WO2024149270A1 - 5-fluorouracil derivative and anti-tumor use thereof - Google Patents
5-fluorouracil derivative and anti-tumor use thereof Download PDFInfo
- Publication number
- WO2024149270A1 WO2024149270A1 PCT/CN2024/071476 CN2024071476W WO2024149270A1 WO 2024149270 A1 WO2024149270 A1 WO 2024149270A1 CN 2024071476 W CN2024071476 W CN 2024071476W WO 2024149270 A1 WO2024149270 A1 WO 2024149270A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- cell carcinoma
- squamous cell
- tumor
- present
- Prior art date
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 10
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 206010041823 squamous cell carcinoma Diseases 0.000 claims abstract description 12
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 16
- 201000002740 oral squamous cell carcinoma Diseases 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 201000002743 tongue squamous cell carcinoma Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229960002949 fluorouracil Drugs 0.000 abstract description 7
- 230000035755 proliferation Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 11
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 101001081170 Homo sapiens Humanin-like 12 Proteins 0.000 description 2
- 102100027737 Humanin-like 12 Human genes 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000002737 cell proliferation kit Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- -1 compound 1 Chemical compound 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Definitions
- the present invention belongs to the field of chemical medicines, and specifically relates to a 5-fluorouracil derivative and its anti-tumor application.
- OSCC oral squamous cell carcinoma
- the purpose of the present invention is to provide a 5-fluorouracil derivative and its anti-tumor use.
- the present invention provides a compound represented by formula I, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof:
- R1 is hydrogen or R2 is hydrogen or And R1 and R2 are not hydrogen at the same time.
- the compound is one of the following compounds:
- the present invention also provides a method for preparing the above compound, the method comprising the following steps:
- the present invention also provides an anti-tumor pharmaceutical composition, which is a preparation prepared by taking the above compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
- the preparation is an oral preparation or an injection preparation.
- the present invention also provides the use of the compound in preparing anti-tumor drugs.
- the tumor is squamous cell carcinoma.
- the squamous cell carcinoma is head and neck squamous cell carcinoma.
- the head and neck squamous cell carcinoma is oral squamous cell carcinoma.
- oral squamous cell carcinoma is tongue squamous cell carcinoma.
- the experimental results show that the compounds provided by the present invention can effectively inhibit the proliferation of squamous cell carcinoma, and the inhibitory effect of compound 3a is significantly better than that of 5-fluorouracil.
- the present invention provides a new option for preparing drugs for preventing and/or treating squamous cell carcinoma.
- Figure 1 The proliferation inhibition ability of each compound on squamous cell carcinoma cells HN30, HN12, Cal-27, and HSC-3.
- Figure 2 IC50 values of compound 3a against HN30 and Cal27 cells.
- Figure 3 IC50 values of compound 1 on HN30 and Cal27 cells.
- the raw materials used in the present invention can be obtained by purchasing commercial products, or can be prepared according to conventional methods in the art.
- Squamous cell carcinoma cell lines HN30, HN12, Cal-27, HSC-3.
- Test compounds Compounds 3a, 3b, 3c; Compound 1 (i.e., 5-fluorouracil).
- the experimental operation is as follows: the above four tumor cell lines are cultured in a standardized incubator at 37 degrees and 5% CO 2 ; the cells in the logarithmic growth phase are digested, counted, and plated with 3000 cells per well of a 96-well plate, and cultured overnight in a cell culture incubator; the test compound is prepared with DMSO at a concentration of 10mM for storage solution, and is diluted in sequence before treating the cells (0, 1.25, 2.5, 5, 10uM), and the control group is added according to the highest concentration of DMSO; the cells are cultured continuously in a cell culture incubator for 48 hours, and the CCK8 cell proliferation kit is used for determination to detect the effect of each compound on the proliferation ability of the four tumor cells.
- the experimental results of compound 3a and compound 1 are analyzed, and their IC 50 values are calculated to compare the effects of the two compounds on tumor cell proliferation.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention belongs to the field of chemical drugs, and provides a 5-fluorouracil derivative and an anti-tumor use thereof. The structure of the 5-fluorouracil derivative is represented by formula (I). The compound provided by the present invention can effectively inhibit the proliferation of squamous cell carcinoma. Moreover, the inhibitory effect of compound (3a) is significantly better than that of 5-fluorouracil. The present invention provides a new option for preparing drugs for preventing and/or treating squamous cell carcinoma.
