阅读说明：本技术 一种化合物及其制备方法和应用 (Compound and preparation method and application thereof ) 是由 刘玉法 高修正 吕绪涛 高翔宇 孙彬 于 2019-10-12 设计创作，主要内容包括：本发明提供了一种化合物及其制备方法和应用,该化合物具有式(I)所示结构：<Image he="342" wi="700" file="DDA0002231304410000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R为未被取代的或被取代基取代的含氮杂环基；所述含氮杂环基为五元或六元含氮脂杂环或含氮芳香杂环；所述取代基选自烷基、卤代烷基、羧基、卤素；以及,本发明还提供了式(I)化合物的药学上可接受的盐。本发明的化合物对胆管癌细胞QBC-939和人胰腺癌细胞PANC-1增殖具有较好的抑制活性,本发明化合物在0.2ug/mL对胆管癌细胞QBC-939和人胰腺癌细胞PANC-1增殖的抑制率普遍都高于80％,现活性远高于临床应用的氟尿嘧啶。(The invention provides a compound, a preparation method and application thereof, wherein the compound has a structure shown in a formula (I): wherein R is an unsubstituted or substituted nitrogen-containing heterocyclic group; the nitrogen heterocyclic group is a five-membered or six-membered nitrogen-containing aliphatic heterocyclic ring or a nitrogen-containing aromatic heterocyclic ring; the substituent is selected from alkyl, halogenated alkyl, carboxyl and halogen; also, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I). The compound has good inhibitory activity on proliferation of bile duct cancer cells QBC-939 and human pancreatic cancer cells PANC-1, the inhibitory rate of the compound on proliferation of the bile duct cancer cells QBC-939 and the human pancreatic cancer cells PANC-1 is higher than 80% generally at 0.2ug/mL, and the compound is activeThe sex is much higher than that of fluorouracil applied clinically.)

1. A compound having the structure shown in formula (I):

wherein R is an unsubstituted or substituted nitrogen-containing heterocyclic group; the nitrogen heterocyclic group is a five-membered or six-membered nitrogen-containing aliphatic heterocyclic ring or a nitrogen-containing aromatic heterocyclic ring; the substituent is selected from alkyl, halogenated alkyl, carboxyl and halogen;

or a pharmaceutically acceptable salt of the compound of formula (I).

2. A compound according to claim 1, wherein the nitrogen-containing heterocycle is selected from pyrrole, thiazole, imidazole, pyrazole, oxazole, isoxazole, pyridine, pyrimidine, pyridazine, pyrazine and piperidine.

3. A compound according to claim 1 or 2, characterised in that it isThe substituents being selected from C_1-3Alkyl, trifluoromethyl and carboxyl;

preferably, the substitution is mono-or di-substituted.

4. A compound according to claim 1 or 2, wherein R is selected from the group consisting of: 2-pyrrolyl, 3-pyrrolyl, 2-methyl-4-pyrrolyl, 2-imidazolyl, 4-methyl-2-imidazolyl, 2-methyl-4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-methyl-3-pyrazolyl, 3-methyl-4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-oxazolylmethyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-isoxazolyl, 3, 5-dimethylisoxazolyl-4-methyl, 2-imidazolyl, 4-pyrazolyl, 4-thiazolyl, 5-thiazolyl, 2-thiazolyl, 4-oxazolyl, 3-dimethylisoxazolyl-4-methyl, 2-oxazolyl, 3-dimethylisoxazolyl, 4-methyl, and mixtures thereof, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-methyl-2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 2-methyl-3-pyridyl group, 4-methyl-3-pyridyl group, 5-methyl-3-pyridyl group, 2-methyl-4-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 4-trifluoromethyl-2-pyridyl group, 5-trifluoromethyl-2-pyridyl group, 2-trifluoromethyl-3-pyridyl group, 4-trifluoromethyl-3-pyridyl group, 5-trifluoromethyl-3-pyridyl group, 3-trifluoromethyl-pyridyl group, 3-pyridyl group, 4-trifluoromethyl-2-pyridyl group, 3-pyridyl group, 4-trifluoromethyl-pyridyl group, 3-, 2-trifluoromethyl-4-pyridyl group, 3-carboxy-2-pyridyl group, 4-carboxy-2-pyridyl group, 5-carboxy-2-pyridyl group, 2-carboxy-3-pyridyl group, 4-carboxy-3-pyridyl group, 5-carboxy-3-pyridyl group, 2-carboxy-4-pyridyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-pyrimidyl group, 4-pyrimidyl group, 5-pyrimidyl group, 4-methyl-2-pyrimidyl group, 5-methyl-2-pyrimidyl group, 2-methyl-4-pyrimidyl group, 3-carboxy-2-pyridyl group, 5-carboxy-3-pyridyl group, 2-methyl-5-pyrimidinyl, 2-pyrimidylmethyl, 4-pyrimidylmethyl, 5-pyrimidylmethyl, 3-pyridazinyl, 4-methyl-3-pyridazinyl, 5-methyl-3-pyridazinyl, 3-methyl-4-pyridazinyl, 3-pyridazinylmethyl, 4-pyridazinylmethyl, 2-pyrazinyl, 3-methyl-2-pyrazinyl and 2-pyrazinylmethyl.

