CN109467560B - Selenocyanine compound and application thereof - Google Patents
Selenocyanine compound and application thereof Download PDFInfo
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Abstract
The invention relates to a selenocyanine compound shown as a formula I, a preparation method thereof and application thereof in preparing medicaments for treating and preventing tumors.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a selenocyanine compound and a preparation method and application thereof.
Background
Cancer is the leading cause of illness and death worldwide, and is expected to increase as modern technology extends life expectancy. During the life of a cell, small changes in DNA called "mutations" occasionally occur. Among these mutations, some mutations (referred to as "silent mutations") do not result in any substantial change in cell function, while others may alter the mode of action of the cell. Various mechanisms can prevent cells that have mutated from continuing the cell cycle and if genetic errors are not corrected, these cells will "suicide" through a process called "apoptosis". However, if mutations occur in proteins involved in cell cycle regulation, this can lead to uncontrolled cell proliferation (known as tumor formation), which can further progress to cancer.
Cancer cells often have adverse effects on the body. Cancer can spread by invasion of adjacent tissues by malignant tumor cells, and can also spread by a process known as "metastasis" in which malignant cells detach from the tumor mass and spread to distant sites. Cancer appears in many different types of tissues in multiple forms and can be characterized by its degree of invasion and invasiveness.
Cancer occurs as a mass of abnormal tissue in a living host organism, which receives nutrients from the host without relying on host hyperproliferation and destroys the host organism. The human organ is composed of a large number of cells. Cancer occurs when normal cells of the human body become abnormal cells and the abnormal cells divide and proliferate without examination. Although genetic factors are closely related to the onset of cancer, environmental factors also have a significant impact on whether an individual develops cancer. Cancer is particularly prevalent in developed countries. It has been reported that the causes of cancer are increased use of pesticides, insecticides, etc. (and thus the amount of such substances remaining in foods) and consumption of processed foods containing additives such as food preservatives and colorants, increased pollution of water, soil and air, stress of modern life, reduction of activities, obesity caused by greasy dietary habits, and the like. In recent years, it has also been pointed out that cancer is caused when the cell signaling system of normal cells fails, when cancer genes are activated, or when cancer suppressor genes fail.
Various cancer treatment methods exist, such as surgical treatment, chemotherapy and radiotherapy. The surgical treatment method effectively removes cancer at an early stage, but has disadvantages in that organs have to be removed from time to time, which causes side effects, and there is uncertainty in spreading cancer to other organs. Radiation therapy is advantageous for effectively treating cancer occurring in a particular organ, but has the following disadvantages: exposure of the patient to other cancer risks due to radiation, failure to prevent the spread of cancer cells to other organs, and significant pain to the patient during treatment. Chemotherapy is generally performed using anticancer drugs, but it is known that toxicity of anticancer drugs acts not only on cancer cells but also on normal cells of patients, causing side effects. Therefore, development of new anticancer drugs having higher cancer cell selectivity and as little toxicity as possible is desired.
Selenium is a trace element essential for life activities of the body. In recent years, studies have been made on selenium compounds, particularly organic selenium compounds, in an attempt to find compounds having anticancer or antitumor activities therefrom. For example, EI-Baulomy et al [ K El-Baulomy, Drugs Future, 1997, 22 (5): 539-545 ] found that benzyl selenium cyanide exhibited anti-tumor effects in a mouse model of DMBA-induced breast cancer. Benzyl selencyanide has a higher anticancer activity than sodium selenite, but has a strong off-taste itself and has side effects that cause significant weight loss in patients.
The research shows that the action mechanism of ebselen is mainly to inhibit the activity of target enzyme thioredoxin reductase and regulate the downstream signal transmission path and the anti-tumor apoptosis path thereof to realize the anti-tumor action of the drug, and the bioactivity and low toxicity of ebselen may be related to the cyclic selenamide structure or the benzisoselenone-containing heterocyclic ring (H J Reich, et al J.Am.chem.Soc., 1987, 109 (18): 5549-, the molecular weight of the ethaneselenoline contains 2 benzisoselenazolone structures, which achieves the synergistic effect and the activity is better than that of the ebselen.
