WO2015149656A1 - 一类2,2'-串联双噻唑类化合物及其制备方法和用途 - Google Patents

一类2,2'-串联双噻唑类化合物及其制备方法和用途 Download PDF

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WO2015149656A1
WO2015149656A1 PCT/CN2015/075247 CN2015075247W WO2015149656A1 WO 2015149656 A1 WO2015149656 A1 WO 2015149656A1 CN 2015075247 W CN2015075247 W CN 2015075247W WO 2015149656 A1 WO2015149656 A1 WO 2015149656A1
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WO2015149656A8 (zh
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南发俊
李佳
谢欣
龚超骏
周宇波
柴辉
张仰明
苏明波
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Shanghai Institute of Materia Medica of CAS
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Priority to US15/301,763 priority patent/US9643941B2/en
Priority to AU2015240237A priority patent/AU2015240237B2/en
Priority to KR1020167030768A priority patent/KR101748229B1/ko
Priority to CA2947912A priority patent/CA2947912C/en
Publication of WO2015149656A1 publication Critical patent/WO2015149656A1/zh
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to a class of thiazole compounds and processes for their preparation and use, and more particularly to a class of 2,2'-tandem bithiazoles, processes for their preparation and their use as histone deacetylase inhibitors Use in the preparation of a medicament for anti-tumor or for the treatment of autoimmune diseases.
  • Epigenetics also known as “pseudogenetics”, “epigenetics”, “exogenetics”, and “epiggenetics”, is a biology discipline that studies when there is no change in the nuclear DNA sequence. Reversible, heritable changes in gene function. It refers to functional modification of the genome without involving alteration of the nucleotide sequence. Epigenetic phenomena include DNA methylation, RNA interference, tissue protein modification, and the like.
  • Histone acetylation and deacetylation play a key role in the structural modification of nuclear chromatin, which are regulated by the activity of histone acetyltransferase (HAT) and histone deacetylase (HDAC), respectively (Saha , RN, Pahan, K., Cell Death Differ 2006, 13(4), 539-50).
  • HAT histone acetyltransferase
  • HDAC histone deacetylase
  • HDAC1 human-derived HDACs
  • type I HDAC1, 2, 3, and 8
  • type II IIa: HDAC 4, 5, 7 and 9, IIb: HDAC6 and 10
  • type IV HDAC11
  • type III HDACs SirT 1-7)
  • its enzymatic activity is dependent on NAD + .
  • HDACi histone deacetylase inhibitors
  • HDAC Hematol Oncol Clin Northam, 2012, 26(3): 671-704.
  • SAHA Stainostat
  • PTCL peripheral T-cell lymphoma
  • HDACi may also be associated with a variety of autoimmune diseases.
  • Pahan et al. reported that the HDAC inhibitor sodium phenylbutyrate can alleviate central nervous system damage in mice in the experimental autoimmune encephalomyelitis (EAE). The direct relationship between this result and HDAC was not addressed; two years later, Camelo et al. found that HDACi TSA can effectively inhibit T cell pairs. Invasion of the central nervous system in mice, he emphasized that it is because of the inhibition of HDAC by TSA that the expression levels of neuroprotective proteins such as IGF-2 and glutamate transporter EAAT2 are increased, thereby exerting therapeutic effects; Many researchers have discovered the use of HDACi in MS.
  • HDACi can enhance the acetylation of the transcription factor Sp1 and protect neuronal cells from oxidative stress (Giuseppe Faraco, etc. , Molecular Medcine, 2011, 17 (5-6), 442-447). Given the unknown mechanism of MS and the lack of sensitive diagnostic markers, HDACi will have a positive impact on its treatment. In addition, according to reports (Charles A Dinarello, etc, Molecular Medcine, 2011, 17 (5-6), 333–352), HDACi is also associated with type II diabetes and its associated complications, neurodegenerative diseases (Huntington's disease, Al It is related to Zheimer's disease, so HDAC is a target with good research prospects.
  • the HDAC inhibitors currently studied mainly contain a three-part structure, which is a Zn 2+ chelate moiety (ZBG), a hydrophobic linker (Linker), and a surface recognition domain. According to the difference of zinc ion chelating groups, it can be divided into hydroxamic acids, o-phenylenediamines, electron-deficient ketones, short-chain fatty acids and the like. According to data from Thomson Reuters in December 2013, more than 100 HDACis are in different stages of drug development. The first marketed SAHA is a hydroxyvalerate HDAC inhibitor for the treatment of CTCL.
  • the inventor of the present application applied for a patent (WO2012152208) in 2012, and reported a new class of thiazole compounds that can be used as HDAC inhibitors for the development of anti-tumor and multiple sclerosis drugs.
  • the compound CFH367-C showed good enzyme inhibitory activity, and the GI50 on HCT-116 cells was also less than 1 ⁇ M, and it can effectively alleviate the clinical symptoms of EAE mice, but due to the shortcomings of the hydroxamic acid group itself, we It is desirable to develop HDAC inhibitors that are more active and less toxic.
  • R 1 and R 2 are each independently one of the following groups:
  • R 1 and R 2 are each independently H, C 1 -C 6 alkyl or R 1 and R 2 form a 5-, 6- or 7-membered saturated cyclic structure with the carbon atom to which they are attached;
  • Y is Or a C 2 -C 6 alkenylene group, wherein n is 1, 2, 3 or 4; more preferably, Y is or
  • R 3 is a group of the following groups:
  • R 3 is C 1 -C 4 alkyl, C 6 -C 10 aryl substituted C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
  • R 3 is C 1 -C 4 alkyl, benzyl, or cyclopropyl.
  • R 4 is R 4a , R 4b , R 4c , R 4d or R 4e :
  • R 5 , R 6 , R 7 and R 8 are selected from one of the following groups:
  • R 5 is hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl or
  • R 5 is hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl or
  • R 6 is H, C 1 -C 6 alkyl
  • R 6 is H, methyl
  • R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxy C 1- C 6 alkylene, C 6 -C 10 aryl or a 5-7 membered heteroaryl group, the 5-7 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, O and S;
  • R 7 is C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 4 alkoxy, hydroxy C 1 -C 4 alkylene, C 6 -C 10 aryl Or a 5-7 membered heteroaryl group, the 5-7 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S (eg, pyridine);
  • R 7 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethyloxy, hydroxymethyl, hydroxyethyl, phenyl, pyridyl , pyridazinyl, pyrimidinyl or pyrazinyl;
  • R 8 is a C 6 -C 10 aryl group
  • R 8 is a phenyl group.
  • the 2,2'-tandem bithiazole compound of the formula I of the present invention is specifically:
  • Another object of the present invention is to provide a process for the preparation of a 2,2'-series bithiazole compound having the structure of the formula I.
  • compound Ia can be achieved by one of the following routes 1 to 3 (compounds 1 and 2 can be obtained by the method described in WO2012152208 or WO2011116663):
  • R 1 , R 2 , R 3 and n have the same meanings as defined in the above formula I;
  • Compound 1 is made into an acid chloride using an acid chlorinating reagent (such as oxalyl chloride, thionyl chloride, etc.), and the acid chloride is further reacted with trifluoroacetic anhydride (TFAA) in the presence of a base such as pyridine at room temperature or under heating.
  • TFAA trifluoroacetic anhydride
  • a substitution reaction occurs and hydrolysis yields compound I a ;
  • R 1 , R 2 , R 3 and n have the same meanings as defined in the above formula I;
  • the compound 2 is formed into an acid chloride by an acid chlorinating reagent (such as oxalyl chloride, thionyl chloride, etc.), and then reacted with concentrated aqueous ammonia in an ice bath to obtain a compound 3;
  • an acid chlorinating reagent such as oxalyl chloride, thionyl chloride, etc.