Description
本发明属于化药领域，具体涉及一种5-氟尿嘧啶衍生物及其抗肿瘤用途。The present invention belongs to the field of chemical medicines, and specifically relates to a 5-fluorouracil derivative and its anti-tumor application.
口腔颌面部恶性肿瘤是头颈部常见的恶性肿瘤，其中约90％以上为口腔鳞状细胞癌(oral squamouscell carcinoma，OSCC)，是全球第八大恶性肿瘤。OSCC通常发现和确诊时间较晚，具有早期转移、术后复发率高、预后不佳等特点，导致OSCC死亡率居高不下。90％的早期OSCC患者采用单一手术治疗可以治愈，但是在确诊患者中，早期病例却不足10％；此外，70％以上的OSCC患者进行根治性手术治疗的术后常伴有容貌畸形和功能障碍等多种并发症。开发出能够有效治疗OSCC的药物具有重要意义。Oral and maxillofacial malignancies are common malignant tumors of the head and neck, of which more than 90% are oral squamous cell carcinoma (OSCC), the eighth largest malignant tumor in the world. OSCC is usually discovered and diagnosed late, and has the characteristics of early metastasis, high postoperative recurrence rate, and poor prognosis, resulting in a high mortality rate of OSCC. 90% of early OSCC patients can be cured with a single surgical treatment, but among the confirmed patients, early cases account for less than 10%; in addition, more than 70% of OSCC patients undergoing radical surgical treatment are often accompanied by various complications such as facial deformity and functional impairment. It is of great significance to develop drugs that can effectively treat OSCC.
文献(黑龙江医药科学，2009年2月，第32卷，第1期)报道了5-氟尿嘧啶能诱导口腔鳞状细胞癌细胞的凋亡。但是，5-氟尿嘧啶的抗肿瘤活性还无法满足临床需求，有待进一步提高。The literature (Heilongjiang Medical Science, February 2009, Vol. 32, No. 1) reported that 5-fluorouracil can induce apoptosis of oral squamous cell carcinoma cells. However, the anti-tumor activity of 5-fluorouracil cannot meet clinical needs and needs to be further improved.
发明内容Summary of the invention
本发明的目的在于提供一种5-氟尿嘧啶衍生物及其抗肿瘤用途。The purpose of the present invention is to provide a 5-fluorouracil derivative and its anti-tumor use.
本发明提供了式I所示化合物、其药学上可接受的盐、其立体异构体：
The present invention provides a compound represented by formula I, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof:
The present invention provides a compound represented by formula I, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof:
其中，R1为氢或R2为氢或且R1和R2不同时为氢。Wherein, R1 is hydrogen or R2 is hydrogen or And R1 and R2 are not hydrogen at the same time.
进一步地，所述化合物为以下化合物之一：
Furthermore, the compound is one of the following compounds:
Furthermore, the compound is one of the following compounds:
本发明还提供了一种制备上述化合物的方法，所述方法包括以下步骤：
The present invention also provides a method for preparing the above compound, the method comprising the following steps:
The present invention also provides a method for preparing the above compound, the method comprising the following steps:
化合物4与化合物1反应，分离纯化，得到式I所示化合物。Compound 4 is reacted with compound 1, separated and purified to obtain a compound of formula I.
本发明还提供了一种抗肿瘤的药物组合物，它是以上述化合物为活性成分，加上药学上可接受的辅料制备而成的制剂。The present invention also provides an anti-tumor pharmaceutical composition, which is a preparation prepared by taking the above compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
进一步地，所述制剂为口服制剂或注射制剂。Furthermore, the preparation is an oral preparation or an injection preparation.
本发明还提供了上述化合物在制备抗肿瘤的药物中的用途。The present invention also provides the use of the compound in preparing anti-tumor drugs.
进一步地，所述肿瘤为鳞状细胞癌。Furthermore, the tumor is squamous cell carcinoma.
