WO2023179205A1 - 二酰亚胺衍生物、其制备方法和应用 - Google Patents

二酰亚胺衍生物、其制备方法和应用 Download PDF

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WO2023179205A1
WO2023179205A1 PCT/CN2023/074050 CN2023074050W WO2023179205A1 WO 2023179205 A1 WO2023179205 A1 WO 2023179205A1 CN 2023074050 W CN2023074050 W CN 2023074050W WO 2023179205 A1 WO2023179205 A1 WO 2023179205A1
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孙天宇
储结根
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湘北威尔曼制药股份有限公司
广州新创忆药物临床研究有限公司
广州新创意生物医药有限公司
广州新创翼有限公司
南京康福顺药业有限公司
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Publication of WO2023179205A1 publication Critical patent/WO2023179205A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to a diimide derivative, its preparation method and application, and belongs to the field of medicinal chemistry.
  • Diimides are an important class of substances in the field of medicinal chemistry and have many interesting pharmacological activities.
  • the diimide When the diimide is further fused with some fused rings, a unique planar structure can be formed, the molecular volume is greatly reduced, and it can be embedded between the base pairs of the DNA double strand, causing the unwinding of the DNA double helix, so for some Cell proliferative diseases, such as cancer, have unique application value.
  • the most common fused rings fused to diimides are naphthalene and anthracene. Many compounds with these structures have reported antitumor activity, but fewer compounds have entered the clinical stage.
  • Aminafate is one of the representative compounds and is reported to have strong cytotoxic activity against various cancer cells such as colon cancer, lung cancer, gastric cancer, esophageal cancer, and leukemia. Antisoma advanced Aminafate into Phase III clinical trials for the treatment of acute myeloid leukemia, but ultimately terminated development due to poor efficacy.
  • the object of the present invention is to provide a fused ring diimide compound which has better properties.
  • the present invention provides a compound having a diimide structure represented by formula I,
  • A is a naphthalene ring or anthracene ring, which is condensed with the diimide through 3 carbon atoms;
  • R 1 is selected from hydrogen atom, alkyloxy group or nitro group
  • n 1, 2 or 3, and m+n ⁇ 4;
  • R 2 is alkyl
  • R 3 is selected from hydrogen atom or alkyl group
  • R 4 or R 5 is selected from alkyl, haloalkyl or nitroso.
  • R3 optionally can form a ring together with R2 .
  • the alkyl group is a C1-C4 alkyl group.
  • the alkyloxy group is a C1-C4 alkyloxy group.
  • the haloalkyl group is a haloC1-C4 alkyl group.
  • the A is preferably a naphthalene ring. Certain preferred compounds of formula I have superior properties, such as greater activity.
  • the R 1 is preferably nitro or C1-C4 alkyloxy. More preferred is nitro. Certain preferred compounds of formula I have superior properties, such as greater activity.
  • the R 3 is preferably a hydrogen atom. Certain preferred compounds of formula I have superior properties, such as greater activity.
  • R 3 and R 2 together form a ring.
  • a ring For example, five-membered rings, six-membered rings, etc.
  • R 3 and R 2 together with the nitrogen atoms to which they are connected form a saturated nitrogen heterocycle.
  • the R 4 is preferably a halo C1-C4 alkyl group, and the R 5 is preferably a nitroso group. Certain preferred compounds of formula I have superior properties, such as greater activity.
  • the C1-C4 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, etc.
  • Halogens include fluorine, chlorine, and bromine.
  • the invention provides a method for preparing a compound of formula I, comprising:
  • the compound of formula M7 and the compound of formula M8 are reacted in the presence of a base to generate the compound of formula I; wherein, A, m, n, R 1 , R 2 , R 3 , R 4 and R in the reaction formula 5 As mentioned above.
  • the base is selected from sodium hydroxide, potassium carbonate, cesium carbonate, or sodium phosphate.
  • the compound of formula M7 and the compound of formula M8 are commercially available or can be obtained through chemical synthesis.
  • the M7 can be prepared by the following methods:
  • reaction formula first react the compound of formula M4 with the compound of formula M5 to generate the compound of formula M6, and then treat the compound of formula M6 in the presence of acid to obtain the compound of formula M7; A, m, n, R 1 , R in the reaction formula 2 and R 3 as previously described.
  • the acid may be a common acid, such as hydrochloric acid.
  • the compound of formula M4 is commercially available or can be obtained through chemical synthesis.
  • the M4 can be prepared by the following methods:
  • reaction formula first react the compound of formula M1 with the compound of formula M2 to form the compound of formula M3, and then react the compound of formula M3
  • the compound is hydrogenated to obtain the compound of formula M4;
  • X in the reaction formula is halogen, Cbz is benzyloxycarbonyl, Boc is tert-butoxycarbonyl, m, n, R2 and R3 are as described above.
