WO2015085459A1 - 用于抑制谷胱甘肽S-转移酶omega1活性的化合物及其制备方法、和包含该化合物的医药组合物 - Google Patents

用于抑制谷胱甘肽S-转移酶omega1活性的化合物及其制备方法、和包含该化合物的医药组合物 Download PDF

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WO2015085459A1
WO2015085459A1 PCT/CN2013/088871 CN2013088871W WO2015085459A1 WO 2015085459 A1 WO2015085459 A1 WO 2015085459A1 CN 2013088871 W CN2013088871 W CN 2013088871W WO 2015085459 A1 WO2015085459 A1 WO 2015085459A1
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compound
general formula
glutathione
halogen
formula
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PCT/CN2013/088871
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French (fr)
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吴永昌
李国雄
张芳荣
庄大纬
杨颛丞
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中国医药大学
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Priority to PCT/CN2013/088871 priority Critical patent/WO2015085459A1/zh
Priority to EP13899167.4A priority patent/EP3081562B1/en
Publication of WO2015085459A1 publication Critical patent/WO2015085459A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a compound which inhibits the activity of glutathione S-transferase omega 1 (hereinafter referred to as GST Omega 1 or GST01.), a K drug composition thereof, and a preparation method.
  • GST Omega 1 glutathione S-transferase omega 1
  • multidrug resistance drug tt (miiltidragresistance; MD) is one of the points of drug research and development, in addition to well-known channel proteins such as P-glycoprotein, MRP1, ABCG2, etc., involved in metabolism
  • the proteases of drugs have gradually become more and more popular in the field of new drug development, among which Glutathione s transferases (GSTs) are the most important proteins.
  • GSTs Glutathione s transferases
  • GSTs are! The class is phase ⁇ metabolizing enzyme, which treats the detoxification of extracellular substances. It can catalyze the adsorption of harmful substances from outside the cell to the glutathione l-peptide (gtatath ⁇ 6 ) to reduce toxicity. Therefore, in this kind of cancer cells, the expression of this GST family enzyme can be found, and in many cases, it is pointed out that GSTs are the key factors involved in the production of drug resistance.
  • the invention of wood - in one aspect is to provide - a kind of glutathione S transferase omega
  • the indole ring is a para-hydroquinol (p-quamol) ring
  • R is selected from the group consisting of the following formula (ia) and formula (lb), wherein n of the formula (la) is 1 or 2, m of formula (lb) is 0 or 1, R 1 is H or ArC3 ⁇ 4—, R 2 is Alkyl—or Aryl—:
  • Formula ( la ) Formula (lb) Another aspect of the present invention provides a pharmaceutical composition for inhibiting glutathione S-transferase omega 1 activity by using butyl, which comprises an effective amount of having the formula (I) A compound of the structure shown, and a pharmaceutically acceptable carrier.
  • the present invention provides a method for preparing a compound for inhibiting the activity of glutathione 1 : "peptide S-transferase omega 1 , which comprises performing 2, 6-monomethoxynaphthalene to i3 ⁇ 4edel-Craft acetylation. The reaction is carried out, and a halogen-containing reagent is added to remove the two methoxy groups. The intermediate I'nj product containing the first-protection* is formed, and a Claisen-Schmidt condensation reaction is carried out with the para-hydroxybenzene having a protecting group. Removing the first protecting group with a halogen catalyst and an acid solution.
  • a high-valent iodine compound is added to carry out an oxidation reaction to obtain a compound having a structure represented by the formula (ia).
  • the halogen-containing reagent used is Boron tnbromide o.
  • the first-protecting group used is a methoxymethyl group.
  • the halogen catalyst is iodine and the acid solution is concentrated _ hydrochloric acid.
  • the halogen-containing unsaturated carbon chain is Geranyl bromide o
  • the valent iodine compound is bisdifluoroacetoxyiodide benzene.
  • the compound having the structure represented by the general formula (I) of the present invention can be used for the inhibition of GST Omega 1, and the preparation method thereof is a chemical synthesis method for producing a derivative of different side chains, which has the advantage of mass production.
  • the compound having the structure represented by the general formula (1) is a ⁇ -naphthoflavone derivative having a side chain (Ia) of isoprene, which is linked by an ether linkage. Or a side chain (Ib) of a bisamide containing a 2-naphthyl side branch.