进一步地，所述鳞状细胞癌为头颈部鳞状细胞癌。Furthermore, the squamous cell carcinoma is head and neck squamous cell carcinoma.
进一步地，所述头颈部鳞状细胞癌为口腔鳞状细胞癌。Furthermore, the head and neck squamous cell carcinoma is oral squamous cell carcinoma.
进一步地，所述口腔鳞状细胞癌为舌鳞状细胞癌。Furthermore, the oral squamous cell carcinoma is tongue squamous cell carcinoma.
实验结果表明，本发明提供的化合物能够有效抑制鳞状细胞癌的增殖，并且，其中化合物3a的抑制效果明显优于5-氟尿嘧啶。本发明为制备预防和/或治疗鳞状细胞癌的药物提供了一种新的选择。The experimental results show that the compounds provided by the present invention can effectively inhibit the proliferation of squamous cell carcinoma, and the inhibitory effect of compound 3a is significantly better than that of 5-fluorouracil. The present invention provides a new option for preparing drugs for preventing and/or treating squamous cell carcinoma.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步
的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above contents of the present invention are further described below by means of specific implementation methods in the form of embodiments. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention.
图1：各化合物对鳞状细胞癌细胞HN30，HN12，Cal-27，HSC-3的增殖抑制能力。Figure 1: The proliferation inhibition ability of each compound on squamous cell carcinoma cells HN30, HN12, Cal-27, and HSC-3.
图2：化合物3a对HN30和Cal27细胞的IC50值。Figure 2: IC50 values of compound 3a against HN30 and Cal27 cells.
图3：化合物1对HN30和Cal27细胞的IC50值。Figure 3: IC50 values of compound 1 on HN30 and Cal27 cells.
本发明所用原料可通过购买市售产品获得，也可按照本领域常规的方法制备得到。The raw materials used in the present invention can be obtained by purchasing commercial products, or can be prepared according to conventional methods in the art.
实施例1：制备化合物3a、3b、3c
Example 1: Preparation of compounds 3a, 3b, 3c
Example 1: Preparation of compounds 3a, 3b, 3c
将等量5-氟尿嘧啶(即化合物1，2mmol)和氢化钠(2mmol)，过量化合物4(6mmol)溶于5mL N,N-二甲基甲酰胺(DMF)中，加热回流反应，通过TLC监测直至反应结束，加水淬灭反应，用二氯甲烷萃取水相3次，合并有机相，用无水硫酸钠干燥，减压旋蒸除去有机溶剂，通过快速柱层析分离纯化依次得到化合物3a、3b、3c，总收率为40％。Equal amounts of 5-fluorouracil (i.e., compound 1, 2 mmol) and sodium hydride (2 mmol) and excess compound 4 (6 mmol) were dissolved in 5 mL of N,N-dimethylformamide (DMF), heated to reflux and monitored by TLC until the reaction was completed. Water was added to quench the reaction, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The organic solvent was removed by rotary evaporation under reduced pressure, and compounds 3a, 3b, and 3c were obtained by separation and purification by rapid column chromatography, with a total yield of 40%.
化合物3a分析数据：1H NMR(DMSO-d6,600MHz)δ9.92(s,1H),9.89(s,1H),8.13(d,J＝6.6Hz,1H),7.48-7.44(m,4H),7.28-7.22(m,4H),4.10(t,J＝7.4Hz,2H),3.97(t,J＝6.7Hz,2H),2.70(t,J＝6.8Hz,2H),2.55(t,J＝7.4Hz,2H),2.02(q,J＝3.1Hz,6H),1.81(t,J＝2.9Hz,12H),1.74-1.67(m,12H).LRMS calcd for C42H49FN4O4[M+Na]+715.36,found 715.36.Analytical data of compound 3a: 1H NMR (DMSO-d6, 600MHz) δ9.92 (s, 1H), 9.89 (s, 1H), 8.13 (d, J = 6.6 Hz, 1H), 7.48-7.44 (m, 4H), 7.28-7.22 (m, 4H), 4.10 (t, J = 7.4 Hz, 2H), 3.97 (t, J = 6.7 Hz, 2H), 2 .70(t,J＝6.8Hz,2H),2.55(t,J＝7.4Hz,2H),2.02(q,J＝3.1Hz,6H),1.81(t,J＝2.9Hz,12H),1.74-1.67(m,12H).LRMS calcd for C42H49FN4O4[M+Na]+715.36, found 715.36.