Despite the discovery of the organic selenium compounds, the existing organic selenium compounds still have the problems of further improvement of antitumor efficacy, limited disease spectrum, and limited structural types of the compounds, and are far from meeting the increasing demands of human beings for tumor prevention and treatment. Therefore, the development of better antitumor drugs, especially organic selenium compounds, has become an urgent need.
Therefore, there is still a great need in the art for new compounds for the treatment or prevention of tumors with good efficacy.
Disclosure of Invention
Through a large number of experimental researches, the inventor unexpectedly discovers that the selenocyanide organic compound has unexpected biological activity for preventing and treating tumors. The compounds are useful in the treatment and/or prevention of various cancers.
The present invention provides a compound of formula I having the chemical name (S) -4-ethyl-4- (selenocyanoacetate) -1H-pyrano [3',4':6,7] indolizino [1,2-b ] quinoline-3, 14- (4H,12H) -dione, or a pharmaceutically acceptable salt thereof:
I
in another aspect, the present invention also provides a process for the preparation of a compound of formula I as described above, said process comprising the steps of:
(i) reacting a compound of formula III
III
Obtaining a compound of formula II by a substitution reaction;
(ii) reacting the compound of formula II with potassium selenocyanate to obtain the compound of formula I.
In the preparation process of the present invention, the compound of formula II is preferably reacted with potassium selenocyanate in step (II) to give the compound of formula I.
In a particularly preferred embodiment, the compounds of formula I are prepared by the following method: firstly, reacting a compound III with bromoacetic acid under the catalysis of DMAP to obtain a compound II (namely, (S) -4-ethyl-4- (bromoacetate) -1H-pyrano [3',4':6,7] indolizino [1,2-b ] quinoline-3, 14- (4H,12H) -diketone), and then reacting the compound II with potassium selenocyanate to obtain a compound I.
Wherein the molar ratio of the compound shown in the formula III to bromoacetic acid is 1: 3-1: 6, the molar ratio of DMAP to camptothecin is 1: 2-1: 6, and the reaction temperature is-10%oC～0 oC, the reaction time is 4 hours; the molar ratio of the compound of formula I to the potassium selenocyanate is 1: 1-1: 2, and the reaction temperature is 0 oC～40 oAnd C, the reaction time is 16-24 hours.
The reaction formula is as follows:
the preparation method of the invention is simple, has high yield, and can easily prepare the compound of the formula I.
In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I of the invention or a pharmaceutically acceptable salt thereof and optionally pharmaceutically acceptable excipients and/or carriers. In the pharmaceutical composition of the present invention, other pharmaceutically active ingredients may be further included in addition to the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the invention may be prepared by conventional techniques, for example as described in Remington: the method described in The Science and Practice of Pharmacy, 19 th edition, 1995, which is incorporated herein by reference. The compositions may be presented in conventional forms, such as capsules, tablets, aerosols, solutions, suspensions or topical application forms.
Typical compositions comprise a compound of formula I of the present invention or a salt thereof and a pharmaceutically acceptable excipient or carrier. For example, the active compound is typically mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet (sachet), paper or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, the carrier can be a solid, semi-solid, or liquid material that serves as a carrier, excipient, or medium for the active compound. The active compound may be adsorbed on a particulate solid carrier (e.g. contained in a sachet). Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono-and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
The formulations may be mixed with adjuvants which do not deleteriously react with the active compound. These additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffering and/or coloring substances, preservatives, sweeteners or flavorings. The composition may also be sterilized, if desired.
The route of administration may be any route which is effective for the transport of a compound of formula I of the present invention to the appropriate or desired site of action, for example the oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal or parenteral routes, for example the rectal, depot (depot), subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments route, the oral route being preferred.
If a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule as a powder or pellet, or it may be in the form of a troche (troche) or lozenge. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.
Injectable dosage forms typically comprise an aqueous or oily suspension, which may be formulated using suitable dispersing or wetting agents and suspending agents. Injectable forms may be in the form of a solution phase or a suspension prepared with a solvent or diluent. Acceptable solvents or carriers include sterile water, ringer's solution, or isotonic saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Preferably, the oil or fatty acid is non-volatile and comprises a natural or synthetic oil, a fatty acid, a monoglyceride, diglyceride, or triglyceride.