  • the standard GST Omega 1 of the compound of the present invention having the structure represented by the general formula (1) is a novel anticancer target, and the long-term development can be used as a combined therapeutic agent for various anticancer drugs, and has a development potential of extremely high. Attached H
  • Figure 1 shows the results of analysis of the effects of compounds having different side chains on the enzymatic activity of GST01.
  • the derivative of the structure of the present invention having the structure represented by the general formula (1) is designed and synthesized for inhibiting the activity of the glutathione S-transferase omega 1 and can be a potential cancer cell toxic agent in the future. Test down 1
  • in Vitro Growth liihibition (Gl 5 o, ⁇ ) is used to evaluate the cancer cell killing activity of a compound having the structure of the general formula (1) and other structural analogs.
  • Sex In the embodiment of the present invention, human I 1 cavity epithelial cancer cell line KB, multi-drug resistant nasopharyngeal carcinoma cell line KB-Vm, human lung adenocarcinoma cell line A549 and prostate cancer cell line # DU145 are selected as test subjects, and cancer cells are poisoned.
  • the agent is a 01 ⁇ 2) agent of paclitaxel. As a control.
  • Table 1 The test results are shown in Table 1 below.
  • R is represented by the number 1 19, wherein the left end of the side chain shown by the numeral 1 19 is attached to the above-described steroid structure to form a compound represented by the formula (1).
  • the compounds having the side chain structure of No. 11 and No. 12 were toxic to the four cancer cell lines tested, compared to the compound having a side chain structure of ⁇ 3 ⁇ 4.
  • the compound having the side chain structure of No. 11 is an isoprenoid having an ether bond
  • the GI 5 of the four cancer cell lines tested were 0.2 ⁇ , 0.269 ⁇ , 0.382 ⁇ , and 0.231 ⁇ , respectively.
  • the ability to kill cells is significantly better.
  • the compound having the number 12 side chain structure has two isopentane bodies in the side chain, and the GI a of the four cancer cell sisters tested are 0.067 ⁇ , 0.335 ⁇ , 0.233 ⁇ , and 0.065 ⁇ , respectively; It has a significant poisoning effect on human sacral epithelial cancer cell line KB and prostate cancer cell line DU145.
  • an enzyme activity analysis is carried out by taking a compound having a side chain structure of Nos. 1 1 and 12 as an example to verify whether the effect of the compound of the general formula (I) having the embodiment of the present invention on killing cancer cells is inhibited from inhibiting gluten Glycopeptide S-transferase omega activity is related.
  • GST01 enzyme activity assay (GSTO) substrate assay is based on the method published by Baehovchin et al. in 2000. Using GST01 tolerate S (4 nitroacetophenone) glutathione ( S-(4-nitropheiiacyl) gltitatliione; Hereinafter referred to as 4NPG).
  • the analytical method was to add 100 ⁇ M in a UV-transparent % well plate and mix it in a buffer (100 mM 'Tns (pH 8.0), 1.5 mM 'EDTA, ⁇ 0 mM 2 ⁇ ⁇ i i ⁇ (2- mercaptoetlmnol) )) GSTOl (2 nM), another 100 ⁇ ! Buffer was used as a blank control group.
  • the compounds having the side chain structures numbered 11 and 12, hereinafter referred to as the compound (I) and the compound (U) ; and the compound A and the compound B are the control group, wherein the compound A does not have the main structure of the present invention.
  • Compound B is a main structure of the present invention plus a methyl side chain.
  • the structures of Compound A, Compound B, Compound (I) and Compound (U) are as follows:
  • Compound A Compound B
  • the compound (1), the compound (11), the compound A and the compound B, and the pharmaceutical solvent Dimethyl sulfoxide were added to the well plate to react at 25 ° C for 30 minutes.
  • the substrate 4NPG was then added to give a final concentration of 0.5 mM.
  • the receptor 4NPG will specifically bind to GST01, and the structures of the compound (1) and the compound (11) of the present invention are designed to compete with the 4NPG for the enzyme binding site, which can be «r ⁇ i at a wavelength of 305.
  • the detected absorbance value is recorded every 1 minute, and the absorbance of the sample in the well plate is detected. The rate of decrease of the absorbance is obtained according to the control group. Understand the interference of the compound (1) and the compound (II). The effect of enzyme binding to the substrate.