  • the present invention provides an application, that is, the use of the compound of formula I as described above in the preparation of a drug for treating cell proliferative diseases.
  • the cell proliferative disease is cancer.
  • the cancers are digestive system tumors, respiratory system tumors and/or hematopoietic system tumors, such as colon tumors, lung tumors, blood tumors, etc.
  • the present invention provides a method for treating cell proliferative diseases, that is, administering a therapeutically effective amount of a compound of formula I as described above to a subject in need.
  • the cell proliferative disease is cancer.
  • the cancer is a tumor of the digestive system, a tumor of the respiratory system, and/or a tumor of the hematopoietic system, such as colon tumors, lung tumors, and blood tumors.
  • the diimide derivative provided by the invention is a novel compound. Research has found that it has excellent anti-tumor activity in vivo and in vitro, and has significant inhibitory effects on various tumors such as colon tumors, lung tumors, and blood tumors. Moreover, the anti-tumor activity is significantly better than that of similar compounds, and it has broad application prospects.
  • intermediate I-01-M3 Dissolve compound I-01-M2 (3.48g, 20mmol) in 30mL DMF, then add K 2 CO 3 (4.16g, 30mmol), NaI (3.00) to the mixture in sequence g, 20 mmol) and compound I-01-M1 (5.14 g, 20 mmol), reacted overnight at 30°C. After the reaction was completed, purified water (120 ml) was added to the reaction solution, extracted three times with ethyl acetate (180 ml), dried with anhydrous MgSO4, filtered, concentrated the mother liquor, and purified by column chromatography to obtain intermediate I-01-M3 (4.07 g, 11.6mmol), yield 58%.
  • intermediate I-01-M4 Dissolve intermediate I-01-M3 (4.07g, 11.6mmol) in methanol (25mL), add 10% Pd/C (0.3g), and replace with hydrogen three times. The reaction was carried out overnight under normal pressure, filtered through diatomaceous earth, and the mother liquor was concentrated to obtain colorless oily intermediate I-01-M4 (2.50g, 11.5mmol), with a yield of 99.1%.
  • intermediate I-01-M6 Preparation of intermediate I-01-M6: Add intermediate I-01-M4 (2.50g, 11.5mmol), ethanol (60ml), and compound I-01-M5 (2.79g, 11.5mmol) to the reaction bottle in sequence. , heated to 80°C for 2 hours, cooled, concentrated the reaction solution, and purified by column chromatography to obtain intermediate I-01-M6 (3.63g, 8.2mmol), with a yield of 71.3%.
  • Compound I-05 was prepared according to the method of Example 1.
  • Compound I-06 was prepared according to the method of Example 1.
  • Compound I-07 was prepared according to the method of Example 1.
  • Compound I-10 was prepared according to the method of Example 1.
  • Test purpose To test the anti-proliferative activity of the compounds of the present invention on various tumor cells.
  • Test compounds Compounds I-01, I-02, I-03, I-04, I-05, I-06, I-07, I-08, I-09, I-10, I-11, I-12; positive compounds Aminafate, Lomustine; and comparative compounds 1, 1d, Cob280, Cob281.
  • Compound 1 is "compond 1" in the literature Journal of Experimental Therapeutics and Oncology, 2005, 5: p 15-22, and compound 1d is "compond 1" in the literature Journal of Cancer Molecules, 2010, 5(2): p 41-47. 1d
  • compound Cob280 is "Cob280" in the document WO2012104788, Example 17a
  • compound Cob281 is “Cob281” in the document WO2012104788, Example 17b.
  • They were all prepared according to the literature method; the positive compounds Aminafate and Lomustine are from Commercially available.
  • Test cells human colon cancer cells (HT-29, COLO 205), human lung cancer cells (NCI-H460, A549), human leukemia cells (HL-60, U-937).
  • Test method Each tumor cell is operated separately. Cells were cultured in culture medium at 37°C for 24 hours before use. Take cells in the exponential growth phase, treat them with trypsin to prepare a cell suspension, centrifuge the cell suspension, and then resuspend the cell pellet in a small amount of fresh culture medium as a reserve cell solution. Dilute this stock solution to the desired cell concentration. The concentration of each cell is shown in Table 1:
  • IC 50 value of each test compound was calculated using Prism7 software. IC 50 is divided into different levels according to the value, namely: SSS: ⁇ 0.5 ⁇ M, SS: 0.5-1 ⁇ M; S: 1-5 ⁇ M; A: 5-10 ⁇ M; B: 11-20 ⁇ M; C: 21-50 ⁇ M; D: 51-100 ⁇ M; E: >100 ⁇ M.