For injection, the formulation may also be a powder suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or microparticles. For injections, the formulation may optionally include stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations of these agents. The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Unit dosage forms for injection may be in ampoules or in multi-dose containers.
The formulations of the present invention may be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by methods well known in the art. Thus, the formulation may also be formulated for controlled release or slow release.
The compounds of formula I of the present invention are effective over a wide dosage range. For example, in the treatment of adults, a dose of about 0.05 to about 5000 mg, preferably about 1 to about 2000 mg, more preferably about 2 to about 2000 mg per day may be used. Typical dosages are from about 10 mg to about 1000 mg per day. When selecting a patient treatment regimen, it may often be necessary to start with a higher dose and reduce the dose when the condition is controlled. The precise dosage will depend upon the mode of administration, the desired treatment, the form of administration, the subject to be treated and the weight of the subject to be treated, as well as the preferences and experience of the attending physician.
Typically, the compounds of formula I of the present invention are dispensed in unit dosage forms containing from about 0.05 mg to about 1000 mg of the active ingredient per unit dose and a pharmaceutically acceptable carrier.
In general, a dosage form suitable for oral, nasal, pulmonary or transdermal administration comprises from about 125 μ g to about 1250 mg, preferably from about 250 μ g to about 500 mg, more preferably from about 2.5 mg to about 250 mg of said compound of formula I in admixture with a pharmaceutically acceptable carrier or diluent.
The dosage form may be administered once daily, or more than once daily, e.g., twice daily or three times daily. Alternatively, the dosage form may be administered less frequently than once daily, for example every other day or weekly, if deemed appropriate by the prescribing physician.
The pharmaceutical compositions of the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquids or gels. Tablets and capsules for oral administration may be in a form suitable for unit dose administration and may contain conventional excipients, such as: binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (PVP); fillers such as lactose, sugars, corn flour, calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate, silicon dioxide, talc, polyethylene glycol or silicon dioxide; disintegrants such as potato starch; acceptable lubricants such as sodium lauryl sulfate. The tablets may be coated according to known methods of conventional pharmaceutical practice. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or tinctures, or may be presented as a dry substance for reconstitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats and oils). Emulsifying agents (e.g. lecithin, sorbitol monooleate or acacia), non-aqueous vehicles (including edible oils such as almond oil, fractionated coconut oil, fats and oils such as glycerol, propylene glycol or ethanol), preservatives (e.g. methyl or propyl p-hydroxybenzoic acid or sorbic acid), and if desired conventional flavouring or colouring agents.
The dosage may vary with the method and dosage form of administration, as well as the age, weight, condition and sensitivity of the patient. In the case of oral administration, an effective daily dosage range, for example, may be from 20mg to 1 g. Single dose units containing a compound of formula I or a pharmaceutically acceptable salt thereof in an amount of from 20mg to 200mg may conveniently be employed to meet the daily dosage requirements. The dosages and dosage units employed may be outside the ranges set forth above.
The percentage of active substance in the pharmaceutical composition of the present invention is variable because the pharmaceutical formulation must be formulated in a suitable proportion of the dosage to achieve the desired therapeutic effect. In general, the pharmaceutical preparations of the invention can be administered orally or by injection in an amount of 1 to 15 mg of the compound of formula I per day per 70kg of body weight. The following examples are for the purpose of illustrating certain aspects of the invention and should not be construed as limiting the scope of the invention in any way.
Drawings
FIG. 1 is a NMR spectrum of a compound of formula II;
FIG. 2 is a NMR spectrum of a compound of formula I;
FIG. 3 is a NMR carbon spectrum of a compound of formula I;
FIG. 4 is a mass spectrum of a compound of formula I;
FIG. 5 is a HPLC purity check spectrum of the compound of formula I synthesized in example 2.
