AN ANTICANCER COMPOUND SUITABLE FOR USE IN COLORECTAL CANCER TREATMENT.

Abstract

The invention belongs to the field of medicinal chemistry and pharmaceutical technology; specifically, it focuses on obtaining novel isatin-based compounds by hybridizing the isatin core with various pharmacophore structures possessing anticancer properties, and on the use of these compounds in the treatment of colorectal cancer. In this context, the invention includes the rational design, chemical synthesis, and therapeutic evaluation of new molecular candidates with anticancer potential, and addresses original and innovative molecular-level approaches to the treatment of colorectal cancer.

Description

SUITABLE FOR USE IN COLORECTAL CANCER TREATMENT ANTICANCER COMPOUND Technical Field to Which the Invention Relates The invention relates to the field of medicinal chemistry and pharmaceutical technology; specifically, isatin. isatin, obtained by combining its scaffold with different anticancer pharmacophores. development of base-based hybrid compounds and the use of these compounds in colorectal cancer treatment It is intended for use in the design of new anticancer agent candidates. It is included within the scope of synthesis and evaluation for therapeutic purposes. and focuses on innovative molecular approaches to the treatment of colorectal cancer. It is receiving. State of the Art Colorectal cancer (CRC), one of the most common types of cancer, is a global disease. It is also among the leading causes of death from cancer worldwide. Globally, more than 600,000 people die each year from this disease. It is reported that he lost his life [1]. Genetic predisposition in CRC pathogenesis dietary habits, lifestyle, obesity, lack of physical activity, smoking, and Environmental factors such as alcohol consumption play a significant role. Epidemiological data, The incidence of CRC in the US and European countries is lower compared to African and Asian countries. This shows that it is approximately ten times higher, which indicates environmental and... This supports the idea that socioeconomic factors influence disease development. Türkiye When evaluated specifically, according to the 2014 statistics of the Turkish Ministry of Health... Colorectal cancer (CRC) is a significant public health problem in our country, with approximately 15,000 new cases annually. It constitutes and is responsible for approximately 7,000 deaths every year [2]. This data, early diagnosis, screening programs and effective treatment strategies for colorectal cancer This clearly demonstrates the need for its development. In early-stage cancers, the primary treatment approach is to achieve local control of the tumor. surgical resection, radiotherapy, ablation, and It relies on methods such as embolization. These local treatments limit the tumor. for curative purposes in cases where there is no metastatic spread. It is applicable. However, lymph node involvement or distant organs may occur. 1 In the presence of advanced stage findings such as metastasis, local treatments alone are insufficient. and systemic treatment approaches need to be implemented. Systemic treatments include chemotherapy, targeted therapies, and immunotherapies. They are divided into different groups. Traditional chemotherapeutic agents, rapidly dividing cells It directly targets cells, exerting a cytotoxic effect, and has been used for many years. It is used as standard treatment in this type of cancer. Colorectal cancer Treatment with cytotoxic agents such as 5-Fluorouracil (5-FU), oxaliplatin and irinotecan [3], among the key treatment options that prolong survival, especially in advanced stage disease. These agents are involved. However, these agents affect both tumor cells and healthy cells. Its effect on cells can lead to serious side effects and treatment This can lead to limitations in tolerance. In the current state of the art, chemotherapeutic agents are only applied directly to cells. not only through lethal effects, but also by triggering immunogenic cell death It is also known to exert an indirect antitumor effect through the immune system. However, this effect varies from person to person, depending on the response to chemotherapy. This reduces predictability and is one of the major factors limiting treatment success. It is accepted as such. In line with these limitations, cancer has become a concern in recent years. There has been an increasing trend towards molecularly targeted approaches in treatment, especially for colorectal diseases. Epidermal growth factor receptor (EGFR) in cancer, vascular endothelial growth Signaling pathways such as factor (VEGF), Wnt / β-catenin and NF-κB are involved in tumor development, It has been shown that these pathways play a significant role in the progression and metastasis of cancer. Targeted biological agents show more selective action against tumor cells. It aims to achieve lower systemic toxicity compared to classical chemotherapies. It aims to provide this. However, the effectiveness of targeted therapies also depends on... It is directly related to the molecular profile of the tumor. Having the same histopathological diagnosis. Even in patients, genetic mutations, differences in signaling pathways, and tumors Treatment responses vary considerably due to the characteristics of the microenvironment. This can demonstrate the heterogeneous nature of colorectal cancer. It is considered a reflection of and standard treatment protocols for each patient. This prevents him from achieving sufficient success. In the current technique, neoadjuvant and adjuvant chemotherapy and / or radiotherapy Supporting surgical treatment with these applications is a common clinical practice. 