WO2017206801A1 - Diarylsulfide derivative, preparation method therefor, and use as serotonin transporter-targeted imaging agent - Google Patents

Diarylsulfide derivative, preparation method therefor, and use as serotonin transporter-targeted imaging agent Download PDF

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WO2017206801A1
WO2017206801A1 PCT/CN2017/086045 CN2017086045W WO2017206801A1 WO 2017206801 A1 WO2017206801 A1 WO 2017206801A1 CN 2017086045 W CN2017086045 W CN 2017086045W WO 2017206801 A1 WO2017206801 A1 WO 2017206801A1
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sert
diaryl sulfide
compound
sulfide derivative
preparation
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Chinese (zh)
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朱霖
孔繁渊
李根熏
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北京师范大学
北京脑重大疾病研究院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/37—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the invention belongs to the field of radiopharmaceutical chemistry and relates to a class of diaryl sulfide derivatives, a preparation method thereof and the use as a serotonin transporter targeting imaging agent.
  • the serotonin transporter is a selective serotonin (5-HT) transmembrane transporter. SERT is able to reuptake 5-HT in the synaptic cleft, thereby regulating the transmission of neural signals.
  • SERT present in the presynaptic membrane of neurons, capable of selectively transferring the neurotransmitter 5-HT from the synaptic cleft back into the intracellular cytosol, thereby terminating the transmitter to the posterior membrane
  • the action of the 5-HT receptor thus plays an extremely important role in the reuptake process after 5-HT release.
  • PET imaging can study the chemical processes and physiological and biochemical processes in the human body in a non-invasive, dynamic and quantitative manner, and study the metabolism of living substances, the distribution and function of receptors, the changes of gene regulation, etc. at the living level. These make the development of nuclear medicine reach the true molecular level.
  • PET imaging is inseparable from positron-labeled PET drugs, in which 18 F positron nuclides (half-life of 110 minutes) have a relatively long half-life compared to 11 C (half-life of 20 minutes), suitable for commercial production and transportation. It is the ideal radionuclide for current PET imaging drugs, and 18 F drugs have become a hot spot of research.
  • non-invasive PET and single photon tomography (SPECT) in vivo imaging techniques to study the distribution of SERT in the brain region will help to explore the pathophysiology and treatment of 5-HT system in neuropsychiatric disorders.
  • SPECT single photon tomography
  • the role played by understanding the relationship between changes in SERT density and the pathology of mental disorders and mental degenerative diseases can also provide very effective information for the study of therapeutic mechanism of action, individualized treatment strategies, and efficacy evaluation.
  • SERT is also the main target of antidepressant drugs.
  • the diaryl sulfide ligand has targeted specific binding to SERT. Its derivatives, as SERT inhibitors, have become drugs for the treatment of depression and neurosis. The new SERT targeting compounds are still being studied, with the aim of finding better therapeutic drugs.
  • the object of the present invention is to provide a diaryl sulfide derivative which has a high specific binding effect of SERT (quine serotonin transporter) in the brain and has good in vivo biological metabolic properties. A better targeted intracellular uptake combined with imaging drugs.
  • SERT quine serotonin transporter
  • Another object of the present invention is to provide a process for producing the above diaryl sulfide derivative.
  • the invention provides a diaryl sulfide derivative of the formula:
  • Y is a fluorine atom and may be [ 18 F] or [ 19 F].
  • a process for the preparation of the above diaryl sulfide derivative which comprises: 2-aminobenzene-(2-(N,N-dimethyl) in the presence of a base Aminomethyl-4-hydroxy)-phenyl) sulfide
  • the nucleophilic substitution reaction is carried out to obtain a diaryl sulfide derivative represented by the above structural formula, wherein the base is potassium carbonate, sodium hydride or cesium carbonate.
  • the reaction formula is as follows:
  • the diaryl sulfide derivative of the present invention is [18 F] of [19 F], or comprises, [19 F] - diaryl sulfide derivatives exhibit central SERT High affinity, while high selectivity for SERT relative to DAT (dopamine transporter) and NET (norepinephrine transporter). Therefore, the corresponding [ 18 F]-diaryl sulfide derivatives can be used as SERT/PET imaging agents, and these compounds are expected to have high brain uptake values and reasonable pharmacokinetic properties, and are expected to develop excellent ones. SERT/PET imaging agent.
  • Figure 1 is a radioactive peak in the HPLC spectrum of compound A5 after preliminary purification by OasisHLB column;
  • Figure 2 is a HPLC confirmation of the compound A5, [ 18 F]-A5, that is, a co-injection spectrum of the radioactive product [ 18 F]-A5 with the compound A2, ie [ 19 F]-A2;
  • FIG 3 is a [18 F] -A6 by HPLC to confirm that the radioactive product [18 F] -A6 and [19 F] -A3 compound coinjection spectrum.
  • fluorine compounds if not stated generally refers to non-radioactive compound of [19 F] a. Accordingly, in the present invention for a particular compound, unless otherwise specified, it refers to a non-radioactive compound of [19 F] a.
  • diaryl sulfide derivative of the present invention and its preparation, as well as the high affinity for SERT, while having high selectivity to SERT with respect to DAT and NET, are more specifically illustrated by the following examples, but it is to be understood that the present invention The scope is not limited to these embodiments.
  • cis-2-butene-1,4-diol 3.16 mmol was dissolved in 15 ml of freshly distilled tetrahydrofuran (THF), and after ice-cooling for 10 min, 1.76 g (9.26 mmol) of p-toluenesulfonyl chloride was added, ice. After stirring for 10 min in the bath, 1 g of sodium tert-butoxide was added to give a white cream which was stirred overnight. After the reaction, the solvent was removed by a rotary evaporator, 20 ml of water was added, and the mixture was extracted three times with dichloromethane.
  • THF tetrahydrofuran
  • reaction solution was further stirred under ice bath for 1 h, and then reacted at room temperature for 3-4 h; after completion of the reaction, it was diluted with 20 ml of dichloromethane, and washed with 1 mol/L HCl solution, 5% Na 2 CO 3 solution and saturated brine. .
  • the reaction solution is added to 5 ml of water without cooling, and purified by Oasis HLB (reverse phase hydrophilic lipophilic column) column: firstly, the crude product is passed through the already processed Oasis HLB column at a rate of about one drop per second. The column was washed with 5 ml of water, blown dry, and blown with a stream of nitrogen for 2 min. The product was then directly rinsed with 1.5 ml of acetonitrile into the second reaction tube (containing 7.5 mg of sodium hydride, 2 mg of the second step precursor: 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl) 10 ml tube of -4-hydroxy)-benzene) thioether).
  • Oasis HLB reverse phase hydrophilic lipophilic column
  • Labeling yield total time of labeling was about 90 min, yield of labeled intermediate was 29.7%, yield of final product: 3.7% (calculated according to the activity of [ 18 F - ], the yield was not corrected by time), Oasis HLB column purification
  • the post product has a radiochemical purity of 64% and the main radioactive impurity is a radioactive intermediate.
  • HPLC conditions for analysis were as follows: solvent A: ACN (acetonitrile), solvent B: 20 mM AFB (ammonium formate); gradient: 0-3 min 95% B, 3-11 min 95%-5% B, 11-19 min 5%-95 %B, 19-21 min 95% B; column: Gemini 3 micron, 140 x 4.6 mm, column: Gemini 3u C18, 110 A, 150 x 4.6 mm, 3 micron.
  • the reaction solution was diluted with 0.5 ml of diethyl ether.
  • the reaction mixture was combined and passed through a silica gel cartridge (Sep-Pak silica) in one portion.
  • the product was initially purified using an Oasis HLB column: 5 ml of water was first added to the crude reaction product, and the mixture was passed through a pre-activated Oasis HLB column. The column was rinsed with 5 ml of water, pushed dry, and the product was rinsed with 1 ml of a 50% ethanol/water solution and was analyzed by HPLC (Fig. 3), [ 18 F]-A6.
  • Labeling yield total time of labeling was about 2 h, time-corrected yield was calculated as the [ 18 F - ] activity of the input: the yield of the labeled intermediate was about 25%, and the yield of the labeled [ 18 F]-A6 was about 1 2%.
  • the product has a radiochemical purity greater than 90% after initial purification by the Oasis cartridge.
  • HPLC conditions for analysis were as follows: solvent A: acetonitrile (ACN), solvent B: 20 mM AFB (ammonium formate); gradient: 0-3 min 95% B, 3-11 min 95%-5% B, 11-19 min 5%-95 %B, 19-21 min 95% B; column: Gemini 3 micron, 140 x 4.6 mm, column: Gemini 3u C18, 110 A, 150 x 4.6 mm, 3 micron.