  • TMS-CF 3 trifluoromethyltrimethylsilane
  • TBAF tetrabutylammonium fluoride
  • H + acid
  • Compound 6 is then obtained, and compound 6 is reacted with 2-chloroethanol in the presence of K 2 CO 3 in DMF to give compound 7, which is sulfonylated in DCM in the presence of TsCl and Et 3 N to give compound 8, compound 8 and Compound 3 is obtained by the action of sodium hydride in DMF, and compound 9 is deprotected by a Lewis acid (such as BBr 3 ) to obtain the compound I a ;
  • a Lewis acid such as BBr 3
  • R 1 , R 2 , R 3 and n have the same meanings as defined in the above formula I;
  • compound 8 is reacted with sodium azide (NaN 3 ) in DMF to obtain compound 10, and compound 10 is hydrogenated to obtain amine 11, and amine 11 and acid 2 are produced in DCM in the presence of a condensing agent (such as EDCI).
  • a condensing agent such as EDCI
  • the condensation reaction gives compound 9, and the compound 9 is deprotected by a Lewis acid (such as BBr 3 ) to obtain the compound I a ;
  • R 1 , R 2 , R 3 and n have the same definitions as in the above formula I.
  • compound 2 is subjected to a Curtius rearrangement reaction to obtain a Boc-protected amine 12, 12 is removed from Boc to obtain a free amine 13; and compound 7 is oxidized by TEMPO and iodobenzene diacetate (BAIB) to obtain an acid.
  • BAIB iodobenzene diacetate
  • the acid 14 and the amine 13 by the action of the condensing agent EDCI to obtain the compound
  • the compound 15 is removed by the action of a Lewis acid (such as BBr 3 ) to obtain the thiazole compound I b of the present invention;
  • Ic compounds can be obtained by the method in Route 5:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , X and Y have the same meanings as defined in the above formula I.
  • R 9 is selected from one of R 4b , R 4c and R 4d .
  • the compound I ab and the corresponding amine or hydrazine are subjected to a dehydration condensation reaction in a solvent (e.g., ethanol, pyridine, etc.) at room temperature or under heating (e.g., 65 ° C) to obtain the bisthiazole compound I c of the present invention. .
  • a solvent e.g., ethanol, pyridine, etc.
  • heating e.g., 65 ° C
  • Another object of the present invention is to provide a use of a bisthiazole compound having the structure of the formula I for the preparation of a drug for a histone deacetylase inhibitor; and to provide a bithiazole compound having the structure of the formula I for the preparation of an antitumor,
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a bithiazole compound selected from the group consisting of the formula I and a pharmaceutically acceptable adjuvant.
  • Figure 1 is a clinical score of the efficacy test of the HDAC inhibitor HD1 in EAE mice.
  • NMR NMR was measured using a Mercury-Vx 300M instrument manufactured by Varian, NMR calibration: ⁇ H 7.26 ppm (CDCl 3 ), 2.50 ppm (DMSO-d 6 ), 3.31 ppm (CD 3 OD); all solvents All are analytically pure reagents and are generally used without treatment. The anhydrous solvent is dried by standard methods.
  • reagents are generally purchased from Sinopharm Chemical Reagent Co., Ltd., Suiyuan Chemical Technology (Shanghai) Co., Ltd., Jill Biochemical (Shanghai) Co., Ltd., Shenzhen Myrill Chemical Technology Co., Aldrich, Alfa-Aesar, Acros, Fluka, Merck, Reagents such as TCI or Lancaster have a small number of reagents purchased from the manufacturer, and unless otherwise specified, these reagents are used without treatment. Self-made reagents are generally subjected to NMR to determine their structure and approximate purity prior to use.
  • TLC thin layer chromatography silica gel plate is produced by Shandong Yantai Huiyou Silicone Development Co., Ltd., model HSGF 254; normal phase column chromatography silica gel used for compound purification is produced by Shandong Qingdao Marine Chemical Plant Branch, model zcx-11, 200-300 mesh .
  • Compound 29 (colorless liquid) can be obtained from ⁇ -caprolactone by the method described in Scheme 2.
  • HDAC1, HDAC3, HDAC4 and HDAC6 were all applied to the baculovirus expression system and purified by Dr. Li Jia from the Shanghai Institute of Materia Medica.
  • Substrate HDAC1, 3, 4: Ac-Lys-Tyr-Lys(Ac)-AMC;
  • HDAC6 Boc-lys(Ac)-AMC
  • Enzyme activity was measured in a 96-well or 384-well flat-bottom microplate using fluorescence detection. After the substrate is deacetylated by HDAC, the product AMC obtained by trypsin hydrolysis can detect the fluorescent signal at 355 nm excitation of 460 nm of the fluorescence detector. The initial velocity of the reaction is calculated by detecting the change in the fluorescence signal over time.
  • Sample treatment Samples were dissolved in DMSO, stored at low temperature, and the concentration of DMSO in the final system was controlled to a range that did not affect the activity of the assay.
  • the activity of the sample was tested by initial screening at a single concentration, for example 20 ⁇ g/ml.
  • the inhibition rate % is greater than 50
  • the active dose-dependent relationship, ie, the IC 50 /EC 50 value is obtained by nonlinearly fitting the sample concentration by the sample activity
  • the calculation software is Graphpad Prism 4
  • the model used for fitting is sigmoidal dose-response (varible slope)
  • the bottom and top of the fitted curve are set to 0 and 100.
  • each sample is provided with a duplicate hole (n ⁇ 2) in the test, and the result is expressed by Standard Deviation (SD) or Standard Error (SE).
  • SD Standard Deviation
  • SE Standard Error
  • the antitumor activity test of the compound of the present invention was carried out, and the in vitro antitumor activity of the compound was evaluated by measuring the growth inhibitory activity of the compound against human multiple myeloma cell line 8266.
  • the analytical method is to metabolically reduce 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyltetrazolium bromide (MTT). Based on.
  • MTT 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyltetrazolium bromide
  • NADP oxidized glutathione
  • the optical density can be measured at a wavelength of 550/690 nm using a microplate reader.
  • Sample treatment Samples were dissolved in DMSO, stored at low temperature, and the concentration of DMSO in the final system was controlled to a range that did not affect the activity of the assay.
  • Cell viability was measured by MTT assay.
  • Cells grown in logarithmic growth phase were digested with 0.05% trypsin, counted, and seeded at a cell density of 2.0 ⁇ 10 3 /well in 100 ⁇ L of 96-well plates at 5%. Incubate overnight at 37 ° C in a CO 2 incubator. Six concentration gradients were set for each compound, and three wells were set for each concentration. Each concentration was added to the corresponding wells, cultured in a 5% CO 2 37 ° C incubator for 72 hours, and 20 ⁇ L of 5 mg/mL MTT was added.
  • IC 50 is fitted by the formula.
  • the activity of the sample was tested by initial screening at a single concentration, for example 20 ⁇ g/ml.
  • the inhibition rate % is greater than 50
  • the active dose-dependent relationship, ie, the IC 50 /EC 50 value is obtained by nonlinearly fitting the sample concentration by the sample activity
  • the calculation software is Graphpad Prism 4
  • the model used for fitting is sigmoidal dose-response (varible slope)
  • the bottom and top of the fitted curve are set to 0 and 100.
  • each sample is provided with a duplicate hole (n ⁇ 2) in the test, and the result is expressed by Standard Deviation (SD) or Standard Error (SE) (IC50 ⁇ SD in the table) .
  • SD Standard Deviation
  • SE Standard Error
  • the activity of the compound as a histone acetylase inhibitor for the treatment of EAE was tested by a pharmacodynamic test of the compound in an EAE mouse model.