  • SSS ⁇ 0.5 ⁇ M
  • SS 0.5-1 ⁇ M
  • S 1-5 ⁇ M
  • A 5-10 ⁇ M
  • B 11-20 ⁇ M
  • C 21-50 ⁇ M
  • D 51-100 ⁇ M
  • E >100 ⁇ M.
  • Table 3 The main results are shown in Table 3:
  • Test results show that lomustine has poor activity against various tumor cells, while aminafate has better activity.
  • the activity of compounds 1d, 1, Cob280 and Cob281 is not better than that of aminafate, and even the activity is reduced.
  • the anti-tumor activity of the compound of the present invention is significantly better than that of amafate, lomustine, and similar compounds 1d, 1, Cob280, and Cob281.
  • Certain preferred compounds of the invention are more than 100 times more active than similar compounds.
  • Example 22 Study on the anti-tumor effect of compounds of formula I in vivo
  • Test purpose to further test the in vivo anti-tumor effect of the compounds of the present invention.
  • Test compounds I-01, I-08.
  • Test animals 5-week-old female BALB/c nude mice. After 7 days of normal feeding, mice with good physical condition were selected for the test.
  • Tumor cells human colon cancer cells COLO 205, cultured in RPMI-1640 medium containing 10% fetal calf serum. Passage 1 to 2 times a week, with a passaging ratio of 1:3 to 1:6.
  • COLO 205 cells in logarithmic growth phase were collected. Injected into the anterior right mammary fat pad of nude mice, the injection volume was 5 ⁇ 10 6 cells per animal to establish a COLO 205 transplanted tumor model. Observe the animal status regularly, measure the tumor diameter, and calculate the tumor volume. After the tumor volume reached approximately 150 mm 3 , tumor-bearing mice with good health and similar tumor volumes were selected and randomly divided into: solvent control group, I-01 group, and I-08 group.
  • Each test compound is dissolved in a solvent, and the corresponding compound or blank solvent is given to each animal group.
  • the administration method is intragastric administration, the dosage is 10 mg/kg, once a day, for a total of 21 times.
  • Tumor volume inhibition rate 100% ⁇ [1-(Tvt-Tvini) ⁇ (Cvt-Cvini)], where Tvt represents the tumor volume at the end of the treatment group test, Tvini represents the tumor volume at the end of the treatment group, and Cvt represents the end of the solvent control test is the tumor volume, and Cvini represents the tumor volume when the solvent control group is grouped.