  • Citalopram (Citalopram), GBR 12909 (varnostrine) and Nisoxetine (Nisoxetine), wherein Citalopram is a known SERT inhibition GBR 12909 is a known DAT inhibitor and Nisoxetine is a known NET inhibitor.
  • the Ki constant was determined by an in vitro competition experiment (data shown in Table 1 below).
  • Table 1 shows that the diaryl sulfide compound B ring 4 was bonded using different small molecular chains, the compound retained a high affinity for SERT.
  • the compounds A1 to A4 of the present invention all have a very high affinity for SERT, especially the compound A1 (0.09 ⁇ 0.01 nM) and A3 (0.02 ⁇ 0.003 nM).
  • binding experiments on DAT and NET showed that these compounds have poor affinity for DAT, and have a general affinity for NET, thereby exhibiting high selectivity.
  • Compound A3 has a DAT/SERT selectivity of up to 34,300 and a NET/SERT selectivity of up to 4010, which is expected to be a SERT imaging agent after labeling with 18 F.
  • Table 1 Competitive Binding Constants of Diaryl Thioether Series Derivatives with SERT, DAT, NET Receptors K i a

Abstract

Disclosed are a class of diarylsulfide derivatives, a preparation method therefor, and the use thereof as a serotonin transporter-targeted imaging agent, belonging to the field of radiopharmaceutical chemistry. The diarylsulfide derivative has the structural formula (1) below, this class of compounds exhibits a high affinity for central SERT, and at the same time exhibits a high selectivity for SERT relative to DAT (a dopamine transporter) and to NET (a norepinephrine transporter). Therefore, [18F]-diarylsulfide derivatives can be used as an SERT/PET imaging agent.

Description

二芳基硫醚衍生物、其制备方法以及作为五羟色胺转运体靶向显像剂的用途Diaryl sulfide derivative, preparation method thereof and use as target for serotonin transporter imaging agent 技术领域Technical field
本发明属于放射性药物化学领域，涉及一类二芳基硫醚衍生物、其制备方法以及作为五羟色胺转运体靶向显像剂的用途。The invention belongs to the field of radiopharmaceutical chemistry and relates to a class of diaryl sulfide derivatives, a preparation method thereof and the use as a serotonin transporter targeting imaging agent.
背景技术Background technique
五羟色胺转运体(SERT)是一种选择性五羟色胺(5-HT)跨膜转运蛋白。SERT能够重新摄取突触间隙的5-HT，从而调节神经信号的传导。在中枢神经***中，存在于神经元突触前膜的SERT，能够选择性地将神经递质5-HT由突触间隙转回到细胞内胞液中，从而终止该递质对突出后膜5-HT受体的作用，因而在5-HT释放后的再摄取过程中发挥极其重要的作用。研究表明，SERT浓度的变化与许多神经精神异常疾病有关，例如抑郁症、忧郁症、焦虑症、精神***、药物滥用、酒瘾、饮食失调、阿尔茲海默氏症(Alzheimer’s disease)以及帕金森氏症(Parkinson’s disease)等。SERT也是普遍使用的抗忧郁处方药物的主要作用靶点。The serotonin transporter (SERT) is a selective serotonin (5-HT) transmembrane transporter. SERT is able to reuptake 5-HT in the synaptic cleft, thereby regulating the transmission of neural signals. In the central nervous system, SERT present in the presynaptic membrane of neurons, capable of selectively transferring the neurotransmitter 5-HT from the synaptic cleft back into the intracellular cytosol, thereby terminating the transmitter to the posterior membrane The action of the 5-HT receptor thus plays an extremely important role in the reuptake process after 5-HT release. Studies have shown that changes in SERT concentrations are associated with many neuropsychiatric disorders such as depression, depression, anxiety, schizophrenia, drug abuse, alcohol addiction, eating disorders, Alzheimer's disease, and Parkinson's disease. Parkinson's disease, etc. SERT is also a major target for the widespread use of antidepressant prescription drugs.
正电子发射断层计算机扫描(PET)显像可以无创、动态、定量地研究人体内的化学过程和生理生化过程，在活体水平研究生命物质的代谢，受体的分布和功能，基因调控的变化等，这些使核医学的发展达到真正意义上的分子水平。PET显像离不开正电子核素标记的PET药物，其中18F正电子核素(半衰期为110分钟)比11C(半衰期为20分钟)具有相对较长的半衰期，适合商品化生产和运输，是当前PET显像药物的理想放射性核素，18F药物成为研究的热点。因此，以非侵入性的PET和单光子断层扫描(SPECT)活体显像技术研究SERT在脑部区域的分布，将有助于探讨5-HT***在神经精神性异常疾病的病理生理学及治疗上所扮演的角色，认识SERT密度的变化与精神紊乱疾病及精神退行性疾病病理的关系，也可为治疗药物作用机制研究、个体化治疗策略制定及疗效评估等提供非常有效的信息。Positron emission tomography (PET) imaging can study the chemical processes and physiological and biochemical processes in the human body in a non-invasive, dynamic and quantitative manner, and study the metabolism of living substances, the distribution and function of receptors, the changes of gene regulation, etc. at the living level. These make the development of nuclear medicine reach the true molecular level. PET imaging is inseparable from positron-labeled PET drugs, in which 18 F positron nuclides (half-life of 110 minutes) have a relatively long half-life compared to 11 C (half-life of 20 minutes), suitable for commercial production and transportation. It is the ideal radionuclide for current PET imaging drugs, and 18 F drugs have become a hot spot of research. Therefore, non-invasive PET and single photon tomography (SPECT) in vivo imaging techniques to study the distribution of SERT in the brain region will help to explore the pathophysiology and treatment of 5-HT system in neuropsychiatric disorders. The role played by understanding the relationship between changes in SERT density and the pathology of mental disorders and mental degenerative diseases can also provide very effective information for the study of therapeutic mechanism of action, individualized treatment strategies, and efficacy evaluation.
过去十多年中以SERT为靶点的显像剂的研究取得了较大的进展，国际上 开发出了一系列有潜力的化合物，目前有多个国家在进行该类显像剂的研发或者临床前研究，该领域已经成为当今世界在显像剂研究方面的热点，主要集中于托烷环类、硝基喹啉哌嗪类、二芳基硫醚类先导化合物的修饰方面。近年来，在二芳基醚类化合物上取得了突破性进展，发展了一批体内外性质优良的分子探针。该类化合物是基于抗抑郁药物moxifetin和403U76(其结构式如下)(Oya S.et al,5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol,J Med Chem,1999；42:333–335)发展而来的，合成简单，没有立体异构体的存在，分离纯化容易，在体内外具有较高的亲和性和选择性。其中用于SPECT显像的[123I]ADAM(其结构式如下)和用于PET显像的[11C]DASB(其结构式如下)已经用于人脑SERT的临床显像研究。但对于18F标记PET显像剂而言，目前还没有临床广泛应用的显像剂问世，国内外研究者正加紧研发具有SERT靶向特异结合的18F显像剂。The research on SERT-targeted imaging agents has made great progress in the past decade, and a series of potential compounds have been developed internationally. Currently, there are many countries that are developing such imaging agents or Preclinical research, this field has become a hot spot in the research of imaging agents in the world, mainly focusing on the modification of lead compounds, nitroquinoline piperazines, and diaryl sulfide precursors. In recent years, breakthroughs have been made in diaryl ether compounds, and a number of molecular probes with excellent properties in vitro and in vivo have been developed. This class of compounds is based on the antidepressant moxifetin and 403U76 (its structural formula is as follows) (Oya S. et al, 5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol, J Med Chem, 1999; 42: 333–335) developed, simple synthesis, no stereoisomers, easy separation and purification, high affinity and selectivity in vitro and in vivo. Among them, [ 123 I]ADAM for SPECT imaging (the structural formula is as follows) and [ 11 C]DASB for PET imaging (the structural formula is as follows) have been used for clinical imaging studies of human brain SERT. However, for 18 F-labeled PET imaging agents, there are no clinically widely available imaging agents, and researchers at home and abroad are stepping up the development of 18 F imaging agents with SERT targeted specific binding.