  • the antigens MOG35-55 (MEVGWYRSPFSRVVHLYRNGK) were emulsified by adding Freund's complete adjuvant (containing inactivated Mycobacterium tuberculosis 5 mg/ml).
  • Eight-week-old female C57BL/6 mice were injected subcutaneously with 200 ⁇ g of emulsified MOG 35-55 antigen, and each mouse was injected with 200 ng of pertussis toxin, and the day of induction was day 0. On day 2, each mouse was given 200 ng of pertussis toxin.
  • the symptoms of the mice were scored and recorded daily, and the scoring rules are as follows.
  • hind limb weakness The single hind limb of the mouse was hung upside down on the cage edge. If the hind limb was weak, the mouse could not climb the cage edge, could not climb back into the cage and fell from the cage. One hind limb was weak for 1.5 points, and both hind limbs were weak. Minute
  • Antigen MOG35 ⁇ 55 Shanghai Jill Biochemical Co., Ltd.;
  • HD 1 was in the form of a pure compound.
  • CFH367-C was used for comparison.
  • the drug was directly mixed with CMC-Na and ultrasonically suspended to a uniform state.
  • the dose was 10 mg/kg, and administered intragastrically twice a day.
  • the control group was given PBS directly.
  • HDACi HD 1 can effectively alleviate the onset of EAE model mice. From the incidence and incidence curve ( Figure 1), HDAC inhibitor HD 1 has a good therapeutic effect on the clinical symptoms of EAE model mice, and the effect is better than CFH367-C. The disease severity of the mice in the treatment group is significantly lower. In the solvent control group (P ⁇ 0.01).

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Abstract

本发明涉及一类噻唑类化合物及其制备方法和用途，更具体而言，本发明涉及一类2,2'-串联双噻唑类化合物（I）及其制备方法以及作为组蛋白去乙酰化酶抑制剂在制备抗肿瘤药物、治疗自身免疫性疾病的药物、治疗II型糖尿病及其并发症的药物或治疗神经退行性病变的药物中的用途。

Description

一类2,2’-串联双噻唑类化合物及其制备方法和用途 技术领域
本发明涉及一类噻唑类化合物及其制备方法和用途，更具体而言，本发明涉及一类2，2’-串联双噻唑类化合物、其制备方法以及其作为组蛋白去乙酰化酶抑制剂在制备抗肿瘤或治疗自身免疫性疾病的药物中的用途。
背景技术
表观遗传学又称“拟遗传学”、“表遗传学”、“外遗传学”以及“后遗传学”(epigenetics)，是一门生物学学科，研究在没有细胞核DNA序列改变的情况时，基因功能的可逆的、可遗传的改变。它是指功能性地修改基因组，而不涉及改变核苷酸序列。表观遗传现象包括DNA甲基化、RNA干扰、组织蛋白修饰等。
组蛋白的转录后修饰主要包括组蛋白乙酰化、甲基化、磷酸化、泛素化和SUMO酰化等，其中乙酰化又是研究最为广泛的一种方式。组蛋白的乙酰化和去乙酰化在核染色质的结构修饰过程中扮演关键的角色，它们分别由组蛋白乙酰化转移酶(HAT)和组蛋白去乙酰化酶(HDAC)的活性调控(Saha,R.N,Pahan,K.,Cell Death Differ 2006,13(4),539-50)。
迄今为止，已经发现并鉴定了18种人源的HDACs，根据其与酵母HDAC的相似性共分为四类。分别是：Ⅰ型(HDAC1、2、3和8)，Ⅱ型(Ⅱa：HDAC 4、5、7和9，Ⅱb：HDAC6和10)，以及Ⅳ型(HDAC11)，这三类HDACs的活性都依赖于Zn2+。对于Ⅲ型HDACs(SirT 1-7)，其酶活性依赖于NAD+。(Karagiannis,T.C.,El-Osta,A.Leukemia 2007,21(1),61-5.)
组蛋白去乙酰化酶抑制剂(HDACi)参与调节的重要生物学功能有：1)通过外在或内在的凋亡通路机制诱导细胞凋亡；2)细胞周期阻滞；3)抑制新生血管的生成；4)微管蛋白乙酰化和破坏聚集体形成；5)改变微管蛋白结构从而影响细胞运动和分化；6)通过影响T细胞受体功能、免疫效应细胞的细胞因子环境和直接上调其他免疫效应因子识别肿瘤细胞的蛋白等方式调节肿瘤免疫。(Zain J.,Hematol Oncol Clin Northam,2012,26(3):671-704.)HDAC的功能紊乱可导致组蛋白乙酰化的不平衡，使染色质结构发生改变，并使细胞生长、分化、凋亡相关基因表达受抑，最后导致肿瘤的形成。HDAC是当前新型抗肿瘤药物研发的一个重要靶点。2006年，FDA批准了SAHA(Vorinostat)为第一个上市的HDACi用于治疗皮肤T细胞淋巴瘤(CTCL)；2009年，FK228作为治疗CTCL和外周T细胞淋巴瘤(PTCL)的药物上市。
近期的研究表明，HDACi可能也与多种自身免疫病有关。早在2003年，Pahan等人就报道了HDAC抑制剂苯丁酸钠可以在多发性硬化症(MS)的小鼠动物模型(Experimental autoimmune encephalomyelitis，EAE)上缓解小鼠的中枢神经系统损伤，但并未阐述这一结果与HDAC的直接关系；两年后，Camelo等人发现HDACi TSA可以有效抑制T细胞对 小鼠中枢神经系统的侵袭，他着重提出正是因为TSA对于HDAC的抑制，才使得神经保护蛋白如IGF-2和谷氨酸转运体EAAT2等的表达量增加，从而发挥治疗作用；随后还有许多研究者发现了HDACi在MS上的应用，比如Ryu等人的研究表明，选择性的HDACi可以提高转录因子Sp1的乙酰化从而保护神经元细胞在氧化应激下的存活能力(Giuseppe Faraco,etc,Molecular Medcine,2011,17(5-6),442-447)。鉴于MS的发生机制不明，以及目前尚缺乏灵敏的诊断标志，HDACi将对它的治疗产生积极的推动作用。此外，据报道(Charles A Dinarello,etc,Molecular Medcine,2011,17(5-6),333–352)，HDACi还与Ⅱ型糖尿病及其相关并发症、神经退行性病变(亨廷顿舞蹈病、阿尔兹海默氏病)等有关，因此HDAC是一个具有良好研究前景的靶点。