化合物3b分析数据：1H NMR(DMSO-d6,600MHz)δ11.78(s,1H),9.94
(s,1H),8.02(d,J＝7.0Hz,1H),7.49-7.43(m,2H),7.29-7.23(m,2H),3.90(t,J＝6.7Hz,2H),2.70(t,J＝6.7Hz,2H),2.03(p,J＝3.1Hz,3H),1.82(d,J＝3.3Hz,6H),1.75-1.68(m,6H).LRMS calcd for C23H26FN3O3[M+Na]+434.19,found 434.18.Compound 3b analytical data: 1H NMR (DMSO-d6, 600MHz) δ11.78 (s, 1H), 9.94 (s,1H),8.02(d,J＝7.0Hz,1H),7.49-7.43(m,2H),7.29-7.23(m,2H),3.90(t,J＝6.7Hz,2H),2.70(t,J＝6.7Hz,2H),2.03(p,J＝3.1Hz,3H),1.82(d,J＝3. 3Hz,6H),1.75-1.68(m,6H).LRMS calcd for C23H26FN3O3[M+Na]+434.19,found 434.18.
化合物3c分析数据：1H NMR(DMSO-d6,600MHz)δ11.09(d,J＝4.0Hz,1H),9.90(s,1H),7.84(t,J＝5.0Hz,1H),7.49-7.43(m,2H),7.28-7.23(m,2H),4.06(t,J＝7.5Hz,2H),2.56(t,J＝7.5Hz,2H),2.04(p,J＝3.4Hz,3H),1.83(d,J＝3.1Hz,6H),1.75-1.69(m,6H).LRMS calcd for C23H26FN3O3[M+Na]+434.19,found 434.19.Analytical data of compound 3c: 1H NMR (DMSO-d6, 600MHz) δ11.09 (d, J＝4.0Hz, 1H), 9.90 (s, 1H), 7.84 (t, J＝5.0Hz, 1H), 7.49-7.43 (m, 2H), 7.28-7.23 (m, 2H), 4.06 (t, J＝7.5Hz, 2H), 2.56 (t, J＝7.5Hz, 2H), 2.04 (p, J＝3.4Hz, 3H), 1.83 (d, J＝3.1Hz, 6H), 1.75-1.69 (m, 6H). LRMS calcd for C23H26FN3O3[M+Na]+434.19, found 434.19.
以下通过实验例证明本发明的有益效果。The beneficial effects of the present invention are demonstrated by experimental examples below.
实验例1：化合物对鳞状细胞癌细胞的增殖抑制作用Experimental Example 1: Inhibitory effect of compounds on proliferation of squamous cell carcinoma cells
1.实验方法1. Experimental Methods
鳞状细胞癌细胞系：HN30，HN12，Cal-27，HSC-3。Squamous cell carcinoma cell lines: HN30, HN12, Cal-27, HSC-3.
受试化合物：化合物3a、3b、3c；化合物1(即5-氟尿嘧啶)。Test compounds: Compounds 3a, 3b, 3c; Compound 1 (i.e., 5-fluorouracil).
