CN105503873B - As the method for preparing one kind of compound dipeptidyl peptidase 4 inhibitor is - Google Patents

As the method for preparing one kind of compound dipeptidyl peptidase 4 inhibitor is Download PDF

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CN105503873B
CN105503873B CN201510891107.4A CN201510891107A CN105503873B CN 105503873 B CN105503873 B CN 105503873B CN 201510891107 A CN201510891107 A CN 201510891107A CN 105503873 B CN105503873 B CN 105503873B
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邵鸿鸣
何人宝
王莺妹
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浙江永太科技股份有限公司
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

本发明涉及一种作为二肽基肽酶‑4(DPP‑IV)抑制剂的双胍衍生物的制备方法,所述的双胍衍生物可用于治疗可因抑制DPP‑IV活性而受益的所有症状或病症,例如I型和II型糖尿病、糖尿病并发症及其它相关疾病。 The present invention relates to a dipeptidyl peptidase -4 (DPP-IV) inhibitor, biguanide preparation of derivatives, the biguanide derivative useful for treating all of the symptoms may be due to inhibiting DPP-IV activity or benefit disorders, such as type I and type II diabetes, complications of diabetes and other related diseases.

Description

一种作为二肽基肽酶-4抑制剂的化合物的制备方法 As the method for preparing one kind of compound dipeptidyl peptidase 4 inhibitor is

[0001] 本申请为申请号为201410829322.7的发明专利申请的分案申请,原申请的申请日为2014年12月26日,公开号为CN104592234 A,公开日为2015年05月06日,发明名称为"一种作为二肽基肽酶-4抑制剂的化合物的制备方法"。 [0001] This application is a Patent Application No. divisional patent application of the invention 201,410,829,322.7, the filing date of the original application for the December 26, 2014, Publication No. CN104592234 A, publication date May 6, 2015, entitled It is "as a method for preparing a compound of dipeptidyl peptidase-4 inhibitors of."

技术领域 FIELD

[0002] 本发明涉及一种作为二肽基肽酶-4抑制剂的化合物的制备方法,所述化合物可用于治疗可因抑制DPP-IV活性而受益的所有症状或病症,例如I型和II型糖尿病、糖尿病并发症等。 [0002] The present invention relates to a dipeptidyl peptidase -4 preparation of compounds of inhibitors, all compounds are useful for treating symptoms or disorders may be due to inhibiting DPP-IV activity benefit, e.g., type I and II diabetes, diabetes complications.

背景技术 Background technique

[0003] 二肽基肽酶-4 (DPP-4)是一种高特异性丝氨酸蛋白酶,它的天然底物是胰高血糖素样肽1 (GLP-1)和葡萄糖促胰岛素多肽(GIP) ALP-1具有多种生理功能,在胰腺可增加葡萄糖依赖的胰岛素分泌、抑制高血糖素的分泌,使胰岛D细胞增生;在胃肠道可延缓餐后胃排空,从而延缓肠道葡萄糖吸收。 [0003] Dipeptidyl peptidase -4 (DPP-4) is a highly specific serine protease, its natural substrates are glucagon-like peptide 1 (GLP-1) and glucose insulinotropic polypeptide (GIP) ALP-1 has a variety of physiological functions, glucose-dependent increase in pancreatic insulin secretion, inhibiting glucagon secretion, islet cell proliferation D; in the gastrointestinal tract can delay postprandial gastric emptying, thereby delaying the intestinal absorption of glucose . GIP具有促胰岛素分泌功能。 GIP has insulin secretion. DPP-4能快速降解体内的GLP-1和GIP,使之失活。 DPP-4 is rapidly degraded in vivo GLP-1 and GIP, so inactivated. 健康人体内的GLP-1主要由回肠和结肠的L细胞分泌,在人体内的基础浓度大约为5~10pm 〇l/L,餐后浓度可升高2~3倍。 Healthy human GLP-1 is secreted primarily from the ileum and colon L cells, based on the concentration of the human body is about 5 ~ 10pm 〇l / L, postprandial concentrations can be increased 2-3 times. 其生物活性半衰期仅有大约2分钟。 Only biological activity half-life of about 2 minutes. DPP-4 抑制剂通过竞争性结合DPP-4活化部位,降低酶的催化活性,从而抑制GLP-1和GIP的降解。 DPP-4 inhibitor by competitive binding DPP-4 active site, reducing the catalytic activity of the enzyme, thereby inhibiting the degradation of GLP-1 and GIP.

[0004] DPP-4广泛存在于血浆、胃肠道、肾脏、淋巴结和结缔组织等体内组织中,其中肾脏最多。 [0004] DPP-4 in plasma is widely present in the body tissue, gastrointestinal tract, kidney, lymph nodes and connective tissue, and the like, wherein the kidney, respectively. 其家族成员包括DPP-1、DPP-2、DPP-3、DPP-4、DPP-8、DPP-9和成纤维细胞活化蛋白-α (FAP)。 Which family members include DPP-1, DPP-2, DPP-3, DPP-4, DPP-8, DPP-9 and fibroblast activation protein -α (FAP). DPP-4的分子量为220kD,活性体为二聚体形式,每个亚单位包含两个结构域,控制底物的出入口位于两个结构域之间的一个大小为30~45A的大型洞穴,其内的袋状结构便是DPP-4的活性部位,凡是结构的N端第二位上是脯氨酸(Pro)或丙氨酸(Ala)的多肽都是DPP-4发挥活性的主要底物。 DPP-4 is a molecular weight of 220kD, active substance dimeric form, each subunit contains two domains, a control gate size of a substrate is positioned between the two domains for large cave 30 ~ 45A, the bag-like structure within the active site is the DPP-4, all of the N-terminal proline (Pro) or alanine (Ala) DPP-4 polypeptide are mainly for activity on the second substrate .

[0005] 由于体内DPP-4的迅速降解作用,GLP-1在体内半衰期很短(<2min),研究发现当DPP-4活性被抑制后GLP-1的作用时间便有效延长,从而发挥降低血糖水平作用。 [0005] Due to rapid degradation in vivo DPP-4 is, GLP-1 is very short in vivo half-life (<2min), found that when GLP-1 treatment time will prolong the DPP-4 activity is inhibited, and thus act to lower blood sugar level role. DPP-4抑制剂作用机理便是基于其结构与天然底物相似,含有Xaa-Pro类似结构,能够竞争性结合DPP-4活性部位,而且亲和力远大于天然底物,因而改变了DPP-4的构象,降低催化活性。 DPP-4 inhibitor mechanism of action is based on its structure and composition similar to the natural substrate, comprising Xaa-Pro similar structure, competitively binding site of DPP-4 activity, and much greater than the affinity of the natural substrate, thereby altering the DPP-4 conformation, reduction in catalytic activity. 实验证明DPP-4抑制剂可在24h内可逆性地抑制大约90 %的DPP-4酶活性。 Experiments show that DPP-4 inhibitor can be reversible inhibition of about 90% of DPP-4 activity within 24h. 因而DPP-4抑制剂能够通过提高体内GLP-1浓度,延长其降糖作用时间,并且抑制胰高血糖素分泌,延长GLP-1对胰岛素分泌的刺激持续时间。 Thus DPP-4 inhibitors are able to increase the in vivo concentration of hormone secretion by GLP-1, prolong the time of hypoglycemic effect, and suppress glucagon, prolong the duration of the stimulation of insulin secretion GLP-1. 因为GLP-1对胰岛素分泌的调节作用呈现严格的血糖浓度依赖性, 只有在血糖升高时,GLP-1才会增加胰岛素分泌,所以DPP-4抑制剂不会引起低血糖发生风险。 Since GLP-1 is to regulate insulin secretion exhibit tight glycemic concentration-dependent, and only at elevated glucose, GLP-1 increases insulin secretion will, therefore DPP-4 inhibitor does not cause the risk of hypoglycemia. DPP-4抑制剂独特作用机理和良好的安全性特点,成为了糖尿病新药研究的热点领域。 DPP-4 inhibitor unique mechanism of action and good safety features, has become a hot research diabetes drugs. 研究发现,一些DPP-4抑制剂和二甲双胍联合治疗糖尿病可显著改善血糖水平,并且低血糖、体重增加和其他不良事件风险较低。 The study found that some of the DPP-4 inhibitor and metformin in the treatment of diabetes can significantly improve blood sugar levels, and hypoglycemia, weight gain and lower risk of other adverse events. 但仍然缺乏低血糖、体重增加和其他不良事件风险低的单一化合物。 But still they lack hypoglycemia, weight gain and other adverse events were low-risk single compound.

发明内容 SUMMARY

[0006] 本发明提供一种作为DPP-IV抑制剂的双胍衍生物的制备方法,所述的双胍衍生物可用于预防或者治疗与在DPP-ΐν抑制作用中受益的相关疾病,具有低血糖、体重增加和其他不良事件风险低发生率。 [0006] The present invention provides a method for preparing a biguanide derivative of the DPP-IV inhibitor, a biguanide derivative useful for preventing or treating a benefit in the inhibition of DPP-ΐν related disease, hypoglycaemia, weight gain and other low-risk incidence of adverse events. 具体地,本发明提供制备如下式(I)所示的化合物、其立体异构体,或者其药学上可接受的盐的方法,所述方法包括使式(II)化合物与双氰胺接触以获得式⑴: In particular, the present invention provides compounds represented by (I) preparing the formula, stereoisomers thereof, or a method of a pharmaceutically acceptable salt thereof, which comprises reacting a compound (II) contacting the formula with dicyandiamide of formula ⑴:

Figure CN105503873BD00051

[0008] 其中, [0008] wherein,

[0009] R1代表Ch烷基,所述Ch烷基可被R11或R12-⑶-取代,并且R 11代表C6-1Q芳基、喹啉基、异喹啉基、喹唑啉基、噌啉基或吲哚基,R 12代表二(&-6烷基)氨基、吡咯烷-1-基、哌啶-1-基或C6- 1Q芳基; [0009] Representative Rl Ch alkyl, said alkyl group may be substituted Ch R11 or R12-⑶-, and represent an aryl group R 11 C6-1Q, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl or indolyl group, R 12 Representing (& -6 alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl or C6- 1Q aryl group;

[0010] R2代表烷基或C6-1Q芳基; [0010] R2 represents an alkyl group or aryl C6-1Q;

[0011] R3代表苄基、C2-8烯基、C2-8炔基或C3-8环烯基甲基,其中苄基中的苯环可被1个或多个卤素或氰基取代; [0011] R3 represents a benzyl group, a C2-8 alkenyl group, a C2-8 alkynyl group or a C3-8 cycloalkenyl group, a benzyl group wherein the phenyl ring may be substituted with one or more halogen or cyano;

[0012] R4代表Ci-8烷基、C3-8环烷基、C3-8元杂环烷基、C6-1Q芳基或C 5-1Q元杂芳基; [0012] R4 Representative Ci-8 alkyl, C3-8 cycloalkyl, C3-8 membered heterocycloalkyl, C6-1Q C 5-1Q-membered aryl or heteroaryl;

[0013] R5代表氢或者氨基保护基。 [0013] R5 represents hydrogen or an amino protective group.

[00M] 其中,所述的氨基保护基是本领域公知的,包括但不限于甲氧羰基、乙氧羰基、叔丁氧基羰基、苄氧羰基、2-联苯基-2-丙氧羰基(BPoc)、对甲苯磺酰基(Tosyl)、三氟乙酰基、 笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、邻苯二甲酰基(Pht)、 对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、邻或对硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、苄基等。 [00M] wherein the amino protecting groups are well known in the art, including, but not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl group, benzyloxycarbonyl group, 2-biphenyl-2-propoxycarbonyl (Bpoc), p-toluenesulfonyl (tosyl), trifluoroacetyl, Wat methoxycarbonyl (Fmoc), allyloxycarbonyl group (of Alloc), trimethylsilyl ethoxycarbonyl (Teoc), phthaloyl ( PHT), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa of the), o- or p-nitrobenzenesulfonyl (Ns of), pivaloyl, benzoyl, trityl (Trt), 2,4 - dimethoxybenzyl (Dmb), p-methoxybenzyl group (PMB), a benzyl group and the like.

[0015] 当式(II)中R5代表氨基保护基时,在与双氰胺接触前需要事先将所述的氨基保护基脱除。 [0015] When the formula (II) wherein R5 represents an amino protecting group, prior to contact with dicyandiamide require prior to removal of the amino protecting group.

[0016] 在一个优选实施方案中,R1代表二甲氨基羰基甲基、吡咯烷-1-基羰基甲基、苯基羰基甲基、苄基、喹啉基甲基、异喹啉基甲基、喹唑啉基甲基或噌啉基甲基。 [0016] In a preferred embodiment, R1 represents dimethylaminocarbonyl-methyl, pyrrolidin-1-ylcarbonyl group, a phenylcarbonyl group, a benzyl group, quinolinyl group, isoquinolinyl-methyl , quinazolinyl or cinnolinyl methyl methyl.

[0017] 在另一个优选实施方案中,R2代表甲基、异丙基或苯基。 [0017] In another preferred embodiment, R2 represents methyl, isopropyl or phenyl.

[0018] 在另一个优选实施方案中,R3代表2-甲基-2-丙烯-1-基、2-丁烯-1-基、2,3_二甲基_2_丁稀-1-基、2_丁块-1-基、1_环戊稀-1-基甲基、1_环己稀-1-基甲基、苄基、2_氛基节基、2,6_二氰基苄基。 [0018] In another preferred embodiment, R3 represents 2-methyl-2-propen-1-yl, 2-buten-1-yl, but-2,3_ dimethyl _2_ dilute -1- yl, but-block 2_ 1-yl, cyclopentyl dilute 1_ 1-ylmethyl, 1_ cyclohexene-1-ylmethyl, benzyl, 2_ group atmosphere base section, two 2,6_ cyanobenzyl group.

[0019] 在另一个优选实施方案中,R4代表正丁基、环己基、苯基、哌啶基或吡啶基。 [0019] In another preferred embodiment, R4 represents n-butyl, cyclohexyl, phenyl, piperidyl or pyridyl.

[0020] 在一个实施方案中,包括使式(III)化合物与式(IV)化合物接触的步骤,以获得R5 代表氨基保护基的式(II)化合物: [0020] In one embodiment, the step comprising reacting the compound of formula (III) and formula (IV) compound in contact, to obtain R5 of formula (II) represents an amino-protecting group of compounds:

Figure CN105503873BD00061

[0022] 其中当需要时为了获得R5代表氢的式(II)化合物,可选地将氨基保护基Pr 1脱除。 [0022] wherein when, in order to obtain (II) compound of formula R5 represents hydrogen, optionally the removal of amino protecting groups Pr 1 when needed.