  • Figure 1 shows the results of analysis of the effects of compounds with different side chains on the enzyme activity of GST01, from Figure 1. It can be seen that the two compounds in the control group, that is, the compound A having no host structure, and the compound B having an i-body structure but not having an iso-pentane body, have a lower ability to bind the interfering enzyme to the substrate, and the wood In the compound (1) and the compound (II) of the present invention, the ability of the interfering enzyme to bind to the substrate is obviously better, and i exhibits a tendency to increase as the side chain is extended, and this result is related to the cancer cell killing test. The results are consistent.
  • the compound (I) and the compound (II) of the examples of the present invention have a significantly better effect on the cancer cell killing test than the other structures, and the structure thereof is confirmed to compete with the substrate 4NPG of C3ST01 for binding to the enzyme. Thereby, the effect of inhibiting the activity of the GSTO1 enzyme is achieved. Therefore, an effective amount of the pharmaceutical composition of the present invention for inhibiting the glutamate It peptide S-transferase omega 3 ⁇ 4tt compound and a pharmaceutically acceptable carrier is indeed a new anticancer target, and the long-term development can be used as a plurality of anticancer drugs.
  • the combined therapeutic agent of the drug has extremely "development potential.
  • the compound of the present invention for inhibiting the activity of glutathione S-transferase omega 1 can be produced by a conventional method.
  • a Fnedel-Cr acetylation reaction comprising 2,6--;methoxynaphthalene can be carried out, and a halogen-containing reagent is added to remove ':methoxy ft.
  • An intermediate product containing the first protection ft is formed and subjected to a Claisen-Sehimdt condensation reaction with a para-hydroxy-benzaldehyde containing a _:protection 3 ⁇ 4, and the first protection is removed with a halogen catalyst and an acid solution.
  • the compound was dissolved in anhydrous dichloromethane, and 6 equivalents of diboron boron was added under nitrogen and minus 78 Torr to remove the two methoxy groups on the naphthalene ring. After stirring for 2 hours, water was added to remove the remaining Dibromoboron. After extracting with chloroformamidine/water, the organic solvent is removed by concentration under reduced pressure, and the tube is subjected to tt S analysis with hexane/ethyl acetate to obtain 1-acetyl-2,6-dihydroxyoxynaphthalene ( L-acetyl-2,6-dihydroxy naphthalene ), yielding "93%.
  • the obtained compound was redissolved in anhydrous dimethylformamidine, and 2 of isopropyl ethylamine CN, N-Diisopropylethykmme) was added under ice bath until the reaction solution became clear. Next, a solution of chloromethyl 3 ⁇ 4 methyl 3 ⁇ 4 ether diluted in dichloromethane (diluted about forty ⁇ ) was added dropwise to the reaction solution, and stirring was continued for about 2 hours. The solvent of the ifi machine was removed under reduced pressure to obtain the compound 1 (containing the first protecting group methoxymethyl group) in a yield of 3 ⁇ 4/ethyl acetate 3 ⁇ 4 tf. 47.3%.
  • Compound 5 was dissolved in ethyl acetate and added with 0% carbon palladium in a ratio of 240 mg hydrazine per 1 mmol of starting material. After reacting overnight under the catalysis of hydrogen, the carbon palladium was removed by filtration, and the solution was concentrated under reduced pressure to obtain a compound 6 which was subjected to removal of a second protecting group (i.e., a benzyl group) in a yield of 40%.
  • a second protecting group i.e., a benzyl group
  • compound 6 is dissolved in an aqueous solution of acetonitrile in a ratio of about 15:1, and 2 equivalents of bis(trifluoroacetoxy)iodoj benzene is added to carry out an oxidation reaction, thereby obtaining a compound (II).
  • the final product was shown to have an isopentane dimer side chain with a yield of 49%.