目前研究的HDAC抑制剂主要含有三部分结构，分别为与Zn2+螯合部分(ZBG)、疏水性连接部分(Linker)和表面识别结构域。根据锌离子螯合基团的不同可分为羟肟酸类、邻苯二胺类、缺电子酮类、短链脂肪酸类等等。据2013年12月Thomson Reuters的数据显示，已有超过100种HDACi处于药物研发的不同阶段。第一个上市的SAHA就是羟戊酸类HDAC抑制剂，用于CTCL的治疗。随着使用的深入，其缺点也暴露出来：它单药治疗效果一般且不是一线药物，高剂量下毒性明显并伴有QT间期延长、骨髓抑制、腹泻等副作用，对实体瘤的治疗效果也不理想；这可能与SAHA为泛抑制剂有关，可能因为与其含有一个很强的锌离子螯合基团羟肟酸基团有关。因此开发更新型高效的HDAC抑制剂已成为本领域研究的一个重要方向。
本申请的发明人所在课题组于2012年申请过一项专利(WO2012152208)，报道了一类新型噻唑类化合物，可以作为HDAC抑制剂用于抗肿瘤及多发性硬化症药物的开发。其中化合物CFH367-C显示出良好的酶抑制活性，在HCT-116细胞上的GI50也小于1μM，且能有效地缓解EAE小鼠的临床症状，但由于异羟肟酸基团本身的缺点，我们希望开发出活性更高，毒性更小的HDAC抑制剂。
基于HDAC抑制剂的基本结构，我们考虑从更换锌离子鳌合基团(ZBG)入手，首先将CFH367-C中的异羟肟酸换为常见的邻苯二胺类，但所得到的化合物在酶水平上IC50由原先的60nM降低至2-5μM；但将ZBG更换为三氟甲基酮乃至未见报道的腙类化合物后，虽然其锌离子螯合能力变弱，但意外发现该类化合物不但酶抑制活性更高(IC50＝30nM)，细胞水平上的抑制活性更强(IC50可达100nM水平)，而且对于EAE小鼠的临床症状治疗效果要明显高于CFH367-C(图1)，显示出了更好的开发前景。
发明内容
本发明的一个目的为提供一种具有下面的通式I结构的2,2’-串联双噻唑类化合物：
Figure PCTCN2015075247-appb-000001
其中：
R1和R2各自独立地为如下基团的一种：
H、C3-C6环烷基、C1-C6烷基、C2-C6链烯基、C2-C6链炔基；或者R1和R2与其所连接的碳原子形成5-7元环状结构；
优选地，R1和R2各自独立地为H、C1-C6烷基或者R1和R2与其所连接的碳原子形成5元、6元或7元的饱和环状结构；
X为
Figure PCTCN2015075247-appb-000002
或
Figure PCTCN2015075247-appb-000003
Y为
Figure PCTCN2015075247-appb-000004
或C2-C6亚烯基，其中n为1、2、3或4；更优选地，Y为
Figure PCTCN2015075247-appb-000005
Figure PCTCN2015075247-appb-000006
或
Figure PCTCN2015075247-appb-000007
R3为如下基团的一种：
H，C1-C6烷基，C6-C10芳基取代的C1-C6烷基，C3-C6环烷基，C1-C6烷基取代的C3-C6环烷基，C2-C8链烯基，C2-C6链炔基，C6-C10芳基，5-7元杂芳基；所述5-7元杂芳基含有1-3个选自N、O和S中的杂原子；
优选地，R3为C1-C4烷基、C6-C10芳基取代的C1-C4烷基或C3-C6环烷基；
更优选地，R3为C1-C4烷基、苯甲基、或环丙基。
R4为R4a、R4b、R4c、R4d或R4e：
Figure PCTCN2015075247-appb-000008
其中R5、R6、R7和R8选自如下基团中的一种：
H，羟基，C1-C6烷基，C1-C6烷氧基，羟基C1-C6亚烷基，C6-C10芳基取代的C1-C6烷基，C3-C6环烷基，C1-C6烷基取代的C3-C6环烷基，C2-C8链烯基，C2-C6链炔基，C6-C10芳基，5-7元杂芳基，
Figure PCTCN2015075247-appb-000009
所述5-7元杂芳基含有1-3个选自N、O和S中的杂原子；
优选地，R5为羟基、C1-C6烷基、C1-C6烷氧基、C6-C10芳基或
Figure PCTCN2015075247-appb-000010
更优选地，R5为羟基、C1-C4烷基、C1-C4烷氧基、苯基或
Figure PCTCN2015075247-appb-000011
优选地，R6为H、C1-C6烷基；
更优选地，R6为H、甲基；
优选地，R7为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、羟基C1-C6亚烷基、C6-C10芳基或5-7元杂芳基，所述5-7元杂芳基含有1-3个选自N、O和S中的杂原子；
更优选地，R7为C1-C4烷基、C3-C5环烷基、C1-C4烷氧基、羟基C1-C4亚烷基、C6-C10芳基或5-7元杂芳基，所述5-7元杂芳基含有1-2个选自N、O和S中的杂原子(例如，吡啶)；
最优选地，R7为甲基、乙基、丙基、异丙基、叔丁基、环丙基、甲氧基、乙基氧基、羟甲基、羟乙基、苯基、吡啶基、哒嗪基、嘧啶基或吡嗪基；
优选地，R8为C6-C10芳基；
更优选地，R8为苯基。
本发明的通式Ⅰ的2,2’-串联双噻唑类化合物具体为：
Figure PCTCN2015075247-appb-000012
Figure PCTCN2015075247-appb-000013
本发明的另一目的为提供具有通式Ⅰ结构的2,2’-串联双噻唑类化合物的制备方法。
其中化合物Ⅰa可以通过下述路线一至路线三中的一种来实现，(化合物1和2可通过专利WO2012152208或WO2011116663中所述方法制得)：
路线一：
Figure PCTCN2015075247-appb-000014
其中，R1、R2、R3和n的定义与上述通式I中的定义相同；
具体来说，将化合物1利用酰氯化试剂(比如草酰氯、二氯亚砜等)制成酰氯，酰氯再与三氟醋酸酐(TFAA)在碱(比如吡啶)的存在下于室温或加热下发生取代反应并水解得到化合物Ⅰa；
路线二：
Figure PCTCN2015075247-appb-000015
其中，R1、R2、R3和n的定义与上述通式I中的定义相同；
具体来说，化合物2利用酰氯化试剂(比如草酰氯、二氯亚砜等)形成酰氯，再在冰浴下与浓氨水作用得到化合物3；
化合物4与三氟甲基三甲基硅烷(TMS-CF3)在四丁基氟化铵(TBAF)催化下，于四氢呋喃中发生加成反应得到化合物5，化合物5经酸(H+)水解后得到化合物6，化合物6与2-氯乙醇在K2CO3存在下于DMF中反应得到化合物7，化合物7在TsCl和Et3N存在下于DCM中磺酰化得到化合物8，化合物8和化合物3在氢化钠的作用下于DMF中得到化合物9，化合物9在路易斯酸(如BBr3)作用下脱去乙二醇保护同样得到化合物Ⅰa；
路线三：
Figure PCTCN2015075247-appb-000016
其中，R1、R2、R3和n的定义与上述通式I中的定义相同；
具体来说，化合物8与叠氮化钠(NaN3)于DMF中反应得到化合物10，化合物10经氢化还原得到胺11，胺11与酸2在缩合剂(如EDCI)存在下于DCM中发生缩合反应得 到化合物9，化合物9在路易斯酸(如BBr3)作用下脱除乙二醇保护同样制得化合物Ⅰa；
Ⅰb类化合物可用路线四中方法制得：
路线四：
Figure PCTCN2015075247-appb-000017
其中，R1、R2、R3和n的定义与上述通式I中的定义相同。
具体来说，化合物2经过库尔修斯(Curtius)重排反应得到Boc保护的胺12，12脱去Boc得到游离的胺13；同时化合物7经TEMPO和二醋酸碘苯(BAIB)氧化得到酸14，酸14与胺13经缩合剂EDCI的作用得到化合物15，化合物15在路易斯酸(如BBr3)作用下脱除乙二醇保护得到本发明所述噻唑类化合物Ⅰb；