实验操作如下：以上4种肿瘤细胞系均在37度5％CO2的标准化培养箱中进行培养；取对数生长期的细胞进行消化，计数，以96孔板每孔3000细胞的数量进行种板，于细胞培养箱中贴壁培养过夜；受试化合物用DMSO以10mM的浓度配置储存液，处理细胞之前依次稀释(0，1.25，2.5，5，10uM)，对照组按照最高浓度的DMSO含量添加；于细胞培养箱中连续培养48小时，用CCK8细胞增殖试剂盒进行测定，以此检测各个化合物对4种肿瘤细胞增殖能力的影响。同时，针对化合物3a和化合物1的实验结果进行分析，计算其IC50值，从而对比两种化合物对肿瘤细胞增殖影响。The experimental operation is as follows: the above four tumor cell lines are cultured in a standardized incubator at 37 degrees and 5% CO 2 ; the cells in the logarithmic growth phase are digested, counted, and plated with 3000 cells per well of a 96-well plate, and cultured overnight in a cell culture incubator; the test compound is prepared with DMSO at a concentration of 10mM for storage solution, and is diluted in sequence before treating the cells (0, 1.25, 2.5, 5, 10uM), and the control group is added according to the highest concentration of DMSO; the cells are cultured continuously in a cell culture incubator for 48 hours, and the CCK8 cell proliferation kit is used for determination to detect the effect of each compound on the proliferation ability of the four tumor cells. At the same time, the experimental results of compound 3a and compound 1 are analyzed, and their IC 50 values are calculated to compare the effects of the two compounds on tumor cell proliferation.
2.实验结果2. Experimental results
结果如图1-图3所示。可以看出，化合物3a的抗肿瘤细胞增殖能力明显高于化合物1、3b和3c；此外，化合物1在更高浓度范围内显示出更高的抗肿瘤活性，然而3b和3c的抗肿瘤活性没有明显提升。进一步比较化合物1和化合物3a的IC50结果发现(图2和图3)，化合物3a的IC50值明显低于化合物1的IC50值，比如对于HN30和Cal27细胞，化合物3a的IC50值分别是7.091uM和6.536uM，而化合物1的IC50值分别是21.72uM和22.78uM。The results are shown in Figures 1 to 3. It can be seen that the anti-tumor cell proliferation ability of compound 3a is significantly higher than that of compounds 1, 3b and 3c; in addition, compound 1 shows higher anti-tumor activity in a higher concentration range, while the anti-tumor activity of 3b and 3c is not significantly improved. Further comparison of the IC 50 results of compound 1 and compound 3a (Figures 2 and 3) shows that the IC 50 value of compound 3a is significantly lower than that of compound 1. For example, for HN30 and Cal27 cells, the IC 50 values of compound 3a are 7.091uM and 6.536uM, respectively, while the IC 50 values of compound 1 are 21.72uM and 22.78uM , respectively.
上述实验结果表明，本发明提供的化合物能够有效抑制鳞状细胞癌的增殖，并且，其中化合物3a的抑制效果明显优于5-氟尿嘧啶。
The above experimental results show that the compounds provided by the present invention can effectively inhibit the proliferation of squamous cell carcinoma, and the inhibitory effect of compound 3a is significantly better than that of 5-fluorouracil.
Claims (10)
- 式I所示化合物、其药学上可接受的盐、其立体异构体：
The compound represented by formula I, its pharmaceutically acceptable salt, and its stereoisomer:
其中，R1为氢或R2为氢或且R1和R2不同时为氢。Wherein, R1 is hydrogen or R2 is hydrogen or And R1 and R2 are not hydrogen at the same time. - 根据权利要求1所述的化合物、其药学上可接受的盐、其立体异构体，其特征在于：所述化合物为以下化合物之一：
The compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof according to claim 1, characterized in that the compound is one of the following compounds:
- 一种制备权利要求1-2任一项所述化合物的方法，其特征在于：所述方法包括以下步骤：
A method for preparing the compound according to any one of claims 1 to 2, characterized in that the method comprises the following steps:
化合物4与化合物1反应，分离纯化，得到式I所示化合物。Compound 4 is reacted with compound 1, separated and purified to obtain a compound of formula I. - 一种抗肿瘤的药物组合物，其特征在于：它是以权利要求1-2任一项所述化合物为活性成分，加上药学上可接受的辅料制备而成的制剂。An anti-tumor pharmaceutical composition, characterized in that it is a preparation prepared by using the compound described in any one of claims 1-2 as an active ingredient and adding pharmaceutically acceptable excipients.
- 根据权利要求4所述的药物组合物，其特征在于：所述制剂为口服制剂或注射制剂。The pharmaceutical composition according to claim 4, characterized in that the preparation is an oral preparation or an injectable preparation.