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Abstract

　本发明涉及一种用于抑制谷胱甘肽 S-转移酶omega 1活性的化合物及其医药组合物。本发明还涉及上述化合物的制备方法。本发明的抑制谷胱甘肽 S-转移酶omega 1活性的化合物具有如下通式（I）所示的结构，其中 A环为对位氢醌醇环，R是选自于由下列通式（Ia）及通式（Ib）所组成的群组，通式（Ia）的n为1或2，通式（Ib）的m为0或1，R1 为 H或ArCH 2 -，R2为Alkyl-或Alkyl-。

Description

用于抑制谷胱甘肽 S-转移酶 omega 1 «性的化合物及其制备方法、 和包含该化合物 医药组合物 技术领域
本发明是有关于一种抑制谷胱廿妝 S-转移酶 omega 1(以下简称 GST Omega 1或 GST01.)活性的化含物、 ：其 K药组合物及.； H:制备方法。 背景披术
在癌 ¾ΐ；的治疗上， 多重药物抗药 tt ( miiltidragresistance; MD ) 是药物 研究与开发的 点项目之一， 除熟知的通道蛋白如 P- glycoprotein、 MRP1、 ABCG2...等外，参与代谢药物的蛋白酶于近来新药开发领域上遂渐受到 ¾视， 其中又以谷胱甘肽 S-转移酶（Glutathione s transferases; GSTs)此.家族的蛋白 最为 要。
GSTs 被！^类为 phase Π代谢酶， 处理细胞外来物质去毒化作用， 它可将 来自细胞外的有害物质催化接上谷舰 l-肽 (gtatath譲 6)而降低毒性。 也因此在 多种癌症细胞中， 都可以发现此 GST家族酶大 Λ表现， 并且在许多 ¾础与临 *证据上都指出 GSTs是参与产生药物抗药性的袁要因子。
先前研究发现， GST 被认为在抗药性产生的过程中相当 «要， 许多药 物研究与开发― L:都集中设计 GST 的抑制剂。 前开发上， 以美国 Telik生物 药剂公司拥有许多 GST pi抑制剂专禾 旗下药物 TELCY1A® ( Canfosfamide HC1) H TEL1NTRA® (Ezatiostat HC1, TL 199 ) 为 GST pi的抑制剂。
然而， 近年来 GST omega 的 ¾要性亦逐渐获得证实， 包含阿 素依托泊 TT¾'l(adnamycin etoposide pktii麵)类抗癌药物都与 GST Omega 1-1有密 的关 连，对于缺乏 GST Omega 1-1的癌症无法对二氧化一.神 (arsenic trioxide.)、顺铂 (cisplatiuni), 道诺導素 (daimorabin) 与依托 l i etoposide)产生抗药性， 而冃 前尚未有针对 GST omega 1开发出的抑制剂， 以处理癌症抗药性的问题。 发明 Λ容
因此，木发明的- -个方面在于提供 · -种用于仰制谷胱甘肽 S转移酶 omega 1活性的化合物， 该化合物具有如下通式 （1) 所小的结构:
Figure imgf000003_0001
ΜΛ(ΐ)
其中 Α环为对位氢醌醇 （p- qumol) 环， R是选自于由下列通式 (ia)及通式 (lb) 所组成的群组， 通式 (la)的 n为 1或 2 , 通式 (lb) 的 m为 0或 1， R1为 H或 ArC¾—， R2为 Alkyl—或 Aryl—:
Figure imgf000003_0002
通式 ( la ) 通式 （lb) 本发明的另一 面在于提供一种用丁抑制谷胱廿肽 S-转移酶 omega 1活 性的医药组合物， 其包含有效量的具有如通式 （I ) 所示结构的化合物， 以及 一药学上可接受的载体。
本发明的 51— 面在于提供一种用于抑制谷胱 1::「肽 S-转移酶 omega 1活 性的化合物的制备 法，包含将 2， 6-一.甲氧基萘进行 i¾edel-Craft乙酰化反应, 并加入含卤素试剂以去除二个甲氧 ¾。 形成含第- -保护 *的中 I'nj产物， 并与 含有第 保护基的对位羟基苯¥^进行 Claisen- Schmidt缩合反应， 再以卤素 催化剂及酸溶液去除第一保护基。 加入含卤素不饱和碳链并去除第二保护基， 再加入高价碘化合物进行氧化反应，得到具冇如通式（ia)所示结构的化合物。 依照木发明的一实施例，使用的含卤素试剂为二溴硼 ( Boron tnbromide)o 依照本发明的另―实施例， 使用的第 -保扩基为甲氧基甲基
(Methoxymethyl; MOM) , 第 保护基为苯甲¾。
依照木发明的一实施例， 卤素催化剂为碘， 酸溶液为浓 _盐酸。
依照木发明的另一实施例， 含卤素不饱和碳链为香叶草溴 ( Geranyl bromide )o
依照木发明的另一实施例， 价碘化合物为双二氟乙酰氧碘化苯。