5. A preparation method of a compound shown in a formula (I) is characterized by comprising the steps of taking diosgenin as an initial reactant to react with RX to prepare the compound shown in the formula (I);

wherein R is as defined in any one of claims 1 to 4 and X is halogen.

6. A preparation method according to claim 5, which comprises dissolving diosgenin in solvent, adding RX and alkaline substance, reacting, and keeping the solution alkaline during the reaction to obtain compound of formula (I);

preferably, the reaction temperature is-20-300 ℃, and the reaction time is 0.1-72 h;

the solvent is selected from one or more of water, methanol, ethanol, propanol, butanol, pentanol, glycerol, dichloromethane, trichloromethane, carbon tetrachloride, benzene, toluene, xylene, 1, 4-dioxane, 1, 2-dichloroethane, tetrahydrofuran, N-dimethylformamide, ethyl acetate and dimethyl sulfoxide;

preferably, the amount of the solvent is such that each mole of diosgenin is dissolved in 5-100L of solvent;

preferably, the alkaline substance is selected from gamma-Al₂O₃-Na、γ-Al₂O₃-K、γ-Al₂O₃-NaOH-Na、γ-Al₂O₃-NaOH-K、γ-Al₂O₃-KOH-Na、γ-Al₂O₃-one or more of KOH-K, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium amide, sodium metal, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium oxide, potassium oxide, calcium oxide, strontium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, ammonia, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine, pyridine, and piperidine;

preferably, the molar ratio of the diosgenin to the RX to the alkaline substance is 1: (0.1-10): (0.01-10), preferably 1 (1.0-1.2): (0.6-1.0).

7. The method as claimed in claim 5 or 6, further comprising detecting the end point of the reaction by chromatography, standing the reaction product at room temperature after the reaction is finished, and preparing the compound of formula (I) by separation and purification;

preferably, the separation and purification method is selected from one or more of filtration, resin treatment, water washing, distillation, crystallization, extraction, activated carbon treatment, molecular sieve treatment and chromatography.

8. A composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a composition according to claim 8, together with at least one pharmaceutical carrier or adjuvant.

10. Use of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a composition of claim 8, or a pharmaceutical formulation of claim 9, in the manufacture of an anti-cancer medicament;

preferably, the cancer is selected from pancreatic cancer and cholangiocarcinoma.