2 It maintains its position. Neoadjuvant therapies, tumor size reduction, and surgery Adjuvant therapies are applied to facilitate resection; eradication of micrometastatic disease and reduction of recurrence risk This is the goal. However, even these approaches have a significant impact on long-term survival. Time is not enough to show sufficient effect. In recent years, immunotherapies, especially in advanced stages, have become more effective. It has emerged as a promising alternative in stage 1 tumors and tumors resistant to classical treatments. Agents such as immune checkpoint inhibitors target tumor cells. Antitumor immune response by targeting mechanisms that evade the immune system It aims to strengthen [the response]. However, the response to immunotherapies also varies. It is observed in a limited group of patients and will predict the response to treatment. The shortage of biomarkers remains a significant problem. In the current state of the technique, the tumor microenvironment also influences cancer development and treatment. The crucial role of tumor stroma in resistance is becoming increasingly better understood. immune cells, cytokines, and extracellular matrix components interact with tumor cells. They are in constant interaction and directly influence the response to treatment. This A complex network of interactions allows for complete control of cancer through a single target. This makes it difficult to remove. In addition, tumor heterogeneity and subclonal structures... the presence of populations, cancer stem cells and ongoing genetic mutations, This creates a زمینه for the development of drug resistance during treatment. A single treatment Elimination of all tumor cell populations with the regimen is often This is not possible; treatment-resistant subclones lead to disease relapse. It can cause many solid cancers, including colorectal cancer. This is considered one of the main reasons limiting treatment success in tumors. As a result, current colorectal cancer treatment includes surgery, many such as chemotherapy, radiotherapy, targeted therapies and immunotherapies numerous methods are applied individually or in combination, but currently It appears to be an area where a complete cure is not possible. Although recent Although significant increases in survival rates have been achieved over several decades, current Treatment approaches do not offer sufficient effectiveness for all patient groups. This The situation, molecular pathogenesis of colorectal cancer, tumor heterogeneity, and treatment. New and improved treatments that can more effectively target factors such as resistance This clearly demonstrates the need for their strategies. 3 Brief Description and Objectives of the Invention The invention involves combining the isatin scaffold with different anticancer pharmacophores. isatin-based hybrid compound obtained and the use of this compound in colorectal cancer treatment Its use is explained. The compound subject to the invention is represented by Formula 1. Formula 1 The anticancer compound that is the subject of the invention, denoted by formula 1, is (Z)-2-(4-(4- as methoxyphenyl)piperazine-1-yl)-N'-(2-oxoindoline-3-ylidene)acetohydrazide It is called. The aim of the invention is to exhibit a high cytotoxic effect on colorectal cancer cells. a novel anticancer agent that limits toxicity to healthy cells The aim is to provide the original chemical composition of the compound shown as Formula 1, which is the subject of the invention. This is achieved thanks to its structure. Formula 1 contains an isatenin nucleus and It is a hydrazone derivative modified with a piperazine side chain, and it is found in cancer cells. to interact with cellular pathways that suppress proliferation It has been designed. In vitro cell viability (MTT) analyses performed have shown that the compound in question... Low IC₅₀ value (9.49 μM) on colorectal cancer cell line HCT116 exhibited, however, more limited toxicity in healthy fibroblast cell lines. It has been shown that it creates a cytotoxic effect with increased selectivity. is provided as follows. One aim of the invention is to treat patients who are resistant or poorly responsive to existing chemotherapeutics. an alternative molecular therapy that may be effective in colorectal cancer cells The aim is to offer an option for the compound that is the subject of the invention to be used without being limited to a single target. thanks to its capacity to affect multiple cancer-related signaling pathways simultaneously RT-qPCR and gene enrichment analyses are being carried out as part of the invention. The compound showed significant activity in the PI3K-AKT, MAPK, HIF-1, and programmed cell death pathways. 