根据上述， 本发明实施例的具有如通式 ( I)所示结构的化合物可用于抑 制 GST Omega 1， 其制备方法是以化学方法全合成产生不同侧链的衍牛物， 具有大量生产的优点， 具有通式 ( 1 ) 所示结构的化合物为一种 β-萘黄酮类 (Protoapigenone ) 衍生物， 具有由醚键 （ether linkage ) 连接的异戊垸 .体衍 牛的侧链 （Ia)， 或是含有 2-萘基侧支的双酰胺类的侧链 （Ib)。
本发明实施例的具有通式 (1)所示结构的化合物的标的 GST Omega 1为 新抗癌标的， 长期发展可做为多种抗癌药物的合并治疗试剂， 具有极 ¾的发 展潜力。 附 H说明
为让木发明的上述和其他 的、 特征、 优点与实施例能更明 易懂， 所 附图式的说明如下：
图 1为具有不同侧链的化合物对 GST01的酶活性的影响的分析结果。 具体实施方式
本发明实施例的具有通式 (1 ) 所示结构的衍生物， 是针对能抑制谷胱 1ί 肽 S-转移酶 omega 1活性的结构设计合成， 未来能成为具有潜力的癌细胞毒 杀剂。 试验倒 1
因此， 以下利用具有通式 ( 1) 结构的化合物及其它结构类似物对癌细胞 的生长抑制作用（In Vitro Growth liihibition(Gl5o, μΜ) )来评估其毒杀癌细胞活 性。本发明实施例选用人类 I 1腔上皮癌细胞株 KB、 多重抗药性鼻咽癌细胞株 KB-Vm, 人类肺腺癌细胞株 A549及前列腺癌细胞 # DU145为受试对象， 并 以癌细胞毒杀剂太甲洋紫杉醇 （Paclita d) 的 0½)剂. 作为对照。 试验结果 显示于下表 1。
表 1 中的化合物均为具有通式 ( 1) 所小结构的衍生物， 其中 i体结构为
Figure imgf000005_0001
R为编号 1 19所示， 其中编号 1 19所示侧链的左端连接 到上述 ΐ体结构以形成通式 (1) 所示化合物。
如下表 1所示， 相较于具冇 ¾它侧链结构的化合物， 具有编号 11及编号 12侧链结构的化合物， 对于受试的 4种癌细胞株均具有毒杀作用。
其中，具有编号 11侧链结构的化合物为具有一个醚键连接的异戊垸 体， 对于受试的 4种癌细胞株的 GI5(分别为 0.2 μΜ、 0.269 μΜ、 0.382 μΜ、及 0.231 μΜ, 毒杀细胞的能力明显较佳。
而具有编号 12侧链结构的化合物为侧链具有两个异戊烷 体， 对于受试 的 4种癌细胞妹的 GIa则分别为 0.067 μΜ、 0.335 μΜ、 0.233 μΜ、及 0.065 μΜ; 其中， 对于人类 Π腔上皮癌细胞株 KB及前列腺癌细胞株 DU145更具有显著 的毒杀效果。
值得注意的是， 当侧链的异戊烷甲-体继续延长至三个时， 如编号 13的结 构， 其对于癌细胞的毒杀效果大幅下降， 可 证欲达成较佳的癌细胞毒杀效 果， 其侧链不仅需耍异戊烷中.体的特异性立体构造， 其异戊垸 体的数 S (侧 链长度） 也,常关键。
表 1、 癌细胞的生长抑制作用
i« v¾r cytotoxicity assay: GIso(p )
人类口腔多重抗药人类肺腺前列腺癌 试验組 上皮癌 tt鼻咽癌 癌细胞 细垂 细胞 细胞 A549 DU145 KB KB-Vm 主体
74 0.763 0.799 结构 Γ 1 i »·· 0.865 0.6
' Y
C)
1 、 I 0.718 0.66 0.895 0.688
、（r' ■、
u
2 · ·ζ 0.694 0.668 0.811 0.694
3 0.669 0.664 0.731 0.695
Figure imgf000006_0001
(1
Ί
4 、 ,'·-、ζ、ζ 0.629 0.663 0.738 0.656
5 、义人 0.644 0.651 0.656 0.795
6 0.607 0.64 0.603 0.617
Figure imgf000006_0002
o
7 ·… 、ir t J、
0.615 0.619 0.536 0—522
8 — OMe 0.871 0.692 0.811 0—707
9 0.68 0.704 0.693 0.682 10 》 -、 ζΛ、.、. 0.786 0.766 0.819 0,865
11 、八人 0.2 0.269 0,382 0.231
12 、0ζ、人〜 ·、· 0.067 0.335 0.233 0.065
13 -·、》··-、·'·人 、· 、·Ζ、··Ζ、 1.1 15 1.883 4.27 1.262
14 \0八 、 0.683 0.841 0.754 0.808
15 0.644 1 .325 0.551 0.685
、·· ·· 、,
16 、,' 、；丫 0.55 0.682 0.584 0.62
,·'、....