[0023] 其中式(IV)化合物可由3-氨基哌啶(式(V)化合物)依次经不同的氨基保护基Pr1、 Pr2保护,然后引入R4基团,再选择性脱除Pr2保护基而制得: Compound [0023] wherein formula (IV) may be 3-amino-piperidine (Formula (V) compound) sequentially via different amino-protecting group Pr1, Pr2 is protected, then introducing R4 groups, and then selectively removing the protecting group Pr2 prepared too:

Figure CN105503873BD00062

[0025] 其中Pr1和Pr2代表氨基保护基。 [0025] wherein Pr1 and Pr2 represents an amino protective group. 本文所述的氨基保护基是本领域公知的那些,包括但不限于甲氧羰基、乙氧羰基、叔丁氧基羰基、苄氧羰基、2-联苯基-2-丙氧羰基(BPoc)、对甲苯磺酰基(Tosyl)、三氟乙酰基、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、邻或对硝基苯磺酰基(Ns)、特戊酰基、苯甲酰基、三苯甲基(Trt)、2,4_二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)、苄基等。 The amino protecting groups described herein are those well known in the art, including, but not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl group, benzyloxycarbonyl group, 2-biphenyl-2-propoxycarbonyl (Bpoc) , p-toluenesulfonyl (tosyl), trifluoroacetyl, Wat methoxycarbonyl (Fmoc), allyloxycarbonyl group (of Alloc), trimethylsilyl ethoxycarbonyl (Teoc), phthaloyl (of Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa of the), o- or p-nitrobenzenesulfonyl (Ns of), pivaloyl, benzoyl, trityl (Trt), 2,4_ dimethyl methoxybenzyl (Dmb), p-methoxybenzyl group (PMB), a benzyl group and the like.

[0026] 式(III)化合物可由8-卤代黄嘌呤衍生物依次被含R1基团的卤代物和R3基团的卤代物取代而制得: Compound [0026] Formula (III) may be sequentially xanthine derivatives 8-halo substituted haloalkyl group-containing halide R1 and R3 radicals is prepared:

Figure CN105503873BD00063

[0028] 式中各X相同或不同,且代表卤素原子。 The same [0028] wherein each X or different, and represent a halogen atom.

[0029] 本发明化合物的盐包括所有的酸加成盐和所有与碱形成的盐。 [0029] The salts of the compounds of the invention include all acid addition salts and all salts with bases. 特别地,该盐包括水不溶性盐以及水溶性盐。 In particular, the salts include water-insoluble salts and water-soluble salts. 适于本发明的酸加成盐的无机酸包括但不限于盐酸、氢溴酸、磷酸、硫酸等。 Inorganic acids suitable for the present invention, acid addition salts include, but are not limited to, hydrochloric, hydrobromic, phosphoric, sulfuric and the like. 适于本发明的酸加成盐的有机酸包括,例如且不限于,柠檬酸、马来酸、富马酸、 琥珀酸、乳酸、酒石酸、甲磺酸等。 Organic acid addition salts suitable for the present invention include, for example and without limitation, citric acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, methanesulfonic acid and the like. 优选地,本发明的化合物的盐可以是用于式(II)化合物或其立体异构体的游离化合物或它们的盐的分离或纯化的盐。 Preferably, the salts of the compounds of the present invention may be used for the free compound of formula (II) or a stereoisomer thereof, or isolated or purified salts thereof salts. 因此,与无机酸或有机酸形成的盐可包括但不限于盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、乳酸盐、酒石酸盐、甲基磺酸盐、扁桃酸盐等。 Thus, salts with inorganic or organic acids may include but are not limited to, hydrochloride, hydrobromide, phosphate, sulfate, citrate, maleate, fumarate, succinate, lactate , tartrate, methanesulfonate, mandelate and the like.

[0030] 除非特别地指出具体的异构体形式,式(II)化合物的所有异构体形式均预期在本发明内,包括所有区域异构体形式和立体异构体形式,例如所有手性形式、对映异构体形式、非对映异构体形式、外消旋形式、互变异构体形式和所有几何异构体形式。 [0030] Unless specifically stated all isomeric forms of the compounds (II) particularly isomeric forms, are contemplated within the formula of the present invention, including all forms of regioisomers and stereoisomeric forms, e.g. all chiral forms, enantiomeric forms, diastereomeric forms, racemic forms, tautomeric forms and all geometric isomeric forms. 很显然,优选药学上最有效且最无副作用的异构体。 Clearly, the most efficient and most preferably no side effects pharmaceutically isomer.

[0031] 应当理解本发明的化合物含有至少一个、两个或多个经不对称取代的碳原子,且可作为纯非对映异构体或非对映异构体混合物以光学活性形式或外消旋形式被分离。 [0031] It should be appreciated that the compounds of the present invention contain at least one, two or more asymmetrically substituted carbon atoms, and may be a pure diastereomers or diastereomer mixtures of isomers or in optically active form outer racemic forms are separated.

[0032] 本发明涵盖所有可能的立体异构体,尤其是本文提及的非对映异构体和对映异构体,例如以基本上纯形式,以富集形式和/或以任何混合比例的形式,包括外消旋形式,以及其盐。 [0032] The present invention encompasses all the possible stereoisomers, in particular referred to herein diastereomers and enantiomers thereof, for example in substantially pure form, in enriched form and / or in any mixing proportion of forms, including the racemic forms, and salts thereof.

[0033] 一般来说,基本上纯的立体异构体可根据本领域技术人员熟知的合成原理获得, 例如通过相应混合物的分离,通过使用立体化学上纯的起始物料和/或通过立体选择性合成获得。 [0033] In general, substantially pure stereoisomers can be synthesized according to the principles well known to those skilled in the art, for example by separation of corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective of synthesis. 本领域已知如何制备光学活性形式,如通过外消旋形式的拆分或通过例如从光学活性起始物料合成和/或通过使用手性试剂来制备。 It is known in the art how to prepare optically active forms, optically active starting materials synthesis and / or prepared by using chiral reagents such as by resolution of racemic forms or by, for example from.

[0034] 本发明的对映异构体纯的化合物可通过不对称合成例如通过制备和分离适当的非对映异构体的化合物/中间体,和/或通过使用手性反应组分(例如手性试剂、手性催化剂、手性配体、手性合成子、手性砌块等)制备,其中所述非对映异构体的化合物/中间体可通过已知的例如手性色谱分离或从适宜溶剂中分级结晶而分离得到。 [0034] The pure enantiomers of the compounds of the present invention may be prepared by asymmetric synthesis, for example, and appropriate compounds prepared by diastereoisomeric separation of body / intermediate, and / or by using chiral reaction components (e.g. chiral reagents, chiral catalysts, chiral ligands, chiral synthons, chiral blocks, etc.) prepared, wherein the diastereomers of compounds / intermediates by known chiral chromatographic separation e.g. isolated or obtained from a suitable solvent by fractional crystallization.

[0035] 此外,本领域的技术人员知晓如何从相应的外消旋混合物制备对映异构体纯的化合物,例如通过在手性分离柱上色谱分离相应的外消旋化合物;或通过使用适当的拆分试剂拆分外消旋化合物;例如通过外消旋化合物与光学活性的酸或碱形成非对映异构体的盐,随后拆分该盐并从该盐中释放所需的化合物;或通过使用手性助剂衍生该相应的外消旋化合物,随后分离非对映异构体并除去该手性辅助基团;通过外消旋物的动力学拆分(例如通过酶法拆分);通过在适宜条件下从镜像晶体的聚集物对映选择性结晶;或通过在手性助剂存在下从适宜溶剂中分级结晶制备。 [0035] Moreover, those skilled in the art knows how pure enantiomer compound was prepared from the corresponding racemic mixture, for example by chiral separation column chromatographic separation of the corresponding racemic compound; or by using a suitable outer resolving agent resolving a racemic compound; e.g. acid or base racemic compound with an optically active diastereomeric salts formed body, followed by resolution of the salts and release of the desired compound from the salt; or by using a chiral auxiliary derived the corresponding racemic compound, followed by separation of the diastereomers and removal of the chiral auxiliary group; by kinetic resolution of a racemate (e.g. by enzymatic resolution ); under suitable conditions by a mirror crystals from aggregates enantioselective crystallization; or by the presence of a chiral auxiliary from a suitable solvent fractional crystallization was prepared.

[0036] 所得到的式(II)的化合物可分离成其对映异构体和/或非对映异构体。 [0036] The compound of formula (II) thus obtained may be separated into its enantiomers and / or diastereomers pair. 例如,顺式/反式混合物可分离成它们的顺式或反式异构体,且具有至少一个光学活性碳原子的化合物可拆分成它们的对映异构体。 For example, cis / trans mixtures can be separated into their cis or trans isomers, and compounds having at least one optically active carbon atom can be split into their enantiomers.

[0037] 对映异构体优选通过以下方法分离:手性相上的柱分离,或从光学活性溶剂中重结晶,或与光学活性物质尤其是酸和其活化的衍生物或醇反应形成盐或衍生物如酯或酰胺,并分离由此得到的盐或衍生物的非对映异构体混合物,例如基于它们溶解性的差异;同时通过适宜试剂的作用,游离对映体可从纯非对映异构体盐或衍生物中释放。 [0037] The enantiomers are preferably separated by the following method: column separation on chiral phases, from an optically active solvent, or recrystallization, or especially an acid or alcohol derivative thereof and the activated salt formed with an optically active substance or derivatives such as esters or amides, and separation of the diastereomeric mixture of salts or derivatives thus obtained, e.g., based on their differences in solubility; while by the action of a suitable reagent, free from pure diastereomers release of diastereomeric salts or derivatives. 常用的光学活性酸为例如D和L型酒石酸或二苯甲酰酒石酸、二-邻甲苯基酒石酸、苹果酸、扁桃酸、樟脑磺酸、谷氨酸、天冬氨酸或奎尼酸。 Common optically active acids such as the D and L forms of tartaric acid or dibenzoyltartaric acid, di - o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. 光学活性醇可为,例如,⑴或㈠ 薄荷醇和酰胺中的光学活性酰基,例如,可为⑴或(_)薄荷基氧基羰基。 Optically active alcohol may be, for example, (i) ⑴ or optically active menthol and an amide group, for example, or may be ⑴ (_) menthyl oxycarbonyl group.

[0038] 本领域的技术人员应当理解有机化合物或它们的盐可与溶剂分子一同分离或可与它们接触的溶剂、它们反应所在的溶剂、它们从中分离的溶剂(例如,沉淀、结晶、冻干等) 等形成络合物。 [0038] Those skilled in the art will appreciate that an organic compound or a salt thereof can be isolated together with a solvent or solvent molecules can be in contact with them, where they are the reaction solvent, they are isolated from the solvent (e.g., precipitation, crystallization, freeze drying etc.), etc. form a complex. 根据本领域技术人员的认识,例如当以固体形式获得或分离时,本发明的一些化合物可含有可变量或固定量的溶剂(包括水性和/或非水性溶剂)。 The recognized by those skilled in the art, for example, when obtained or isolated in solid form, some of the compounds of the present invention may contain a solvent or a fixed amount (including aqueous and / or non-aqueous solvent) can be variable. 因此,本发明的化合物的溶剂合物(包括水合物、有机溶剂合物和混合的水合物/有机溶剂合物)包括在本发明的范围内。 Thus, solvates of the compounds of the present invention (including hydrates, solvates and organic mixed hydrates / solvates organic) included within the scope of the present invention. 本发明化合物的溶剂合物可包括化学计量的溶剂合物或非化学计量的溶剂合物、紧密结合的溶剂合物或弱结合的溶剂合物,以及同种溶剂合物或异种溶剂合物。 Solvates of the compounds of the present invention can include solvates and solvates of non-stoichiometric stoichiometric solvate or solvate tightly bound weakly bound, and the isotype solvate or solvate dissimilar. 优选地,所用的溶剂为药学可接受的溶剂,例如水和/或低分子量脂肪醇如乙醇等。 Preferably, the solvent used is a pharmaceutically acceptable solvent, such as water and / or low molecular weight aliphatic alcohols such as ethanol and the like. 在一项实施方案中,本发明化合物的溶剂合物可包括,例如,水合物或醇合物,或混合的水合物/醇合物。 In one embodiment, solvates of the compounds of the present invention may comprise, for example, hydrates or alcoholates, or mixed hydrates / alcoholates. 本发明包括未溶剂化形式和所有的溶剂化形式。 The present invention includes all unsolvated forms and solvated forms. 同样地,本发明包括任何溶剂合物、非溶剂合物、水合物、无水物、吸湿性和/或非吸湿性的形式。 Likewise, the present invention includes any solvate, a non-solvate, hydrate, anhydrous, hygroscopic and / or non-hygroscopic form.