4 This has been shown to lead to regulations. This multiple pathway effect is similar to the classical single-target effect. It allows for overcoming the resistance mechanisms that develop against the agents. Another aim of the invention is to alter the cell cycle in colorectal cancer cells. The aim is to stop apoptosis and to effectively induce it. This objective is... the effects of the compound that is the subject of the invention on cell cycle and apoptosis mechanisms This is achieved through direct effects. Flow cytometry analyses are shown in Formula 1. The compound significantly increased the G0 / G1 phase of the cell cycle in the treated cells. that it was stopped (64.52%) and late-stage apoptosis was significantly increased This has been demonstrated. Furthermore, caspase activation and SMAC / DIABLO-XIAP-mediated apoptosis have also been shown. Its effects on regulation, the molecule's ability to technically induce programmed cell death. It reveals that it triggered it. Another aim of the invention is to analyze tumor heterogeneity and subclonal cell populations. The aim is to reduce treatment failures caused by the presence of certain factors. This objective is reflected in the invention. The issue is that the anticancer compound targets not only proliferative cells, but also... cell populations that have developed mechanisms to escape apoptosis This is achieved by its ability to target certain substances. The molecule causes necrosis, necroptosis, and Effects on mitochondria-mediated cell death pathways, heterogeneous cells within the tumor It contributes to the elimination of groups. Live cell fluorescence. Imaging studies showed impaired mitochondrial function and cytoskeleton. This indicates that structural changes have occurred. One aim of the invention is to create a suitable combination of different chemotherapeutic or The goal is to develop an anticancer molecule that can be used in conjunction with targeted agents. The mechanism of action of the compound subject to this invention is similar to that of classical 5-Fluorouracil and oxaliplatin. Unlike agents that act via DNA synthesis or microtubule stability, It offers the potential for synergistic use in combination therapies. The molecule regulation of multiple signaling pathways, chemoradiotherapy or immunotherapy When used in conjunction with other regimens, it will allow for increased treatment effectiveness. It creates a technical infrastructure. Another aim of the invention is to treat colorectal cancer and other solid tumors. The goal is to develop a new anticancer molecule with potential applications, such as isatin. its core's known biological versatility and the multicellular nature of the compound that is the subject of this discovery The effects on pathways mean the molecule is not limited to colorectal cancer. This allows testing in different types of cancer without being limited to this area. structural and functional features expand the technical scope of the invention, making it different. This makes it adaptable to oncological indications. Detailed Description of the Invention The invention relates to colorectal cancer or other solid tumors or hematological malignancies. It relates to an isatin-based hybrid anticancer compound intended for use in treatment. The compound that is the subject of the invention is represented by Formula 1. Formula 1 The anticancer compound that is the subject of the invention, denoted by formula 1, is (Z)-2-(4-(4- as methoxyphenyl)piperazine-1-yl)-N'-(2-oxoindoline-3-ylidene)acetohydrazide It is called. The synthesis method of the compound represented by Formula 1, which is the subject of the invention, is as follows: i. Dissolving isatin in methanol as a starting material, word The subject is the addition of hydrazine hydrate (50%) to the solution and the resulting... The reaction mixture was refluxed under reflux for approximately 15 hours. isatin hydrazone intermediate obtained by means of, ii. the isateine ​​hydrazone intermediate obtained in the previous step Dissolving in dimethylformamide (DMF) without purification, Adding triethylamine as a base to the reaction medium, then controlled addition of bromoacetyl bromide and placing the mixture at room temperature 2-bromo-N'- by stirring at a temperature for approximately 4 hours Formation of the intermediate (2-oxoindoline-3-ylidene)acetohydrazide, iii. The bromo intermediate obtained in the second step is treated with 4-(4-methoxyphenyl)piperazine. Addition in the presence of triethylamine, the reaction mixture is placed in the room 6 stirring overnight at the given temperature, the reaction After completion, the mixture is diluted with ice water, which causes it to precipitate. Filtering, isolating and drying the solid, iv. The obtained crude product is processed using a hexane:ethyl acetate mixture. obtaining the target compound by crystallization It includes the steps involved in the process. Synthesis Method of Compound Represented by Formula 1 (SMY370): The compound represented by formula 1 is (Z)-2-(4-(4-methoxyphenyl)piperazin-1-yl)-N'-(2- Oxoindoline-3-ylidene acetohydrazide is obtained by a multi-step synthesis method. The synthesis method involves the three basic reaction steps summarized below. It includes. Reaction 1 related to the synthesis is shown below. - Step 1: Synthesis of Isatine Hydrazone Intermediate Isatine was used as the starting material. Isatine was dissolved in methanol. Hydrazine hydrate (50%) was added and the reaction mixture was refluxed. The mixture was refluxed for approximately 15 hours. After the reaction was complete, the mixture... The cooled, precipitated yellow solid was filtered and isolated. This intermediate product It was used in the next step without purification. In this step, the reaction... This was achieved with approximately 88% efficiency. - Step 2: Obtaining the Bromoacetyl Hydrazide Intermediate The resulting isatin hydrazone derivative was dissolved in DMF and added to the reaction medium. Triethylamine (TEA) was added as a base. Then bromoacetyl