17 \ 0.499 0.675 0,483 0.541
(r -、 v
18 、 8 0,628 0.693
、 \、■' 、. ) 0.552 1 , 10
·'
19 —OH 0.944 0.738 0.806 0,709 对照组 >1画
4.64 nM 3.56 nM 3.00 nM 太平洋紫杉醇 （Paciitaxel) nM 试验例 2
以下再以具有编号 1 1及 12的侧链结构的化合物为例， 进行酶活性分析， 以验证具有本发明实施例的通式 ( I) 的化合物对于毒杀癌细胞的效应是否与 抑制谷胱甘肽 S-转移酶 omega〗活性有关。
GST01的酶活性分析 （GSTO〗 substrate assay) 是以 Baehovchin等人于 200 年发表的方法》 利用 GST01 受质 S (4 硝基苯乙酮）谷胱卄肽 ( S-(4-nitropheiiacyl)gltitatliione； 以下简称为 4NPG )进行。 分析方法为于 UV 可穿透式％孔盘中加入 100 μΐ混合于缓冲液 ( 100 mM' Tns (pH8.0),1 .5 mM 'EDTA,】0 mM 2巯基乙 i©(2- mercaptoetlmnol) ) 的 GSTOl (2 nM) , 另以 100 μ!缓冲液作为空白对照组。
受试的具有编号 11及 12的侧链结构的化合物， 以下简称为化合物 （I) 及化合物（U); 另外化合物 A及化合物 B为对照组， 其中化合物 A不具有本 发 1 实施例主体结构， 化合物 B为本发明的主体结构加上甲基侧链。 化合物 A、 化合物 B、 化合物 （I) 及化合物（U) 的结构如下所示：
Figure imgf000008_0001
化合物 （I) 化合物（ΙΓ)
Figure imgf000008_0002
化合物 A 化合物 B 将化合物 （1)、 化合物（11 )、 化合物 A及化合物 B及药物溶剂一.甲亚俱 (Dimethyl sulfoxide)加入孔盘中 '于 25°C反应 30分钟。 之后将受质 4NPG加入 使终浓度为 0.5 mM。
受质 4NPG会与 GST01进行专一性结合，而本发明实施例的化合物（1 )、 化合物（11) 的结构则被设计为可与 4NPG竞争酶结合位， 此可 « r†i于波长 305 nm下， 每间隔 1分钟记录一次侦测到的吸光值， 侦测孔盘中样品的吸光 值， 以控制组为准得到吸光值的下降速率， 了解化合物 （1)、 化合物 （II) 对 于干扰酶与受质结合的效应。
图 1为具有不同侧链的化合物对 GST01的酶活性影响分析结果， 从图 1 中可知， 对照组的两个化合物， 即不具有主体结构的化合物 A、 以及虽具有 i体结构但不具冇异戊烷 体的化合物 B , 对于干扰酶与受质结合的能力较 低， 而木发明实施例的化合物（1)及化合物（II) , 其干扰酶与受质结合的能 力明显较佳， i呈现随着侧链延长则效果提升的趋势， 此一结果与癌细胞毒 杀试验的结果吻合。 根据上述， 本发明实施例的化合物 （I) 及化合物 （II) 对于癌细胞毒杀 试验的效果显著优于其他结构者， H.其结构证实可与 C3ST01的受质 4NPG竞 争酶结含位， 从而达成抑制 GSTO1酶活性的效果。 故， 包含有效量的本发明用于抑制谷胱 It肽 S-转移酶 omega 〗 ¾tt化合 物以及药学上可接受载体的医药组合物， 确为新抗癌标的， 长期发展可做为 多种抗癌药物的合并治疗试剂， 具有极「 的发展潜力。 合成倒
本发明的用于抑制谷胱 1」—肽 S-转移酶 omega 1活性的化合物可经由常规 方法制得。 例如， 可将包含将 2, 6- -；甲氧基萘进行 Fnedel- Cra 乙酰化反应， 并加入含卤素试剂去除'：个甲氧 ft。 形成含第一保护 ft的中间产物， 并与含 有第 _：保护 ¾的对位羟 «苯甲醛迸行 Claisen- Sehimdt缩合反应， 再以卤素催 化剂及酸溶液去除第一保护《。 加入含卤素不饱和碳链并去除第—：保护《， 再加入高价碘化合物进行氧化反应， 得到具冇如通式（I)所示结构的化合物。 以下将以本发明的化合物（U) 为例， 描述本案化合物的制备方法。 化合物 （II) 的合成方法流程图如下。