Technical Field

The invention relates to the field of biological medicines, and particularly relates to a compound and a preparation method and application thereof.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Cholangiocarcinoma is a common biliary tract malignant tumor, with high malignancy, very poor prognosis, and increasing morbidity and mortality year by year (wangxian, et al, the clinical treatment progress of hepatoportal cholangiocarcinoma [ J ], electronic journal of Chinese liver surgery, 2018, 7(4): 253-containing 257). The common chemotherapy drugs in the clinic of bile duct cancer are 5-fluorouracil and cisplatin. When the 5-fluorouracil reaches 20ug/mL, the traditional Chinese medicine composition has a good effect of inhibiting the growth of human bile duct cancer QBC939 cells, and has side effects of bone marrow inhibition such as leukopenia and platelet drop, and gastrointestinal reactions such as inappetence, nausea, vomiting, stomatitis, gastritis, abdominal pain and diarrhea. When the cisplatin reaches 3.0 mu g/mL, the cisplatin has a good effect of inhibiting cell growth of human bile duct cancer QBC939, and mainly has severe digestive tract reactions such as nausea and vomiting, renal toxicity such as renal tubular injury, and more common neurotoxicity such as tinnitus and hearing loss caused by auditory nerve damage. Because biliary duct cancer has hidden onset and difficult early diagnosis and has late clinical symptoms, epidemiological studies show that only 10-15% of patients are likely to be cured by operation, and many patients find that the patients are in late stage, but the postoperative recurrence rate is still 50-60%, and the five-year survival rate is only 30%. At present, the treatment principle of the bile duct cancer still adopts a comprehensive treatment scheme mainly based on surgical resection, but only patients with deficiency of 1/3 can be surgically resected when the diagnosis is confirmed, the surgical prognosis is poor, and the combined chemotherapy has no ideal effect on locally advanced or metastatic unresectable bile duct cancer. Therefore, the development of new therapeutic drugs is urgently required.

Pancreatic cancer is a common pancreatic tumor, is a digestive tract malignant tumor with high malignancy degree and difficult diagnosis and treatment, and has 5-year survival rate of less than 1 percent. The early diagnosis rate of pancreatic cancer is low, the operative mortality rate is high, and the early diagnosis rate is one of the worst malignant tumors. At present, the main therapeutic drugs comprise fluorouracil, doxorubicin, ifosfamide, semustine, paclitaxel, gemcitabine, cisplatin and the like, but the clinical cure rate is very low, so that research and development of anti-pancreatic cancer drugs with better curative effect are very necessary.

Diosgenin (CAS number 512-06-1) is a steroid compound obtained by hydrolyzing and deglycosylating dioscin contained in rhizome of Dioscoreaceae plants such as Dioscorea zingiberensis, Dioscorea nipponica, Dioscorea panthaica and the like, and is an important raw material for synthesizing steroid hormone drugs and steroid contraceptives. Dioscin has certain anticancer activity (application of protodioscin in preparation of drug-resistant osteosarcoma medicine CN201810091212.3), has activity on lung cancer cells A549(Wei Y, et al. Anti-cancer effects of Dioscin on third genes of human lung cancer cells line identification DNA damage and activating mitotic cancer therapy, 2013, 59), stomach cancer cells MGC-803 (Zhuao X, et al. patent effects of diosgenin targeting cancer in vitro and vivo. phytochrome therapy, 2016, 23), liver cancer cells Hu 7(Hsieh M J, et al. autoinjection therapy, apoptosis induced breast cancer cells 7. basic, and cancer cells ROS, and has activity on lung cancer cells A549 (cancer cells ROS, tissue culture cell ROS, see 3, 2016. 3, 23), liver cancer cells Hu-7 (tumor diagnosis cells, mouse tissue culture medium J, et al. apoptosis inducing hormone, cancer cells, calcium cancer, diosgenin also has certain activity on sarcoma-180, hepatoma ascites type, mouse cervical cancer and ehrlich ascites carcinoma (new medicinal use of diosgenin CN01129317.9), and diosgenin 3-site amide nitrogen-containing derivative has certain antitumor activity (a diosgenin antitumor derivative and its synthesis method CN 201711083013; Geng Qian, et al. Huaxi J. Pharmacology, 2009,24, 475; Jianhongping, et al. Pharmacology, 2011,46, 539; Yingchun Yao, et al. Huaxi J. Pharmacology, 2011,26, 423; Dingyong, et al. Pharmacology, 2012,46, 539; Wuyaki, et al. Huaxi J. Pharmacology, 2012,27,22), and diosgenin 3-site derivative can inhibit ocular abnormal angiogenesis (use of diosgenin-3-site derivative CN201310325890.9), and amino acid diosgenin ester has anti-inflammatory and antitumor effects (diosgenin-3-site derivative CN201310325890.9), The preparation method and the application of CN 201210303318.8; foudao, et al, journal of western medicine, 2010,25,658), diosgenin amino acid derivatives have growth inhibitory effects to different degrees on human colon cancer cells Caco-2, human gastric adenocarcinoma cells, human lung adenocarcinoma cells, and human neuroblastoma cells (diosgenin amino acid derivatives and their use in preparing anti-tumor drugs CN 201410250801.3; the food safety quality detection report 2015,3,1061), diosgenin 3-glycoside such as pentaglycoside and disaccharide, has certain inhibiting effect on breast cancer cells and human liver cancer cells.