  • Tumor weight inhibition rate 100% ⁇ (Cw-Tw) ⁇ Cw, where Cw represents the tumor weight of the solvent control group at the end of the test, and Tw represents the tumor weight of the treatment group at the end of the test.
  • test results show that the compound of the present invention also has strong anti-tumor effect in vivo.

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Abstract

提供了一种二酰亚胺衍生物、其制备方法和应用。该二酰亚胺衍生物具有优异的抗肿瘤活性，对多种癌细胞的抗增殖活性显著优于类似化合物。（I）

Description

二酰亚胺衍生物、其制备方法和应用 技术领域
本发明涉及一种二酰亚胺衍生物，其制备方法和应用，属于药物化学领域。
背景技术
二酰亚胺类化合物是药物化学领域中的一类重要物质，具有许多感兴趣的药理活性。
当二酰亚胺与一些稠环进一步稠合之后，可形成独特的平面结构，分子体积大大缩小，并可嵌入DNA双链的碱基对之间，造成DNA双螺旋的解链，因此对于一些细胞增殖性疾病，例如癌症等，具有独特的应用价值。与二酰亚胺稠合的稠环中最常见的是萘和蒽。许多这些结构的化合物都有抗肿瘤活性的报道，但进入临床阶段的化合物较少。
氨萘非特是其中的一种代表性化合物，据报道对结肠癌、肺癌、胃癌、食管癌、白血病等多种癌细胞具有较强的细胞毒活性。Antisoma公司将氨萘非特推进到临床III期阶段用于治疗急性髓性白血病，但最终因为疗效不佳而终止开发。
目前业界仍在研究其他的二酰亚胺类化合物，以期得到更优的潜在化合物，但寻找比氨萘非特具有更强活性的化合物仍然存在困难。
发明内容
本发明的目的在于提供一种稠环二酰亚胺类化合物，其具有更优的性质。
第一方面，本发明提供了一种化合物，具有式I所示的二酰亚胺结构，
式I中，
A为萘环或蒽环，其通过3个碳原子与二酰亚胺稠合；
R1选自氢原子、烷基氧基或硝基；
m或n为1、2或3，且m+n≤4；
R2为烷基；
R3选自氢原子或烷基；
R4或R5选自烷基、卤代烷基或亚硝基。
另外，在式I中，R3任选可以与R2一起成环。
在一些实例中，所述式I中，所述的烷基为C1-C4烷基。
在一些实例中，所述式I中，所述的烷基氧基为C1-C4烷基氧基。
在一些实例中，所述式I中，所述的卤代烷基为卤代C1-C4烷基。
在一些实例中，所述式I中，所述的A优选为萘环。某些优选的式I化合物具有更优的性质，例如具有更强的活性。
在一些实例中，所述式I中，所述R1优选为硝基或C1-C4烷基氧基。更优选的是硝基。某些优选的式I化合物具有更优的性质，例如具有更强的活性。
在一些实例中，所述式I中，所述R3优选为氢原子。某些优选的式I化合物具有更优的性质，例如具有更强的活性。
在一些实例中，所述式I中，R3与R2一起成环。例如五元环、六元环等。例如R3、R2与各自所连接的氮原子一起形成饱和的氮杂环。
在一些实例中，所述式I中，所述R4优选为卤代C1-C4烷基，所述R5优选为亚硝基。某些优选的式I化合物具有更优的性质，例如具有更强的活性。
在一些实例中，所述式I中，所述m和n优选为：m＝1且n＝3，m＝1且n＝2，或者m＝2且n＝2。更优选的是m＝2且n＝2。某些优选的式I化合物具有更优的性质，例如具有更强的活性。
在一些实例中，所述式I中，所述的C1-C4烷基包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基等，卤素包括氟、氯、溴。
第二方面，本发明提供了一种式I化合物的制备方法，包括：
如反应式所示，将式M7化合物与式M8化合物在碱的存在下反应生成式I化合物；其中，反应式中的A、m、n、R1、R2、R3、R4和R5如前所述。
在一些实例中，所述的碱选自氢氧化钠、碳酸钾、碳酸铯或磷酸钠。
式M7化合物与式M8化合物可通过市售获得，也可以通过化学合成得到。
在一些实例中，所述的M7可以通过以下方法制备得到：
如反应式所示，先将式M4化合物与式M5化合物反应生成式M6化合物，再在酸的存在下处理式M6化合物得到式M7化合物；反应式中的A、m、n、R1、R2和R3如前所述。
在一些实例中，所述的酸可以是常见的酸，例如盐酸等。
式M4化合物可通过市售获得，也可以通过化学合成得到。
在一些实例中，所述的M4可通过以下方法制备得到：
如反应式所示，先将式M1化合物与式M2化合物反应生成式M3化合物，再将式M3 化合物氢化得到式M4化合物；反应式中的X为卤素，Cbz为苄氧羰基，Boc为叔丁氧羰基，m、n、R2和R3如前所述。