[0039] 由于本发明的式(I)化合物、其立体异构体及其盐具有抑制DPP-IV活性和调节血糖水平的能力,其适于治疗可因抑制DPP-IV活性而受益的所有症状或病症。 All symptoms [0039] Since the compounds of formula (I) of the present invention, stereoisomers and salts thereof having the ability to inhibit DPP-IV activity and regulate blood glucose levels, which may be suitable for the treatment by inhibiting DPP-IV activity benefit or condition. 因此,预期根据本发明的化合物将适于预防或治疗的疾病或症状,如I型与II型糖尿病、糖尿病并发症(譬如视网膜病、肾病或神经病)、新陈代谢酸中毒或酮症、反应性低血糖、胰岛素抗药性、代谢综合症、不同来源的脂肪代谢障碍、关节炎、动脉粥样硬化及相关疾病、肥胖、同种移植物移植及降血钙素所引起的骨质疏松症。 Thus, the compounds according to the invention is expected to be suitable for prevention or treatment of diseases or conditions, such as type I and type II diabetes, diabetic complications (such as retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive low blood glucose, insulin resistance, metabolic syndrome, lipodystrophy different origin, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and calcitonin osteoporosis caused. 此外,这些物质也适于预防β-细胞变性,譬如胰β-细胞的细胞凋零或坏死。 In addition, these substances are also suitable for preventing β- cell degeneration, such as pancreatic β- cells dying or necrosis. 该物质也适于改善或恢复胰细胞的功能,以及增加肢细胞的数目与大小。 The substance is also suitable for improving or restoring the function of pancreatic cells, and an increase in the number of cells and size of limb. 此外,且基于因胰高血糖素肽如GLP-1与GLP-2的作用及其与DPP-IV抑制的连结,同样地,根据本发明的化合物适用于达到另外的镇静或焦虑舒解作用,且亦有利地影响手术或激素应力回应后的降解代谢状态,或降低心肌梗塞后的死亡率或发病率。 Moreover, and based on a result of the glucagon peptides such as GLP 1-acting GLP-2 and their link with DPP-IV inhibition, in the same manner, the compounds according to the invention applied to achieve an additional effect of sedation or relieve anxiety, Qieyi favorably affect post-operative catabolic state or hormonal stress responses or to reduce mortality or morbidity after myocardial infarction. 它也适合于治疗与上文所提及的作用有关,且通过GLP-1或GLP-2所引入的全部症状。 It is also suitable for the treatment of effects associated with the above mentioned, and all the symptoms introduced by GLP-1 or GLP-2. 根据本发明的化合物亦可作为利尿剂或抗高血压剂使用,且适用于预防与治疗急性肾衰竭。 It can also be used as a diuretic or antihypertensive agents the compounds according to the invention, and is useful for the prevention and treatment of acute renal failure. 此外,根据本发明的化合物可用于治疗呼吸道炎性疾病。 Furthermore, the compounds according to the invention can be used in the treatment of respiratory inflammatory diseases. 同样它也适于预防与治疗慢性炎性肠疾病,如刺激性肠综合症(IBS)、克隆氏病或溃疡性结肠炎以及胰腺炎。 Likewise, it is also suitable for the prevention and treatment of chronic inflammatory bowel diseases, such as irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis and pancreatitis. 同样地,其可用于胃肠道的所有伤害种类或损害,如结肠炎与肠炎。 Similarly, it may be used for all kind of injury or damage to the gastrointestinal tract, such as colitis and enteritis. 亦预期DPP-IV抑制剂且因此根据本发明的化合物,也可在人类或哺乳动物中用于治疗不孕症或改善生育能力,特別是当不孕症是与胰岛素抗药性或多囊卵巢综合症有关时。 It is also contemplated and thus the DPP-IV inhibitor compounds according to the invention may also be useful in the treatment of infertility or to improve fertility in humans or mammals, particularly when infertility is integrated with insulin resistance or with polycystic ovary when related disease. 另一方面,这些物质是适用于影响精子的能动性,且因此可作为男性避孕药使用。 On the other hand, these substances are applied to affect sperm motility and can therefore be used as a male contraceptive. 另外该物质也适合治疗与矮小有关的生长激素缺乏,且也有利地使用于其中可使用生长激素的任何症状。 In addition, this material is also suitable for the treatment of short stature associated with growth hormone deficiency, and can also be used advantageously for any symptoms which can be used growth hormone. 根据本发明的化合物,基于其对DPP-IV的抑制作用,亦适合治疗各种自身免疫疾病,譬如风湿性关节炎、多发性硬化、甲状腺症及巴塞杜氏病等。 The compounds according to the invention, inhibition of DPP-IV-based, also suitable for the treatment of various autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Basedow disease, thyroid disease and the like. 其亦可用于治疗病毒疾病,以及例如在HIV感染中,刺激血液制造,在良性前列腺增生、牙龈炎中,以及治疗神经元缺陷,与神经变性疾病,譬如阿尔茨海默氏疾病。 Which can be used for the treatment of viral diseases, for example, in HIV infection, and to stimulate blood formation, benign prostate hyperplasia, gingivitis, and treatment of neuronal defects, and neurodegenerative diseases, such as Alzheimer's disease. 所述化合物亦可用于治疗胖瘤,特别是改变肿瘤侵入以及转移;这里的实例为其在治疗T-细胞淋巴瘤、急性淋巴细胞淋巴瘤白血病、以细胞基的甲状腺癌、基底细胞癌或乳腺癌中的用途。 The compounds may also be useful for treating tumors fat, especially tumor invasion and metastasis change; here for example in the treatment of T- cell lymphoma, acute lymphocytic leukemia, lymphoma, thyroid cancer in a cell group, basal cell carcinoma or breast cancer in a mammal. 其他适应症为中风、各种起源的心肌缺血、帕金森氏病及偏头痛。 Other indications are stroke, myocardial ischemia of various origins, Parkinson's disease and migraine. 此外,其他适应症包括毛囊炎与表皮角化过度、增加的角质细胞增生、牛皮癣、脑脊髄炎、肾小球肾炎、脂肪代谢障碍以及所有不同成因的身心学、抑郁及神经性精神病学疾病。 In addition, other indications include folliculitis with epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, cerebral spinal marrow inflammation, glomerulonephritis, lipodystrophy and all the different causes of mental and physical science, depression and neurological psychiatric disorders.

[0040] 本发明的式⑴化合物或其药学上可接受的盐可用作药物,例如以用于肠内、胃肠外或局部给药的药物组合物的形式。 [0040] The present invention ⑴ Formula compound or a pharmaceutically acceptable salt thereof used as medicaments, e.g. in the form for enteral, parenteral or pharmaceutical composition for topical administration. 它们可以本领域可用的任何普遍接受的给药方式给药,例如口服给药,例如以片剂、包衣片剂、糖衣片剂、硬明胶胶囊和软明胶胶囊、溶液、乳剂或混悬液的形式,经直肠给药,例如以栓剂的形式,经胃肠外(包括经静脉)给药,例如以注射溶液或输注溶液的形式,或局部给药,例如以软膏剂、乳膏剂或油的形式。 They can be administered in any mode of administration available in the art generally accepted, for example oral administration, such as tablets, coated tablets, sugar-coated tablets, hard gelatine capsules and soft gelatine capsules, solutions, emulsions or suspensions form, rectally, e.g. in the form of suppositories, parenterally (including intravenous) administration, for example in the form of injection solutions or infusion solutions, or topically, for example, ointments, creams or in the form of oil. 在可能的给药方式中,优选口服和静脉递送。 In a possible mode of administration, preferably oral and intravenous delivery.

[0041] 本发明的药物组合物通常可含有总量为从约0.05至80重量%或从约0.1至50重量%的至少一种本发明的式(I)化合物,任选地和药学上可接受的载体和/或赋形剂。 [0041] The pharmaceutical compositions of the invention may typically contain from total amount of formula (I) from about 0.05 to 80 wt%, or from about 0.1 to 50 wt% of at least one compound of the present invention, and optionally pharmaceutically acceptable carriers and / or excipients.

[0042] 除一种或多种赋形剂外,包含于本发明的剂型或药物组合物中的本发明式(I)化合物或其互变异构体或盐的量,可以为至少0.1 %至0.5%,或至少0.5%至1.5%,或至少1% 至3%〇 [0042] In addition to one or more excipients, contained in an amount or a tautomer thereof or a salt of a compound of the dosage form or pharmaceutical composition of the present invention of formula (I) present, it may be at least 0.1% to 0.5%, or at least 0.5% to 1.5%, or at least 1-3% billion

[0043] 本领域的技术人员基于他/她的专业知识熟悉药学可接受的赋形剂,如稀释剂、载体、粘合剂、崩解剂、表面活性剂、润滑剂、载体、助剂、佐剂和/或,其它已知适于制备药物组合物的添加剂。 [0043] Those skilled in the art based on his / her expert knowledge familiar with pharmaceutically acceptable excipients, such as diluents, carriers, binders, disintegrators, surfactants, lubricants, carriers, adjuvants, adjuvants and / or other known pharmaceutical compositions suitable for the preparation of additives.

[0044] 作为药学可接受的赋形剂,通常已知适于药物组合物的任何赋形剂在考虑之中。 [0044] As pharmaceutically acceptable excipient, any suitable excipient commonly known pharmaceutical compositions under consideration. 其实例包括但不限于,稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、溶剂、分散剂、乳化剂、增溶剂、凝胶形成剂、软膏剂基质、抗氧化剂、防腐剂、稳定剂、载体、增稠剂、络合剂、缓冲剂、pH调节剂(例如,以得到中性、碱性或酸性制剂)、渗透促进剂、聚合物、包衣剂、推进剂、张力调节剂、表面活性剂、着色剂、调味剂、甜味剂和染料。 Examples include, but are not limited to, diluents, fillers, binders, disintegrants, lubricants, glidants, solvents, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants , preservatives, stabilizers, carriers, thickeners, complexing agents, buffers, pH regulators (e.g. to obtain neutral, alkaline or acidic formulations), permeation promoters, polymers, coating agents, to promote agents, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes.

[0045] 通常,适宜的载体材料不仅为无机载体材料,还为有机载体材料。 [0045] Generally, suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. 因此,例如乳糖、 淀粉(如玉米淀粉)或其衍生物、滑石、二氧化硅、聚乙烯吡咯烷酮、硬脂酸或其盐可用作片剂、包衣片剂、糖衣片剂和硬明胶胶囊的载体材料。 Thus, such as lactose, starch (e.g. corn starch) or derivatives thereof, talc, silica, polyvinylpyrrolidone, stearic acid or its salts can be used for tablets, coated tablets, dragees and hard gelatine capsules the carrier material. 用于软明胶胶囊的适宜的载体材料为, 例如植物油、蜡、脂肪以及半固体和液体多元醇。 Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols. 用于溶液和糖浆剂生产的适宜的载体材料为,例如水、多元醇、蔗糖、转化糖等。 Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. 用于注射或输注溶液的适宜的载体材料为,例如水、 醇、多元醇、甘油和植物油。 Suitable carrier materials for injection or infusion solutions, for example, water, alcohols, polyols, glycerol and vegetable oils. 用于栓剂的适宜的载体材料为,例如中性油或硬化油、蜡、脂肪以及半液体或液体多元醇或聚乙二醇。 Suitable carrier materials for suppositories are, for example, neutral oil or hardened oils, waxes, fats and semi-liquid or liquid polyols or polyethylene glycols. 用于局部制剂的适宜的载体材料为甘油酯、半合成和合成的甘油酯、氢化油、液体蜡、液体石蜡、液体脂肪醇、留醇、聚乙二醇和纤维素衍生物。 Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, leaving alcohol, polyethylene glycols and cellulose derivatives.

[0046] 使用适合所需药物组合物、配方或制剂以及所需给药方式的类型的赋形剂、载体和/或稀释剂。 [0046] suitable for the intended use of the pharmaceutical composition, formulation or preparation and the desired type of administration, excipients, carriers and / or diluents.

[0047] 本发明的药物组合物可通过将一种或多种式(I)的化合物或其药学可接受的盐与适宜的赋形剂例如已知的惰性稀释剂、载体、崩解剂、佐剂、表面活性剂、粘合剂和/或润滑剂混合而得到。 The pharmaceutical composition of [0047] the present invention can be prepared by mixing one or more compounds of Formula (I) compound or a pharmaceutically acceptable salt thereof with suitable excipients, for example inert diluents known, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants to obtain mixed. 所述片剂还可由数层构成。 The tablets may also consist of several layers. 本发明的组合物还可含有其它活性物质。 The composition of the present invention may also contain other active substances.

[0048]因此,本发明的组合物可通过本身已知的和本领域技术人员熟悉的方法制备,例如通过将所述的式(I)的化合物或其药学可接受的盐任选地和一种或多种常规的固体或液体载体和/或稀释剂,掺入至常规制剂例如普通片剂或包衣片剂、胶囊、粉末剂、混悬剂或栓剂中制备。 [0048] Thus, preparing a composition of the present invention may be known per se familiar to those skilled in the art and, for example, by reacting a compound of the formula (I) or a pharmaceutically acceptable salt thereof and optionally a one or more conventional solid or liquid carriers and / or diluents to be incorporated into conventional preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories prepared. 所述载体的实例包括但不限于玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、 聚乙烯吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨醇、水/聚乙二醇、聚乙二醇、鲸蜡硬脂醇、羧甲基纤维素或脂肪物质如硬脂或其适宜的混合物。 Examples of carriers include, but are not limited to, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, polyethylene glycol, cetyl stearyl alcohol, such as stearyl or suitable mixtures carboxymethylcellulose or fatty substances.

[0049] 本发明化合物的适宜的稀释剂的实例可包括纤维素粉、磷酸氢钙、赤藓糖醇、低取代的羟基丙基纤维素、甘露糖醇、预胶化淀粉或木糖醇。 [0049] Examples of suitable diluents of the compounds of the present invention may include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.

[0050] 取决于所给予的化合物、所治疗或预防的疾病的性质和严重性、患者的年龄和个体状况和给药方式和频率,本发明化合物的剂量可在宽范围内变化,并且当然符合各具体病例中个体的需求。 [0050] Depending on the compound administered, the nature and severity, the age and the individual condition of the patient and the mode of administration and frequency of treatment or prevention of disease, the dosage of the compound of the present invention may vary within a wide range, and of course in line with each particular case individual needs. 通常,本发明化合物的量考虑DPP-IV抑制剂常用的数量级。 Generally, the amount of the compound of the present invention contemplates conventional DPP-IV inhibitors of magnitude. 当以静脉途径给药时,本发明化合物通常所需的剂量可为O.OOlmg至10mg,或O.Olmg至10mg,或0. lmg至10mg,如0 · 25mg至5mg,而当以口服途径给药时,可为0 · 005mg至100mg,或0 · 05mg至100mg,或0 · 5mg至lOOmg,如2 · 5mg至50mg或0 · 5mg至10mg,优选2 · 5mg至10mg或lmg至5mg,各种情况中一天1至4次给药。 When administered by intravenous route, the dosage typically required of a compound of the present invention may be O.OOlmg to 10mg, or O.Olmg to 10mg, or 0. lmg to 10mg, such as 0 · 25mg to 5mg, when oral route when administered, can be 0 · 005mg to 100mg, or 0 · 05mg to 100mg, or lOOmg to 0 · 5mg, such as 2 · 5mg to 50mg or 0 · 5mg to 10mg, preferably 2 · 5mg to 10mg or lmg to 5mg, in each case administered 1 to 4 times a day. 取决于所述剂量,以若干剂量单位给予日剂量可能是便利的。 Depending on the dose, in several dosage units administered in a daily dose may be convenient. 具体实施例 Specific Example

[0051] 式(III)化合物的制备 Preparation of compounds [0051] Formula (III)

[0052] 8-溴-7-(2-丁炔-i-基)-3-甲基-1-( (4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤(化合物m-ι)的制备 [0052] 8-Bromo-7- (2-butynyl -i- yl) -3-methyl-1- ((4-methyl-quinazolin-2-yl) methyl) -3,7-yellow purine (compound m-ι) of

Figure CN105503873BD00101

[0054] (1) 3-甲基-7-(2-丁炔-1-基)-8-溴-3,7-黄嘌呤的制备 Preparation of 3,7--8- bromo xanthine [0054] (1) 3-methyl-7- (2-butyn-1-yl)