bromide was administered under controlled conditions. The ingredients were added in this way and the mixture was stirred at room temperature for approximately 4 hours. This At the end of the step, the intermediate product 2-bromo-N'-(2-oxoindolin-3-ylidene)acetohydrazide is obtained. processed, and the intermediate product is not isolated but directly proceeds to the next step. It has been used. - Step 3: Synthesis of the Final Product (SMY370 / SM771) The bromo intermediate obtained in the previous step is added to 4-(4-methoxyphenyl)piperazine. added and the reaction was again left overnight at room temperature in the presence of TEA. The mixture was stirred. After the reaction was complete, the mixture was diluted with ice water. The precipitated solid was filtered and dried. The crude product is a mixture of hexane and ethyl acetate. 7 The target compound was obtained by crystallizing it using [method name]. At the end of this step... The compound was obtained with approximately 53% yield. Reaction 1 The compound SMY370, obtained within the scope of the invention and denoted by Formula 1, is a reaction compound. After completion, it was isolated by precipitation as a solid product. The reaction... The mixture was diluted with ice water, the resulting solid product was filtered under vacuum, and It has been dried. The resulting raw product is processed using a hexane:ethyl acetate mixture. It has been purified by the recrystallization method. This purification... As a result of the process, the target compound is obtained in pure form. Within the scope of the invention, Column chromatography is essential for the purification of the synthesized SMY370 compound. However, the crystallization method ensured that the product was obtained with sufficient purity. However, silica gel can be used when needed or in process scaling studies. Alternative purification techniques such as column chromatography are equally effective. It is anticipated that it can be used. The synthesis of the compound SMY370, denoted by Formula 1, is included within the scope of the invention. not limited to the reaction scheme described in the specification, but also by experts in the field. known and equivalent synthesis pathways that allow the achievement of the same chemical structure, and This can also be achieved using alternative reaction schemes. In this context, bromoacetyl bromide derivative intermediate used in the synthesis pathway described in the specification. instead; chloroacetyl chloride, iodoacetyl derivatives, p-toluene sulfonate (tosylate) or using acetyl derivatives containing different leaving groups, such as methanesulfonate (mesilate) 8 Equivalent intermediate products can also be obtained. These intermediate products are 4-(4-methoxyphenyl)piperazine. As a result of nucleophilic substitution reactions it carries out with, the same target It is possible to reach the compound. In an alternative synthesis approach, the reaction by changing the order of the steps; first with 4-(4-methoxyphenyl)piperazine piperazinyl acetohydrazide intermediate via haloacetate or active ester derivatives can be obtained, then this intermediate product is condensed with Formula 1 via isotin. The SMY370 compound shown can be synthesized. This approach also uses the same hydrazone. It is observed that the structure is formed and the final product is chemically equivalent. In another equivalent synthesis pathway, bromoacetic acid is used instead of acyl halides. EDC, DCC, HOBt or CDI of carboxylic acid derivatives such as acid or chloroacetic acid activation with the help of binding / activation agents such as hydrazone or by reacting it with piperazine derivatives, the same molecular skeleton can be preserved. can be obtained. In addition, the base used during synthesis (for example, instead of triethylamine) diisopropylethylamine, N-methylmorpholine or inorganic carbonates), solvent (instead of DMF) DMSO, acetonitrile or tetrahydrofuran), reaction temperature and time, etc. Changing the parameters does not alter the essence of the synthesis method, resulting in an equivalent result. These are evaluated within the scope of applications. Heated or microwave-assisted. Reaction conditions are also included in this scope. For these reasons, the SMY370 compound... synthesis; not limited to the examples described in the specification, but including those with the same chemical structure and all equivalent reactions that yield a compound with biological effect Schematics, alternative synthesis routes and process variations are within the scope of the invention. is being evaluated. The compound SMY370, represented by the formula 1, has acid-base properties due to its chemical structure. They contain functional groups, and are therefore considered pharmaceuticals. forming solvable salts, solvates, hydrates, isomers, and polymorphic forms. It has potential. The SMY370 compound obtained within the scope of the invention is a free base compound. It has been synthesized and characterized in this form. However, the compound The piperazine nitrogen atoms and hydrazone functional group in its structure react with suitable acids. They react and form salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate, by adding acid) acetate, citrate, maleate, fumarate or similar pharmaceutically acceptable salts) This allows for the formation of these salt forms, which increase the solubility of the compound. It can be preferred in order to improve its bioavailability and