Figure imgf000010_0001
Figure imgf000010_0002
首先， 在氮气下将含有2, 6-二甲氧¾蔡（2，6-dlmethoxyna{)hthalene )的无 水苯溶液中， 缓慢加入 1.6当量的四氯化锡， 并加以搅拌。 再将 1.5 S乙 ft 氯逐滴加入反应溶液中。 于室温下隔夜搅拌后将苯在减压浓缩下去除， 以二 氯甲; K/水进行萃取。将二氯甲烷以减压浓缩去除后以 .iH己垸 /乙酸乙酯进行管 杵]3析， 即可得到 1-乙酰- 2, 6-二甲氧基萘 （ 1- acetyl- 2,6- dimetlioxy naphthalene) , 产率为 86.5%>。
着， 将此化合物溶于无水二氯甲烷中， 并在氮气及零下 78Γ加入 6当 量二渙硼以去除萘环上的二个甲氧基， 持续搅拌 2 小时后， 加入水以去除剩 余的二溴硼。 以一.氯甲垸 /水萃取后在减压浓缩下去除有机溶剂， 并以 己烧 / 乙酸乙酯进行管 tt S析， 即可得到 1-乙酰 -2, 6-二氢氧基萘 ( l-acetyl-2,6-dihydroxy naphthalene )， 产冲《为 93%。 将得到的化合物再次溶于无水二氣甲垸中， 在冰浴下加入 2 当 a的 异 丙某乙基胺 CN,N- Diisopropylethykmme ), 直到反应溶液变澄洁。接着将经巾 二氯甲烷稀释过的氯甲 ¾甲¾醚溶液（稀释约四十侪） 逐滴加入反应溶液中， 持续搅拌约 2小时。 于减压浓缩下将所 iffi机溶剂移除， 以正己;) ¾/乙酸乙酯 ¾tf了管柱层析， 即可得到化合物 1 (包含第一保护基 甲氧基甲基）， 产率 为 47.3%。
将化合物 1与 4-1?氧基苯甲醛 (4-benzyloxy- benzaldehyde)进行 Ciaisen -Schmidt缩合反应（Ciaisen- Schmidt Condensation) ,在含有化合物 1的乙醉溶 液中加入 3当量的 4- 氧 ¾苯甲醛， S拌后加入与乙醇溶液等 的 50%氢氧 化钾水溶液， 于 55tTF搅拌 1.5 小时后， 进行减压浓缩以去除溶剂， 再以 J 己垸 /乙酸乙酯进行管杵 析， 即可得到 Chalcone 化合物 2 (包含第一.保护 基 苯甲基）， 产率为 92.6%。
将化合物 2溶解于适量 ft啶， 并加入 2 当量的碘。 隔夜加热回流后， 加 入硫代硫酸钠并以乙酸以酯 Z水萃取 有机 S经减压浓缩后以管柱层析分离可 得到 β-萘黄酮化合物 3， 产卓为 65%。
在溶有化合物 3的适量二氯甲烷溶液中， 加入浓盐酸 /异丙醇溶液， 比例 约为 1 : 10。经¾温下隔夜搅拌后将沉淀物过滤即得到去除第 -保护基的化合 物 4。于氮气及冰浴下， 在含有 2 ¾ ¾氢化钠的无水'：甲基甲酰胺溶液中¾滴 加入含有化合物 4 的'：甲 «甲酰胺溶液， 直到反应溶液变成红 再加入 2 ¾ ¾的香叶草溴（Geranyi bromide)溶液。将冰浴移除于 ¾温下搅拌 2小时候 加水并以乙酸乙酯萃取。 经减压浓缩移除有机溶剂后以_：氣甲 甲醇进行管 杵层析分離可得到化合物 5， 产率为 94%。
将化合物 5溶于乙酸乙酯屮并加入 ]0%碳钯， 比例为 240毫克 Ζ每 1毫摩 尔原料。 在氢气的催化下隔夜反应， 过滤除去碳钯之后， 将溶液进行减压浓 缩， 即可得到脱除第二保护基 （即节基） 的化合物 6, 产率为 40%。
最后将化合物 6溶于比例约 15: 1的乙腈 Ζ水溶液中， 加入 2当量的双三 氟乙酰氧蘭化苯 ( [bis(trifluoroacetoxy)iodoj benzene) 进行氧化反应， 即可得 到如化合物 （II) 所示具有异戊烷二聚体侧链的最终产物， 产率为 49%。