[0055] 将3-甲基-8-溴-黄嘌呤与N-乙基二异丙基胺(DIPEA)的N,N-二甲基甲酰胺溶液混合,加入1-溴-2-丁炔,并于室温下搅拌过夜。 [0055] 3-methyl-8-bromo - xanthine with N- ethyl diisopropylamine (DIPEA) in N, N- dimethylformamide, a mixed solution of 1-bromo-2-butyne and stirred overnight at room temperature. 为进行处理,将反应混合物倒入水中。 For workup, the reaction mixture was poured into water. 将所析出的沉淀物抽滤,以水洗涤,并干燥,得3-甲基-7-(2-丁炔-1-基)-8-溴-黄嘌呤(分子式: C10H9BrN4〇2) 〇 The precipitate was filtered off with suction, washed with water, and dried to give 3-methyl-7- (2-butyn-1-yl) -8-bromo - xanthine (Formula: C10H9BrN4〇2) square

[0056] 质谱(ESI+) :m/z = 298 [M+H] + [0056] Mass spectrum (ESI +): m / z = 298 [M + H] +

[0057] 元素分析:C,40.43;H,3.05;Br,26.89;N,18.86;0,10.77 [0057] Elemental analysis: C, 40.43; H, 3.05; Br, 26.89; N, 18.86; 0,10.77

[0058] (2) 8-溴-7- (2-丁炔-1-基)-3-甲基-1- ((4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤的制备 [0058] (2) 8-Bromo-7- (2-butyn-1-yl) -3-methyl-1- ((4-methyl-quinazolin-2-yl) methyl) -3, 7 - preparation of xanthine

[0059] 将2- (2-溴乙基)-4-甲基喹唑啉添加至3-甲基-7- (2-丁炔-1-基)-8-氯-黄嘌呤与碳酸钾的N,N-二甲基甲酰胺混合溶液中。 [0059] 2- (2-bromoethyl) -4-methyl-quinazoline was added to 3-methyl-7- (2-butyn-1-yl) -8-chloro - xanthine and potassium carbonate of N, N- dimethylformamide mixed solution. 将反应混合物于室温下搅拌8小时。 The reaction mixture was stirred at room temperature for 8 hours. 水溶液处理后,使粗产物经过硅股柱层析纯化,以二氯甲烷/甲醇洗脱,得8-溴-7- (2-丁炔-1-基)-3-甲基-卜((4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤(分子式:C2〇H17BrN 6〇2)。 After aqueous workup, the crude product was purified by column chromatography through silica shares with dichloromethane / methanol to give 8-bromo-7- (2-butyn-1-yl) -3-methyl - Bu (( 4-methyl-quinazolin-2-yl) methyl) -3,7-xanthine (formula: C2〇H17BrN 6〇2).

[0060] 质谱(ESI+) :m/z = 454 [M+H] + [0060] Mass spectrum (ESI +): m / z = 454 [M + H] +

[0061] 元素分析:C,52.99;H,3.78;Br,17.63;N,18.54;0,7.06 [0061] Elemental analysis: C, 52.99; H, 3.78; Br, 17.63; N, 18.54; 0,7.06

[0062] 匪R(d6-DMS0) :8.12 (1H) ,7.84 (1H) ,7.82 (1H) ,7.58 (1H) ,4.42 (4H) ,3.41 (3H),2 · 94 (3H),1 · 80 (3H)。 [0062] bandit R (d6-DMS0): 8.12 (1H), 7.84 (1H), 7.82 (1H), 7.58 (1H), 4.42 (4H), 3.41 (3H), 2 · 94 (3H), 1 · 80 (3H).

[0063] 2. 8-溴-7- (2-氰基苄基)-3-甲基-1-(喹啉-2-基甲基)-3,7_黄嘌呤(化合物III- 2)的制备 [0063] 2. The 8-bromo-7- (2-cyanobenzyl) -3-methyl-1- (quinolin-2-ylmethyl) -3,7_ xanthine (Compound III- 2) preparation

Figure CN105503873BD00102

[0065] (1) 8-溴-7-(2-氰基苄基)-1,3-二甲基-3,7-黄嘌呤的制备 Preparation of 3,7-xanthine [0065] (1) 8-Bromo-7- (2-cyanobenzyl) -1,3-dimethyl-

[0066] 将3-甲基-8-溴-黄嘌呤与N-乙基二异丙基胺(DIPEA)的N,N-二甲基甲酰胺溶液混合,加入2-氰基苄基溴,并于室温下搅拌过夜。 [0066] 3-methyl-8-bromo - xanthine with N- ethyl diisopropylamine (DIPEA) in N, N- dimethylformamide mixture was added 2-cyanobenzyl bromide, and stirred at room temperature overnight. 为进行处理,将反应混合物倒入水中。 For workup, the reaction mixture was poured into water. 将所析出的沉淀物抽滤,以水洗涤,并干燥,得3-甲基-7- (2-氰基苄基)-8-溴-黄嘌呤(分子式: Ci4HioBrN5〇2)。 The precipitate was filtered off with suction, washed with water, and dried to give 3-methyl-7- (2-cyanobenzyl) -8-bromo - xanthine (Formula: Ci4HioBrN5〇2).

[0067] 质谱(ESI+) :m/z = 36 [1M+H] +; [0067] Mass spectrum (ESI +): m / z = 36 [1M + H] +;

[0068] 元素分析:C,46.69;H,2.80;Br,22.19;N,19.44;0,8.88。 [0068] Elemental analysis: C, 46.69; H, 2.80; Br, 22.19; N, 19.44; 0,8.88.

[0069] (2) 8-溴-7-(2-氰基苄基)-3-甲基-1-(喹啉-2-基甲基)-3,7-黄嘌呤的制备 [0069] (2) 8-Bromo-7- (2-cyanobenzyl) (quinolin-2-yl-methyl) -3,7-xanthine -3-methyl-1-

[0070] 将2- (2-溴乙基)_喹啉添加至3-甲基-7- (2-氰基苄基)-8-氯-黄嘌呤与碳酸钾的N,N-二甲基甲酰胺混合溶液中。 [0070] Add 2- (2-bromoethyl) _ to 3-methyl-quinoline-7- (2-cyanobenzyl) -8-chloro - xanthine and potassium carbonate in N, N- dimethyl formamide mixed solution. 将反应混合物于室温下搅拌8小时。 The reaction mixture was stirred at room temperature for 8 hours. 水溶液处理后,使粗产物经过硅股柱层析纯化,以二氯甲烷/甲醇洗脱,得1-(喹啉-2-基甲基)-3-甲基-7-(2-氰基苄基)-8-溴-3,7-黄嘌呤(分子式:GMHnBrNf^)。 After aqueous workup, the crude product was purified by column chromatography through silica shares with dichloromethane / methanol to give 1- (quinolin-2-yl) -3-methyl-7- (2-cyano benzyl) -8-bromo-3,7-xanthine (formula: GMHnBrNf ^).

[0071] 质谱(ESI+) :m/z = 502 [M+H] +; [0071] Mass spectrum (ESI +): m / z = 502 [M + H] +;

[0072] 元素分析:C,57.50;H,3.42;Br,15.94;N,16.76;0,6.38。 [0072] Elemental analysis: C, 57.50; H, 3.42; Br, 15.94; N, 16.76; 0,6.38.

[0073] 匪R(d6-DMS0) :8.07 (1H) ,8.01 (1H) ,7.79 (1H) ,7.64 (1H) ,7.48-7.55 (4H), 7.32 (2H) ,5.47 (2H) ,4.76 (2H) ,3.40 (3H) [0073] bandit R (d6-DMS0): 8.07 (1H), 8.01 (1H), 7.79 (1H), 7.64 (1H), 7.48-7.55 (4H), 7.32 (2H), 5.47 (2H), 4.76 ( 2H), 3.40 (3H)

[0074] 3. 8-溴-7-(1-环己烯基甲基)-3-甲基-1-(二甲氨基羰基甲基)-3,7_黄嘌呤(化合物III-3)的制备 [0074] 3. 8-bromo-7- (1-cyclohexenyl) -3-methyl-1- (dimethylamino carbonyl methyl) -3,7_ xanthine (Compound III-3) preparation

Figure CN105503873BD00111

[0076] (1) 3-甲基-7-(1-环己烯基甲基)-8-溴-黄嘌呤的制备 -8-bromo [0076] (1) 3-Methyl-7- (1-cyclohexenyl-ylmethyl) - Preparation of xanthine

[0077] 将3-甲基-8-溴-黄嘌呤与N-乙基二异丙基胺(DIPEA)的N,N_二甲基甲酰胺溶液混合,加入1-环己烯基甲基溴,并于室温下搅拌过夜。 [0077] 3-methyl-8-bromo - xanthine with N- ethyl diisopropylamine (DIPEA) in N, N_-dimethylformamide mixture was added 1-cyclohexenyl methyl bromine, and stirred overnight at room temperature. 为进行处理,将反应混合物倒入水中。 For workup, the reaction mixture was poured into water. 将所析出的沉淀物抽滤,以水洗涤,并干燥,得3-甲基-7-(1-环己烯基甲基)-8-溴-黄嘌呤(分子式:Ci3Hi5BrN4〇2)。 The precipitate was filtered off with suction, washed with water, and dried to give 3-methyl-7- (1-cyclohexenyl-ylmethyl) -8-bromo - xanthine (Formula: Ci3Hi5BrN4〇2).

[0078] 质谱(ESI+) :m/z = 340 [M+H] +; [0078] Mass spectrum (ESI +): m / z = 340 [M + H] +;

[0079] 元素分析:C,46.03;H,4.46;Br,23.56;N,16.52;0,9.43。 [0079] Elemental analysis: C, 46.03; H, 4.46; Br, 23.56; N, 16.52; 0,9.43.

[0080] (2) 8-溴-7-(1-环己烯基甲基)-3-甲基-1-(二甲氨基羰基甲基)-3,7-黄嘌呤的制鱼 [0080] (2) 8-Bromo-7- (1-cyclohexenyl) -3-methyl-1- (dimethylamino-carbonyl-methyl) -3,7-made fish xanthine

[0081] 将N,N-二甲基-2-溴代乙酰胺添加至3-甲基-7-(1-环己烯基甲基)-8-氯-黄嘌呤与碳酸钾的N,N-二甲基甲酰胺混合溶液中。 [0081] The N, N- dimethyl-2-bromoacetamide was added to 3-methyl-7- (1-cyclohexenyl-ylmethyl) -8-chloro - xanthine and potassium carbonate in N, N- dimethylformamide mixed solution. 将反应混合物于室温下搅拌8小时。 The reaction mixture was stirred at room temperature for 8 hours. 水溶液处理后,使粗产物经过硅股柱层析纯化,以二氯甲烷/甲醇洗脱,得1_(二甲氨基羰基甲基)-3_甲基-7- (1-环己烯基甲基)-8-溴-3,7-黄嘌呤(分子式:&7Η22ΒγΝ5〇3)。 After aqueous workup, the crude product was purified by column chromatography through silica shares with dichloromethane / methanol to give 1_ (dimethylaminocarbonyl-methyl) -3_ methyl-7- (1-cyclohexenyl group A yl) -8-bromo-3,7-xanthine (formula: & 7Η22ΒγΝ5〇3).

[0082] 质谱(ESI+) :m/z = 425 [Μ+Η] +; [0082] Mass spectrum (ESI +): m / z = 425 [Μ + Η] +;

[0083] 元素分析:C,48.12;H,5.23;Br,18.83;N,16.51;0,11.31。 [0083] Elemental analysis: C, 48.12; H, 5.23; Br, 18.83; N, 16.51; 0,11.31.

[0084] 匪R(d6-DMS0) :5.40 (1H) ,4.41 (2H) ,4.29 (2H) ,3.42 (3H) ,2.99 (6H) ,1.95- 1.99 (4H) ,1.75 (2H) ,1.61 (2H)。 [0084] bandit R (d6-DMS0): 5.40 (1H), 4.41 (2H), 4.29 (2H), 3.42 (3H), 2.99 (6H), 1.95- 1.99 (4H), 1.75 (2H), 1.61 ( 2H).

[0085] 4. 1-(吡咯烷-1-基羰基甲基)-3-甲基-7- (2-丁炔-1-基)-8-溴-3,7-黄嘌呤(化合物III-4)的制备 [0085] 4. 1- (pyrrolidin-1-yl-carbonyl) -3-methyl-7- (2-butyn-1-yl) -8-bromo-3,7-xanthine (Compound III -4) preparation

Figure CN105503873BD00121

[0087] 将卜(2-溴代乙酰基)吡咯烷添加至3-甲基-7- (2-丁炔-卜基)-8-氯-黄嘌呤与碳酸钾的N,N-二甲基甲酰胺混合溶液中。 [0087] Add Bu (2-bromoacetyl) pyrrolidine to 3-methyl-7- (2-butynyl - Buji) -8-chloro - xanthine and potassium carbonate in N, N- dimethyl formamide mixed solution. 将反应混合物于室温下搅拌6小时。 The reaction mixture was stirred at room temperature for 6 hours. 水溶液处理后, 使粗产物经过硅股柱层析纯化,以二氯甲烷/甲醇洗脱,得1_(吡咯烷-1-基羰基甲基)-3_甲基-7- (2-丁炔-卜基)-8-溴-3,7-黄嘌呤(分子式:C16H18BrN5〇3)。 After aqueous workup, the crude product was purified by column chromatography through silica shares with dichloromethane / methanol to give 1_ (pyrrolidin-1-yl-carbonyl-methyl) -3_ methyl-7- (2-butyn - Buji) -8-bromo-3,7-xanthine (formula: C16H18BrN5〇3).

[0088] 质谱(ESI+) :m/z = 409 [M+H] +; [0088] Mass spectrum (ESI +): m / z = 409 [M + H] +;

[0089] 元素分析:C,47.07;H,4.44;Br,19.57;N,17.15;0,11.76。 [0089] Elemental analysis: C, 47.07; H, 4.44; Br, 19.57; N, 17.15; 0,11.76.