Disclosure of Invention

Specifically, the invention has the following technical scheme:

in a first aspect of the invention, the invention provides a compound having the structure shown in formula (I):

wherein R is an unsubstituted or substituted nitrogen-containing heterocyclic group; the nitrogen heterocyclic group is a five-membered or six-membered nitrogen-containing aliphatic heterocyclic ring or a nitrogen-containing aromatic heterocyclic ring; the substituent is selected from alkyl, halogenated alkyl, carboxyl and halogen; the halogen is selected from F, Cl, Br and I.

Also, the present invention provides pharmaceutically acceptable salts of the compounds of formula (I).

Examples of the "pharmaceutically acceptable salt" include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; organic acid salts such as acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate and ascorbate; inorganic base salts such as sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt and aluminum salt; and organic base salts such as arginine salt, benzathine salt, choline salt, diethylamine salt, dialcohol amine salt, glycinate salt, lysine salt, meglumine salt, ethanolamine salt, and tromethamine salt.

In an embodiment of the invention, the nitrogen-containing heterocycle is selected from pyrrole, thiazole, imidazole, pyrazole, oxazole, isoxazole, pyridine, pyrimidine, pyridazine, pyrazine and piperidine.

In an embodiment of the invention, the substituents are selected from C_1-3Alkyl, trifluoromethyl and carboxyl; the alkyl group is in particular methyl.

In embodiments of the invention the substitution is one or more substitutions, for example, in some embodiments of the invention the nitrogen-containing heterocycle is isoxazole, which is disubstituted with methyl in the positions C-3 and C-5 respectively of isoxazole, then R is 3, 5-dimethylisoxazol-4-yl, which can be represented by

The nitrogen-containing heterocycle is isoxazole, which is trisubstituted by methyl, the substituted positions are respectively C-3 position, C-4 position and C-5 position of the isoxazole, and R is 3, 5-dimethyl isoxazolyl-4-methyl and can be expressed as

In some embodiments of the invention, the nitrogen-containing heterocycle is unsubstituted, then R is selected from 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 2-pyrazinyl.

In some embodiments of the invention, R is selected from the group consisting of: 2-pyrrolyl, 3-pyrrolyl, 2-methyl-4-pyrrolyl, 2-imidazolyl, 4-methyl-2-imidazolyl, 2-methyl-4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-methyl-3-pyrazolyl, 3-methyl-4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-oxazolylmethyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-isoxazolyl, 3, 5-dimethylisoxazolyl-4-methyl, 2-imidazolyl, 4-pyrazolyl, 4-thiazolyl, 5-thiazolyl, 2-thiazolyl, 4-oxazolyl, 3-dimethylisoxazolyl-4-methyl, 2-oxazolyl, 3-dimethylisoxazolyl, 4-methyl, and mixtures thereof, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-methyl-2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 2-methyl-3-pyridyl group, 4-methyl-3-pyridyl group, 5-methyl-3-pyridyl group, 2-methyl-4-pyridyl group, 3-trifluoromethyl-2-pyridyl group, 4-trifluoromethyl-2-pyridyl group, 5-trifluoromethyl-2-pyridyl group, 2-trifluoromethyl-3-pyridyl group, 4-trifluoromethyl-3-pyridyl group, 5-trifluoromethyl-3-pyridyl group, 3-trifluoromethyl-pyridyl group, 3-pyridyl group, 4-trifluoromethyl-2-pyridyl group, 3-pyridyl group, 4-trifluoromethyl-pyridyl group, 3-, 2-trifluoromethyl-4-pyridyl group, 3-carboxy-2-pyridyl group, 4-carboxy-2-pyridyl group, 5-carboxy-2-pyridyl group, 2-carboxy-3-pyridyl group, 4-carboxy-3-pyridyl group, 5-carboxy-3-pyridyl group, 2-carboxy-4-pyridyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-pyrimidyl group, 4-pyrimidyl group, 5-pyrimidyl group, 4-methyl-2-pyrimidyl group, 5-methyl-2-pyrimidyl group, 2-methyl-4-pyrimidyl group, 3-carboxy-2-pyridyl group, 5-carboxy-3-pyridyl group, 2-methyl-5-pyrimidinyl, 2-pyrimidylmethyl, 4-pyrimidylmethyl, 5-pyrimidylmethyl, 3-pyridazinyl, 4-methyl-3-pyridazinyl, 5-methyl-3-pyridazinyl, 3-methyl-4-pyridazinyl, 3-pyridazinylmethyl, 4-pyridazinylmethyl, 2-pyrazinyl, 3-methyl-2-pyrazinyl and 2-pyrazinylmethyl.