pharmaceutical stability. Furthermore, during the synthesis, purification, or storage of the SMY370 compound 9 depending on the solvents used, solvate (e.g. methanolate, ethanolate, DMF solvate) It is possible for solute and hydrate forms to form. These types of solute and hydrate forms... also, preserving the chemical integrity of the molecule and exhibiting the same biological effect. They are considered equivalent forms. The compound, represented by formula 1, is due to the geometric configuration of the hydrazone bond. It can exhibit E / Z isomerism. The invention primarily focuses on the Z-isomer. Although defined, it depends on the reaction conditions, solvent or crystallization. Depending on the conditions, the formation of the E-isomer is also possible. These isomers are single. They may be found individually or as a mixture of isomers, and all fall within the scope of the invention. is being evaluated. In addition, different crystalline forms of the SMY370 compound in the solid state are being considered. It is predicted that it will form polymorphic forms with interwoven patterns. Polymorphic The forms are influenced by factors such as crystallization method, solvent system, temperature, cooling rate, and humidity. It can occur depending on the parameters and physical properties (melting point, Resolution and stability may vary. Therefore, the following applies to Formula 1: The free base form of the compound SMY370, along with its salts and solvates, Hydrates, geometric isomers, and polymorphic forms all exhibit the same technical effect. Equivalent structures fall within the scope of invention protection. The anticancer activity of the SMY370 compound developed within the scope of the invention is colorectal. HCT116, a cancer cell line, and L929 (mouse), which is used as a healthy cell model. (fibroblast) cell lines were evaluated experimentally. Cell MTT cell viability analysis for the quantitative determination of viability flow was applied to assess cell cycle distribution and apoptosis. Flow cytometry analyses were performed. Effects at the molecular level. Gene enrichment analyses, RT-qPCR, for the purpose of investigating their mechanisms. This was done using the method. Additionally, cellular morphology and organelle-level studies were also conducted. Nucleus, cytoskeleton and mitochondria stains for observing changes Live cell fluorescence imaging studies were performed using [method]. Based on the experimental findings obtained, the compound SMY370 is effective against HCT116 colorectal disease. It has been found to kill more than 70% of the cells in the cancer cell line. Based on MTT analysis results, the half-maximal inhibitor for the compound in question. Concentration (IC₅₀) and selectivity index (SI) values ​​were calculated for SMY370. The IC₅₀ value was determined as 9.49 μM, and the SI value as 2.1. Flow cytometry analyses, SMY370 application had a significant effect on the cell cycle and It was found that it caused the accumulation of cells in the G0 / G1 phase (64.52%). It was also found that SMY370 significantly induced late-stage apoptosis in cells. Molecular analyses have shown that SMY370 is involved in cancer-related cellular signaling pathways. It has been shown to have far-reaching effects. In this context, the compound Modulates gene expression associated with PI3K-AKT, MAPK, and HIF-1 signaling pathways. It causes programmed cell death, caspase activation, necrosis, SMAC / DIABLO–XIAP Regulation of mediated apoptosis response and mechanisms of necroptotic cell death Evidence has been obtained indicating that it has an effect. All these experimental results... When evaluated together, the compound SMY370 represents a novel treatment for colorectal cancer. an important molecular target and a promising candidate for an anticancer agent. It appears to have potential. Considering the chemical structure and physicochemical properties of the compound SMY370... When taken, the compound contains pharmaceutically acceptable carriers and auxiliaries. These substances are converted into different dosage forms using various methods. In this context, The compound is available in tablet or capsule formulations for oral use, parenteral use. Injectable solutions or suspensions for applications, targeted drug delivery. Nanoparticle, liposomal or polymeric carrier systems within the scope of these approaches It is possible to formulate it as follows. Industrial Applicability of the Invention The invention describes an isatin-based hybrid for use in the treatment of colorectal cancer. It is related to an anticancer compound and has industrial applicability. The invention is not limited to the above descriptions, and a person skilled in the field can easily make further discoveries. It can demonstrate different applications of the invention. These are the claims and demands of the invention. It should be evaluated within the scope of the protection granted. 11 REFERENCES [1] Weng W, Feng J, Qin H, Ma Y. Molecular therapy of colorectal cancer: Progress and future 2015;502:493–502. [2] Sokmen S. Colorectal Cancer Clinical Protocol, Republic of Turkey Ministry of Health General Directorate of Health Services, Department of Health Technology Assessment Bloodshed, Ankara. 2021. [3] Zhao X, Han Z, Ma J, Jiang S, Li X. A novel n-sulfonylamidine-based derivative Inhibits proliferation, migration, and invasion in human colorectal cancer cells by suppressing wnt / β-catenin signaling pathway. Pharmaceutics. 2021;13(5). 12