Figure PCTCN2017086045-appb-000001
Figure PCTCN2017086045-appb-000001
SERT又是抗抑郁药物的主要作用靶标，二芳基硫醚类配基与SERT具有靶向特异结合，其衍生物作为SERT抑制剂，已成为治疗抑郁症和精神神经疾病的药物。目前新的SERT靶向化合物还在继续研究，其目的是寻找性能更优秀的治疗药物。在SERT/PET显像剂的开发中，本发明人研究发现，当在骨架B环4位引入侧链(如下结构式所示)，能够调节该系列化合物的药代动力学性质，因此本发明人提供一种含F的二芳基硫醚类衍生物，在骨架B环4位引入了不同侧链，提高了与SERT的靶向结合性，从而改善目前此类化合物作为SERT显像剂存在的缺陷。同时，当用18F-标记作为放射性靶向药物研究时，使其具有更高的体内靶/非靶比值，更适宜的体内动力学性质，有望满足今后临床SERT显像需要。 SERT is also the main target of antidepressant drugs. The diaryl sulfide ligand has targeted specific binding to SERT. Its derivatives, as SERT inhibitors, have become drugs for the treatment of depression and neurosis. The new SERT targeting compounds are still being studied, with the aim of finding better therapeutic drugs. In the development of SERT/PET imaging agents, the inventors have found that when a side chain is introduced at the 4-position of the skeleton B ring (shown by the following structural formula), the pharmacokinetic properties of the series of compounds can be adjusted, and thus the inventors Providing a F-containing diaryl sulfide derivative, introducing different side chains at the 4-position of the backbone B ring, thereby enhancing the targeted binding to SERT, thereby improving the existence of such compounds as SERT imaging agents. defect. At the same time, when using 18 F - label as a radioactive targeted drug, it has a higher in vivo target/non-target ratio, and more suitable in vivo kinetic properties are expected to meet the needs of future clinical SERT imaging.
Figure PCTCN2017086045-appb-000002
Figure PCTCN2017086045-appb-000002
发明内容Summary of the invention
本发明的目的在于提供一种二芳基硫醚衍生物，该类化合物具有较高的脑内SERT(五羟色氨转运蛋白)特异性结合效果，同时具有较好的体内生物代谢性质，是较好的脑内摄取的靶向结合显像药物。The object of the present invention is to provide a diaryl sulfide derivative which has a high specific binding effect of SERT (quine serotonin transporter) in the brain and has good in vivo biological metabolic properties. A better targeted intracellular uptake combined with imaging drugs.
本发明的另一目的在于提供一种上述二芳基硫醚衍生物的制备方法。Another object of the present invention is to provide a process for producing the above diaryl sulfide derivative.
本发明的还一目的在于提供上述二芳基硫醚衍生物作为五羟色胺转运体靶向显像剂的用途。It is still another object of the present invention to provide the use of the above diaryl sulfide derivative as a serotonin transporter targeting imaging agent.
根据本发明的一个方面，本发明提供结构式如下的二芳基硫醚衍生物：According to one aspect of the invention, the invention provides a diaryl sulfide derivative of the formula:
Figure PCTCN2017086045-appb-000003
Figure PCTCN2017086045-appb-000003
其中，R为直接键、
Figure PCTCN2017086045-appb-000004
(n为1-4的自然数)、C1-4的亚烷基、未取代或C1-4烷基取代的-CH＝CH-或者-C≡C-；Where R is a direct key,
Figure PCTCN2017086045-appb-000004
(n is a natural number from 1 to 4), an alkylene group of C 1-4 , an unsubstituted or C 1-4 alkyl group-substituted -CH=CH- or -C≡C-;
Y为氟原子，可以为[18F]或者[19F]。Y is a fluorine atom and may be [ 18 F] or [ 19 F].
根据本发明的另一个方面，本发明提供一种上述二芳基硫醚衍生物的制备方法，该方法包括：在碱存在下，2-氨基苯-(2-(N,N-二甲基)氨甲基-4-羟基)-苯)硫醚与
Figure PCTCN2017086045-appb-000005
进行亲核取代反应，得到上述结构式所示的二芳基硫醚衍生物，其中所述的碱为碳酸钾、氢化钠或者碳酸铯等。该反应式如下：According to another aspect of the present invention, there is provided a process for the preparation of the above diaryl sulfide derivative, which comprises: 2-aminobenzene-(2-(N,N-dimethyl) in the presence of a base Aminomethyl-4-hydroxy)-phenyl) sulfide
Figure PCTCN2017086045-appb-000005
The nucleophilic substitution reaction is carried out to obtain a diaryl sulfide derivative represented by the above structural formula, wherein the base is potassium carbonate, sodium hydride or cesium carbonate. The reaction formula is as follows:
Figure PCTCN2017086045-appb-000006
Figure PCTCN2017086045-appb-000006
根据本发明的又一个方面，本发明的二芳基硫醚衍生物，为含有[19F]或[18F]的化合物，[19F]-二芳基硫醚衍生物表现出对中枢SERT的高亲合力，同时相对于DAT(多巴胺转运体)以及NET(去甲肾上腺素转运体)对SERT的高选择性。因此，相应的[18F]-二芳基硫醚衍生物，可以作为SERT/PET显像剂，这些化合物有望获得较高的脑摄取值，合理的药代动力学性质，有望开发出优良的SERT/PET显像剂。According to another aspect of the present invention, the diaryl sulfide derivative of the present invention, the compound is [18 F] of [19 F], or comprises, [19 F] - diaryl sulfide derivatives exhibit central SERT High affinity, while high selectivity for SERT relative to DAT (dopamine transporter) and NET (norepinephrine transporter). Therefore, the corresponding [ 18 F]-diaryl sulfide derivatives can be used as SERT/PET imaging agents, and these compounds are expected to have high brain uptake values and reasonable pharmacokinetic properties, and are expected to develop excellent ones. SERT/PET imaging agent.
附图说明DRAWINGS
图1为化合物A5经过OasisHLB柱子初步提纯后HPLC谱图中的放射性峰；Figure 1 is a radioactive peak in the HPLC spectrum of compound A5 after preliminary purification by OasisHLB column;
图2为化合物A5即[18F]-A5的HPLC确认，即放射性产物[18F]-A5与化合物A2即[19F]-A2共注射谱图；Figure 2 is a HPLC confirmation of the compound A5, [ 18 F]-A5, that is, a co-injection spectrum of the radioactive product [ 18 F]-A5 with the compound A2, ie [ 19 F]-A2;
图3为[18F]-A6的HPLC确认，即放射性产物[18F]-A6与[19F]-A3化合物共注射谱图。FIG 3 is a [18 F] -A6 by HPLC to confirm that the radioactive product [18 F] -A6 and [19 F] -A3 compound coinjection spectrum.
具体实施方式detailed description
下面更具体地描述本发明。The invention is described more specifically below.
在有机化学领域，对于氟化合物，如果没有说明，一般是指非放射性的[19F]的化合物。因此，在本发明中对于具体的化合物，如果没有特别指明，则是指非放射性的[19F]的化合物。In the field of organic chemistry, fluorine compounds, if not stated generally refers to non-radioactive compound of [19 F] a. Accordingly, in the present invention for a particular compound, unless otherwise specified, it refers to a non-radioactive compound of [19 F] a.
在本发明优选的实施方案中，所述二芳基硫醚衍生物，其中，R优选为
Figure PCTCN2017086045-appb-000007
(n为1-4的自然数)、-CH＝CH-或者-C≡C-。In a preferred embodiment of the invention, the diaryl sulfide derivative, wherein R is preferably
Figure PCTCN2017086045-appb-000007
(n is a natural number of 1-4), -CH=CH- or -C≡C-.
通过以下实施例更具体地说明本发明的二芳基硫醚衍生物及其制备，以及对SERT的高亲合力，同时相对于DAT和NET对SERT的高选择性，但要理解的是本发明的范围不限于这些实施例。The diaryl sulfide derivative of the present invention and its preparation, as well as the high affinity for SERT, while having high selectivity to SERT with respect to DAT and NET, are more specifically illustrated by the following examples, but it is to be understood that the present invention The scope is not limited to these embodiments.