- 权利要求1-2任一项所述化合物在制备抗肿瘤的药物中的用途。Use of the compound according to any one of claims 1 to 2 in the preparation of anti-tumor drugs.
- 根据权利要求6所述的用途，其特征在于：所述肿瘤为鳞状细胞癌。The use according to claim 6, characterized in that the tumor is squamous cell carcinoma.
- 根据权利要求7所述的用途，其特征在于：所述鳞状细胞癌为头颈部鳞状细胞癌。The use according to claim 7 is characterized in that the squamous cell carcinoma is head and neck squamous cell carcinoma.
- 根据权利要求8所述的用途，其特征在于：所述头颈部鳞状细胞癌为口腔鳞状细胞癌。The use according to claim 8 is characterized in that the head and neck squamous cell carcinoma is oral squamous cell carcinoma.
- 根据权利要求9所述的用途，其特征在于：所述口腔鳞状细胞癌为舌鳞状细胞癌。 The use according to claim 9, characterized in that the oral squamous cell carcinoma is tongue squamous cell carcinoma.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310034758.6A CN115850190B (en) | 2023-01-10 | 2023-01-10 | 5-Fluorouracil derivative and anti-tumor application thereof |
| CN202310034758.6 | 2023-01-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024149270A1 true WO2024149270A1 (en) | 2024-07-18 |
Family
ID=85657242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2024/071476 WO2024149270A1 (en) | 2023-01-10 | 2024-01-10 | 5-fluorouracil derivative and anti-tumor use thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN115850190B (en) |
| WO (1) | WO2024149270A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117986195A (en) * | 2023-01-10 | 2024-05-07 | 四川大学 | Novel heterocyclic compound and preparation method and application thereof |
| CN115850190B (en) * | 2023-01-10 | 2024-09-10 | 四川大学 | 5-Fluorouracil derivative and anti-tumor application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0010941A1 (en) * | 1978-10-30 | 1980-05-14 | Fujisawa Pharmaceutical Co., Ltd. | 5-Fluorouracil derivatives, preparation thereof and their pharmaceutical compositions |
| US4336381A (en) * | 1979-11-08 | 1982-06-22 | Shionogi & Co., Ltd. | 5-Fluorouracil derivatives |
| CN107698521A (en) * | 2016-03-23 | 2018-02-16 | 上海华理生物医药有限公司 | A kind of preparation of 5 FU 5 fluorouracil substituted carboxylic acid derivative and purposes |
| CN110467574A (en) * | 2019-07-17 | 2019-11-19 | 蒋周倩 | Compound adamantane acid -5 FU 5 fluorouracil methyl esters synthesis and application |
| CN115850190A (en) * | 2023-01-10 | 2023-03-28 | 四川大学 | 5-fluorouracil derivative and anti-tumor application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2021011209A (en) * | 2019-03-15 | 2022-01-19 | Massachusetts Gen Hospital | Novel small molecule inhibitors of tead transcription factors. |
| CN114773274A (en) * | 2022-04-29 | 2022-07-22 | 四川大学华西医院 | Novel 4, 6-pyrimidine derivatives and application thereof in antitumor drugs |
| CN114907274A (en) * | 2022-05-11 | 2022-08-16 | 宁夏医科大学 | 5-fluorouracil-1-alkyl acid derivative, preparation method and application thereof |
| CN117986195A (en) * | 2023-01-10 | 2024-05-07 | 四川大学 | Novel heterocyclic compound and preparation method and application thereof |
-
2023
- 2023-01-10 CN CN202310034758.6A patent/CN115850190B/en active Active
-
2024
- 2024-01-10 WO PCT/CN2024/071476 patent/WO2024149270A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0010941A1 (en) * | 1978-10-30 | 1980-05-14 | Fujisawa Pharmaceutical Co., Ltd. | 5-Fluorouracil derivatives, preparation thereof and their pharmaceutical compositions |
| US4336381A (en) * | 1979-11-08 | 1982-06-22 | Shionogi & Co., Ltd. | 5-Fluorouracil derivatives |
| CN107698521A (en) * | 2016-03-23 | 2018-02-16 | 上海华理生物医药有限公司 | A kind of preparation of 5 FU 5 fluorouracil substituted carboxylic acid derivative and purposes |
| CN110467574A (en) * | 2019-07-17 | 2019-11-19 | 蒋周倩 | Compound adamantane acid -5 FU 5 fluorouracil methyl esters synthesis and application |