化合物（ID 以核磁: 振光潜仪进行核磁共振光¾分析数据为： NM (400 MHz, CDC13) 5 = 9.78 (d, J = 9.2 Hz, 1H),7.90 (d,J= 9.2 Hz, 1H), 7.37 (dd, J = 9.2, 2.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, IH), 7.18 (d, J = 2.4Hz,lH),7.03- 7.00(m，3H),6.41(d,J=10.0Hz,2H),5.47(bs，lH), 4.16-4.07 (m,2H), 1.94- 1.86(m,lH),1.73- 1.61(m,2H),1.59- 1.49(m，lH)，1.40- 1.14 (m, 6H), 0.98 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.8 Hz, 6H) ppm; 1 C NMR (100 MHz, CDC13) δ = 185.4 180.9, 164.0, 158.0, 156.5, 146.7, 135.2, 132.7, 130.0, 128.6, 124.7, 121.2, 117.8, 117.4, 111 .6, 108.6, 69.9, 66.7, 39.5, 37.5, 36.3, 30.1 , 28.2, 24.9, 22.9, 22.8, 19.9 ppm; IR ( Br) (cm— 1 ): 3294, 2954, 2927, 2869, 1644, 1599, 1514, 1465, 1427, 1410,〗385, 1367, 1245, 1176, 1129, 1058, 1009; HRESI- MS: C29H3305, calcd. 461.2323, found 461.2328.
虽然木发明已以实施方式揭露如上， 然其并非用以限定本发明， 在木发 明所属技术领域中任何具有通常知识 ， 在不脱离本发明的精神和范 Μ Λ , 当可作各种的更动与润饰， 因此本发明的保护范围当视后附的权利要求书所 界定的范围为准。
ϋ

Claims

权利要求书
1. —种用于抑制谷胱 肽 S-转移酶画 ega 1活性的化合物， 具冇如下通 式 (1) 所示的结构：
Figure imgf000013_0001
通式 (
其中 Α环为对位氢醒醇环， R是选自于由下列通式 (la)及通式 (ft)所组成的群 组， 通式 (la)的 n为 1或 2, 通式 ( lb) 的 m为 0或 1， R1为 11或 ArCl ½—， R2 为 Alkvl—或 AryF:
Figure imgf000013_0002
通式 (la) 通式 ( lb )
2.一种用于抑制谷胱甘肽 S-转移酶瞧 ega 1活性的医药组合物, 有效量的权利耍求 1所述的化合物以及一药学上可接受的载体。
3. - 种权利要求 1所述的化合物的制备方法， 包含下列歩骤： 将 2, 6二甲氧 S萘进行 Fnedel Craft乙酰化反应；
加入含卤素试剂去除二个甲氧 « ; 形成含第 ·保护 S的中间产物，并与含 第― ^保扩基的对位经 *苯甲醛进行 Claisen-Schmidt缩合反应；
加入卤素催化剂；
加入酸溶液， 去除第 保扩基；
加入含卤素不饱和碳链；
去除第二保护 ¾; 以及
加入高价碘化合物以进行氧化反应， 得到权利要求〗所述的化合物。
4. 如权利要求 3所述的制备方法， ^中所述含 ! 素试剂为二溴硼。
10
5. 如权利要求 3所述的制备方法， 其中所述第一保护基为 ff:i氧基甲 ¾£
6. 如权利要求 3所述的制备方法， 其中所述第二保护基为苯甲基。
15 7. 如权利要求 3所述的制备方法， ¾巾所述卤素催化剂为碘。
8. 如权利要求 3所述的制备方法， 其中该所述酸溶液为浓盐酸。
9. 如权利要求 3所述的制备方法， 其中所述含卤素不饱和碳链为香叶草
?0 ¾¾ c
10. 如权利要求 3所述的制备方法， 中所述高价碘化合物为双二》乙酰 氧碘化苯。
PCT/CN2013/088871 2013-12-09 2013-12-09 用于抑制谷胱甘肽S-转移酶omega1活性的化合物及其制备方法、和包含该化合物的医药组合物 WO2015085459A1 (zh)

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