第三方面，本发明提供了一种应用，即如前所述的式I化合物在制备治疗细胞增殖性疾病的药物中的应用。
在一些实例中，所述的细胞增殖性疾病为癌症。
在一些实例中，所述的癌症为消化系统肿瘤、呼吸系统肿瘤和/或造血系统肿瘤，例如结肠肿瘤、肺肿瘤、血液肿瘤等。
第四方面，本发明提供了一种治疗细胞增殖性疾病的方法，即向所需要的对象给与治疗有效量的如前所述的式I化合物。
在一些实例中，所述的细胞增殖性疾病为癌症。
在一些实例中，所述的癌症为消化系统肿瘤、呼吸系统肿瘤和/或造血系统肿瘤，例如结肠肿瘤、肺肿瘤、血液肿瘤。
本发明提供的二酰亚胺衍生物是一种新颖的化合物，研究发现其具有优异的体内和体外抗肿瘤活性，对于结肠肿瘤、肺肿瘤、血液肿瘤等各种肿瘤均具有显著的抑制作用，并且抗肿瘤活性显著优于类似化合物，具有广阔的应用前景。
具体实施方式
下面用实施例对本发明进行进一步的描述，并例举某些优选的化合物。需要指出的是，实施例并不是对本发明技术方案和技术效果的限制。
实施例1：化合物I-01
反应式：
按照反应式，制备化合物I-01，具体如下：
1.1中间体I-01-M3的制备：化合物I-01-M2(3.48g,20mmol)溶解于30mL DMF中,然后往混合液中依次加入K2CO3(4.16g,30mmol)，NaI(3.00g,20mmol)和化合物I-01-M1(5.14g,20mmol)，30℃下反应过夜。反应完成后，向反应液中加入纯化水(120ml)，用乙酸乙酯(180ml)萃取3次，无水MgSO4干燥，过滤，浓缩母液，柱层析纯化得到中间体I-01-M3(4.07g,11.6mmol)，收率58％。
1.2中间体I-01-M4的制备：将中间体I-01-M3(4.07g,11.6mmol)溶解于甲醇中(25mL)，加入10％Pd/C(0.3g)，氢气置换3次，常压下反应过夜，硅藻土过滤，浓缩母液，得无色油状物中间体I-01-M4(2.50g,11.5mmol)，收率99.1％。
1.3中间体I-01-M6的制备：往反应瓶中依次加入中间体I-01-M4(2.50g,11.5mmol)，乙醇(60ml)，化合物I-01-M5(2.79g,11.5mmol)，加热至80℃反应2小时，冷却，浓缩反应液，柱层析纯化得到中间体I-01-M6(3.63g,8.2mmol)，收率71.3％。
1.4中间体I-01-M7的制备：中间体I-01-M6(3.63g,8.2mmol)溶解于4％氯化氢乙酸乙酯溶液(50ml)中，室温反应过夜，过滤，干燥，得到中间体I-01-M7(2.67g,7.8mmol)，收率95.1％。
1.5化合物I-01的合成：往反应瓶中依次加入化合物I-01-M8(2.46g,9mmol)，二氯甲烷(30ml)，三乙胺(2.02g,20mmol),冷却至0℃，分批加入中间体I-01-M7(2.67g,7.8mmol)，0℃下反应过夜，用水(20ml)洗涤，无水MgSO4干燥，过滤，浓缩母液，柱层析纯化得到化合物I-01(2.14g,4.5mmol)，收率57.7％。产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:2.97(s, 3H),3.34-3.40(m,2H),3.46-3.51(m,2H),3.58(t,J＝6.5Hz,2H),3.72-3.77(m,2H),3.98-4.11(m,2H),4.46(t,J＝6.2Hz,2H),8.06(dd,J＝8.2,7.4Hz,1H),8.67–8.62(dd,J＝7.3,1.1Hz,1H),8.78(dd,J＝8.5,1.1Hz,1H),8.89(d,J＝2.3Hz,1H),9.00(t,J＝5.5Hz,1H),9.48(d,J＝2.3Hz,1H)。
实施例2：化合物I-02
参照实施例1的方法，制备得到化合物I-02，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:1.04(t,J＝7.6Hz,3H),2.81-2.84(m,4H),2.92(s,3H),3.45–3.50(m,2H),3.52-3.55(m,2H),3.70(t,J＝2.9Hz,2H),3.82(t,J＝2.9Hz,2H),4.46(t,J＝4.6Hz,2H),8.06(dd,J＝8.2,7.4Hz,1H),8.67–8.62(dd,J＝7.3,1.1Hz,1H),8.78(dd,J＝8.5,1.1Hz,1H),8.89(d,J＝2.3Hz,1H),9.00(t,J＝5.5Hz,1H),9.48(d,J＝2.3Hz,1H)。
实施例3：化合物I-03
参照实施例1的方法，制备得到化合物I-03，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:1.73-1.79(m,2H),2.94(s,3H),3.25(t,J＝5.1Hz,2H),2.47–2.53(m,2H),3.55(t,J＝2.9Hz,2H),3.78(t,J＝2.9Hz,2H),4.76(d,J＝2.9Hz,2H),8.06(dd,J＝8.2,7.4Hz,1H),8.67–8.62(dd,J＝7.3,1.1Hz,1H),8.78(dd,J＝8.5,1.1Hz,1H),8.90(d,J＝2.3Hz,1H),9.00(t,J＝5.5Hz,1H),9.48(d,J＝2.3Hz,1H)。