Ⅰc类化合物可以用路线五中的方法得到：
路线五：
Figure PCTCN2015075247-appb-000018
其中，R1、R2、R3、R5、R6、R7、X和Y的定义与上述通式I中的定义相同。
R9选自R4b、R4c和R4d中的一种。
具体来说，化合物Ⅰab与相应的胺或肼在室温或加热条件下(如65℃)于溶剂(如乙醇、吡啶等)中发生脱水缩合反应可得本发明所述双噻唑类化合物Ⅰc。
本发明的另一目的为提供具有通式Ⅰ结构的双噻唑类化合物在制备组蛋白去乙酰化酶抑制剂的药物中的用途；提供具有通式I结构的双噻唑类化合物在制备抗肿瘤、治疗自身免疫性疾病的药物、治疗II型糖尿病及其并发症的药物或治疗神经退行性病变的药物中的用途，其中，所述肿瘤为多发性骨髓瘤、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤等，所述自身免疫性疾病为多发性硬化症，所述神经退行性病变为亨廷顿舞蹈病或阿尔兹海默氏病等。
本发明的另一目的为提供一种药物组合物，其包含治疗有效量的选自具有通式I结构的双噻唑类化合物以及药学上可接受的辅料。
附图说明
图1为HDAC抑制剂HD1在EAE小鼠上药效试验的临床评分。
具体实施方式
下面结合具体实施例对本发明做进一步阐述，但本发明不局限于这些实施例。
制备实施例
下述制备实施例中，NMR用Varian生产的Mercury-Vx 300M仪器测定，NMR定标：δH 7.26ppm(CDCl3)，2.50ppm(DMSO-d6)，3.31ppm(CD3OD)；所有溶剂均为分析纯试剂，一般都未经处理直接使用。无水溶剂按标准方法干燥处理。其他试剂一般都购自国药集团化学试剂有限公司、韶远化学科技(上海)有限公司、吉尔生化(上海)有限公司、深圳迈瑞尔化学技术公司、Aldrich、Alfa-Aesar、Acros、Fluka、Merck、TCI或者Lancaster等试剂公司，有少数试剂购自生产厂家，除非特别说明，这些试剂都未经处理直接使用。自制试剂在使用前一般要经过NMR确定其结构和大致纯度。TLC薄层层析硅胶板由山东烟台会友硅胶开发有限公司生产，型号HSGF 254；化合物纯化使用的正相柱层析硅胶为山东青岛海洋化工厂分厂生产，型号zcx-11，200-300目。
制备实施例一(化合物编号HD 1-路线一)
Figure PCTCN2015075247-appb-000019
化合物16的制备方法已在专利WO2012152208中报道过，合成步骤不再详述。将化合物16(87mg,0.25mmol)溶于无水DCM(5mL)中，冰浴冷却。N2保护下，滴加二氯亚砜(177mg,1.49mmol)。加毕70-80℃回流2h，静置冷却。旋干溶剂，油泵上抽去二氯亚砜，得到酰氯粗品。将粗品直接溶于5mL无水DCM中，冰浴下缓慢滴加三氟醋酸酐(313mg，1.49mmol)。滴毕保温5min，再滴加无水吡啶(157mg，1.98mmol)，室温搅拌反应2h。TLC检测原料消失后，0℃下加入5mL H2O，缓慢升温搅拌一段时间。反应液用DCM萃取两次，合并有机相，分别用1N HCl和饱和食盐水洗涤，无水Na2SO4干燥。浓缩柱层析(PE:Acetone＝3:1)，得产物HD 1(8mg，8％，白色固体)。1H NMR(300MHz,CDCl3)δ7.85(d,J＝3.3Hz,1H),7.48(s,1H),7.44(d,J＝3.3Hz,1H),3.49(q,J＝7.2Hz,2H),3.46–3.40(m,1H),2.82(t,J＝6.9Hz,2H),1.81–1.73(m,2H),1.72–1.62(m,2H),1.37–1.28(m,2H),0.81–0.77(m,2H)。ESIMS(m/z):426.1[M+Na+]
制备实施例二(化合物编号HD 1-路线二)
Figure PCTCN2015075247-appb-000020
化合物17的制备方法已在专利WO2012152208中报道过，合成步骤不再详述。化合物17(252mg，1mmol)溶于4mL无水THF中，加入20μL DMF。0℃下滴入草酰氯0.25mL，滴毕室温反应3h。随后再次冷却至0℃，加入1.5mL浓氨水和4.5mL水的混合液，室温搅拌30min，过滤，得化合物18(118mg，47％，白色固体)。1H NMR(300MHz,CDCl3)δ7.85(d,J＝3.3Hz,1H),7.44(d,J＝3.3Hz,1H),7.24–7.19(s,1H),5.54(s,1H),3.49–3.33(m,1H),1.37–1.32(m,2H),0.85–0.79(m,2H)，ESIMS(m/z):274.0[M+Na+]；
化合物19(25g，0.25mol)和三氟甲基三甲基硅烷(39g，0.27mol)溶于150mL无水THF中。0℃，N2保护下，小心滴入TBAF(1M in THF)2.7mL，之后自然升温，室温反应过夜。旋去溶剂，残余物油泵上减压蒸馏，收集72-74℃的馏分，得化合物20。(46.3g，77％，无色液体)1H NMR(300MHz,CDCl3)δ3.79(dd,J＝6.4,2.6Hz,2H),1.72–1.57(m,6H),0.21(s,9H)。
直接将化合物20溶于1N HCl溶液中，室温搅拌过夜，乙醚萃取，无水Na2SO4干燥，小心旋干溶剂后得到化合物21，无需纯化。将化合物21粗品(37g，0.11mol)和2-氯乙醇(26.5g，0.33mol)溶于250mLDMF中。室温搅拌反应2h后，再加入K2CO3(45.6g，0.33mol)，室温反应过夜。加入大量H2O稀释反应液，EA萃取三次，合并有机相，水和饱和食盐水洗涤，无水Na2SO4干燥。旋干溶剂，得到化合物22(28.8g，70％in two steps，无色液体)，无需纯化。1H NMR(300MHz,CDCl3)δ4.15–4.11(m,2H),4.11–4.07(m,2H),3.64(t,J＝6.3Hz,2H),2.03(s,1H),1.88–1.80(m,2H),1.62–1.43(m,4H),ESIMS(m/z):237.1[M+Na+]。
化合物22(28g，0.13mol)溶于250mLDCM中，加入4-甲基苯磺酰氯(37g，0.19mol)和吡啶(20.6g，0.26mol)，室温反应过夜。旋去溶剂，EA溶解，分别用H2O、1N HCl、H2O、饱和NaHCO3溶液、饱和食盐水洗涤有机相，无水Na2SO4干燥。浓缩，柱层析(PE:EA＝10:1-4:1)，得化合物23。(20.5g，43％，无色油状物)1H NMR(300MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),4.15–4.13(m,2H),4.08–4.05(m,2H),4.02(t,J＝6.3Hz,2H),2.45(s,3H),1.79–1.62(m,4H),1.48–1.45(m,2H),ESIMS(m/z): 391.1[M+Na+]。
将化合物23(587mg，1.59mmol)和化合物18(600mg，2.39mmol)溶于20mL无水DMF中，N2保护下加入NaH(100mg，2.5mmol)，之后室温反应3h。TLC检测化合物23已基本消失，向反应液中加入10mL 1N HCl，EA萃取三次，合并有机相。分别用H2O和饱和食盐水洗涤有机相三次，无水Na2SO4干燥。浓缩，柱层析(PE:Acetone＝6:1)得化合物24。(266mg，37.5％，无色油状物)1H NMR(300MHz,CDCl3)δ7.84(d,J＝3.0Hz,1H),7.45(s,1H),7.43(d,J＝3.0Hz,1H),4.15–4.11(m,2H),4.13–4.07(m,2H),3.46(t，J＝6.3Hz，2H),3.42–3.39(m,1H),1.93–1.85(m,2H),1.72–1.67(m,2H),1.56–1.50(m,2H),1.34–1.27(m,2H),0.83–0.79(m,2H),ESIMS(m/z):470.1[M+Na+]。
