶于IOmL CH2CI2中,室温下搅拌,加入间氯过氧苯甲酸(mCPBA,1.72g,IOmmol),反应混合物在室温下搅拌1小时,而后升温回流3小时,TLC检测反应完成。 [0023] Compound VI-I (0.67g, 2mmol) was dissolved in IOmL CH2CI2 and stirred at room temperature m-chloroperoxybenzoic acid (mCPBA, 1.72g, IOmmol), the reaction mixture was stirred at room temperature for 1 hour, then heated refluxed for 3 h, TLC the reaction was complete. 反应混合物倾倒入200mL冰水中,搅拌,用CH2Cl2 (60mL X 3)萃取,合并萃取相,依次用饱和NaHCO3溶液和盐水洗涤,无水硫酸钠干燥。 The reaction mixture was poured into 200mL of ice water, stirred, and extracted with CH2Cl2 (60mL X 3), combined extracts were washed with saturated NaHCO3 solution and brine successively, dried over anhydrous sodium sulfate. 抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,得到的残余物使用柱层析纯化,得到化合物I,白色固体。 Filtered to remove the drying agent, the filtrate was evaporated to dryness on a rotary evaporator, the resulting residue was purified using column chromatography to give compound I, as a white solid. ESI-MS,m/z = 386 ([M+H] +)。 ESI-MS, m / z = 386 ([M + H] +).

[0024] 实施例2参比化合物RI的合成 Reference Example 2 Synthesis of Compound RI [0024] Embodiment

[0025] 为了进一步比较本发明的药理效果,申请人在本申请中记载了同为申请人发明的未知化合物RI (尚未公开)。 [0025] In order to further compare the pharmacological effects of the present invention, the Applicant describes a known compound of the invention RI same applicant (not yet published) in the present application.

Figure CN106831559AD00051

[0027] A.化合物IV-2的合成 Synthesis [0027] A. Compound IV-2 of

[0028] 化合物II (1.55g,10mmol)、化合物III-2 (1.71g,10mmol)和固体K2⑶3 (5.53g, 40mmol)加入30mL干燥的DMF中,室温下搅拌过夜,TLC跟踪发现反应完成。 [0028] Compound II (1.55g, 10mmol), compound III-2 (1.71g, 10mmol) and solid K2⑶3 (5.53g, 40mmol) was added 30mL of dry DMF, stirred at room temperature overnight, TLC tracking reaction was complete. 反应混合物倾倒入200mL冰水中,搅拌,用浓盐酸调节pH=4-5,用CH2Cl2 (60mL X 3)萃取,合并萃取相,用盐水洗涤,无水硫酸钠干燥。 The reaction mixture was poured into 200mL of ice water, stirred, adjusted with concentrated hydrochloric acid, pH = 4-5, and extracted with CH2Cl2 (60mL X 3), combined extracts were washed with brine, dried over anhydrous sodium sulfate. 抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,得到的残余物使用柱层析纯化,得到化合物IV-2,白色固体。 Filtered to remove the drying agent, the filtrate was evaporated to dryness on a rotary evaporator, the resulting residue was purified using column chromatography, to give compound IV-2, as a white solid. ES I -MS,m/z = 244 ([MH]-)。 ES I -MS, m / z = 244 ([MH] -).

[0029] B.化合物VI-2的合成 Synthesis [0029] B. Compound VI-2 of

[0030] 化合物1¥-2(1.238,5111111〇1)、化合物¥-1(0.438,5111111〇1)、00:(1.248,6111111〇1)和4-二甲氨基吡啶(DMAP,0.3g)溶于干燥的20mL THF中,室温下搅拌过夜,TLC跟踪发现反应完成。 [0030] Compound 1 ¥ -2 (1.238,5111111〇1), compound ¥ -1 (0.438,5111111〇1), 00: (1.248,6111111〇1) and 4-dimethylaminopyridine (DMAP, 0.3g) in dry 20mL THF and stirred at room temperature overnight, TLC tracking reaction was complete. 反应混合物倾倒入200mL冰水中,搅拌,用CH2Cl2 (60mL X 3)萃取,合并萃取相,依次用2%稀盐酸和盐水洗涤,无水硫酸钠干燥。 The reaction mixture was poured into 200mL of ice water, stirred, and extracted with CH2Cl2 (60mL X 3), combined extract phases were washed with 2% hydrochloric acid and brine successively, dried over anhydrous sodium sulfate. 抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,得到的残余物使用柱层析纯化,得到化合物VI-2,白色固体。 Filtered to remove the drying agent, the filtrate was evaporated to dryness on a rotary evaporator, the resulting residue was purified using column chromatography, to give compound VI-2, as a white solid. ESI-MS,m/z = 313 ([M+H] +)。 ESI-MS, m / z = 313 ([M + H] +).