Detailed Description
Examples
Examples of synthetic preparations
Example 1: synthesis of Compounds of formula II
Camptothecin (200 mg, 0.57 mmol) was dissolved in anhydrous dichloromethane (100 ml) in a three-necked flask, DMAP (139 mg, 1.14 mmol) was added, bromoacetic acid (240 mg, 1.72 mmol) was added under ice bath, and the mixture was stirred for 5 hours to complete the reaction by TLC. The reaction was washed twice with 1N HCl (35 ml), 1% NaHCO3(35 ml) washed twice with Na2SO3And (5) drying. After evaporation of the solvent, the solid was dissolved in EtOAc under heating and crystallized on standing. Filtration gave a light brown solid, compound II (191 mg, 71% yield).
Nuclear magnetic resonance:1H NMR (CDCl3) δ(ppm): 1.06 (s, 3H, -CH3), 2.06-2.36 (m, 2H, -CH2- ), 3.97 (s, 2H, -CH2-), 5.34 (s, 2H, -CH2-), 5.4-5.7 (dd, 2H, -CH2-), 7.27 (s, 1H, Ar-H), 7.6-7.7 (t, 1H, Ar-H), 7.86-7.9 (t, 1H, Ar-H), 7.97-7.99 (d, 1H, Ar-H), 8.24-8.28 (d, 1H, Ar-H), 8.65 (s, 1H, Ar-H)
example 2: synthesis of Compounds of formula I
In a three-hole flask, compound II (180 mg, 0.38mmol) was dissolved in acetonitrile (20 ml), and potassium selenocyanate (55 mg, 0.38mmol) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated and dropped into 100ml of water, and the obtained solid was filtered with 5% CH3OH/ CH2Cl2Plate chromatography was performed for the developing solvent to give compound I (95 mg, 51% yield) as a white solid.
Nuclear magnetic resonance:1H NMR (CDCl3) δ(ppm): 1.02 (s, 3H, -CH3), 2.16-2.38 (m, 2H, -CH2- ), 3.97 (s, 2H, -CH2-), 5.26 (s, 2H, -CH2-), 5.3-5.7 (dd, 2H, -CH2-), 7.27 (s, 1H, Ar-H), 7.6-7.7 (t, 1H, Ar-H), 7.82-7.86 (t, 1H, Ar-H), 7.93-7.95 (d, 1H, Ar-H), 8.22-8.24 (d, 1H, Ar-H), 8.41 (s, 1H, Ar-H).
13C NMR (CDCl3) δ(ppm): 7.59, 27.12, 31.75, 50.07, 67.23, 78.00, 95.57, 99.95, 120.21, 128.18, 128.22, 128.43, 129.72, 130.78, 131.26, 144.79, 146.72, 148.92, 152.15, 157.27, 166.50, 166.69
MS [ESI]: C23H17N3O5Se [M+H]+ = 495.03
HPLC, purity 93.15%
Pharmacological Activity
EXAMPLE 1 screening of antitumor Activity in vitro (preliminary inhibition experiment)
Positive control drug: hydroxycamptothecin injection (HCPT), 5ml 5 mg/vial, Harbin Triplex pharmaceuticals GmbH, lot number 170501. The tested cell strain is selected from four cell strains of human poorly differentiated gastric adenocarcinoma cell BGC-823, human hepatoma cell SMMC-7721, human lung carcinoma cell A549 and human promyelocytic leukemia cell HL-60.
The test method comprises the following steps: taking a bottle of cells in an exponential growth phase, adding 0.25% trypsin digestion solution, digesting to make adherent cells fall off, and counting by 2-4 multiplied by 104And (4) preparing cell suspension per ml. Inoculating the cell suspension on a 96-well plate at a concentration of 180 μ l/well, and placing in a constant temperature CO2The culture was carried out in an incubator for 24 hours. The solution was changed, the test drug was added at 20. mu.l/well, and the culture was carried out for 48 hours. MTT was added to a 96-well plate at 20. mu.l/well and reacted in an incubator for 4 hours. The supernatant was aspirated, DMSO was added at 150. mu.l/well, and shaken on a shaker for 5 minutes. Test substance three concentrations (1X 10)-7，1×10-6, 1×10-5(ii) a mol/L), measuring the light absorption value of each hole at the position with the wavelength of 570nm by using a microplate reader, and respectively calculating the cell inhibition rate at each concentration.