实施例1Example 1
二芳基硫醚衍生物的合成Synthesis of diaryl sulfide derivatives
2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(2-(2-氟乙氧基)-乙氧基)-苯)硫醚(化 合物A1)的合成2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(2-(2-fluoroethoxy)-ethoxy)-benzene) sulfide Synthesis of Compound A1)
合成反应方程式：Synthetic reaction equation:
Figure PCTCN2017086045-appb-000008
Figure PCTCN2017086045-appb-000008
合成方法：resolve resolution:
将0.15-0.2mmol 2-氨基苯-(2-(N,N-二甲基)甲氨基-4-羟基)-苯)硫醚(合成参考文献：(Shunichi Oya et al,Nuclear Medicine and Biology,34(2007),129–139)溶解在4ml DMF(HPLC纯)中，加入2倍摩尔量的碳酸钾以及1-对甲苯磺酰基-2-氟乙氧基乙烷(1.2倍摩尔量)，之后通入氮气3-5min，将反应液在80-90℃条件下油浴加热过夜。反应完成后加入30ml水终止反应，并用乙酸乙酯萃取产物，合并有机相并使用无水硫酸钠干燥，然后通过硅胶柱提纯，所使用的淋洗液为甲醇:二氯甲烷:二乙胺＝4:100:1(体积比)，得到目标产物化合物A1，产率：24.8％。0.15-0.2 mmol of 2-aminobenzene-(2-(N,N-dimethyl)methylamino-4-hydroxy)-benzene) sulfide (Synichi Oya et al, Nuclear Medicine and Biology, 34 (2007), 129-139) dissolved in 4 ml of DMF (HPLC pure), adding 2 times the molar amount of potassium carbonate and 1-p-toluenesulfonyl-2-fluoroethoxyethane (1.2 times the molar amount), After the reaction was carried out for 5 to 5 minutes, the reaction mixture was heated overnight in an oil bath at 80-90 ° C. After the reaction was completed, 30 ml of water was added to terminate the reaction, and the product was extracted with ethyl acetate. After purification by a silica gel column, the eluent used was methanol:dichloromethane:diethylamine=4:100:1 (volume ratio) to give the desired product compound A1, yield: 24.8%.
化合物A1的确认：Confirmation of Compound A1:
1H NMR(200MHz,CDCl3)δ2.37(s,6H),3.59(s,2H),3.65-3.75(m,1H),3.80-3.92(m,3H),4.05-4.20(m,2H),4.46-4.50(m,1H),4.70-4.74(m,1H),6.68-6.72(m,3H),6.89-7.02(m,2H),7.10-7.17(m,1H),7.35-7.45(m,1H)。 1 H NMR (200MHz, CDCl 3 ) δ2.37 (s, 6H), 3.59 (s, 2H), 3.65-3.75 (m, 1H), 3.80-3.92 (m, 3H), 4.05-4.20 (m, 2H ), 4.46-4.50 (m, 1H), 4.70-4.74 (m, 1H), 6.68-6.72 (m, 3H), 6.89-7.02 (m, 2H), 7.10-7.17 (m, 1H), 7.35-7.45 (m, 1H).
LRMS(M++1)：理论值365.16，实测值：365.1674LRMS (M + +1): theoretical 365.16, found: 365.1674
实施例2Example 2
二芳基硫醚衍生物的合成Synthesis of diaryl sulfide derivatives
2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(2-(2-(2-氟乙氧基)-乙氧基)-乙氧基)-苯)硫醚(化合物A2)的合成2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(2-(2-(2-fluoroethoxy)-ethoxy)-ethoxy)-benzene) Synthesis of Thioether (Compound A2)
合成反应方程式：Synthetic reaction equation:
Figure PCTCN2017086045-appb-000009
Figure PCTCN2017086045-appb-000009
将0.15-0.2mmol 2-氨基苯-(2-(N,N-二甲基)氨甲基-4-羟基)-苯)硫醚溶解在4ml DMF中(HPLC纯)，加入2倍摩尔量的碳酸钾以及1-对甲苯磺酰基-(2-(2-氟乙氧基)-乙氧基)乙烷(1.2倍摩尔量)，之后通入氮气3-5min，将反应液在80-90℃条件下油浴加热过夜。反应完后加入30ml水终止反应，并用乙酸乙酯萃取产物，合并有机相混合并使用无水硫酸钠干燥，然后通过硅胶柱提纯，所使用的淋洗液为甲醇:二氯甲烷:二乙胺＝4:100:1(体积比)，得到目标产物化合物A2，产率：22.6％。Dissolve 0.15-0.2 mmol of 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-hydroxy)-benzene) sulfide in 4 ml of DMF (HPLC pure), add 2 times molar amount Potassium carbonate and 1-p-toluenesulfonyl-(2-(2-fluoroethoxy)-ethoxy)ethane (1.2 times molar amount), followed by nitrogen gas for 3-5 min, the reaction solution was at 80- The oil bath was heated overnight at 90 °C. After the completion of the reaction, the reaction was quenched by the addition of 30 ml of water, and the product was extracted with ethyl acetate. The combined organic phases were combined and dried over anhydrous sodium sulfate and then purified by silica gel column eluting with methanol: dichloromethane: diethylamine = 4:100:1 (volume ratio), the target product compound A2 was obtained, yield: 22.6%.
化合物A2的确认：Confirmation of Compound A2:
1H NMR(200MHz,CDCl3)δ2.37(s,6H),3.69-3.82(m,7H),3.83-3.88(m,3H),4.09-4.21(m,2H),4.44-4.48(m,1H),4.68-4.72(m,1H),6.68-6.74(m,3H),6.94-6.98(m,2H),7.12-7.22(m,1H),7.38-7.42(m,1H)。 1 H NMR (200MHz, CDCl 3 ) δ 2.37 (s, 6H), 3.69-3.82 (m, 7H), 3.83-3.88 (m, 3H), 4.09-4.21 (m, 2H), 4.44-4.48 (m) , 1H), 4.68-4.72 (m, 1H), 6.68-6.74 (m, 3H), 6.94-6.98 (m, 2H), 7.12-7.22 (m, 1H), 7.38-7.42 (m, 1H).
LRMS(M++1):理论值409.19，实测值409.1959。LRMS (M + +1): Theory 409.19, found 409.1959.
实施例3Example 3
二芳基硫醚衍生物的合成Synthesis of diaryl sulfide derivatives
2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(顺-4-氟代-2-烯丁氧基)-苯)硫醚(化合物A3)的合成Synthesis of 2-Aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(cis-4-fluoro-2-butoxy)-benzene) Sulfide (Compound A3)
合成反应方程式：Synthetic reaction equation:
Figure PCTCN2017086045-appb-000010
Figure PCTCN2017086045-appb-000010
合成方法：resolve resolution:
①1,4-二对甲苯磺酰基-2-丁烯的制备Preparation of 11,4-di-p-toluenesulfonyl-2-butene
将0.3ml的顺-2-丁烯-1,4-二醇(3.16mmol)溶解在15ml新蒸四氢呋喃(THF)中，冰浴10min后，加入对甲苯磺酰氯1.76克(9.26mmol)，冰浴下搅拌10min后，加入1克叔丁醇钠，得到白色乳状物，继续搅拌过夜。反应完后用旋转蒸发仪除去溶剂，加入20ml水，并用二氯甲烷萃取三次，合并有机相，经无水硫酸钠干燥后通过柱层析法提纯，淋洗液为乙酸乙酯:石油醚 ＝1:4(体积比)，得到1,4-二对甲苯磺酰基-2-丁烯。产率:12.2％。0.3 ml of cis-2-butene-1,4-diol (3.16 mmol) was dissolved in 15 ml of freshly distilled tetrahydrofuran (THF), and after ice-cooling for 10 min, 1.76 g (9.26 mmol) of p-toluenesulfonyl chloride was added, ice. After stirring for 10 min in the bath, 1 g of sodium tert-butoxide was added to give a white cream which was stirred overnight. After the reaction, the solvent was removed by a rotary evaporator, 20 ml of water was added, and the mixture was extracted three times with dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate and purified by column chromatography. =1: 4 (volume ratio), 1,4-di-p-toluenesulfonyl-2-butene was obtained. Yield: 12.2%.
②1-氟代-4-对甲苯磺酰基-2-丁烯的制备Preparation of 21-fluoro-4-p-toluenesulfonyl-2-butene
将1mmol 1,4-二对甲苯磺酰基-2-丁烯加入两口圆底烧瓶中，并加入3ml乙腈将其溶解，然后加入1ml 1mol/L四正丁基氟化铵的四氢呋喃溶液(1mol/L溶液)，通氮气3min后将反应液在80℃条件下加热30min，移除溶剂并且将所得紫色油状混合物溶于10ml***中，并加入10ml 5％Na2CO3溶液，使粗产物在两相间平衡10min。之后，使用***进行萃取(10ml×2)，合并有机相并用无水硫酸钠干燥，然后使用硅胶柱进行提纯，淋洗液为乙酸乙酯：石油醚＝1:4(体积比)，得到1-氟代-4-对甲苯磺酰基-2-丁烯。产率:19.8％。1 mmol of 1,4-di-p-toluenesulfonyl-2-butene was added to a two-neck round bottom flask, and dissolved in 3 ml of acetonitrile, and then 1 ml of a solution of 1 mol/L tetra-n-butylammonium fluoride in tetrahydrofuran (1 mol/) was added. L solution), after passing nitrogen for 3 min, the reaction solution was heated at 80 ° C for 30 min, the solvent was removed and the obtained purple oily mixture was dissolved in 10 ml of diethyl ether, and 10 ml of 5% Na 2 CO 3 solution was added to make the crude product in two The phase is balanced for 10 min. After that, it was extracted with diethyl ether (10 ml × 2), and the organic phase was combined and dried over anhydrous sodium sulfate, and then purified using silica gel column, ethyl acetate: petroleum ether = 1:4 (volume ratio) - Fluoro-4-p-toluenesulfonyl-2-butene. Yield: 19.8%.