将化合物24(656mg。1.46mmol)溶于10mL无水DCM中。0℃，N2保护下，缓慢滴入5mLBBr3(2N in DCM)溶液，之后自然升温反应。1h后，TLC检测原料已消失。冰浴冷却反应液，小心滴入5mLH2O淬灭，之后DCM萃取，饱和食盐水洗涤有机相，无水Na2SO4干燥，旋干得粗品。将粗品溶于5mL丙酮，加入5mL 1N HCl，50℃反应过夜。冷却后，旋去溶剂，1N NaOH调节pH≈2，有固体析出，过滤，用少量1N NaOH洗涤固体，得产物HD 1(260mg，44％，白色固体)。1H NMR同上。
制备实施例三(化合物编号HD 1-路线三)
Figure PCTCN2015075247-appb-000021
将化合物23(20g，0.054mol)溶于200mLDMF中，加入叠氮化钠(7g，0.108mol)和K2CO3(22.4g，0.162mol)，室温反应。2h后TLC检测原料已消失，向反应液中加入100mLH2O，再用乙酸乙酯萃取(100mL*3)，有机相分别用H2O(150mL*3)和饱和食盐水(150mL)洗涤，无水Na2SO4干燥。旋干溶剂即得化合物25(11.9g，92％，无色液体)，无需纯化。1H NMR(300MHz,CDCl3)δ4.20–4.14(m,2H),4.13–4.09(m,2H),3.29(t,J＝6.6Hz,2H),1.86(t,J＝7.5Hz,2H),1.66–1.58(m,2H),1.56–1.48(m,2H)。
将化合物25(8.39g，0.035mol)溶于150mL乙酸乙酯中，置换N2后，加入10％钯碳加氢催化剂839mg，再置换N2，最后置换H2三次，室温反应。5h后TLC检测原料消失，重新置换N2，硅藻土过滤，乙酸乙酯洗涤滤饼，滤液旋干后得到化合物26(7.38g。98％，淡黄色液体)。1H NMR(300MHz,CDCl3)δ4.16–4.11(m,2H),4.09–4.07(m,2H),2.70(t,J＝6.3Hz,2H),1.83(t,J＝7.8Hz,2H),1.47(s,4H),ESIMS(m/z):214.1[M+H+]。
将化合物17(6.82g，0.027mol)和化合物26(7.38g，0.035mol)溶于150mLDCM中，加入DMAP(4.9g，0.04mol)。搅拌10min后，冰浴下加入EDCI(7.76g，0.04mol)，室温反应过夜。分别用1N HCl和饱和食盐水洗涤有机相，无水Na2SO4干燥。浓缩后柱 层析(PE:Acetone＝6:1)，得化合物24(6.37g，53％，无色油状物)，1H NMR数据同上。用路线二的方法将化合物24保护基脱除，同样可以得到化合物HD 1。1H NMR同上。
用以上三种路线的其中一种均可得到下列化合物：
Figure PCTCN2015075247-appb-000022
Figure PCTCN2015075247-appb-000023
制备实施例四(化合物编号HD 60)
Figure PCTCN2015075247-appb-000024
将化合物17(1g，3.96mmol)置于20mL叔丁醇中，N2保护，30℃下滴入三乙胺(600mg，5.9mmol)和叠氮磷酸二苯酯(DPPA，1.4g，5.15mmol)，之后避光回流反应过夜。将反应液冷却至室温，加入大量H2O后，乙酸乙酯萃取，合并有机相。分别用H2O、饱和NaHCO3溶液、5％柠檬酸溶液和饱和食盐水洗涤有机相，无水Na2SO4干燥。浓缩柱层析(PE:EA＝10:1)得化合物27(245mg，20％，淡黄色固体)。1H NMR(300MHz,CDCl3)δ7.82(d,J＝3.0Hz,1H),7.39(d,J＝3.0Hz,1H),6.50(s,1H),2.12–2.04(m,1H),1.51(s,9H),1.14–1.06(m,2H),0.77–0.71(m,2H)。ESIMS(m/z):346.1[M+Na+]。
将化合物27(90mg，0.278mmol)溶于5mL DCM中，0℃下滴入5mL 2N HCl/EA溶液，之后自然升至室温反应。4h后，TLC检测反应完全，加入饱和NaHCO3溶液调节pH为碱性，DCM萃取，饱和食盐水洗涤有机相，无水Na2SO4干燥。浓缩得化合物28(40mg，65％，黄色油状物)。1H NMR(300MHz,CDCl3)δ7.79(d,J＝3.3Hz,1H),7.33(d,J＝3.3Hz,1H),4.13(s,2H),1.74–1.67(m,2H),1.02–0.97(m,2H),0.70–0.65(m,2H)。ESIMS(m/z):246.0[M+Na+]。
化合物29(无色液体)可由ε-己内酯经路线二中所述方法得到。1H NMR(300MHz,CDCl3)δ4.19–4.13(m,2H),4.11–4.05(m,2H),3.65(t,J＝6.3Hz,2H),1.84(t,J＝6.0Hz，2H),1.63–1.54(m,2H),1.45–1.36(m,4H)。
化合物29(113mg，0.495mmol)溶于CH3CN:H2O＝1:1g共2mL溶剂中，加入二醋酸碘苯(BAIB，479mg，1.49mmol)和2,2,6,6-四甲基哌啶-1-氧基自由基(TEMPO，23mg， 0.149mmol)，室温反应过夜。TLC检测反应物消失，向反应液中加入1mL饱和Na2S2O3溶液，乙酸乙酯萃取，饱和食盐水洗涤有机相，无水Na2SO4干燥。浓缩后柱层析(PE:丙酮＝4:1)得到化合物30(100mg，83％，近白色固体)。1H NMR(300MHz,CDCl3)δ4.16–4.11(m,2H),4.09–4.07(m,2H),2.37(t,J＝7.5Hz,2H),1.84(t,J＝7.5Hz,2H),1.69–1.61(m,2H),1.50–1.43(m,2H)。ESIMS(m/z):241.0[M-H+]。
将化合物28(41mg，0.186mmol)和化合物30(45mg，0.186mmol)溶于DCM中，加入DMAP(68mg，0.557mmol)，N2保护，0℃下加入EDCI(53mg，0.276mmol)，之后室温反应过夜。向反应液中加入H2O，乙酸乙酯萃取，饱和食盐水洗涤有机相，无水Na2SO4干燥。浓缩后柱层析(PE:丙酮＝10:1-4::1)得到化合物31(35mg，42％，淡黄色固体)。1H NMR(300MHz,CDCl3)δ7.83(d,J＝3.0Hz,1H),7.61(s,1H),7.39(d,J＝3.0Hz,1H),4.15–4.11(m,2H),4.11–4.08(m,2H),2.44(t，J＝6.9Hz，2H),1.87–1.76(m,4H),1.53–1.43(m,2H),1.16–1.08(m,2H),0.85–0.71(m,2H),ESIMS(m/z):470.1[M+Na+]。
化合物31经与路线二类似的方法脱去保护基可以得到化合物HD 60(白色固体)。
1H NMR(300MHz,CDCl3)δ7.84(d,J＝3.3Hz,1H),7.48(s,1H),7.41(d,J＝3.3Hz,1H),2.79(s,2H),2.48(s,2H),2.04–2.03(m,1H),1.80–1.68(m,4H),1.11–1.02(m,2H),0.79–0.73(m,2H)。ESIMS(m/z):404.1[M+H+]。
制备实施例五(化合物编号HD 46)
Figure PCTCN2015075247-appb-000025