Further, the compounds of formula (I) of the present invention include the structures shown in table 1:

TABLE 1 Structure of the compound of formula (I) and HR-MS structural analysis thereof

In a second aspect of the invention, there is also provided a process for the preparation of a compound of formula (I), said process comprising reacting diosgenin as an initial reactant with RX to produce a compound of formula (I); wherein R is as defined above for the first aspect of the invention and X is halogen.

In an embodiment of the present invention, the method comprises dissolving diosgenin in a solvent, adding RX to react with an alkaline substance, and keeping the solution alkaline during the reaction to obtain the compound of formula (I).

In the embodiment of the invention, the reaction temperature is-20-300 ℃, and the reaction time is 0.1-72 h; preferably, the reaction temperature is-20 to 120 ℃, at which the reaction proceeds more easily.

In an embodiment of the present invention, the solvent is selected from one or more of water, methanol, ethanol (absolute ethanol is preferred), propanol, butanol, pentanol, glycerol, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, 1, 4-dioxane, 1, 2-dichloroethane, tetrahydrofuran, N-Dimethylformamide (DMF), and ethyl acetate and dimethyl sulfoxide (DMSO); preferably any one of toluene, absolute ethanol, methanol, n-propanol, isopropanol, n-butanol, ethyl acetate, butyl acetate, methylene chloride, carbon tetrachloride, DMF and tetrahydrofuran, in which the reaction proceeds more easily.

In an embodiment of the present invention, the solvent is used in an amount of 5-100L per mole of diosgenin dissolved in the solvent.

In an embodiment of the invention, the alkaline substance is selected from γ -Al₂O₃-Na、γ-Al₂O₃-K、γ-Al₂O₃-NaOH-Na、γ-Al₂O₃-NaOH-K、γ-Al₂O₃-KOH-Na、γ-Al₂O₃-one or more of KOH-K, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium amide, sodium metal, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium oxide, potassium oxide, calcium oxide, strontium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, ammonia, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine, pyridine, and piperidine.

In some preferred embodiments, the alkaline material is sodium hydride, potassium hydride, sodium ethoxide, strontium carbonate, potassium carbonate, γ -Al₂O₃-K, potassium carbonate, triethylamine, sodium tert-butoxide, sodium ethoxide, gamma-Al₂O₃KOH-Na or diethylamine, the reaction proceeds more easily in the presence of these basic substances.

In an embodiment of the present invention, the molar ratio of the diosgenin, RX, and the alkaline substance is 1: (0.1-10): (0.01-10), preferably 1 (1.0-1.2): (0.6-1.0).

In some embodiments of the present invention, the weight ratio of the diosgenin, RX and the alkaline substance is (4-20): (1.5-10): (0.01-5).

In an embodiment of the present invention, the preparation method of the compound of formula (I) according to the present invention further comprises detecting the end point of the reaction by chromatography, standing to room temperature after the reaction is finished, and separating and purifying to prepare the compound of formula (I).

In an embodiment of the present invention, the separation and purification method is selected from a combination of one or more of filtration, resin treatment, water washing, distillation, crystallization, extraction, activated carbon treatment, molecular sieve treatment, and chromatography.

The separation and purification method of the invention can be as follows: for example, in some embodiments, TLC detects the total reaction of diosgenin, heats to room temperature, adds water, extracts with dichloromethane, chloroform, acetone or ethyl acetate for 1 to more times, such as 3 times (e.g., 50mL × 3-300mL × 3), follows the reaction and separation and purification process of the product by TLC, recovers the extract, and dries the solid substance, such as at 60 ℃, for 4h to obtain the target product.