③2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(顺-4-氟代-2-烯丁氧基)-苯)硫醚的制备Preparation of 32-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(cis-4-fluoro-2-enebutoxy)-benzene) sulfide
将0.15-0.2mmol 2-氨基苯-(2-(N,N-二甲基)氨甲基-4-羟基)-苯)硫醚溶解在4ml DMF中(HPLC纯)，加入2倍摩尔量的碳酸钾以及1-氟代-4-对甲苯磺酰基-2-丁烯(1.2倍摩尔量)，之后通入氮气3-5min，将反应液在80-90℃条件下油浴加热过夜。反应完后加入30ml水终止反应，并用乙酸乙酯萃取产物，合并有机相并使用无水硫酸钠干燥，然后通过硅胶柱提纯，所使用的淋洗液为甲醇:二氯甲烷:二乙胺＝4:100:1(体积比)，得到目标产物化合物A3，产率：17％。Dissolve 0.15-0.2 mmol of 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-hydroxy)-benzene) sulfide in 4 ml of DMF (HPLC pure), add 2 times molar amount Potassium carbonate and 1-fluoro-4-p-toluenesulfonyl-2-butene (1.2 times molar amount), followed by nitrogen gas for 3-5 min, and the reaction solution was heated in an oil bath at 80-90 ° C overnight. After the completion of the reaction, the reaction was quenched by the addition of 30 ml of water, and the product was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate, and then purified by silica gel column using methanol: dichloromethane: diethylamine = 4:100:1 (volume ratio), the target product compound A3 was obtained, yield: 17%.
结构确认：Structure confirmation:
①化合物1,4-二对甲苯磺酰基-2-丁烯1 compound 1,4-di-p-toluenesulfonyl-2-butene
1H NMR(400MHz,CDCl3):δ2.39(s,6H),4.47(d,J＝5.85Hz,4H),5.60-5.62(m,2H),7.28(d,J＝8.08Hz,4H),7.69(d,J＝8.20Hz,4H)； 1 H NMR (400MHz, CDCl 3 ): δ2.39 (s, 6H), 4.47 (d, J = 5.85Hz, 4H), 5.60-5.62 (m, 2H), 7.28 (d, J = 8.08Hz, 4H ), 7.69 (d, J = 8.20 Hz, 4H);
②化合物1-氟-4-对甲苯磺酰基-2-丁烯2 compound 1-fluoro-4-p-toluenesulfonyl-2-butene
1H NMR(400MHz,CDCl3):δ2.38(s,3H),4.57(d,J＝6.6Hz 2H),4.83(dd,J＝46.6,5.64Hz,2H),5.58-5.64(m,1H),5.70-5.76(m,1H),7.28(d,J＝8.12Hz,2H),7.72(d,J＝8.12Hz,2H)； 1 H NMR (400MHz, CDCl 3 ): δ2.38 (s, 3H), 4.57 (d, J = 6.6Hz 2H), 4.83 (dd, J = 46.6,5.64Hz, 2H), 5.58-5.64 (m, 1H), 5.70-5.76 (m, 1H), 7.28 (d, J = 8.12 Hz, 2H), 7.72 (d, J = 8.12 Hz, 2H);
③化合物A3的确认：1H NMR(200MHz,CDCl3)δ2.34(s,6H),3.60(s,2H),4.75(dt,JFH＝5.2Hz,JHH＝1.4Hz,2H),4.99(dd,JFH＝47Hz,JHH＝1.6Hz,2H),5.88-5.91(m,2H)6.72-6.77(m,3H),6.90-6.98(m,2H),7.16-7.19(m,1H), 7.42-7.46(m,1H).13C NMR(50MHz,CDCl3)δ43,62,65,81,114,116,116.5,117,126.5,127,129,129.5,130,132,135,148,157.3 confirmation of compound A3: 1 H NMR (200 MHz, CDCl 3 ) δ 2.34 (s, 6H), 3.60 (s, 2H), 4.75 (dt, J FH = 5.2 Hz, J HH = 1.4 Hz, 2H), 4.99 (dd, J FH = 47 Hz, J HH = 1.6 Hz, 2H), 5.88-5.91 (m, 2H) 6.72-6.77 (m, 3H), 6.90-6.98 (m, 2H), 7.16-7.19 (m, 1H), 7.42-7.46 (m, 1H). 13 C NMR (50MHz, CDCl 3 ) δ 43, 62, 65, 81, 114, 116, 116.5, 117, 126.5, 127, 129, 129.5, 130, 132, 135, 148, 157.
LRMS(M++1):理论值:347.16，实测值:347.1592.LRMS (M + +1): Theoretical value: 347.16, found: 347.1592.
实施例4Example 4
二芳基硫醚衍生物的合成Synthesis of diaryl sulfide derivatives
2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(4-氟代-2-炔丁氧基)-苯)硫醚(化合物A4)的合成Synthesis of 2-Aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(4-fluoro-2-acetylbutoxy)-benzene) Sulfide (Compound A4)
合成反应方程式：Synthetic reaction equation:
Figure PCTCN2017086045-appb-000011
Figure PCTCN2017086045-appb-000011
合成方法：resolve resolution:
①化合物1,4-二对甲苯磺酰基-2-丁炔的制备Preparation of a compound 1,4-di-p-toluenesulfonyl-2-butyne
在圆底烧瓶中，将相应的10mmol的1,4-丁炔二醇(860mg)溶解在10ml的二氯甲烷中，冰浴降温至0℃，逐滴加入1.4ml三乙胺(20mmol)，以及20mg 4-N,N-二甲基吡啶，之后继续搅拌溶液5min；并将3.8g TsCl溶解在3ml二氯甲烷中，通过恒压滴液漏斗逐滴加入到圆底烧瓶中，滴完后，反应液继续在冰浴条件下搅拌1h，后于室温反应3-4h；反应完后加入20ml二氯甲烷稀释，并用1mol/L HCl溶液、5％Na2CO3溶液、饱和食盐水依次洗涤。洗涤后的有机相经过无水硫酸钠干燥后，使用旋转蒸发仪除去溶剂，并用硅胶柱提纯，淋洗液为乙酸乙酯：石油醚＝1:4(体积比)，得到1,4-二对甲苯磺酰基-2-丁炔。In a round bottom flask, the corresponding 10 mmol of 1,4-butynediol (860 mg) was dissolved in 10 ml of dichloromethane, cooled to 0 ° C in an ice bath, and 1.4 ml of triethylamine (20 mmol) was added dropwise. And 20 mg of 4-N,N-lutidine, after which the solution was stirred for 5 min; 3.8 g of TsCl was dissolved in 3 ml of dichloromethane, and added dropwise to a round bottom flask through a constant pressure dropping funnel. The reaction solution was further stirred under ice bath for 1 h, and then reacted at room temperature for 3-4 h; after completion of the reaction, it was diluted with 20 ml of dichloromethane, and washed with 1 mol/L HCl solution, 5% Na 2 CO 3 solution and saturated brine. . The organic phase after washing was dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator, and purified by silica gel column, ethyl acetate: petroleum ether = 1:4 (volume ratio) to give 1,4- p-Toluenesulfonyl-2-butyne.