[0090] 匪R (d6-DMS0) : 4 · 42 (2H),4 · 29 (2H),3 · 42 (3H),3 · 10 (4H),1 · 84 (4H),1 · 80 (3H) 〇 [0090] bandit R (d6-DMS0): 4 · 42 (2H), 4 · 29 (2H), 3 · 42 (3H), 3 · 10 (4H), 1 · 84 (4H), 1 · 80 ( 3H) square

[0091] 5. 8-溴-7-(2-丁炔-1-基)-3-甲基-1-( (4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤(化合物III-5)的制备 [0091] The 8-bromo-7- (2-butyn-1-yl) -3-methyl-1- ((4-methyl-quinazolin-2-yl) methyl) -3,7 - preparation of xanthine (compound III-5) is

Figure CN105503873BD00122

[0093] (1) 3-甲基-7- (2,3-甲基-2-丁烯-1-基)-8-溴-3,7-黄嘌呤的制备 Preparation of 3,7--8- bromo xanthine [0093] (1) 3-Methyl-7- (2,3-methyl-2-buten-1-yl)

[0094] 将3-甲基-8-溴-黄嘌呤与N-乙基二异丙基胺(DIPEA)的N,N-二甲基甲酰胺溶液混合,加入1-溴-2,3-甲基-2-丁烯,并于室温下搅拌过夜。 [0094] 3-methyl-8-bromo - xanthine with N- ethyl diisopropylamine (DIPEA) in N, N- dimethylformamide, a mixed solution of 1-bromo-2,3 methyl-2-butene, and stirred at room temperature overnight. 将反应混合物倒入水中,过滤析出的沉淀物,以水洗涤,并干燥,得3-甲基-7-(2,3_甲基-2-丁烯-1-基)-8-溴-黄嘌呤(分子式:&2Η 15ΒγΝ4〇2)。 The reaction mixture was poured into water and precipitate was filtered, washed with water, and dried to give 3-methyl-7- (2,3_-methyl-2-buten-1-yl) -8-bromo - xanthine (formula: & 2Η 15ΒγΝ4〇2).

[0095] 质谱(ESI+) :m/z = 328 [Μ+Η] +; [0095] Mass spectrum (ESI +): m / z = 328 [Μ + Η] +;

[0096] 元素分析:C,44.05;H,4.62;Br,24.42;N,17.12;0,9.78。 [0096] Elemental analysis: C, 44.05; H, 4.62; Br, 24.42; N, 17.12; 0,9.78.

[0097] (2) 8-溴-7-(2,3-甲基-2-丁烯-1-基)-3-甲基-1-((4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤的制备 [0097] (2) 8-bromo-7- (2,3-methyl-2-buten-1-yl) -3-methyl-1 - ((4-methyl-quinazolin-2-yl ) methyl) -3,7 preparation of xanthine

[0098] 将2- (2-溴乙基)-4-甲基喹唑啉添加至3-甲基-7- (2,3-甲基-2-丁烯-1-基)-8-氯-黄嘌呤与碳酸钾的N,N-二甲基甲酰胺混合溶液中。 [0098] 2- (2-bromoethyl) -4-methyl-quinazoline was added to 3-methyl-7- (2,3-methyl-2-buten-1-yl) -8- chloro - xanthine and potassium carbonate in N, N- dimethylformamide mixed solution. 将反应混合物于室温下搅拌8小时。 The reaction mixture was stirred at room temperature for 8 hours. 水溶液处理后,使粗产物经过硅股柱层析纯化,以二氯甲烷/甲醇洗脱,得8-溴-7- (2,3-甲基-2-丁烯-1-基)-3-甲基-1-( (4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤(分子式: C22H23BrN6〇2)。 After aqueous workup, the crude product was purified by column chromatography through silica shares with dichloromethane / methanol to give 8-bromo-7- (2,3-methyl-2-buten-1-yl) -3 - methyl-1- ((4-methyl-quinazolin-2-yl) methyl) -3,7-xanthine (formula: C22H23BrN6〇2).

[0099] 质谱(ESI+) :m/z = 484 [M+H] +; [0099] Mass spectrum (ESI +): m / z = 484 [M + H] +;

[0100] 元素分析:C,54.67;H,4.80;Br,16.53;N,17.39;0,6.62。 [0100] Elemental analysis: C, 54.67; H, 4.80; Br, 16.53; N, 17.39; 0,6.62.

[0101] 匪R (d6-DMS0) : 8 · 14 (1H),7 · 85 (1H),7 · 82 (1H),7 · 57 (1H),4 · 43 (2H),4 · 39 (2H),3 · 42 (3H),2 · 95 (3H),1 · 78 (9H)。 [0101] bandit R (d6-DMS0): 8 · 14 (1H), 7 · 85 (1H), 7 · 82 (1H), 7 · 57 (1H), 4 · 43 (2H), 4 · 39 ( 2H), 3 · 42 (3H), 2 · 95 (3H), 1 · 78 (9H).

[0102] 式(IV)化合物的制备 Preparation of compounds [0102] Formula (IV)

[0103] 1. N-正丁基-N-((R)_哌啶-3-基)氨基甲酸叔丁酯(化合物IV-1)的制备 Preparation of ((R & lt) _ piperidin-3-yl) tert-butyl ester (Compound IV-1) amino acid - [0103] 1. N- -N-n-butyl

Figure CN105503873BD00131

[0105] (1) (R) -3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯的制备 Preparation of [0105] (1) (R) -3- (tert-butoxycarbonylamino) piperidine-1-carboxylic acid benzyl ester

[0106] 在0-5°C下先后用三乙胺和氯甲酸苄酯处理(R) -3-(叔丁氧羰基氨基)哌啶的THF 溶液,并在该温度下搅拌24小时。 [0106] successively at 0-5 ° C triethylamine and benzyl chloroformate process (R) with 3- (tert-butoxycarbonylamino) piperidine in THF, and stirred at this temperature for 24 hours. 然后将反应混合物真空蒸发至大约1/4体积,并在乙酸乙酯和1M盐酸溶液之间分配。 The reaction mixture was evaporated in vacuo to approximately 1/4 volume and partitioned between ethyl acetate and 1M hydrochloric acid solution. 分出有机相,按顺序用另外部分的1M盐酸溶液、饱和NaHC0 3水溶液和盐水溶液洗涤。 The organic phase was separated, washed sequentially with 1M hydrochloric acid solution and an additional portion of saturated NaHC0 3 solution and brine solution. 然后将有机相部分用无水硫酸镁干燥,过滤,并真空蒸发得到(R) -3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯(分子式:C18H26N2〇4)。 The organic portion was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give (R) -3- (tert-butoxycarbonylamino) piperidine-1-carboxylic acid benzyl ester (Formula: C18H26N2〇4).

[0107] 质谱(ESI+) :m/z = 335 [M+H] +; [0107] Mass spectrum (ESI +): m / z = 335 [M + H] +;

[0108] 元素分析:C,64.65;H,7.84;N,8.38;0,19.14。 [0108] Elemental analysis: C, 64.65; H, 7.84; N, 8.38; 0,19.14.

[0109] (2) (R) -3-(叔丁氧羰基(正丁基)氨基)哌啶-1-羧酸苄酯的制备 Preparation of [0109] (2) (R) -3- (tert-butoxycarbonyl (n-butyl) amino) piperidine-1-carboxylic acid benzyl ester

[0110] 将(R) -3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯在0_5°C下溶于DMF,并用氢化钠的60 %悬浮液处理。 [0110] The (R) -3- (tert-butoxycarbonylamino) piperidine-1-carboxylate was dissolved in DMF at 0_5 ° C, and treated with sodium hydride 60% suspension. 将反应混合物升温至室温lOmin,然后再次冷却,并加入溴丁烷。 The reaction mixture was warmed to room temperature lOmin, then cooled again and added bromobutane. 2小时后, 升温至室温,加入额外量的溴丁烷,并将反应混合物搅拌16小时。 After 2 hours, warmed to room temperature, an additional amount of bromobutane was added and the reaction mixture stirred for 16 hours. 然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。 The reaction mixture was evaporated in vacuo to ~ 1/4 volume and partitioned between ethyl acetate and water. 然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物,将其用乙酸乙酯/己烷进行硅胶层析以获得N-正丁基化产物(分子式:C22H34N2O4)。 The brine solution was then washed organic portion dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a residue, which was chromatographed on silica gel using ethyl acetate / n-hexane to obtain N- product (Formula : C22H34N2O4).

[0111] 质谱(ESI+) :m/z = 391 [M+H]+; [0111] Mass spectrum (ESI +): m / z = 391 [M + H] +;

[0112] 元素分析:C,67.66;H,8.78;N,7.17;0,16.39。 [0112] Elemental analysis: C, 67.66; H, 8.78; N, 7.17; 0,16.39.

[0113] (3) N-正丁基-N- ((R)-哌啶-3-基)氨基甲酸叔丁酯的制备 Acid tert-butyl carbamate - N- n-butyl -N- (piperidin-3-yl (R)) [0113] (3)

[0114] 将N-正丁基化产物溶于乙醇中,用10%钯碳处理,并在60-70psi氢气下氢化6小时。 [0114] The n-butyl-N- product dissolved in ethanol, treated with 10% palladium on carbon, and hydrogenated at 60-70psi hydrogen for 6 hours. 然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇,将其通过尼龙注射器式过滤器过滤以除去残留催化剂。 The crude reaction mixture was filtered through celite, evaporated in vacuo, and dissolved in ethanol again, filtered to remove residual catalyst through a nylon syringe filter. 将混合物蒸发以获得标题化合物(分子式:C 14H28N2〇2)。 The mixture was evaporated to obtain the title compound (Formula: C 14H28N2〇2).

[0115] 质谱(ESI+) :m/z = 257 [M+H]+; [0115] Mass spectrum (ESI +): m / z = 257 [M + H] +;

[0116] 元素分析:C,65.59;H,11.01;N,10.93;0,12.48。 [0116] Elemental analysis: C, 65.59; H, 11.01; N, 10.93; 0,12.48.

[0117] ^-NMR (d6-DMS0) : 3.61 (1H) , 3.09 (1H) , 2.95 (2H) , 2.85 (1H) , 2.75 (2H) , 2.0 (1H), 1.86 (1H) ,1.61 (1H) ,1.51 (3H) ,1.45 (1H),1.42(9H) ,1.30 (2H),0.89(3H)。 [0117] ^ -NMR (d6-DMS0): 3.61 (1H), 3.09 (1H), 2.95 (2H), 2.85 (1H), 2.75 (2H), 2.0 (1H), 1.86 (1H), 1.61 (1H ), 1.51 (3H), 1.45 (1H), 1.42 (9H), 1.30 (2H), 0.89 (3H).

[0118] 2. (R) -N-环己基-N-(哌啶-3-基)氨基甲酸叔丁酯(化合物IV-2)的制备 Preparation [0118] 2. (R) -N- cyclohexyl -N- (piperidin-3-yl) carbamic acid tert-butyl ester (Compound IV-2) is

Figure CN105503873BD00132

[0120] 将(R) -3-(叔丁氧羰基氨基)哌啶-1-羧酸苄酯溶于DMF中,并用氢化钠的60%悬浮液处理。 [0120] The (R) -3- (tert-butoxycarbonylamino) piperidine-1-carboxylate was dissolved in DMF and treated with sodium hydride 60% suspension. 将反应混合物升温至室温15分钟,然后再次冷却,并加入溴代环己烷。 The reaction mixture was warmed to room temperature for 15 minutes, then cooled again and added bromocyclohexane. 2小时后,升温至室温,加入额外量的溴代环己烷,并将反应混合物搅拌16小时。 After 2 hours, warmed to room temperature, an additional amount of bromocyclohexane and the reaction mixture stirred for 16 hours. 然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。 The reaction mixture was evaporated in vacuo to ~ 1/4 volume and partitioned between ethyl acetate and water. 然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物,将其用乙酸乙酯/己烷进行硅胶层析以获得N-环己烷基化的中间体。 The brine solution was then washed organic portion dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a residue, which was chromatographed on silica gel with ethyl acetate / hexane to obtain N- cyclohexane group of intermediate body. 将N-环己烷基化的中间体溶于乙醇中,用10 %钯碳处理,并在60-70psi氢气下氢化6小时。 The intermediate is N- cyclohexane dissolved in ethanol, treated with 10% palladium on carbon, and hydrogenated at 60-70psi of hydrogen for 6 hours. 然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇, 过滤以除去残留催化剂。 The crude reaction mixture was filtered through celite, evaporated in vacuo, and dissolved in ethanol again, filtered to remove residual catalyst. 将混合物蒸发以获得标题化合物(分子式:C 16H3QN2〇2)。 The mixture was evaporated to obtain the title compound (Formula: C 16H3QN2〇2).

[0121] 质谱(ESI+) :m/z = 283 [M+H]+; [0121] Mass spectrum (ESI +): m / z = 283 [M + H] +;

[0122] 元素分析:C,68.04;H,10.71;N,9.92;0,11.33。 [0122] Elemental analysis: C, 68.04; H, 10.71; N, 9.92; 0,11.33.

[0123] ^-NMR (d6-DMS0) : 3.61 (1H) , 3.55 (1H) , 3.09 (1H) , 2.85 (1H) , 2.74 (2H) , 2.0 (1H), 1 · 86 (1H),1 · 72 (2H),1 · 61 (1H),1 · 51 (2H),1 · 48 (2H),1 · 45 (2H),1 · 43 (9H),1 · 16 (4H)。 [0123] ^ -NMR (d6-DMS0): 3.61 (1H), 3.55 (1H), 3.09 (1H), 2.85 (1H), 2.74 (2H), 2.0 (1H), 1 · 86 (1H), 1 · 72 (2H), 1 · 61 (1H), 1 · 51 (2H), 1 · 48 (2H), 1 · 45 (2H), 1 · 43 (9H), 1 · 16 (4H).

[0124] 3. (R) -N-苯基-N-(哌啶-3-基)氨基甲酸叔丁酯(化合物IV-3)的制备 [0124] 3. (R) -N- phenyl -N- (piperidin-3-yl) carbamate (Compound IV-3) of

Figure CN105503873BD00141

[0126] 将(R)-3_(叔丁氧羰基氨基)哌啶-1-羧酸苄酯在0_5°C下溶于DMF,用氢化钠的60 %悬浮液处理。 [0126] The (R) -3_ (tert-butoxycarbonyl) piperidine-1-carboxylate was dissolved in DMF at 0_5 ° C, treated with sodium hydride 60% suspension. 将反应混合物升温至室温30分钟,然后再次冷却,并加入三氟甲磺酸苯酯。 The reaction mixture was warmed to room temperature for 30 minutes and then cooled again, and trifluoroacetic acid phenyl ester. 3小时后,升温至室温,加入额外量的三氟甲磺酸苯酯,并将反应混合物搅拌18小时。 After 3 hours, warmed to room temperature, an additional amount of trifluoromethanesulfonic acid phenyl ester, and the reaction mixture stirred for 18 hours. 然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。 The reaction mixture was evaporated in vacuo to ~ 1/4 volume and partitioned between ethyl acetate and water. 然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物,将其用乙酸乙酯/己烷进行硅胶层析以获得N-苯基化的中间体。 The brine solution was then washed organic portion dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a residue, which was chromatographed on silica gel with ethyl acetate / hexane to obtain N- phenyl intermediate. 将N-苯基化的中间体溶于乙醇中,用10%钯碳处理, 并在60-70psi氢气下氢化6小时。 The intermediates of phenyl N- dissolved in ethanol, treated with 10% palladium on carbon, and hydrogenated at 60-70psi hydrogen for 6 hours. 然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇,过滤以除去残留催化剂。 The crude reaction mixture was filtered through celite, evaporated in vacuo, and dissolved in ethanol again, filtered to remove residual catalyst. 将混合物蒸发以获得标题化合物(分子式:C 16H24N2〇2)。 The mixture was evaporated to obtain the title compound (Formula: C 16H24N2〇2).