实施例4：化合物I-04
参照实施例1的方法，制备得到化合物I-04，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:1.04(t,J＝7.6Hz,3H),1.18(t,J＝7.6Hz,3H),2.64-2.68(m,4H),2.96(s,3H),3.28(q,J＝5.8Hz,2H),3.44(t,J＝4.5Hz 2H),3.78-3.82(m,2H),4.44(t,J＝4.4Hz 2H),8.06(dd,J＝8.2,7.4Hz,1H),8.67–8.62(dd,J＝7.3,1.1Hz,1H),8.81(dd,J＝8.5,1.1Hz,1H),8.89(d,J＝2.3Hz,1H),9.07(t,J＝5.5Hz,1H),9.48(d,J＝2.3Hz,1H)。
实施例5：化合物I-05
参照实施例1的方法，制备得到化合物I-05，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:2.98(s,3H),3.16(s,3H),3.44-3.47(m,2H),3.56-3.63(m,4H),4.33(t,J＝4.6Hz,2H),8.06(dd,J＝8.2,7.4Hz,1H),8.67–8.62(dd,J＝7.3,1.1Hz,1H),8.81(dd,J＝8.5,1.1Hz,1H),8.89(d,J＝2.3Hz,1H),9.02(t,J＝5.5Hz,1H),9.51(d,J＝2.3Hz,1H)。
实施例6：化合物I-06
参照实施例1的方法，制备得到化合物I-06，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:1.17(t,J＝5.8Hz,6H),2.87(s,3H),3.15(q,J＝5.8Hz,4H),3.22-3.25(m,2H),3.38(t,J＝4.5Hz,2H),3.89(s,3H),4.86(s,2H),7.65(t,J＝7.8Hz,1H),8.06(dd,J＝8.2,7.4Hz,1H),8.13(d,J＝8.4Hz,1H),8.32–8.42(m,2H),8.62–8.68(m,1H)。
实施例7：化合物I-07
参照实施例1的方法，制备得到化合物I-07，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:1.77-1.83(m,2H),2.91(s,3H),2.94(s,6H),3.25(t,J＝5.1Hz,2H),3.54–3.58(m,2H),4.84(d,J＝3.5Hz,2H),7.65(d,J＝7.4Hz,1H),7.83-7.86(m,2H),8.43–8.52(m,4H)。
实施例8：化合物I-08
按照反应式，制备化合物I-08，具体方法如下：
8.1中间体I-08-M3的合成：化合物I-08-M2(3.72g,20mmol)溶解于30mL DMF；然后往混合液中依次加入K2CO3(4.16g,30mmol)，NaI(3.00g,20mmol)，化合物I-08-M1(5.14g,20mmol)，30℃反应过夜。反应完成后，向反应液中加入纯化水(120ml)，用乙酸乙酯(180ml)萃取3次，无水MgSO4干燥，过滤，浓缩母液，柱层析纯化得到中间体I-08-M3(4.39g,12.1mmol)，收率60.5％。
8.2中间体I-08-M4的合成：中间体I-08-M3(4.39g,12.1mmol)溶解于甲醇(20mL)，加入10％Pd/C(0.3g)，氢气置换3次，常压下反应过夜，硅藻土过滤，浓缩母液，得无色油状物中间体I-08-M4(2.75g,12.0mmol)，收率99.2％。
8.3中间体I-08-M6的合成：往反应瓶中依次加入中间体I-08-M4(2.75g,12.0mmol)，乙 醇(50ml)，化合物I-08-M5(2.92g,12.0mmol)，加热至80℃反应2小时，冷却，浓缩反应液，柱层析纯化得到中间体I-08-M6(4.22g,9.3mmol)，收率77.5％。
8.4中间体I-08-M7的合成：中间体I-08-M6(4.22g,9.3mmol)溶解于4％氯化氢乙酸乙酯溶液(60ml)，室温反应过夜，过滤，干燥得到中间体I-08-M7(3.12g,8.8mmol)，收率94.6％。
8.5化合物I-08的合成：往反应瓶中依次加入化合物I-08-M8(2.62g,9.6mmol)，二氯甲烷(35ml)，三乙胺(2.02g,20mmol)，冷却至0℃，分批加入中间体I-08-M7(3.12g,8.8mmol)，0℃下反应过夜，用水(25ml)洗涤，无水MgSO4干燥，过滤，浓缩母液，柱层析纯化得到化合物I-08(2.54g,5.2mmol)，收率59.1％。产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:2.61–2.73(m,4H),2.94-2.98(m,2H),3.19–3.34(m,4H),3.57(t,J＝2.9Hz,2H),3.78(t,J＝2.9Hz,2H),4.45(t,J＝4.6Hz,2H),8.67–8.62(dd,J＝7.3,1.1Hz,1H),8.78(dd,J＝8.5,1.1Hz,1H),8.89(d,J＝2.3Hz,1H),9.00(t,J＝5.5Hz,1H),9.48(d,J＝2.3Hz,1H)。