②化合物1-氟代-4-对甲苯磺酰基-2-丁炔的制备Preparation of 2 compound 1-fluoro-4-p-toluenesulfonyl-2-butyne
将1mmol的1,4-二对甲苯磺酰基-2-丁炔加入到两口圆底烧瓶中，并加入3ml乙腈将其溶解，然后加入1ml 1mol/L四正丁基氟化铵的四氢呋喃溶液， 通氮气3min后，将反应液在80℃条件下加热30min，移除溶剂并且将所得紫色油状混合物溶于10ml***，并加入10ml 5％Na2CO3溶液，让粗产物在两相间平衡10min。之后，使用***进行萃取(10ml×2)，合并有机相并用无水硫酸钠干燥，使用硅胶柱提纯产物，淋洗液为乙酸乙酯：石油醚＝1:6(体积比)，得到1-氟代-4-对甲苯磺酰基-2-丁炔。产率：42％。1 mmol of 1,4-di-p-toluenesulfonyl-2-butyne was added to a two-neck round bottom flask, and dissolved in 3 ml of acetonitrile, and then 1 ml of a solution of 1 mol/L tetra-n-butylammonium fluoride in tetrahydrofuran was added. After passing nitrogen for 3 min, the reaction was heated at 80 ° C for 30 min, solvent was removed and the obtained purple oily mixture was dissolved in 10 ml of diethyl ether, and 10 ml of 5% Na 2 CO 3 solution was added, and the crude product was allowed to equilibrate between the two phases for 10 min. After that, it was extracted with diethyl ether (10 ml × 2), and the organic phase was combined and dried over anhydrous sodium sulfate, and the product was purified using silica gel column, ethyl acetate: petroleum ether = 1:6 (volume ratio) to give 1- Fluoro-4-p-toluenesulfonyl-2-butyne. Yield: 42%.
③2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(4-氟代-2-炔丁氧基)-苯)硫醚的制备Preparation of 32-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(4-fluoro-2-acetylbutoxy)-benzene) sulfide
将0.15-0.2mmol 2-氨基苯-(2-(N,N-二甲基)氨甲基-4-羟基)-苯)硫醚溶解在4ml DMF中(HPLC纯)，加入2倍摩尔量的碳酸钾以及1-氟代-4-对甲苯磺酰基-2-丁炔(1.2倍摩尔量)，之后通入氮气3-5min，将反应液在80-90℃条件下油浴加热过夜，反应完后加入30ml水终止反应，并用乙酸乙酯萃取产品，将有机相混合后使用无水硫酸钠干燥，并通过硅胶柱提纯。淋洗液为甲醇：二氯甲烷：二乙胺＝4:100:1(体积比)，得到目标产物，产率：22.1％。Dissolve 0.15-0.2 mmol of 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-hydroxy)-benzene) sulfide in 4 ml of DMF (HPLC pure), add 2 times molar amount Potassium carbonate and 1-fluoro-4-p-toluenesulfonyl-2-butyne (1.2 times molar amount), followed by nitrogen gas for 3-5 min, and the reaction solution was heated in an oil bath at 80-90 ° C overnight. After the reaction, the reaction was quenched by the addition of 30 ml of water, and the product was extracted with ethyl acetate. The eluent was methanol:dichloromethane:diethylamine = 4:100:1 (volume ratio) to give the desired product, yield: 22.1%.
结构确认：Structure confirmation:
①化合物1,4-二对甲苯磺酰基-2-丁炔1 compound 1,4-di-p-toluenesulfonyl-2-butyne
1H NMR(400MHz,CDCl3):δ2.40(s,6H),4.51(s,4H),7.28(d,J＝8.12Hz,4H),7.69(d,J＝8.24Hz,4H)； 1 H NMR (400MHz, CDCl 3 ): δ2.40 (s, 6H), 4.51 (s, 4H), 7.28 (d, J = 8.12Hz, 4H), 7.69 (d, J = 8.24Hz, 4H);
②化合物1-氟代-4-对甲苯磺酰基-2-丁炔2 compound 1-fluoro-4-p-toluenesulfonyl-2-butyne
1H NMR(400MHz,CDCl3):δ2.38(s,3H),4.67-4.70(m,2H),4.77(d,J＝45.6Hz,2H),7.29(d,J＝8.04Hz,2H),7.74(d,J＝8.04Hz,2H)； 1 H NMR (400MHz, CDCl 3 ): δ2.38 (s, 3H), 4.67-4.70 (m, 2H), 4.77 (d, J = 45.6Hz, 2H), 7.29 (d, J = 8.04Hz, 2H ), 7.74 (d, J = 8.04 Hz, 2H);
③化合物2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(4-氟代-2-炔丁氧基)-苯)硫醚3 compound 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(4-fluoro-2-alkynyloxy)-benzene) sulfide
1H NMR(200MHz,CDCl3)δ2.34(s,6H),3.60(s,2H),4.72-4.77(m,2H),4.99(dd,JFH＝47Hz,JHH＝1.6Hz,2H),6.71-6.77(m,3H),6.91-6.98(m,2H),7.15-7.20(m,1H),7.42-7.46(m,1H)；13C NMR(50MHz,CDCl3)δ43,56,62,68,72,85,115,115.5,117,119,128,130,136,138,148,155。 1 H NMR (200MHz, CDCl 3 ) δ2.34 (s, 6H), 3.60 (s, 2H), 4.72-4.77 (m, 2H), 4.99 (dd, J FH = 47Hz, J HH = 1.6Hz, 2H ), 6.71-6.77 (m, 3H), 6.91-6.98 (m, 2H), 7.15-7.20 (m, 1H), 7.42-7.46 (m, 1H); 13 C NMR (50 MHz, CDCl 3 ) δ 43, 56 , 62, 68, 72, 85, 115, 115.5, 117, 119, 128, 130, 136, 138, 148, 155.
LRMS(M++1):理论值345.13，实测值345.1391。LRMS (M + +1): theoretical value 345.13, found 345.1391.
实施例5Example 5
[18F]-2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(2-(2-(2-氟乙氧基)-乙氧基)-乙 氧基)-苯)硫醚(化合物A5)的合成[ 18 F]-2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(2-(2-(2-fluoroethoxy)-ethoxy)-ethoxy Synthesis of phenyl)-phenyl)thioether (Compound A5)
Figure PCTCN2017086045-appb-000012
Figure PCTCN2017086045-appb-000012
(1)[18F]-1-对甲苯磺酰基-2-((2-氟乙氧基)-乙氧基))乙烷的制备(1) Preparation of [ 18 F]-1-p-toluenesulfonyl-2-((2-fluoroethoxy)-ethoxy))ethane
干燥[18F]KF/K222的准备：将水溶液中的[18F-]一次性通过QMA小柱(4-(4-甲基哌啶)吡啶阴离子交换树脂小柱)并推干，后使用11mg K222/2mg K2CO3溶液(0.8ml乙腈,0.2ml水)淋洗下放射性活度。之后将所得溶液在100℃条件下吹干，并依次加入2ml无水乙腈(每次1ml)吹干，得干燥[18F]KF/K222。Preparation of dry [ 18 F]KF/K222: [ 18 F - ] in aqueous solution is passed through a QMA cartridge (4-(4-methylpiperidine)pyridine anion exchange resin cartridge) and pushed dry, then used The radioactivity was eluted with 11 mg K222/2 mg K 2 CO 3 solution (0.8 ml acetonitrile, 0.2 ml water). Thereafter, the resulting solution was dried at 100 ° C, and dried by adding 2 ml of anhydrous acetonitrile (1 ml each time) to dry [ 18 F]KF/K 222.
将2mg的1-对甲苯磺酰基-2-((2-对甲苯磺酰基乙氧基)-乙氧基)-乙烷前体溶于1ml无水乙腈中，加入制备好的干燥的[18F]KF/K222中。充分摇荡均匀后置于85℃环境中加热5min，停止加热进行提纯。2 mg of 1-p-toluenesulfonyl-2-((2-p-toluenesulfonylethoxy)-ethoxy)-ethane precursor was dissolved in 1 ml of anhydrous acetonitrile and added to the prepared dry [ 18] F] KF/K222. After fully shaking, it was heated in an environment of 85 ° C for 5 min, and heating was stopped for purification.
提纯方式：反应液无需冷却即加入5ml水，通过Oasis HLB(反相亲水亲脂小柱)柱子提纯：首先将粗产品一次性以约每秒一滴的速度通过已经处理好的Oasis HLB柱子，使用5ml水洗柱子，吹干，并且用氮气流吹2min。之后用1.5ml乙腈直接淋洗产品至第二步反应管中(含有7.5mg氢化钠，2mg第二步前体：2-氨基苯-(2-(N,N-二甲基)氨甲基-4-羟基)-苯)硫醚的10ml试管)。Purification method: the reaction solution is added to 5 ml of water without cooling, and purified by Oasis HLB (reverse phase hydrophilic lipophilic column) column: firstly, the crude product is passed through the already processed Oasis HLB column at a rate of about one drop per second. The column was washed with 5 ml of water, blown dry, and blown with a stream of nitrogen for 2 min. The product was then directly rinsed with 1.5 ml of acetonitrile into the second reaction tube (containing 7.5 mg of sodium hydride, 2 mg of the second step precursor: 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl) 10 ml tube of -4-hydroxy)-benzene) thioether).