[0127] 质谱(ESI+) :m/z = 277 [M+H] +; [0127] Mass spectrum (ESI +): m / z = 277 [M + H] +;

[0128] 元素分析:C,69.53;H,8.75;N,10.14;0,11.58。 [0128] Elemental analysis: C, 69.53; H, 8.75; N, 10.14; 0,11.58.

[0129] 匪R (d6-DMS0) : 7 · 72 (2H),7 · 32 (2H),6 · 99 (1H),3 · 60 (1H),3 · 28 (1H),3 · 03 (1H),2 · 75 (2H),2 · 03 (1H),2 · 01 (1H),1 · 77 (1H),1 · 46-1 · 50 (2H),1 · 42 (9H)。 [0129] bandit R (d6-DMS0): 7 · 72 (2H), 7 · 32 (2H), 6 · 99 (1H), 3 · 60 (1H), 3 · 28 (1H), 3 · 03 ( 1H), 2 · 75 (2H), 2 · 03 (1H), 2 · 01 (1H), 1 · 77 (1H), 1 · 46-1 · 50 (2H), 1 · 42 (9H).

[0130] 4. 3-(叔丁氧羰基((3R)-哌啶-3-基)氨基)哌啶-1-羧酸叔丁酯(化合物IV-4)的制备 Preparation of - (piperidin-3-yl) amino-t-butoxycarbonyl ((3R)) piperidine-1-carboxylate (Compound IV-4) carboxylic acid [0130] 4. 3-

Figure CN105503873BD00142

[0132] 将(R)-3_(叔丁氧羰基氨基)哌啶-1-羧酸苄酯在0_5°C下溶于DMF,用氢化钠的60%悬浮液处理。 [0132] The (R) -3_ (tert-butoxycarbonyl) piperidine-1-carboxylate was dissolved in DMF at 0_5 ° C, treated with sodium hydride 60% suspension. 将反应混合物升温至室温lOmin,然后再次冷却,并加入3-溴哌啶-1-羧酸叔丁酯。 The reaction mixture was warmed to room temperature lOmin, then cooled again and added piperidine-1-carboxylate 3-bromo. 2小时后,升温至室温,加入额外量的3-溴哌啶-1-羧酸叔丁酯,并将反应混合物搅拌16小时。 After 2 hours, warmed to room temperature, an additional amount of 3-bromo-piperidine-1-carboxylate, and the reaction mixture stirred for 16 hours. 然后将反应混合物真空蒸发至~1/4体积,并在乙酸乙酯和水之间分配。 The reaction mixture was evaporated in vacuo to ~ 1/4 volume and partitioned between ethyl acetate and water. 然后将有机相部分用盐水溶液洗涤,用无水硫酸镁干燥,过滤,并真空蒸发得到残余物。 The brine solution was then washed organic portion dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a residue.

[0133] 将残余物溶于乙醇中,用10%钯碳处理,并在60_70psi氢气下氢化6.5小时。 [0133] The residue was dissolved in ethanol, treated with 10% palladium on carbon and hydrogenated under a hydrogen 60_70psi 6.5 hours. 然后将粗反应混合物用硅藻土过滤,真空蒸发,并再次溶于乙醇,过滤以除去残留催化剂。 The crude reaction mixture was filtered through celite, evaporated in vacuo, and dissolved in ethanol again, filtered to remove residual catalyst. 将混合物蒸发,用乙酸乙酯/己烷进行硅胶层析以获得标题化合物(分子式:C 2QH37N3〇4)。 The mixture was evaporated and chromatographed on silica gel with ethyl acetate / hexane to obtain the title compound (Formula: C 2QH37N3〇4).

[0134] 质谱(ESI+) :m/z = 384 [M+H] +; [0134] Mass spectrum (ESI +): m / z = 384 [M + H] +;

[0135] 元素分析:C,62.63;H,9.72;N,10.96;0,16.69。 [0135] Elemental analysis: C, 62.63; H, 9.72; N, 10.96; 0,16.69.

[0136] 匪R(d6-DMS0) :3.75 (2H) ,3.61 (1H) ,3.54 (2H) ,3.49 (1H) ,3.08 (1H) ,2.86 (1H),2 · 74 (2H),2 · 12 (1H),1 · 87 (2H),1 · 70 (2H),1 · 61 (2H),1 · 49 (2H),1 · 42 (18H)。 [0136] bandit R (d6-DMS0): 3.75 (2H), 3.61 (1H), 3.54 (2H), 3.49 (1H), 3.08 (1H), 2.86 (1H), 2 · 74 (2H), 2 · 12 (1H), 1 · 87 (2H), 1 · 70 (2H), 1 · 61 (2H), 1 · 49 (2H), 1 · 42 (18H).

[0137] 式(II)化合物的制备 Preparation of compounds [0137] Formula (II)

[0138] 丨.丨-((4-甲基-喹唑啉-2-基)甲基)-3-甲基-7-(2-丁炔-1-基)-8-( (R)-3-正丁氨基-哌啶-1-基)-黄嘌呤(化合物II-1) [0138] Shu Shu - ((4-methyl - quinazolin-2-yl) methyl) -3-methyl-7- (2-butyn-1-yl) -8- ((R) 3-n-butylamino - piperidin-1-yl) - xanthine (compound II-1)

Figure CN105503873BD00151

[0140] 将(R) -3-叔丁氧羰基(正丁基)氨基哌啶(化合物IV-1)添加至1- ((4-甲基-喹唑啉-2-基)甲基)-3-甲基-7- (2-丁炔-1-基)-8-氯-黄嘌呤(化合物II1-1)与碳酸钠的二甲亚砜混合溶液中。 [0140] The (R) -3- tert-butoxycarbonyl group (n-butyl) amino piperidine (Compound IV-1) was added to 1- ((4-methyl - quinazolin-2-yl) methyl) -3-methyl-7- (2-butyn-1-yl) -8-chloro - xanthine (compound II1-1) and dimethylsulfoxide mixed solution of sodium carbonate. 将反应混合物于60°C下搅拌18小时。 The reaction mixture was stirred at 60 ° C for 18 h. 为进行处理,将其与水混合,并抽滤所形成的沉淀物。 For treatment, it is mixed with water, and the precipitate formed is suction filtered. 使固体沉淀物溶于二氯甲烷中,与三氟醋酸混合,并于室温下搅拌半小时。 The solid precipitate was dissolved in dichloromethane, mixed with trifluoroacetic acid, and stirred at room temperature for half an hour. 为进行处理,将反应混合物以二氯甲烷稀释,并以饱和碳酸钾溶液洗涤,有机相用无水硫酸钠干燥,蒸干,并经过硅胶柱层析,以二氯甲烷/甲醇(1: 〇至4:1)洗脱,得(R) -8- (3-正丁基氨基哌啶-1-基)-7- (2-丁炔-1-基)-3-甲基-1- ((4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤(分子式:C29H36N8O2)。 For workup, the reaction mixture was diluted with dichloromethane and washed with saturated potassium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness and subjected to silica gel column chromatography with dichloromethane / methanol (1: square to 4: 1) to give (R) -8- (3- amino-piperidin-1-n-butyl-yl) -7- (2-butyn-1-yl) -3-methyl-1- ((4-methyl-quinazolin-2-yl) methyl) -3,7-xanthine (molecular formula: C29H36N8O2).

[0141] 质谱(ESI+) :m/z = 529 [M+H]+ [0141] Mass spectrum (ESI +): m / z = 529 [M + H] +

[0142] 元素分析:C,65.89;H,6.86;N,21.20;0,6.05; [0142] Elemental analysis: C, 65.89; H, 6.86; N, 21.20; 0,6.05;

[0143] 咕匪R(d6-DMS0) :8.12 (1H) ,7.84 (2H) ,7.59 (1H) ,4.43 (4H) ,3.49 (1H) ,3.38 (3H) ,3.33 (1H) , 3.22-3.28 (3H) ,2.95 (3H) ,2.65 (1H) ,2.53 (2H) ,1.80 (3H) ,1.70 (1H), 1.30-1.58 (7H) ,0.89 (3H)。 [0143] cushions bandit R (d6-DMS0): 8.12 (1H), 7.84 (2H), 7.59 (1H), 4.43 (4H), 3.49 (1H), 3.38 (3H), 3.33 (1H), 3.22-3.28 (3H), 2.95 (3H), 2.65 (1H), 2.53 (2H), 1.80 (3H), 1.70 (1H), 1.30-1.58 (7H), 0.89 (3H).

[0144] 2. 1-(喹啉-2-基甲基)-3-甲基-7-(2-氰基苄基)-8-( (R)-3-正丁基氨基-哌啶-1-基)-黄嘌呤(化合物II-2)的制备 [0144] 2. 1- (quinolin-2-yl) -3-methyl-7- (2-cyanobenzyl) -8- ((R) -3- n butylamino - piperidine l-yl) - preparation of xanthine (compound II-2) is

Figure CN105503873BD00161

[0146] 将(R) -3-叔丁氧羰基(正丁基)氨基哌啶(化合物IV-1)添加至1-((喹啉-2-基)甲基)-3-甲基-7- (2-氰基苄基)-8-氯-黄嘌呤(化合物III-2)与碳酸钠的二甲亚砜混合溶液中。 [0146] The (R) -3- tert-butoxycarbonyl group (n-butyl) amino piperidine (Compound IV-1) was added to 1 - ((quinolin-2-yl) methyl) -3-methyl - 7- (2-cyanobenzyl) -8-chloro - xanthine (compound III-2) with dimethyl sulfoxide solution of a mixture of sodium carbonate. 将反应混合物于60°C下搅拌18小时。 The reaction mixture was stirred at 60 ° C for 18 h. 为进行处理,将其与水混合,并抽滤所形成的沉淀物。 For treatment, it is mixed with water, and the precipitate formed is suction filtered. 使固体沉淀物溶于二氯甲烷中,与三氟醋酸混合,并于室温下搅拌半小时。 The solid precipitate was dissolved in dichloromethane, mixed with trifluoroacetic acid, and stirred at room temperature for half an hour. 为进行处理, 将反应混合物以二氯甲烷稀释,并以饱和碳酸钾溶液洗涤,有机相用无水硫酸钠干燥,蒸干,并经过硅胶柱层析,以二氯甲烷/甲醇(1:0至4:1)洗脱,得(R) -8- (3-正丁基氨基哌啶-1-基)-7- (2-氰基苄基)-3-甲基-1-((喹啉-2-基)甲基)-3,7-黄嘌呤(分子式:C33H36N 8〇2;)。 For workup, the reaction mixture was diluted with dichloromethane and washed with saturated potassium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness and subjected to silica gel column chromatography with dichloromethane / methanol (1: 0 to 4: 1) to give (R) -8- (3- amino-piperidin-1-n-butyl-yl) -7- (2-cyanobenzyl) -3-methyl-1 - (( quinolin-2-yl) methyl) -3,7-xanthine (formula: C33H36N 8〇2;).

[0147] 质谱(ESI+) :m/z = 577 [M+H] +; [0147] Mass spectrum (ESI +): m / z = 577 [M + H] +;

[0148] 元素分析:C,68.73;H,6.29;N,19.43;0,5.55; [0148] Elemental analysis: C, 68.73; H, 6.29; N, 19.43; 0,5.55;

[0149] 匪R(d6-DMS0) :8.07 (1H) ,8.02 (1H) ,7.76 (1H) ,7.61 (1H) ,7.48-7.59 (4H), 7.32 (2H) ,5.46 (2H) ,4.75 (2H) ,3.38 (1H) ,3.35 (3H) ,3.32 (1H) ,3.27 (3H) ,2.63 (1H) ,2.53 (2H) ,1.70 (1H) ,1.50 (1H) ,1.42 (2H) ,1.35 (4H) ,0.89 (3H)。 [0149] bandit R (d6-DMS0): 8.07 (1H), 8.02 (1H), 7.76 (1H), 7.61 (1H), 7.48-7.59 (4H), 7.32 (2H), 5.46 (2H), 4.75 ( 2H), 3.38 (1H), 3.35 (3H), 3.32 (1H), 3.27 (3H), 2.63 (1H), 2.53 (2H), 1.70 (1H), 1.50 (1H), 1.42 (2H), 1.35 ( 4H), 0.89 (3H).

[0150] 3. 1-(二甲基氨基羰基甲基)-3-甲基-7-(环己烯-1-基甲基)-8-( (R)-3-环己基氨基-哌啶-1-基)-黄嘌呤(化合物II-3)的制备 [0150] 3. 1- (dimethylamino-carbonyl) -3-methyl-7- (cyclohexen-1-yl-methyl) -8- ((R) -3- cyclohexylamino - piperidine preparation of xanthine (compound II-3) - a-1-yl)

Figure CN105503873BD00162

[0152] 将(R) -3-叔丁氧羰基(环己基)氨基哌啶(化合物IV-2)添加至1-(二甲基氨基羰基甲基)-3-甲基-7-(环己烯-卜基甲基)-8-氯-黄嘌呤(化合物III-3)与碳酸钠的二甲亚砜混合溶液中。 [0152] The (R) -3- tert-butoxycarbonyl group (cyclohexyl) amino-piperidine (Compound IV-2) was added to 1- (dimethylamino-carbonyl) -3-methyl-7- (cyclo hexene - Buji) -8-chloro - xanthine (compound III-3) was mixed with dimethyl sulfoxide solution of sodium carbonate. 将反应混合物于55°C下搅拌18小时。 The reaction mixture was stirred at 55 ° C for 18 h. 为进行处理,将其与水混合,并抽滤所形成的沉淀物。 For treatment, it is mixed with water, and the precipitate formed is suction filtered. 使固体沉淀物溶于二氯甲烷中,与三氟醋酸混合,并于室温下搅拌半小时。 The solid precipitate was dissolved in dichloromethane, mixed with trifluoroacetic acid, and stirred at room temperature for half an hour. 为进行处理,将反应混合物以二氯甲烷稀释,并以饱和碳酸钾溶液洗涤,有机相用无水硫酸钠干燥,蒸干,并经过硅胶柱层析,以二氯甲烷/甲醇(1: 〇至4:1)洗脱,得(R) -1-(二甲基氨基羰基甲基)-3-甲基-7-(环己烯-1-基甲基)-8- (3-正丁基氨基哌啶-1-基)-3,7-黄嘌呤(分子式:C28H43N7O3;)。 For workup, the reaction mixture was diluted with dichloromethane and washed with saturated potassium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness and subjected to silica gel column chromatography with dichloromethane / methanol (1: square to 4: 1) to give (R & lt) -1- (dimethylaminocarbonyl-yl) -3-methyl-7- (cyclohexen-1-yl-methyl) -8- (3-n butyl-amino-piperidin-1-yl) -3,7-xanthine (molecular formula: C28H43N7O3;).