实施例9：化合物I-09
参照实施例1的方法，制备得到化合物I-09，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:2.61–2.73(m,4H),2.94-2.98(m,2H),3.19–3.34(m,4H),3.57(t,J＝2.9Hz,2H),3.78(t,J＝2.9Hz,2H),4.47(t,J＝4.6Hz,2H),7.53(t,J＝6.1Hz,1H),7.58–7.65(m,1H),7.79(t,J＝7.8Hz,1H),8.04–8.10(m,1H),8.33-8.35(m,1H),8.49(d,J＝6.3Hz,1H),8.84(s,1H),9.38(d,J＝7.8Hz,1H)。
实施例10：化合物I-10
参照实施例1的方法，制备得到化合物I-10，产物鉴定：1H-NMR(400MHz,d6-DMSO) δ:1.72-177(m,2H),2.95(s,3H),3.35-3.38(m,2H),3.54(t,J＝2.9Hz,2H),3.68(t,J＝5.1Hz,2H),3.82(t,J＝2.9Hz,2H),4.65(s,2H),7.73-7.81(m,2H),8.27(d,J＝6.2Hz,1H),8.39–8.50(m,2H),8.87(d,J＝6.2Hz,1H),9.28(d,J＝2.6Hz,1H),9.52(d,J＝7.9Hz,1H)。
实施例11：化合物I-11
参照实施例1的方法，制备得到化合物I-11，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:2.94(s,3H),2.95–3.05(m,2H),3.40(t,J＝4.5Hz,2H),3.56(t,J＝2.9Hz,2H),3.80-3.82(m,2H),3.84(t,J＝2.9Hz,2H),4.49(t,J＝4.5Hz,2H),7.53(t,J＝6.1Hz,1H),7.59–7.66(m,1H),7.78(t,J＝6.2Hz,1H),8.04–8.10(m,2H),8.33-8.35(m,1H),8.49(d,J＝6.2Hz,1H),8.73(s,1H),9.38(d,J＝7.8Hz,1H)。
实施例12：化合物I-12
参照实施例1的方法，制备得到化合物I-12，产物鉴定：1H-NMR(400MHz,d6-DMSO)δ:1.04(t,J＝7.2Hz,3H),2.56(q,J＝5.8Hz,2H),2.94(t,J＝4.4Hz,2H),3.27–3.31(m,2H),3.45(t,J＝4.4Hz,2H),3.54(t,J＝2.9Hz,2H),3.77(t,J＝2.9Hz,2H),4.14(t,J＝4.6Hz,2H),7.53(t,J＝6.2Hz,1H),7.59–7.66(m,1H),7.78(t,J＝6.2Hz,1H),8.04–8.10(m,2H),8.33-8.35(m,1H),8.49(d,J＝6.2Hz,1H),8.73(s,1H),9.38(d,J＝7.8Hz,1H)。
实施例13：式I化合物体外抗肿瘤活性的研究
试验目的：测试本发明化合物对多种肿瘤细胞的抗增殖活性。
测试化合物：本发明化合物I-01、I-02、I-03、I-04、I-05、I-06、I-07、I-08、I-09、I-10、I-11、I-12；阳性化合物氨萘非特、洛莫司汀；以及对比化合物1、1d、Cob280、Cob281。 其中化合物1为文献Journal of Experimental Therapeutics and Oncology,2005,5:p 15-22中的“compond 1”，化合物1d为文献Journal of Cancer Molecules,2010,5(2):p 41-47中的“1d”，化合物Cob280为文献WO2012104788实施例17a中的“Cob280”，化合物Cob281为文献WO2012104788实施例17b中的“Cob281”，它们均按照文献方法制备得到；阳性化合物氨萘非特、洛莫司汀来自市售。
测试细胞：人结肠癌细胞(HT-29、COLO 205)、人肺癌细胞(NCI-H460、A549)、人白血病细胞(HL-60、U-937)。
测试方法：各肿瘤细胞分别操作。细胞于37℃下在培养基中培养24小时备用。取处于指数生长期的细胞，用胰蛋白酶处理制备细胞悬液，将细胞悬液离心，然后将细胞沉淀重新悬浮于少量的新鲜培养基中作为储备细胞液。将该储备液稀释至所需的细胞浓度。各细胞浓度如表1所示：
表1：各肿瘤细胞浓度
取96孔板，设置空白对照组、细胞对照组、化合物组。空白对照组每孔只加10％PBS。细胞对照组和化合物组每孔加100μL的上述浓度的细胞。剩余孔用200μL的10％PBS填充。将板置于培养箱中过夜。化合物组加100μL不同稀释浓度的各测试化合物。化合物稀释浓度 如表2所示。
表2：测试化合物稀释浓度