(2)[18F]-2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(2-(2-(2-氟乙氧基)-乙氧基)-乙氧基)-苯)硫醚(化合物A5)的制备(2) [ 18 F]-2-Aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(2-(2-(2-fluoroethoxy)-ethoxy) -Ethoxy)-benzene) thioether (Compound A5) preparation
在氮气流条件下把上述加入了[18F]-1-对甲苯磺酰基-2-((2-氟乙氧基)-乙氧基))乙烷的试管中的溶液在120℃条件下吹干。然后加入1ml无水DMF，摇匀后继续在120℃条件下反应15min，反应结束使用Oasis HLB柱子初步提纯产品：即先往反应粗产物中加入5ml水，将混合液一次性通过预先活化好的OasisHLB柱子。使用5ml水淋洗柱子，推干，并使用1ml乙醇淋洗产物，用HPLC检测(参见图1)，最终用半制备HPLC分离纯化即可得到18F标记目标 产物[18F]-A5。The above solution in a test tube to which [ 18 F]-1-p-toluenesulfonyl-2-((2-fluoroethoxy)-ethoxy))ethane was added under a nitrogen stream at 120 ° C Blow dry. Then add 1 ml of anhydrous DMF, shake well and continue to react at 120 ° C for 15 min. At the end of the reaction, the product is initially purified using Oasis HLB column: firstly, 5 ml of water is added to the crude reaction product, and the mixture is pre-activated once. OasisHLB pillars. The column was rinsed with 5 ml of water, pushed dry, and the product was rinsed with 1 ml of ethanol, detected by HPLC (see Figure 1), and finally purified by semi-preparative HPLC to obtain the 18 F-labeled target product [ 18 F]-A5.
标记产率：标记总体时间约90min，标记中间体产率29.7％，最终产物产率：3.7％(按照投入的[18F-]的活度计算，产率未经时间校正)，OasisHLB柱子提纯后产品放射化学纯度为64％，主要放射性杂质是放射性中间体。Labeling yield: total time of labeling was about 90 min, yield of labeled intermediate was 29.7%, yield of final product: 3.7% (calculated according to the activity of [ 18 F - ], the yield was not corrected by time), Oasis HLB column purification The post product has a radiochemical purity of 64% and the main radioactive impurity is a radioactive intermediate.
[18F]-A5的结构确证为将如上所述制得的标记产物[18F]-A5与实施例2制备的化合物A2即[19F]-A2，在相同的条件下共注射进行HPLC分析，通过比对保留时间进行确认(参见图2)。The structure of [ 18 F]-A5 confirmed that the labeled product [ 18 F]-A5 prepared as described above and the compound A2 prepared in Example 2, [ 19 F]-A 2 , were co-injected under the same conditions for HPLC. Analysis, by confirming the retention time (see Figure 2).
分析用HPLC条件如下：溶剂A:ACN(乙腈)，溶剂B:20mM AFB(甲酸铵)；梯度：0-3min 95％B，3-11min 95％-5％B，11-19min 5％-95％B，19-21min 95％B；柱子：Gemini 3micron,140x 4.6mm,column:Gemini 3u C18,110A,150×4.6mm,3micron。The HPLC conditions for analysis were as follows: solvent A: ACN (acetonitrile), solvent B: 20 mM AFB (ammonium formate); gradient: 0-3 min 95% B, 3-11 min 95%-5% B, 11-19 min 5%-95 %B, 19-21 min 95% B; column: Gemini 3 micron, 140 x 4.6 mm, column: Gemini 3u C18, 110 A, 150 x 4.6 mm, 3 micron.
实施例6Example 6
[18F]-2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(顺-4-氟代-2-烯丁氧基)-苯)硫醚(化合物A6)的合成[ 18 F]-2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(cis-4-fluoro-2-enebutoxy)-benzene) sulfide (compound) Synthesis of A6)
Figure PCTCN2017086045-appb-000013
Figure PCTCN2017086045-appb-000013
(1)[18F]-1-氟代-4-对甲苯磺酰基-2-丁烯的制备(1) Preparation of [ 18 F]-1-fluoro-4-p-toluenesulfonyl-2-butene
干燥[18F]KF/K222的准备同实施例5。The preparation of dry [ 18 F]KF/K222 was the same as in Example 5.
将3mg的1,4-二对甲苯磺酰基-2-丁烯前体溶于1ml无水乙腈中，加入制备好的干燥的[18F]KF/K222中。充分摇荡均匀后置于60℃环境中加热10min，停止加热进行提纯。3 mg of the 1,4-di-p-toluenesulfonyl-2-butene precursor was dissolved in 1 ml of anhydrous acetonitrile and added to the prepared dry [ 18 F]KF/K222. After fully shaking, it was heated in an environment of 60 ° C for 10 min, and heating was stopped for purification.
提纯方式：使用0.5ml***稀释反应液。将反应液合并，并一次性通过硅胶小柱(Sep-Pak silica)后使用1.5ml***将放射性中间体淋下。Purification method: The reaction solution was diluted with 0.5 ml of diethyl ether. The reaction mixture was combined and passed through a silica gel cartridge (Sep-Pak silica) in one portion.
(2)[18F]-2-氨基苯-(2-(N,N-二甲基)氨甲基-4-(顺-4-氟代-2-烯丁氧基)-苯)硫醚(化合物A6)制备 (2) [ 18 F]-2-Aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-(cis-4-fluoro-2-enebutoxy)-benzene)sulfur Preparation of ether (compound A6)
在氮气流条件下把加入了[18F]-1-氟代-4-对甲苯磺酰基-2-丁烯的试管中的***在60℃条件下吹干。然后加入1ml无水DMF，摇匀后，转移到含有7.5mg碳酸铯，2mg 2-氨基苯-(2-(N,N-二甲基)氨甲基-4-羟基)-苯)硫醚的试管中。混合均匀，并在20℃室温下反应10min。反应结束使用OasisHLB柱子初步提纯产品：即先往反应粗产物中加入5ml水，将混合液一次性通过预先活化好的OasisHLB柱子。使用5ml水淋洗柱子，推干，并使用1ml 50％乙醇/水溶液淋洗产物，用HPLC检测(图3)，[18F]-A6。The ether in a test tube to which [ 18 F]-1-fluoro-4-p-toluenesulfonyl-2-butene was added was dried at 60 ° C under a nitrogen stream. Then add 1 ml of anhydrous DMF, shake well, transfer to contain 7.5 mg of cesium carbonate, 2 mg of 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-hydroxy)-benzene) thioether In the test tube. Mix well and react at room temperature of 20 ° C for 10 min. At the end of the reaction, the product was initially purified using an Oasis HLB column: 5 ml of water was first added to the crude reaction product, and the mixture was passed through a pre-activated Oasis HLB column. The column was rinsed with 5 ml of water, pushed dry, and the product was rinsed with 1 ml of a 50% ethanol/water solution and was analyzed by HPLC (Fig. 3), [ 18 F]-A6.
标记产率：标记总体时间约2h，以投入的[18F-]活度计算的不经时间校正产率：标记中间体产率约25％，[18F]-A6标记产率约1-2％。经过Oasis小柱初步提纯后的产品放射化学纯度大于90％。Labeling yield: total time of labeling was about 2 h, time-corrected yield was calculated as the [ 18 F - ] activity of the input: the yield of the labeled intermediate was about 25%, and the yield of the labeled [ 18 F]-A6 was about 1 2%. The product has a radiochemical purity greater than 90% after initial purification by the Oasis cartridge.
[18F]-A6的结构确证为将如上所述制得的标记产物[18F]-A6与实施例3制备的化合物A3即[19F]-A3，在相同的条件下共注射进行HPLC分析，通过比对保留时间进行确认(参见图3)。The structure of [ 18 F]-A6 confirmed that the labeled product [ 18 F]-A6 prepared as described above and the compound A3 prepared in Example 3, [ 19 F]-A3, were co-injected under the same conditions for HPLC. Analysis, by confirming the retention time (see Figure 3).