[0153] 质谱(ESI+) :m/z = 526 [M+H] +; [0153] Mass spectrum (ESI +): m / z = 526 [M + H] +;

[0154] 元素分析:C,63.97;H,8.25;N,18.65;0,9.13; [0154] Elemental analysis: C, 63.97; H, 8.25; N, 18.65; 0,9.13;

[0155] 匪R(d6-DMS0) :5.41 (1H) ,4.40 (2H) ,4.28 (2H) ,3.48 (1H) ,3.41 (3H) ,3.34 (1H),3 · 27 (2H),3 · 21 (1H),2 · 98 (6H),2 · 63 (1H),2 · 55 (1H),1 · 99 (2H),1 · 92 (2H),1 · 74 (2H), 1 · 71 (1H),1 · 61 (4H),1 · 57 (1H),1 · 47 (4H),1 · 35 (2H),1 · 21 (2H),1 · 10 (2H)。 [0155] bandit R (d6-DMS0): 5.41 (1H), 4.40 (2H), 4.28 (2H), 3.48 (1H), 3.41 (3H), 3.34 (1H), 3 · 27 (2H), 3 · 21 (1H), 2 · 98 (6H), 2 · 63 (1H), 2 · 55 (1H), 1 · 99 (2H), 1 · 92 (2H), 1 · 74 (2H), 1 · 71 (1H), 1 · 61 (4H), 1 · 57 (1H), 1 · 47 (4H), 1 · 35 (2H), 1 · 21 (2H), 1 · 10 (2H).

[0156] 4.丨-(吡咯烷-丄-基羰基甲基)-3-甲基- 7-(2-丁炔-1-基)-8-( (R)-3-苯基氨基-哌啶-1-基)-黄嘌呤(化合物II-4)的制备 [0156] 4. Shu - (pyrrolidin - Shang - ylcarbonyl) -3-methyl - 7- (2-butyn-1-yl) -8- ((R) -3- phenylamino - (compound II-4) preparation of xanthine - piperidin-1-yl)

Figure CN105503873BD00171

[0158] 将(R) -3-叔丁氧羰基(苯基)氨基哌啶(化合物IV-3)添加至1-(吡咯烷-1-基羰基甲基)-3-甲基-7- (2-丁炔-1-基)-8-氯-黄嘌呤(化合物II1-1)与碳酸钠的二甲亚砜混合溶液中。 [0158] The (R) -3- tert-butoxycarbonyl group (phenyl) aminopiperidine (Compound IV-3) was added to 1- (pyrrolidin-1-yl-carbonyl) -3-methyl-7- (2-butyn-1-yl) -8-chloro - xanthine (compound II1-1) and dimethylsulfoxide mixed solution of sodium carbonate. 将反应混合物于60°C下搅拌20小时。 The reaction mixture was stirred at 60 ° C for 20 hours. 为进行处理,将其与水混合,并抽滤所形成的沉淀物。 For treatment, it is mixed with water, and the precipitate formed is suction filtered. 使固体沉淀物溶于二氯甲烷中,与三氟醋酸混合,并于室温下搅拌半小时。 The solid precipitate was dissolved in dichloromethane, mixed with trifluoroacetic acid, and stirred at room temperature for half an hour. 为进行处理,将反应混合物以二氯甲烷稀释,并以饱和碳酸钾溶液洗涤,有机相用无水硫酸钠干燥, 蒸干,并经过硅胶柱层析,以二氯甲烷/甲醇(1:0至4:1)洗脱,得1-(吡咯烷-1-基羰基甲基)-3-甲基-7- (2-丁炔-1-基)-8- ((R) -3-苯基氨基-哌啶-1-基)-黄嘌呤(分子式: C27H33N7O3;) 〇 For workup, the reaction mixture was diluted with dichloromethane and washed with saturated potassium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness and subjected to silica gel column chromatography with dichloromethane / methanol (1: 0 to 4: 1) to give 1- (pyrrolidin-1-yl-carbonyl) -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3- phenylamino - piperidin-1-yl) - xanthine (molecular formula: C27H33N7O3;) square

[0159] 质谱(ESI+) :m/z = 504 [M+H] +; [0159] Mass spectrum (ESI +): m / z = 504 [M + H] +;

[0160] 元素分析:C,64.39;H,6.61;N,19.47;0,9.53。 [0160] Elemental analysis: C, 64.39; H, 6.61; N, 19.47; 0,9.53.

[0161] 匪R(d6-DMS0) :7.08 (2H) ,6.83 (2H) ,6.67 (1H),5· 15 (1H) ,4.42 (2H) ,4.28 (2Η) ,3.58 (1Η) ,3.42 (3H) ,3.34 (1H) ,3.28 (2H) ,3.09 (4H) ,2.63 (1H) ,1.83(4H) ,1.81 (1H), 1.78(3H) ,1.55 (2H) ,1.46 (1H)。 [0161] bandit R (d6-DMS0): 7.08 (2H), 6.83 (2H), 6.67 (1H), 5 · 15 (1H), 4.42 (2H), 4.28 (2Η), 3.58 (1Η), 3.42 ( 3H), 3.34 (1H), 3.28 (2H), 3.09 (4H), 2.63 (1H), 1.83 (4H), 1.81 (1H), 1.78 (3H), 1.55 (2H), 1.46 (1H).

[0162] 5. 1- (4-喹唑啉-2-基甲基)-3-甲基-7- (2,3-二甲基丁-2-烯-1-基)-8- ((R) -3-(哌啶-3-基氨基)哌啶-1-基)-黄嘌呤(化合物II-5)的制备 [0162] The 1- (4-quinazolin-2-yl) -3-methyl-7- (2,3-dimethoxy-2-en-1-yl) -8- ( preparation of xanthine (compound II-5) a - (R) -3- (piperidin-3-yl-amino) piperidin-1-yl)

Figure CN105503873BD00172

[0164] 将(R) -3-叔丁氧羰基(正丁基)氨基哌啶(化合物IV-1)添加至1- ((4-甲基-喹唑啉-2-基)甲基)-3-甲基-7- (2,3-二甲基丁-2-烯-1-基)-8-氯-黄嘌呤(化合物III-1)与碳酸钠的二甲亚砜混合溶液中。 [0164] The (R) -3- tert-butoxycarbonyl group (n-butyl) amino piperidine (Compound IV-1) was added to 1- ((4-methyl - quinazolin-2-yl) methyl) -3-methyl-7- (2,3-dimethoxy-2-en-1-yl) -8-chloro - xanthine (compound III-1) was mixed with dimethyl sulfoxide solution of sodium carbonate . 将反应混合物于55°C下搅拌20小时。 The reaction mixture was stirred at 55 ° C for 20 hours. 为进行处理,将其与水混合,并抽滤所形成的沉淀物。 For treatment, it is mixed with water, and the precipitate formed is suction filtered. 使固体沉淀物溶于二氯甲烷中,与三氟醋酸混合,并于室温下搅拌半小时。 The solid precipitate was dissolved in dichloromethane, mixed with trifluoroacetic acid, and stirred at room temperature for half an hour. 为进行处理,将反应混合物以二氯甲烷稀释,并以饱和碳酸钾溶液洗涤,有机相用无水硫酸钠干燥,蒸干,并经过硅胶柱层析,以二氯甲烷/甲醇(1:0至4:1)洗脱,得Ια-喹唑啉-2-基甲基) -3-甲基-7- (2 , 3-二甲基丁-2-烯-1-基) -8- ((R) -3- (哌啶-3-基氨基)哌啶-卜基)-黄嘌呤(分子式:C32H43N9〇2 ;)。 For workup, the reaction mixture was diluted with dichloromethane and washed with saturated potassium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness and subjected to silica gel column chromatography with dichloromethane / methanol (1: 0 to 4: 1) to give Ια- quinazolin-2-yl) -3-methyl-7- (2, 3-dimethylamino-2-en-1-yl) -8- ((R & lt) -3- (piperidin-3-yl-amino) piperidin - Bu Ji) - xanthine (formula: C32H43N9〇2;).

[0165] 质谱(ESI+) :m/z = 586 [M+H] +; [0165] Mass spectrum (ESI +): m / z = 586 [M + H] +;

[0166] 元素分析:C,65.62;H,7.40;N,21.52;0,5.46; [0166] Elemental analysis: C, 65.62; H, 7.40; N, 21.52; 0,5.46;

[0167] 匪R(d6-DMS0) :8.11 (1H) ,7.85 (2H) ,7.59 (1H) ,4.43 (2H) ,4.39 (2H) ,3.49 (1H) ,3.39 (3H) ,3.31 (1H) ,3.27 (2H) ,3.22 (1H) ,2.94 (3H) ,2.87 (1H) ,2.76 (2H) ,2.71 (1H), 2 · 63 (2H),2 · 02 (1H) , 1 · 79 (9H) , 1 · 71 (2H) , 1 · 58 (4H) , 1 · 48 (2H)。 [0167] bandit R (d6-DMS0): 8.11 (1H), 7.85 (2H), 7.59 (1H), 4.43 (2H), 4.39 (2H), 3.49 (1H), 3.39 (3H), 3.31 (1H) , 3.27 (2H), 3.22 (1H), 2.94 (3H), 2.87 (1H), 2.76 (2H), 2.71 (1H), 2 · 63 (2H), 2 · 02 (1H), 1 · 79 (9H ), 1 · 71 (2H), 1 · 58 (4H), 1 · 48 (2H).

[0168] 以类似方法还可制备得到以下化合物: [0168] In a similar manner the following compound can also be prepared:

Figure CN105503873BD00181

[0172] 式⑴化合物的制备 Preparation of compounds [0172] Formula ⑴

[0173]丄·制备卜((4-甲基-喹唑啉-2-基)甲基)-3-甲基-7- (2-丁炔-1-基)-8- ((R) -3-(N1-正丁基双胍基)-哌啶-1-基)-黄嘌呤(化合物1-1) [0173] Preparation of Bu-Shang ((4-methyl - quinazolin-2-yl) methyl) -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3- (N1- n butylbiguanide yl) - piperidin-1-yl) - xanthine (compound 1-1)

Figure CN105503873BD00182

[0175] 将双氰胺溶于异丙醇中,加入(R) -8- (3-正丁基氨基哌啶-丨-基)-7- (2-丁炔-丄-基)-3-甲基-1-((4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤(化合物11-1),用36 %HC1调节pH 5~6,控制温度在80~100°C反应6小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C 31H4QN12〇2;)。 [0175] The dicyandiamide was dissolved in isopropanol, was added (R) -8- (3- piperidin-n-butylamino - Shu - yl) -7- (2-butyn - Shang - yl) -3 - methyl - 1 - ((4-methyl-quinazolin-2-yl) methyl) -3,7-xanthine (compound 11-1), adjusted with 36% HC1 pH 5 ~ 6, the temperature control 80 ~ 100 ° C for 6 hours. after completion of the reaction was allowed to stand cooling, precipitated white crystals were large, suction filtered, washed, and recrystallized with anhydrous ethanol and dried to give the title compound (formula: C 31H4QN12〇2;).

[0176] 质谱(ESI+) :m/z = 613 [M+H] +; [0176] Mass spectrum (ESI +): m / z = 613 [M + H] +;

[0177] 元素分析:C,60.77;H,6.58;N,27.43;0,5.22; [0177] Elemental analysis: C, 60.77; H, 6.58; N, 27.43; 0,5.22;

[0178] 匪R(d6-DMS0) :8.12 (1H) ,7.85 (2H,br) ,7.80 (2H) ,7.59 (1H) ,6.63 (2H,br), 4 · 43 (4H),3 · 59 (1H),3 · 38 (3H),3 · 34 (1H),3 · 30 (2H),3 · 28 (2H),2 · 95 (3H),2 · 65 (1H),2 · 0 (lH,br) ,1.80 (3H) ,1.70 (1H) ,1.30-1.58 (7H) ,0.89 (3H)。 [0178] bandit R (d6-DMS0): 8.12 (1H), 7.85 (2H, br), 7.80 (2H), 7.59 (1H), 6.63 (2H, br), 4 · 43 (4H), 3 · 59 (1H), 3 · 38 (3H), 3 · 34 (1H), 3 · 30 (2H), 3 · 28 (2H), 2 · 95 (3H), 2 · 65 (1H), 2 · 0 ( lH, br), 1.80 (3H), 1.70 (1H), 1.30-1.58 (7H), 0.89 (3H).

[0179] 2. 1-( (4-甲基-喹唑啉-2-基)甲基)-3-甲基-7-(2-氰基苄基)-8-( (R)-3-(Nl-正丁基双胍基)-哌啶-1-基)-黄嘌呤(化合物1-2)的制备 [0179] 2. 1- ((4-methyl - quinazolin-2-yl) methyl) -3-methyl-7- (2-cyanobenzyl) -8- ((R) -3 - (n-butyl biguanide nL- yl) - piperidin-l-yl) - xanthine (compound 1-2)

Figure CN105503873BD00191

[0181] 将双氰胺溶于异丙醇中,加入(R) -8- (3-正丁基氨基哌啶-丨-基)-7- (2-丁炔-丄-基)-3-甲基-1-((4-甲基喹唑啉-2-基)甲基)-3,7-黄嘌呤(化合物11-1),用36 %HC1调节pH 5~6,控制温度在80~100°C反应6小时,反应完成后静置冷却,析出大量白色晶体,抽滤,洗涤,干燥后用无水乙醇重结晶,得标题化合物(分子式:C 35H4QN1202)。 [0181] The dicyandiamide was dissolved in isopropanol, was added (R) -8- (3- piperidin-n-butylamino - Shu - yl) -7- (2-butyn - Shang - yl) -3 - methyl - 1 - ((4-methyl-quinazolin-2-yl) methyl) -3,7-xanthine (compound 11-1), adjusted with 36% HC1 pH 5 ~ 6, the temperature control 80 ~ 100 ° C for 6 hours. after completion of the reaction was allowed to stand cooling, precipitated white crystals were large, suction filtered, washed, and recrystallized with anhydrous ethanol and dried to give the title compound (formula: C 35H4QN1202).