Cell inhibition% = (negative control OD value-drug sensitive group OD value)/negative control OD value × 100%
TABLE 1
The test results show that the compound I has in vitro effect on four tumor cell strainsThe inhibition effect on BGC-823, SMMC-7721 and A549 cell lines is better than that of control drug 10-Hydroxycamptothecin (HCPT), especially on SMMC-7721 and A549 cells is obviously better than that of HCPT, wherein IC of SMMC-7721 is higher than that of HCPT50The value was only 0.06. mu.M.
Experimental example 2 in vivo antitumor Activity
The experimental animal selects SPF level male Kunming mouse with the body mass of 19-22 g, is provided by animal experiment center of Wuhan university, and tumor strain mouse S180 sarcoma is introduced by pharmaceutical research institute of Chinese medical academy of sciences, and is frozen and preserved in laboratory at low temperature, the S180 cell for experiment is cell suspension for 4 th generation after recovery, and the positive control drug selects topoxicam.
The tumor-bearing mouse model is established by aseptically extracting ascites from S180 mouse, counting the cell suspension under microscope, and adjusting the cell concentration to 2.0 × 107and/mL, 0.2 mL of the S180 ascites tumor fluid was inoculated subcutaneously in the right armpit of the mouse aseptically, and 20 healthy mice were divided into groups at random according to body weight.
The administration method and the tumor inhibition rate are calculated as follows: the administration is started 2 days after the mice are inoculated with tumor cells, the mice are randomly divided into 3 dose groups of high, medium and low compounds I, positive control groups (1.5 mg/kg of topoxicam) and negative control groups according to body weight, the intraperitoneal administration is carried out 1 time every day, the administration volume is 0.5 mL/mouse, the experimental administration time is 9 days, the animals are killed 24 hours after the last administration, the body mass is weighed, tumor masses are dissected, the weighing mass is obtained, and the tumor growth inhibition rate is calculated according to the following formula.
TABLE 2 inhibitory Effect of Compound I on mouse S180
Animal experiment results show that the compound I has the effect of inhibiting tumor growth on S180-bearing mice, the tumor inhibition effect is obvious, and the antitumor effect is better than that of a control compound topotecan under the same dose (5 mg/kg). Thus, compound 1 exhibited a higher tumor growth inhibition efficiency than topotecan.
Claims (6)
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof.
2. A process for preparing the compound of claim 1, comprising the steps of:
(i) reacting a compound of formula III
By substitution to give the compounds of the formula II
(ii) reacting the compound of formula II with potassium selenocyanate to obtain the compound of formula I.
3. The process of claim 2, wherein the compound of formula III is reacted with bromoacetic acid in step (i) to give the compound of formula II.
4. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient and/or carrier.
5. The use of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of tumors.
6. The use of claim 5, wherein the tumor is selected from the group consisting of colon cancer, breast cancer, prostate cancer, cervical cancer, liver cancer, and lung cancer.
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| WO2012066578A2 (en) * | 2010-11-18 | 2012-05-24 | Kasina Laila Innova Pharmaceuticals Private Limited | Substituted 4-(selenophen-2(or 3)-ylamino)pyrimidine compounds and methods of use thereof |
| CN106620717A (en) * | 2016-12-13 | 2017-05-10 | 上海交通大学 | Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012066578A2 (en) * | 2010-11-18 | 2012-05-24 | Kasina Laila Innova Pharmaceuticals Private Limited | Substituted 4-(selenophen-2(or 3)-ylamino)pyrimidine compounds and methods of use thereof |
| CN106620717A (en) * | 2016-12-13 | 2017-05-10 | 上海交通大学 | Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof |
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| Title |
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| ( 20S)-O-硒代乙酰喜树碱衍生物的合成及其抗肿瘤活性研究;冯新江等;《浙江大学学报》;20040731;第31卷(第4期);参见第421页左栏及第423页表1 * |
| Anticancer camptothecin-N-poly(lactic acid) nanoconjugates with facile hydrolysable linker;Qian Yin et al.;《Polym. Chem.》;20131003;第5卷;第1582页Fig.1 * |
| 冯新江等.( 20S)-O-硒代乙酰喜树碱衍生物的合成及其抗肿瘤活性研究.《浙江大学学报》.2004,第31卷(第4期),第420-423页. * |
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