分析用HPLC条件如下：溶剂A:乙腈(ACN),溶剂B:20mM AFB(甲酸铵)；梯度：0-3min 95％B,3-11min 95％-5％B,11-19min 5％-95％B,19-21min 95％B；柱子:Gemini 3micron,140x 4.6mm,column:Gemini 3u C18,110A,150×4.6mm,3micron。The HPLC conditions for analysis were as follows: solvent A: acetonitrile (ACN), solvent B: 20 mM AFB (ammonium formate); gradient: 0-3 min 95% B, 3-11 min 95%-5% B, 11-19 min 5%-95 %B, 19-21 min 95% B; column: Gemini 3 micron, 140 x 4.6 mm, column: Gemini 3u C18, 110 A, 150 x 4.6 mm, 3 micron.
实施例7Example 7
体外竞争结合试验(方法参见文献Shunichi Oya,J.Med.Chem.2002,45,4716-4723)。In vitro competition binding assay (for the method see Shunichi Oya, J. Med. Chem. 2002, 45, 4716-4723).
体外竞争结合试验中使用的三个测定非特异性结合的化合物如下：Citalopram(西酞普兰)、GBR 12909(伐诺司林)和Nisoxetine(尼索西汀)，其中，Citalopram是已知的SERT抑制剂，GBR 12909是已知的DAT抑制剂，Nisoxetine是已知的NET抑制剂。The three compounds used in the in vitro competition binding assay to determine non-specific binding are as follows: Citalopram (Citalopram), GBR 12909 (varnostrine) and Nisoxetine (Nisoxetine), wherein Citalopram is a known SERT inhibition GBR 12909 is a known DAT inhibitor and Nisoxetine is a known NET inhibitor.
通过体外竞争实验测得Ki常数(数据见下表1)，当二芳基硫醚化合物B环4位使用不同小分子链结合后，化合物保有对SERT的高亲和能力。由表1中的数据可知，本发明的化合物A1-A4均对SERT有非常高的亲和性，尤其是化合物A1(0.09±0.01nM)、A3(0.02±0.003nM)。而且，对DAT和NET的结合试验显示，这些化合物对DAT的亲和性很差，对NET的亲和性也一般， 从而表现出了高选择性。例如，化合物A3的DAT/SERT选择性高达34300，NET/SERT选择性也高达4010，利用18F标记后可有望作为SERT显像剂。The Ki constant was determined by an in vitro competition experiment (data shown in Table 1 below). When the diaryl sulfide compound B ring 4 was bonded using different small molecular chains, the compound retained a high affinity for SERT. From the data in Table 1, it is known that the compounds A1 to A4 of the present invention all have a very high affinity for SERT, especially the compound A1 (0.09 ± 0.01 nM) and A3 (0.02 ± 0.003 nM). Moreover, binding experiments on DAT and NET showed that these compounds have poor affinity for DAT, and have a general affinity for NET, thereby exhibiting high selectivity. For example, Compound A3 has a DAT/SERT selectivity of up to 34,300 and a NET/SERT selectivity of up to 4010, which is expected to be a SERT imaging agent after labeling with 18 F.
表1:二芳基硫醚系列衍生化合物与SERT、DAT、NET受体的竞争性结合常数Ki a Table 1: Competitive Binding Constants of Diaryl Thioether Series Derivatives with SERT, DAT, NET Receptors K i a
Figure PCTCN2017086045-appb-000014
Figure PCTCN2017086045-appb-000014
a.每个Ki值都是三次实验所得。a. Each Ki value is obtained from three experiments.
b.SERT结合性能测定实验中，LLC-SERT细胞膜匀浆与0.1nM[125I]IDAM(Kd＝0.2nM)；DAT结合性能测定实验中，LLC-DAT细胞膜匀浆与0.08nM[125I]IPT(Kd＝1.2)；NET结合性能测定实验中，LLC-NET细胞膜匀浆与0.06nM[125I]2-INXT(Kd＝0.06nM)。b. SERT binding performance assay, LLC-SERT cell membrane homogenate with 0.1 nM [ 125 I]IDAM (Kd = 0.2 nM); DAT binding performance assay, LLC-DAT cell membrane homogenate with 0.08 nM [ 125 I] IPT (Kd = 1.2); NET binding performance assay in experiments, LLC-NET cell membrane homogenate with 0.06 nM [ 125 I] 2-INXT (Kd = 0.06 nM).
c.n＝1。C.n=1.
上述用于放射性受体结合实验的标准化合物化学结构如下：The chemical structures of the above standard compounds for radioactive receptor binding experiments are as follows:
Figure PCTCN2017086045-appb-000015
Figure PCTCN2017086045-appb-000015

Claims (8)

  1. 一种结构式如下的二芳基硫醚衍生物：A diaryl sulfide derivative of the formula:
    Figure PCTCN2017086045-appb-100001
    Figure PCTCN2017086045-appb-100001
    其中，R为直接键、
    Figure PCTCN2017086045-appb-100002
    C1-4的亚烷基、未取代或C1-4烷基取代的-CH＝CH-或者-C≡C-；    Where R is a direct key,
    Figure PCTCN2017086045-appb-100002
    C 1-4 alkylene, unsubstituted or C 1-4 alkyl substituted -CH=CH- or -C≡C-;
    Y为氟原子，可以为[18F]或者[19F]，Y is a fluorine atom and may be [ 18 F] or [ 19 F],
    其中，n为1-4的自然数。Where n is a natural number from 1 to 4.
  2. 如权利要求1所述的二芳基硫醚衍生物，其特征是，所述R为
    Figure PCTCN2017086045-appb-100003
    -CH＝CH-或者-C≡C-，其中，n为1-4的自然数。    The diaryl sulfide derivative according to claim 1, wherein said R is
    Figure PCTCN2017086045-appb-100003
    -CH=CH- or -C≡C-, where n is a natural number from 1 to 4.
  3. 如权利要求1所述的二芳基硫醚衍生物，其特征是，所述R为
    Figure PCTCN2017086045-appb-100004
    -CH＝CH-或者-C≡C-，其中，n为1-2的自然数。    The diaryl sulfide derivative according to claim 1, wherein said R is
    Figure PCTCN2017086045-appb-100004
    -CH=CH- or -C≡C-, where n is a natural number of 1-2.
  4. 如权利要求1所述的二芳基硫醚衍生物，其特征是，所述二芳基硫醚衍生物为如下结构式的化合物：The diaryl sulfide derivative according to claim 1, wherein the diaryl sulfide derivative is a compound of the following formula:
    Figure PCTCN2017086045-appb-100005
    Figure PCTCN2017086045-appb-100005
  5. 如权利要求1所述的二芳基硫醚衍生物，其特征是，所述二芳基硫醚衍生物为如下结构式的化合物： The diaryl sulfide derivative according to claim 1, wherein the diaryl sulfide derivative is a compound of the following formula:
    Figure PCTCN2017086045-appb-100006
    Figure PCTCN2017086045-appb-100006
  6. 一种二芳基硫醚衍生物的制备方法，该方法包括：在碱存在下，使2-氨基苯-(2-(N,N-二甲基)氨甲基-4-羟基)-苯)硫醚与
    Figure PCTCN2017086045-appb-100007
    进行亲核取代反应，得到所述二芳基硫醚衍生物，反应式如下：    A process for the preparation of a diaryl sulfide derivative, which comprises: 2-aminobenzene-(2-(N,N-dimethyl)aminomethyl-4-hydroxy)-benzene in the presence of a base Thioether
    Figure PCTCN2017086045-appb-100007
    The nucleophilic substitution reaction is carried out to obtain the diaryl sulfide derivative, and the reaction formula is as follows:
    Figure PCTCN2017086045-appb-100008
    Figure PCTCN2017086045-appb-100008
    其中，R为直接键、
    Figure PCTCN2017086045-appb-100009
    C1-4的亚烷基、未取代或C1-4烷基取代的-CH＝CH-或者-C≡C-；    Where R is a direct key,
    Figure PCTCN2017086045-appb-100009
    C 1-4 alkylene, unsubstituted or C 1-4 alkyl substituted -CH=CH- or -C≡C-;
    Y为氟原子，可以为[18F]或者[19F]，Y is a fluorine atom and may be [ 18 F] or [ 19 F],
    其中，n为1-4的自然数。Where n is a natural number from 1 to 4.
  7. 如权利要求6所述的制备方法，其特征是，所述碱为碳酸钾、氢化钠或者碳酸铯。The process according to claim 6, wherein the base is potassium carbonate, sodium hydride or cesium carbonate.
  8. 权利要求1至5中任一项所述的二芳基硫醚衍生物在制备五羟色胺转运体靶向显像剂中的用途。 Use of the diaryl sulfide derivative according to any one of claims 1 to 5 for the preparation of a serotonin transporter targeting imaging agent.
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