[0182] 质谱(ESI+) :m/z = 661 [M+H] + [0182] Mass spectrum (ESI +): m / z = 661 [M + H] +

[0183] 元素分析:C,63.62;H,6.10;N,25.44;0,4.84。 [0183] Elemental analysis: C, 63.62; H, 6.10; N, 25.44; 0,4.84.

[0184] 匪R(d6-DMS0) :8.06 (1H) ,8.01 (1H) ,7.83 (2H) ,7.75 (1H) ,7.63 (1H) ,7.52 (3H) ,7.46 (1H) ,7.30 (2H) ,6.62 (2H) ,5.47 (2H) ,4.76 (2H) ,3.61 (1H) ,3.39 (3H) ,3.34 (1H), 3.30 (2H) ,3.25 (2H) ,2.63 (1H) ,2.15 (1H) ,1.83 (1H) ,1.48-1.58 (5H) ,1.30 (2H) ,0.89 (3H)。 [0184] bandit R (d6-DMS0): 8.06 (1H), 8.01 (1H), 7.83 (2H), 7.75 (1H), 7.63 (1H), 7.52 (3H), 7.46 (1H), 7.30 (2H) , 6.62 (2H), 5.47 (2H), 4.76 (2H), 3.61 (1H), 3.39 (3H), 3.34 (1H), 3.30 (2H), 3.25 (2H), 2.63 (1H), 2.15 (1H) , 1.83 (1H), 1.48-1.58 (5H), 1.30 (2H), 0.89 (3H).

[0185] 以类似方法制备以下化合物 [0185] The following compounds were prepared in a similar manner

Figure CN105503873BD00192

Figure CN105503873BD00201

[0189] 生物学实施例 Example [0189] Biological

[0190] 1、DPP_IV 检测 [0190] 1, DPP_IV detection

[0191] 使用人类结肠癌细胞系Caco-2的萃取物作为DPP-IV来源。 [0191] using human colon cancer cell line Caco-2 extract as sources of DPP-IV. 为诱发DPP-IV表达,细胞的分化按文献(Reiher等,"肠细胞系Caco-2的增加表达",在Proc.Natl.Acad.Sci.第90 卷,第5757-5761页(1993))中所述进行。 To induce DPP-IV expression, cell differentiation according to the literature (Reiher et al., "Intestinal cell line Caco-2 expression increased" in Proc. 90th, pp 5757-5761 (1993)) in the performed. 细胞萃取物是于4°C下,通过在35,000g下离心30分钟(以去除细胞碎肩),将其溶解于缓冲剂(ΙΟμπι Tns HC1,0.15M似(:1,0.04^11.抑酶肽, 0.5%Nonidet-P40,pH8.0)中而得到。 Cell extracts is at 4 ° C, by centrifugation at 35,000g for 30 minutes (to remove cell debris shoulder), which was dissolved in buffer (ΙΟμπι Tns HC1,0.15M like (: 1,0.04 suppression ^ 11 enzyme peptide, 0.5% Nonidet-P40, pH8.0) are obtained.

[0192] 将50微升最后浓度为100μπι的酰氨基-4-三氟甲基香豆素(AFC)基质溶液放置在黑色微滴定板中。 [0192] A final concentration of 50 [mu] l of 100μπι amido-4-trifluoromethyl coumarin (AFC) substrate solution is placed in a black microtiter plate. 将20微升检测缓冲液(最后浓度为50μπι Tns-HCl,pH 7·8,50μπι NaCl,l% DMSO)以吸移管吸取。 20 microliters of the assay buffer (final concentration 50μπι Tns-HCl, pH 7 · 8,50μπι NaCl, l% DMSO) to suction pipette. 反应是通过添加30微升已溶解的Caco-2蛋白质(每孔最后浓度为0.14 微克蛋白质)开始。 The reaction by adding 30 [mu] l solubilized Caco-2 protein (final concentration 0.14 [mu] g protein per well) starts. 通常将要被研究的待测物质,预先稀释在20微升检测缓冲液而再添加, 其中检测缓冲液的体积相应减少。 Test substances are generally to be studied, previously diluted in assay buffer and add 20 microliters, wherein the assay buffer volume is reduced accordingly. 反应是在室温下进行,培养60分钟。 The reaction is carried out at room temperature, incubated for 60 min. 然后,在Vict〇rl4Multilabel计数器中测量萤光,激发波长为405毫微米,而发射波长为535毫微米。 Then, in the measuring counter Vict〇rl4Multilabel fluorescence excitation wavelength of 405 nm and an emission wavelength of 535 nm. 空白试验读数(相当于0%活性)是在没有任何Caco-2蛋白质(体积由检测缓冲液置換)的混合物中获得,对照值(相当于100%活性)是在未添加物质的混合物中获得。 Blank reading (corresponding to 0% activity) were obtained in mixtures without any Caco-2 protein (volume replaced with assay buffer), a control value (corresponding to 100% activity) were obtained in mixtures without addition of substances. 于讨论中的待测物质的药效,以IC 5Q值代表,是由剂量/活性曲线计算,其在各情况中包含11个测量点。 In the efficacy of the test substance in question, to the representative value IC 5Q, is calculated from the dose / activity curve, which comprises 11 measuring points in each case.

[0193] 本发明的实施例化合物1-1~13 (双胍衍生物)的IC5Q值<10nM,并且其IC5Q值显著低于相应的氨基衍生物,例如低于大约1/5~1/10。 [0193] Example Compound 1-1 to the present invention 13 (biguanide derivative) IC5Q value of <10nM, and which is significantly lower than IC5Q corresponding amino derivative, for example, less than about 1/5 ~ 1/10. 详细结果见下表2。 Detailed results in Table 2 below.

[0194] 表2:本发明化合物对DPP-IV的抑制作用 [0194] Table 2: Inhibition of compounds of the invention of DPP-IV

Figure CN105503873BD00202

Figure CN105503873BD00211

[0196] 2.本发明化合物对四氧嘧啶糖尿病小鼠血糖的影响 Effect of the compound [0196] 2. The present invention alloxan diabetic mice Blood Glucose

[0197] 选健康小鼠60只,随机分出10只作为正常对照组(生理盐水0.5ml/只),其余50只小鼠禁食不禁水24小时,各鼠均腹腔注射四氧嘧啶180mg/kg,其后72小时眼眶采血测定血糖,血糖浓度高于11. lmmol/L者为糖尿病模型小鼠。 [0197] is selected from healthy mice were randomly separated and 10 normal control group (saline 0.5ml / only), 50 mice were fasted for the remainder of water for 24 hours, mice were injected in each alloxan 180mg / kg, 72 hours thereafter orbital blood glucose, blood glucose concentration is higher than 11. lmmol / L were diabetic model mice. 将50只糖尿病模型小鼠随机分为5组: 实验性糖尿病空白组(生理盐水0.5ml/只),利格列汀组(5mg/kg),本发明化合物的高剂量组(5mg/kg)、中剂量组(lmg/kg)、低剂量组(0 · 2mg/kg)。 50 The diabetic mice were randomly divided into 5 groups: control group of experimental diabetic (saline 0.5ml / only), linagliptin group (5mg / kg), high dose group of compounds of the present invention (5mg / kg) dose group (lmg / kg), low dose (0 · 2mg / kg). 每天上午8:00~9:00灌胃给药,连续30d。 8 hours a day: 00 to 9:00 oral administration, continuous 30d. 禁食12h从后小鼠眼眶后静脉丛取血测血糖值。 12h fasted mice orbital venous plexus from the measured blood glucose values.

[0198] 结果显示,本发明的实施例化合物1-1~13 (双胍衍生物)均不同程度表现出比相应的氨基衍生物更强烈的降血糖作用和显著延长的作用时间,而且不易出现低血糖。 [0198] The results show that the compounds of the present invention embodiments Example 1-1 to 13 (biguanide derivative) exhibit different degrees stronger than the corresponding amino derivatives and the hypoglycemic action significantly prolonged duration of action and less prone to low blood sugar. 例如, 实施例1-1~13的化合物的低剂量组均表现出具有比利格列汀组更强且更持久的降血糖能力,具有显著性差异(Ρ<〇·〇5)。 For example, low-dose group of the compounds of Examples 1-1 to embodiment 13 having 比利格列汀 group exhibited a stronger and longer lasting hypoglycemic capacity, with significant difference (Ρ <square-〇5).

Claims (6)

1. 一种制备式(I)所示的化合物、其立体异构体,或者其药学上可接受的盐的方法,包括使式(Π )化合物与双氰胺接触的步骤: 1. A process for preparing a compound of formula (I), and pharmaceutically method of its stereoisomers, or a pharmaceutically acceptable salt thereof, comprising ([pi) contacting the compound of formula with dicyandiamide steps of:
Figure CN105503873BC00021
其中, R1代表烷基,所述烷基可R12-C〇-取代,并且R12代表二(&- 6烷基)氨基、吡咯烷-1-基、哌啶-1-基或Cmo芳基; R2代表烷基或C6-1Q芳基; R3代表苄基、C2-8烯基、C2-8炔基或C3-8环烯基甲基,其中苄基中的苯环可被1个或多个卤素或氰基取代; R4代表8烷基、C3-8环烷基、C3-8元杂环烷基、C6- 1Q芳基或、C5-1Q元杂芳基; R5代表氢或者氨基保护基;并且当R5代表氨基保护基时,在与双氰胺接触前还包括将所述的氨基保护基脱除的步骤。 Wherein, R1 stands for an alkyl group, the alkyl group may be substituted C〇--R12, and R12 represents di (& - 6 alkyl) amino, pyrrolidin-1-yl, piperidin-1-yl or an aryl group Cmo; R2 represents an alkyl group or aryl C6-1Q group; R3 represents a benzyl group, a C2-8 alkenyl group, a C2-8 alkynyl group or a C3-8 cycloalkenyl group, a benzyl group wherein the phenyl ring may be substituted with one or more halogen or cyano; R4 representatives 8 alkyl, C3-8 cycloalkyl, C3-8 membered heterocycloalkyl, C6- 1Q aryl group or a, C5-1Q membered heteroaryl; R5 represents hydrogen or an amino-protecting group; and when R5 represents an amino-protecting group, with the dicyandiamide before the step of contacting further comprises removing the amino protecting group of the.
2. 根据权利要求1所述的方法,其特征在于所述的氨基保护基选自甲氧羰基、乙氧羰基、叔丁氧基羰基、苄氧羰基、2-联苯基-2-丙氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻或对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4-二甲氧基苄基、对甲氧基苄基或苄基。 2. The method according to claim 1, characterized in that the amino protecting group selected from methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl group, the benzyloxycarbonyl group, 2-biphenyl-2-propoxymethyl a carbonyl group, allyloxycarbonyl group, trimethylsilyl ethoxycarbonyl, phthalyl, p-toluenesulfonyl, trifluoroacetyl, o- or p-nitrobenzenesulfonyl group, a pivaloyl group, a benzoyl group, a trityl methyl, 2,4-dimethoxybenzyl group, a methoxybenzyl group or a benzyl group pair.
3. 根据权利要求1或2所述的方法,其特征在于还包括使式(III)化合物与式(IV)化合物接触的步骤: 3. The method of claim 1 or claim 2, characterized by further comprising the step of reacting a compound of formula (III) with a compound of formula (IV) in contact:
Figure CN105503873BC00022
其中Pr1代表氨基保护基; 当需要时为了获得R5代表氢的式(II)化合物,可选地将氨基保护基Pr1脱除, 其中R1-!?5如权利要求1所定义。 Wherein Pr1 represents an amino-protecting group; and when required in order to obtain (II) compound of formula R5 represents hydrogen, optionally removing the amino-protecting group Pr1, wherein R1 - !? 5 requirements as defined in claim 1.
4. 根据权利要求3所述的方法,其特征在于还包括制备式(III)化合物的步骤:包括使8_卤代黄嘌呤衍生物与含R3基团的卤代物接触,然后使所得产物与含R 1基团的卤代物接触: 4. The method according to claim 3, characterized by further comprising the step of preparing a compound of formula (III): comprising reacting xanthine derivatives with a halogenated 8_ contacting halide-containing R3 groups, then reacting the resulting product with R 1 groups containing halogenated contacting:
Figure CN105503873BC00031
其中RlR3如权利要求1所定义,且X代表卤素原子。 As defined and X represents a halogen atom wherein RlR3 as claimed in claim.
5. 根据权利要求3所述的方法,其特征在于还包括制备式(IV)化合物的步骤,其中包括使3-氨基哌啶(式(V)化合物)依次经不同的氨基保护基Pr\Pr 2保护,然后与含R4基团的卤代物接触,再选择性脱除Pr2氨基保护基: 5. The method according to claim 3, characterized by further comprising the step of preparing a compound of formula (IV), which comprises reacting 3-amino-piperidine (Formula (V) compound) sequentially via different amino protecting group Pr \ Pr protective, and then contacted with halide-containing group R4, then selective removal of the amino protecting group Pr2:
Figure CN105503873BC00032
其中RlR5如权利要求1所定义,Pr1和Pr2彼此独立的代表相同或不同的氨基保护基。 Wherein RlR5 defined as claimed in claim 1, Pr1 and Pr2 same as each other or different independently represent amino protecting groups.
6. 根据权利要求4或5所述的方法,其特征在于Pr1和Pr2相同或不同,彼此独立的代表甲氧羰基、乙氧羰基、叔丁氧基羰基、苄氧羰基、2-联苯基-2-丙氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、三氟乙酰基、邻或对硝基苯磺酰基、特戊酰基、苯甲酰基、三苯甲基、2,4_二甲氧基苄基、对甲氧基苄基或苄基。 6. The method according to claim 4 or claim 5, wherein Pr1 and Pr2 - are the same or different, each independently represent methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl group, benzyloxycarbonyl group, 2-biphenylyl -2-oxo-carbonyl group, allyloxycarbonyl group, trimethylsilyl ethoxycarbonyl, phthalyl, p-toluenesulfonyl, trifluoroacetyl, o- or p-nitrobenzenesulfonyl group, pivaloyl group, benzyl formyl, trityl, 2,4_-dimethoxybenzyl, methoxybenzyl or benzyl pairs.
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