将化合物GCJ403(403mg，1mmol)溶于10mL乙醇中，加入羟基乙酰肼(180mg，2mmol)和0.5mL冰醋酸，65℃反应过夜。停止加热，冷却后旋去乙醇，残余物用乙酸乙酯溶解，分别用H2O和饱和食盐水洗涤有机相，无水Na2SO4干燥。浓缩后柱层析(PE:丙酮＝4:1-1:1)得到化合物HD 46(275mg，62％，白色固体)。1H NMR(300MHz,CDCl3)δ10.68(s,1H),7.85(d,J＝3.3Hz,1H),7.74(s,1H),7.44(d,J＝3.3Hz,1H),4.48(d,J＝4.5Hz,2H),3.78–3.72(m,1H),3.57(dd,J＝11.4,6.6Hz,2H),3.12(s,1H),2.68(t,J＝8.4Hz,2H),1.77–1.73(m,2H),1.73–1.70(m,2H),1.42–1.37(m,2H),0.87–0.76(m,2H)。ESIMS(m/z):498.0[M+Na+]。
用同样方法合成以下化合物：
Figure PCTCN2015075247-appb-000026
Figure PCTCN2015075247-appb-000027
Figure PCTCN2015075247-appb-000028
Figure PCTCN2015075247-appb-000029
Figure PCTCN2015075247-appb-000030
生物实验实施例
实验实施例一：组蛋白去乙酰化酶1、3、4、6(HDAC1、3、4、6)抑制活性测试实验
1.实验目的：
进行本专利中化合物对人源组蛋白去乙酰化酶1、3、4、6的抑制活性测试。
2.实验材料：
人源HDAC1、HDAC3、HDAC4和HDAC6，均应用杆状病毒表达系统，由上海药物研究所李佳博士课题组纯化得到。
底物：HDAC1、3、4：Ac-Lys-Tyr-Lys(Ac)-AMC；
HDAC6：Boc-lys(Ac)-AMC
均购自上海吉尔生化有限公司；
3.测试原理：
采用荧光检测法，在96孔或384孔平底微孔板中检测酶活性。底物经HDAC去乙酰化后，利用胰酶水解得到的产物AMC在荧光检测仪的355nm激发460nm发射光下可被检测到荧光信号。通过检测随时间荧光信号的变化，计算得到反应初速度。
4.实验过程：
样品处理：样品用DMSO溶解，低温保存，DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
数据处理和结果说明：初筛选择单浓度条件下，例如20μg/ml，对样品的活性进行测试。对于在一定条件下表现出活性的样品，例如抑制率％大于50，测试活性剂量依赖关系，即IC50/EC50值，通过样品活性对样品浓度进行非线性拟和得到，计算所用软件为Graphpad Prism 4，拟合所使用的模型为sigmoidal dose-response(varible slope)，对于大多数抑制剂筛选模型，将拟合曲线底部和顶部设定为0和100。一般情况下，每个样品在测试中均设置复孔(n≥2)，在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示。每次测试均有已上市的化合物SAHA(Vorinostat)作为参照。
5.部分化合物实验结果：
表1
Figure PCTCN2015075247-appb-000031
Figure PCTCN2015075247-appb-000032
由上表的实验结果可以看出：R4部位从之前CFH467-C的异羟肟酸改为三氟乙酰基酮类后，HDAC各亚型的活性均有了数倍的提高，其中HD 1对HDAC1、3、4的抑制活性都很高，IC50可达约20nM；而将三氟乙酮类进一步改造成腙类化合物时(HD 37、HD46)，可以提高HDAC6的活性。并且噻唑环上不论是烷基还是芳香基取代都呈现良好的HDAC抑制活性。
实验实施例二：细胞水平抗肿瘤活性测试实验
1.实验目的：
进行本发明化合物的抗肿瘤活性测试，通过测定化合物对人源多发性骨髓瘤细胞株8266的生长抑制活性来评价化合物的体外抗肿瘤活性。
2.实验材料：
人源多发性骨髓瘤细胞株8266：上海长征医院侯建博士馈赠。
3.测试原理：
采用四甲基偶氮唑盐(MTT)比色法，该分析方法以代谢还原3-(4,5-二甲基-2-噻唑)-2,5-二苯基溴化四唑(MTT)为基础。活细胞的线粒体中存在与NADP相关的脱氢酶，可将黄色的MTT还原为不溶性的蓝紫色的甲臜(Formazan),死细胞此酶消失，MTT不被还原。用DMSO溶解Formazan后可用酶标仪在550/690nm波长处测量光密度。
4.实验过程：
样品处理：样品用DMSO溶解，低温保存，DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
运用MTT法检测细胞存活率，即将生长在对数生长期的细胞，经0.05％的胰酶消化，计数，以2.0×103/孔的细胞密度接种在96孔板中100μL，置于5％CO2培养箱内37℃培养过夜。每一化合物设六个浓度梯度，每一浓度设三复孔，每一浓度分别加入到对应孔中，5％CO237℃培养箱内培养72小时，加入20μL的5mg/mL MTT。37℃孵育3小时后，吸弃上清，加入100μL的DMSO溶解，使用SpectraMAX 340测550nm(L1)光吸收值，参考波长690nm(L2)，将(L1-L2)值对抑制剂不同浓度作图，经公式拟合得IC50。
数据处理和结果说明：初筛选择单浓度条件下，例如20μg/ml，对样品的活性进行测试。对于在一定条件下表现出活性的样品，例如抑制率％大于50，测试活性剂量依赖关系，即IC50/EC50值，通过样品活性对样品浓度进行非线性拟和得到，计算所用软件为Graphpad Prism 4，拟合所使用的模型为sigmoidal dose-response(varible slope)，对于大多数抑制剂筛选模型，将拟合曲线底部和顶部设定为0和100。一般情况下，每个样品在测试中均设置复孔(n≥2)，在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示(表中为IC50±SD)。每次测试均有已上市的化合物SAHA(Vorinostat)作为参照。
4.部分化合物实验结果：
在人多发性骨髓瘤细胞株8266上的活性结果：
表2
Figure PCTCN2015075247-appb-000033
从上表可以看出，本专利所述的化合物亦呈现出良好的抑制肿瘤细胞增殖活性，相对于之前报道的化合物CFH367-C(IC50＝1.139μM)，细胞水平上活性有接近10倍的提高(HD46：IC50＝0.117μM)，化合物在细胞上的活性基本与在酶上的活性吻合。
实验实施例三：化合物在EAE小鼠模型上的药效检测试验。
1.实验目的：
通过化合物在EAE小鼠模型上的药效实验，检测化合物作为组蛋白乙酰化酶抑制剂的治疗EAE的活性。
抗原MOG35～55(MEVGWYRSPFSRVVHLYRNGK)加入弗氏完全佐剂(含灭活结核分枝杆菌5mg/ml)乳化。8周大雌性C57BL/6小鼠皮下注射200μg乳化后的MOG35～55抗原，同时每只老鼠注射200ng百日咳毒素，诱导当天为第0天。在第2天每只老鼠追加200ng百日咳毒素。每天对老鼠的症状进行评分并记录，评分细则如下，
0分：正常，无症状
0.5分：尾巴尖端无力，无法竖立
1分：整条尾巴完全无力，
2分：后肢无力。将小鼠单只后肢倒挂在笼沿上，若此后肢无力则小鼠不能攀附笼沿，无法爬回笼内并从笼沿掉落，一只后肢无力为1.5分，两只后肢都无力为2分
3分：小鼠后肢瘫痪，丧失行动能力
4分：小鼠前肢无力或瘫痪
5分：小鼠死亡或奄奄一息
2.实验材料：
EAE小鼠：上海斯莱克实验动物有限公司；
抗原MOG35～55：上海吉尔生化有限公司；
3.实验方法：
HD 1是纯化合物的形式，同时以CFH367-C作比较，药物直接加CMC-Na研磨超声混悬成均匀状态，剂量都为10mg/kg，一天两次灌胃给药。对照组直接给以PBS。
4.实验结果：