[0031] C.化合物RI的合成 [0031] C. Synthesis of Compound RI

[0032] 化合物VI-2 (0.62g,2mmol)溶于IOmL CH2CI2中,室温下搅拌,加入间氯过氧苯甲酸(mCPBA,1.72g,IOmmol),反应混合物在室温下搅拌1小时,而后升温回流3小时,TLC检测反应完成。 [0032] Compound VI-2 (0.62g, 2mmol) was dissolved in IOmL CH2CI2 and stirred at room temperature m-chloroperoxybenzoic acid (mCPBA, 1.72g, IOmmol), the reaction mixture was stirred at room temperature for 1 hour, then heated refluxed for 3 h, TLC the reaction was complete. 反应混合物倾倒入200mL冰水中,搅拌,用CH2Cl2 (60mL X 3)萃取,合并萃取相,依次用饱和NaHCO3溶液和盐水洗涤,无水硫酸钠干燥。 The reaction mixture was poured into 200mL of ice water, stirred, and extracted with CH2Cl2 (60mL X 3), combined extracts were washed with saturated NaHCO3 solution and brine successively, dried over anhydrous sodium sulfate. 抽滤除去干燥剂,滤液在旋转蒸发仪上蒸干,得到的残余物使用柱层析纯化,得到化合物R-1,白色固体。 Filtered to remove the drying agent, the filtrate was evaporated to dryness on a rotary evaporator, the resulting residue was purified using column chromatography, to give compound R-1, as a white solid. ESI-MS,m/z = 361 ([M+H] +)。 ESI-MS, m / z = 361 ([M + H] +).

[0033] 实施例3化合物体外对PTPlB的抑制试验 [0033] Example 3 In vitro inhibition test compounds embodiment of PTPlB

[0034] 将原始浓度为50mM的化合物溶液用95 %DMS0进行1/2梯度稀释,共稀释11个浓度梯度。 [0034] 1/2 of the original concentration gradient of 50mM compound solution is diluted with 95% DMS0, 11 concentrations were diluted gradient. 酶活反应体系共计102yL,其中化合物加入体积为2yL。 Enzyme reaction system totaled 102yL, wherein the compound is added to a volume of 2yL. 首先,在96孔板中依次加入50μ L PTPlB蛋白,2yL不同浓度的待测化合物,震荡lmin,30°C孵育30min,然后加入50yL ρΝΡΡ (对硝基苯磷酸盐),震荡IOs。 First, 96-well plate were successively added 50μ L PTPlB proteins, various concentrations of test compound 2yL shock lmin, 30 ° C incubated for 30min, then added 50yL ρΝΡΡ, shock IOs (p-nitrophenyl phosphate). 测定405nm波长下吸光度随反应时间的变化,6秒测一次,测60 个点,平行测定三次,并绘制出反应过程曲线,从而计算不同浓度下各个化合物对酶的抑制活性,利用软件GraphPad Prism 5软件进行非线性拟合分析,以剩余活性值为纵坐标,化合物浓度对数值为横坐标绘制曲线,计算该化合物的IC50值。 Measuring the absorbance against reaction time at 405nm wavelength, six seconds measuring time, measuring 60 points, parallel measured three times, and the drawn reaction curve, thereby calculating the inhibitory activity of each compound at various concentrations of the enzyme, using the software GraphPad Prism 5 nonlinear fitting analysis software, the residual activity to the ordinate value, the concentration of the compound plotted as abscissa values, calculated IC50 values ​​of the compounds.

[0035] 测试结果见下表。 [0035] The test results in the table below.

Figure CN106831559AD00061

[0037] 从上表结果可以看出,本发明的化合物对PTPlB具有很强的抑制作用,可以作为制备治疗II型糖尿病的的药物。 [0037] The results can be seen from the table, the compounds of the present invention have a strong inhibitory effect PTPlB, can be used as medicament for the treatment of type II diabetes.

Claims (2)

1. 一种式I结构的化合物, CLAIMS 1. A compound of structural formula I,
Figure CN106831559AC00021
(!)。 (!).
2. 权利要求1之一所述式I化合物在制备治疗2型糖尿病药物方面的应用。 A compound of formula I one aspect of the application type 2 diabetes drug preparation in treatment claim.
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CN101484440A (en) * 2006-07-06 2009-07-15 艾尼纳制药公司 Modulators of metabolism and the treatment of disorders related thereto

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WO2002018321A2 (en) * 2000-08-29 2002-03-07 Abbott Laboratories Amino(oxo)acetic acid protein tyrosine phosphatase inhibitors
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