| CN115850190A (en) * | 2023-01-10 | 2023-03-28 | 四川大学 | 5-fluorouracil derivative and anti-tumor application thereof |
Non-Patent Citations (2)
| Title |
|---|
| KODE NAGESWARA RAO, DEVANGACHINTA DAKSHINAMURTHY, PHADTARE SHASHIKANT: "3-(Adamantan-1-yl)-4-hydroxybenzyl Substituted Purines and Pyrimidines: Synthesis and Cytotoxic Activity", LETTERS IN DRUG DESIGN & DISCOVERY, vol. 9, no. 10, 1 January 2012 (2012-01-01), US , pages 926 - 933, XP093190466, ISSN: 1570-1808, DOI: 10.2174/1570180811209050926 * |
| ZHANG YUTING, LIU JIANG;ZHAO HANG;HE YANG;CHEN QIANMING: "Synthesis of 5-fluorouracil-lactoside derivatives and experimental study on their anti-oral squamous cell carcinoma activity", WEST CHINA JOURNAL OF STOMATOLOGY, vol. 40, no. 1, 1 February 2022 (2022-02-01), pages 32 - 38, XP093190465, ISSN: 1000-1182, DOI: 10.7518/hxkq.2022.01.005 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115850190B (en) | 2024-09-10 |
| CN115850190A (en) | 2023-03-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2024149270A1 (en) | 5-fluorouracil derivative and anti-tumor use thereof | |
| CN110072866A (en) | Condensed 1,4- diaza * as BET protein degradation agent | |
| AU2020340299B2 (en) | Crystalline forms of a CD73 inhibitor | |
| CN118434722A (en) | Methionine adenosyltransferase 2A (MAT 2A) inhibitors and uses thereof | |
| CN101195597A (en) | 1-substituted-4,4-2 substituted thiosemicarbazide compounds, production method and uses of the same | |
| WO2024149269A1 (en) | Novel heterocyclic compound, preparation method therefor, and use thereof | |
| CN115554303A (en) | Tricyclic compound, preparation method and application thereof | |
| JP2021529175A (en) | Crystal form of CDK4 / 6 activity inhibitor compound and its use | |
| CN108530436B (en) | Pyrazole compound and preparation method and application thereof | |
| WO2017020869A1 (en) | B crystal form of 2-[(2r)-2-methyl-2-pyrrolidinyl]-1h-benzimidazole-7-carboxamide, preparation method and use | |
| CN111718325A (en) | 2,4, 5-substituted pyrimidine compound and preparation method and application thereof | |
| CN117285590A (en) | Compound, preparation method thereof, composition comprising compound and application of compound | |
| CN106187923A (en) | 2 aryl 4 aroyl triazole compounds and application thereof | |
| CN113620930B (en) | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof | |
| EP4098647A1 (en) | Disubstituted adamantyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for suppressing cancer growth comprising same as active ingredient | |
| WO2022227923A1 (en) | Hexadecane tromethamine compound, synthesis method therefor, and use thereof in anti-tumor and anti-fungal aspects | |
| CN117412953A (en) | Axl inhibitors | |
| CN112920133B (en) | (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound and preparation method and application thereof | |
| KR20050059132A (en) | Novel crystals | |
| EP3677581A1 (en) | Deuterated indoleamine 2,3-dioxygenase inhibitor and application thereof | |
| JP2021531302A (en) | Borate of azetidine derivative | |
| CN112300235B (en) | Benzimidazole derivative BI321 and preparation method and application thereof | |
| WO2014167446A1 (en) | Derivatives of 1-(substituted sulfonyl)-2-aminoimidazoline as antitumor and antiproliferative agents | |
| CN112358517B (en) | Benzimidazole derivative BI305 and preparation method and application thereof | |
| CN114478509B (en) | Five-membered heterocycle substituted benzamide compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 24741267 Country of ref document: EP Kind code of ref document: A1 |