HDACi HD 1可以有效缓解EAE模型小鼠的发病。从发病率和发病曲线(图1)表明，HDAC抑制剂HD 1对EAE模型小鼠的临床症状有良好的治疗作用，且效果优于CFH367-C，治疗组小鼠的疾病严重程度显著的低于溶剂对照组(P<0.01)。
发病率：
  发病个数/总数
空白对照 6/6
HD 1 3/6
CFH367-C 5/6

Claims (10)

  1. 一种具有下面的通式I结构的2,2’-串联双噻唑类化合物：
    Figure PCTCN2015075247-appb-100001
    其中：
    R1和R2各自独立地为如下基团的一种：
    H、C3-C6环烷基、C1-C6烷基、C2-C6链烯基、C2-C6链炔基；或者R1和R2与其所连接的碳原子形成5-7元环状结构；
    X为
    Figure PCTCN2015075247-appb-100002
    Y为
    Figure PCTCN2015075247-appb-100003
    或C2-C6亚烯基，其中n为1、2、3或4；
    R3为如下基团的一种：
    H，C1-C6烷基，C6-C10芳基取代的C1-C6烷基，C3-C6环烷基，C1-C6烷基取代的C3-C6环烷基，C2-C8链烯基，C2-C6链炔基，C6-C10芳基，5-7元杂芳基；所述5-7元杂芳基含有1-3个选自N、O和S中的杂原子；
    R4为R4a、R4b、R4c、R4d或R4e：
    Figure PCTCN2015075247-appb-100004
    其中R5、R6、R7和R8选自如下基团中的一种：
    H，羟基，C1-C6烷基，C1-C6烷氧基，羟基C1-C6亚烷基，C6-C10芳基取代的C1-C6烷基，C3-C6环烷基，C1-C6烷基取代的C3-C6环烷基，C2-C8链烯基，C2-C6链炔基，C6-C10芳基，5-7元杂芳基，
    Figure PCTCN2015075247-appb-100005
    所述5-7元杂芳基含有1-3个选自N、O和S中的杂原子。
  2. 根据权利要求1所述的2,2’-串联双噻唑类化合物，其中，
    R1和R2各自独立地为H、C1-C6烷基或者R1和R2与其所连接的碳原子形成5元、6元或7元的饱和环状结构；
    Y为
    Figure PCTCN2015075247-appb-100006
    R3为C1-C4烷基、C6-C10芳基取代的C1-C4烷基或C3-C6环烷基；
    R5为羟基、C1-C6烷基、C1-C6烷氧基、C6-C10芳基或
    Figure PCTCN2015075247-appb-100007
    R6为H、C1-C6烷基；
    R7为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、羟基C1-C6亚烷基、C6-C10芳基或5-7元杂芳基，所述5-7元杂芳基含有1-3个选自N、O和S中的杂原子；
    R8为C6-C10芳基。
  3. 根据权利要求2所述的2,2’-串联双噻唑类化合物，其中，
    R3为C1-C4烷基、苯甲基、或环丙基；
    R5为羟基、C1-C4烷基、C1-C4烷氧基、苯基或
    Figure PCTCN2015075247-appb-100008
    R6为H、甲基；
    R7为C1-C4烷基、C3-C5环烷基、C1-C4烷氧基、羟基C1-C4亚烷基、C6-C10芳基或5-7元杂芳基，所述5-7元杂芳基含有1-2个选自N、O和S中的杂原子(例如，吡啶)；
    R8为苯基。
  4. 根据权利要求3所述的2,2’-串联双噻唑类化合物，其中，
    R7为甲基、乙基、丙基、异丙基、叔丁基、环丙基、甲氧基、乙基氧基、羟甲基、羟乙基、苯基、吡啶基、哒嗪基、嘧啶基或吡嗪基。
  5. 根据权利要求1至4中任一项所述的2,2’-串联双噻唑类化合物，其选自下列化合物中：
    Figure PCTCN2015075247-appb-100009
    Figure PCTCN2015075247-appb-100010
    Figure PCTCN2015075247-appb-100011
  6. 如权利要求1所述的2,2’-串联双噻唑类化合物的制备方法，
    其中，化合物Ⅰa通过下述路线一至路线三中的一种来制备：
    路线一：
    Figure PCTCN2015075247-appb-100012
    其中，R1、R2、R3和n的定义与权利要求1所述的通式I中的定义相同；
    将化合物1利用酰氯化试剂制成酰氯，酰氯再与TFAA在碱的存在下于室温或加热下发生取代反应并水解得到化合物Ⅰa；
    路线二：
    Figure PCTCN2015075247-appb-100013
    其中，R1、R2、R3和n的定义与权利要求1所述的通式I中的定义相同；
    化合物2利用酰氯化试剂形成酰氯，再在冰浴下与浓氨水作用得到化合物3；
    化合物4与TMS-CF3在TBAF催化下，于四氢呋喃中发生加成反应得到化合物5，化合物5经H+水解后得到化合物6，化合物6与2-氯乙醇在K2CO3存在下于DMF中反应得到化合物7，化合物7在TsCl和Et3N存在下于DCM中磺酰化得到化合物8，化合物8和化合物3在NaH的作用下于DMF中得到化合物9，化合物9在路易斯酸作用下脱去乙二醇保护得到化合物Ⅰa；
    路线三：
    Figure PCTCN2015075247-appb-100014
    其中，R1、R2、R3和n的定义与如权利要求1所述的通式I中的定义相同；
    化合物8与NaN3于DMF中反应得到化合物10，化合物10经氢化还原得到胺11，胺11与酸2在缩合剂存在下于DCM中发生缩合反应得到化合物9，化合物9在路易斯酸作用下脱除乙二醇保护同样制得化合物Ⅰa；
    Ⅰb类化合物通过路线四制备：
    路线四：
    Figure PCTCN2015075247-appb-100015
    其中，R1、R2、R3和n的定义与如权利要求1所述的通式I中的定义相同；
    化合物2经过库尔修斯重排反应得到Boc保护的胺12，12脱去Boc得到游离的胺13；同时化合物7经TEMPO和BAIB氧化得到酸14，酸14与胺13经缩合剂的作用得到化合物15，化合物15在路易斯酸作用下脱除乙二醇保护得到化合物Ⅰb；
    Ⅰc类化合物通过路线五制备：
    路线五：
    Figure PCTCN2015075247-appb-100016
    其中，R1、R2、R3、R5、R6、R7、X和Y的定义与如权利要求1所述的通式I中的定义相同；
    R9选自R4b、R4c和R4d中的一种；
    化合物Ⅰab与
    Figure PCTCN2015075247-appb-100017
    在室温或加热条件下于溶剂中发生脱水缩合反应，得化合物Ⅰc。
  7. 如权利要求1所述的具有通式Ⅰ结构的2,2’-串联双噻唑类化合物在制备作为组蛋白去乙酰化酶抑制剂的药物中的用途。
  8. 如权利要求1所述的具有通式Ⅰ结构的2,2’-串联双噻唑类化合物在制备抗肿瘤的药物、治疗自身免疫性疾病的药物、治疗II型糖尿病及其并发症的药物或治疗神经退行性病变的药物中的用途。
  9. 如权利要求8所述的用途，其中，所述肿瘤为多发性骨髓瘤、皮肤T细胞淋巴瘤或外周T细胞淋巴瘤；所述自身免疫性疾病为多发性硬化症；所述神经退行性病变为亨廷顿舞蹈病或阿尔兹海默氏病。
  10. 一种药物组合物，其包含治疗有效量的选自权利要求1所述的具有通式I结构的2,2’-串联双噻唑类化合物中的一种或多种以及药学上可接受的辅料。
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