For example, in some embodiments, the separation and purification method may be: detecting all reactions of diosgenin by HPLC, distilling off solvent until liquid volume is reduced to 1/4, cooling and crystallizing overnight, such as cooling to 5 deg.C and crystallizing overnight, filtering, tracking reaction and product separation and purification process by HPLC, and drying solid, such as drying at 60 deg.C for 4 hr, to obtain target product.

For example, in some further embodiments, the separation and purification method may be: detecting the total reaction of diosgenin by HPLC, reducing pressure to remove solvent, performing chromatography, such as chromatography with chromatography column, eluting with ethyl acetate-ethanol (v/v ═ 10:1) or dichloromethane-methanol (v/v ═ 5:1), tracking the separation and purification process of reaction and product by HPLC, collecting and combining product fractions, and evaporating solvent by rotary evaporator (such as at 60 deg.C) to obtain the target product.

In a third aspect of the invention, the present invention also provides a composition comprising a compound of formula (I) as described in the above first aspect of the invention or a pharmaceutically acceptable salt thereof.

In a fourth aspect of the invention, the invention also provides a pharmaceutical formulation comprising a compound of formula (I) as described in the above first aspect of the invention or a pharmaceutically acceptable salt thereof or a composition comprising said compound of formula (I) or a salt thereof, together with at least one pharmaceutical carrier or adjuvant.

The pharmaceutical compositions of the present invention are generally safe, non-toxic and biologically desirable, the pharmaceutically acceptable carriers or excipients of the present invention are non-toxic and safe, and their combinations with the compounds of the present invention are also non-toxic and safe. The pharmaceutically acceptable carriers and excipients of the present invention are generally well known to those skilled in the art or can be determined by those skilled in the art based on the actual circumstances. Examples of suitable carriers and excipients include glucose, water, glycerol, ethanol, propylene glycol, corn starch, gelatin, lactose, sucrose, alginic acid, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, croscarmellose sodium and sodium starch glycolate and the like polysorbate 80, polyethylene glycol 300, polyethylene glycol 400, cyclodextrins or derivatives thereof such as ((2-hydroxypropyl) -cyclodextrin) and (2-hydroxyethyl) -cyclodextrin, which are also known as HPCD, pegylated castor oil, poloxamers such as poloxamer 407 or 188; hydrophilic carriers, hydrophobic carriers, or combinations thereof, and the like. Hydrophobic carriers include, for example, fat emulsions, lipids, pegylated phospholipids, biocompatible polymers, lipid spheres, liposomes, vesicles, polymer matrices, particles, and the like. Furthermore, one skilled in the art will appreciate that diluents are included within the term carrier and adjuvant.

The amount of carrier or adjuvant in the pharmaceutical composition may be from 1% to 98% by weight, usually about 80% by weight. For convenience, the local anesthetic, preservative, buffer, etc. may be dissolved directly in the vehicle.

Pharmaceutical compositions of the compounds of the present invention may be administered in any manner selected from: oral, aerosol inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous administration being preferred. The pharmaceutical dosage form can be a liquid dosage form, a solid dosage form. The liquid dosage form can be true solution, colloid, microparticle, emulsion, or mixed suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, landfill, patch, liniment, etc.

In a fifth aspect, the present invention also provides the use of a compound of formula (I) as described in the above first aspect of the present invention or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or a salt thereof, or a pharmaceutical formulation comprising a compound of formula (I) or a salt thereof, in the manufacture of a medicament for the treatment of cancer; in an embodiment of the invention, the cancer is preferably pancreatic cancer and/or cholangiocarcinoma.

In some embodiments of the invention, the inhibition rate of 0.2ug/mL of the compound of formula (I) of the invention on the proliferation of bile duct cancer cells QBC-939 is higher than 70%, and can reach 95%; the inhibition rate of 0.2ug/mL of the compound shown in the formula (I) on the proliferation of human pancreatic cancer cells PANC-1 is higher than 70% and can reach 95%. The activity of the compound of the invention is far higher than that of 5-fluorouracil used clinically.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.