加药完成后将板置于培养箱中培养96小时，每孔加入22μL的刃天青钠溶液(Alarm blue,SIGMA R7017)，将板放回培养箱再培养4小时。取出后摇动10秒，在530/590nm处记录各孔的荧光值。
上述操作重复进行3次。
用Prism7软件计算出各测试化合物的IC50值。将IC50按照值的大小分为不同等级，即：SSS：﹤0.5μM，SS：0.5-1μM；S：1-5μM；A：5-10μM；B：11-20μM；C：21-50μM；D：51-100μM；E：﹥100μM。主要结果见表3：
表3：化合物对肿瘤细胞抑制作用的IC50级别

测试结果显示，洛莫司汀对各种肿瘤细胞的活性较差，氨萘非特的活性更优。化合物1d、1、Cob280和Cob281的活性均未优于氨萘非特，甚至活性还有所降低。但令人惊讶的是，本发明化合物抗肿瘤活性显著优于氨萘非特和洛莫司汀，以及类似化合物1d、1、Cob280、Cob281。本发明某些优选化合物的活性达到类似化合物活性的100倍以上。
实施例22：式I化合物体内抗肿瘤作用的研究
试验目的：进一步测试本发明化合物的体内抗肿瘤作用。
测试化合物：I-01、I-08。
试验动物：5周龄雌性BALB/c裸鼠，正常喂养7天后，选取体征状况良好的小鼠进行试验。
肿瘤细胞：人结肠癌细胞COLO 205，在含10％胎牛血清的RPMI-1640培养基中进行细胞培养。每周传代1到2次，传代比例1:3到1:6。
造模和分组：收取对数生长期的COLO 205细胞。注射于裸鼠前右侧乳腺脂肪垫，注射量为每只动物5×106细胞，建立COLO 205移植瘤模型。定期观察动物状态，测量肿瘤直径，计算肿瘤体积。待瘤体积达到约150mm3后，挑选健康状况良好、肿瘤体积相近的荷瘤鼠，随机分为：溶剂对照组、I-01组、I-08组。
给药：各测试化合物用溶剂溶解，按动物组别分别给与对应化合物或空白溶剂。给药方式为灌胃，给药量10mg/kg，每天一次，共给药21次。
结果：实验最后一天，测量肿瘤直径和肿瘤重量，计算肿瘤体积抑制率(GI)、肿瘤重量抑制率(IR)。主要结果见表4。
肿瘤体积抑制率＝100％×[1-(Tvt-Tvini)÷(Cvt-Cvini)]，其中Tvt表示治疗组试验结束时肿瘤体积，Tvini表示治疗组分组时肿瘤体积，Cvt表示溶剂对照试验结束时肿瘤体积，Cvini表示溶剂对照组分组时肿瘤体积。
肿瘤重量抑制率＝100％×(Cw-Tw)÷Cw，其中Cw表示试验结束时溶剂对照组肿瘤重量，Tw表示试验结束时治疗组肿瘤重量。
表4：化合物的体内肿瘤抑制作用
该试验结果表明本发明化合物在体内也具有很强的抗肿瘤作用。
以上用一般性说明及具体实施方式对本发明作了详尽的描述。本领域技术人员可以在本发明基础上对之做一些修改或改进，这些在不偏离本发明思路的基础上所做的修改或改进，均属于本发明要求保护的范围。

Claims (13)

  1. 式I所示的二酰亚胺衍生物，
    式I中，
    A为萘环或蒽环，其通过3个碳原子与二酰亚胺稠合；
    R1选自氢原子、烷基氧基或硝基；
    m或n为1、2或3，且m+n≤4；
    R2为烷基；
    R3选自氢原子或烷基；
    R4或R5选自烷基、卤代烷基或亚硝基。
  2. 根据权利要求1所述的二酰亚胺衍生物，所述的烷基为C1-C4烷基，所述的烷基氧基为C1-C4烷基氧基，所述的卤代烷基为卤代C1-C4烷基。
  3. 根据权利要求1所述的二酰亚胺衍生物，所述的A为萘环。
  4. 根据权利要求1所述的二酰亚胺衍生物，所述R1为硝基或C1-C4烷基氧基。
  5. 根据权利要求1所述的二酰亚胺衍生物，所述R3为氢原子。
  6. 根据权利要求1所述的二酰亚胺衍生物，所述R3与R2一起成环。
  7. 根据权利要求1所述的二酰亚胺衍生物，所述R4为卤代C1-C4烷基，所述R5为亚硝基。
  8. 根据权利要求1所述的二酰亚胺衍生物，所述m和n选自：m＝1且n＝3，m＝1且n＝2，或者m＝2且n＝2。
  9. 一种式I所示二酰亚胺衍生物的制备方法，包括：
    按反应式，将式M7化合物与式M8化合物在碱的存在下反应生成式I化合物；其中，反应式中的A、m、n、R1、R2、R3、R4和R5如权利要求1中所述。
  10. 根据权利要求9所述的制备方法，其中式M7化合物通过下列方法制备得到：
    按反应式，先将式M4化合物与式M5化合物反应生成式M6化合物，再在酸的存在下处理式M6化合物得到式M7化合物；反应式中的A、m、n、R1、R2和R3如权利要求1中所述。
  11. 根据权利要求10所述的制备方法，其中式M4化合物通过下列方法制备得到：
    按反应式，先将式M1化合物与式M2化合物反应生成式M3化合物，再将式M3化合物氢化得到式M4化合物；反应式中的X为卤素，Cbz为苄氧羰基，Boc为叔丁氧羰基，m、n、R2和R3如权利要求1中所述。
  12. 权利要求1-8中任一项所述二酰亚胺衍生物在制备治疗细胞增殖性疾病的药物中的应用。
  13. 根据权利要求12所述的应用，所述细胞增殖性疾病为癌症。
PCT/CN2023/074050 2022-03-23 2023-01-31 二酰亚胺衍生物、其制备方法和应用 WO2023179205A1 (zh)

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