Claims

1. The compound represented by formula 1: Formula 1 2. (Z)-2-(4-(4-methoxyphenyl)piperazin-1-yl)-N'-(2-oxoindolin-3- A compound with the formula (ilidene)acetohydrazide according to Claim 1.

3. According to claim 2, it is a compound with the property of (Z)-2-(4-(4-methoxyphenyl) piperazine-1- Formula 1 with the formula (2-oxoindolin-3-ylidene)acetohydrazide The synthesis yield of the demonstrated compound is 53%.

4. It is a compound represented by formula 1, and its characteristic is that its IC₅₀ value is 9.49 μM. It is the fact that.

5. According to claim 1, it is a compound and its characteristic is that the compound in question is pharmaceutically used. acceptable acid addition salts, solvates, hydrates, isomers and / or It encompasses polymorphic forms.

6. Compounds according to claim 5, and their characteristic is that the salts of the said acid addition hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, maleate, fumarate or among similar pharmaceutically acceptable salts It is the selection process.

7. The compound is defined as a compound according to claim 5 or 6, and its characteristic is that the compound in question is a methanolate. It is found in the form of ethanolate, DMF solute, or hydrate.

8. The compound is defined as a compound according to any of claims 5–7, and its characteristic is that the compound is a hydrazone. one of the geometric isomers E and / or Z resulting from the bond or These are found in the form of a mixture of isomers.

9. According to claim 8, it is a compound, and its characteristic is that it is the Z-isomer of the compound in question.

10. Which is a synthesis method for a compound according to any of the previous requirements? feature; i. Dissolving isatin in methanol as a starting material, Adding hydrazine hydrate (50%) to the solution in question and obtaining 13 The resulting reaction mixture is kept under reflux for approximately 15 hours. isatin hydrazone intermediate is obtained by refluxing for a period of time. being done, ii. the isateine ​​hydrazone intermediate obtained in the previous step Dissolving in dimethylformamide (DMF) without purification, Adding triethylamine as a base to the reaction medium, then controlled addition of bromoacetyl bromide and placing the mixture at room temperature 2-bromo- by stirring at a certain temperature for approximately 4 hours. Formation of the intermediate N'-(2-oxoindolin-3-ylidene)acetohydrazide, iii. The bromo intermediate obtained in the second step is 4-(4- Addition of methoxyphenylpiperazine in the presence of triethylamine, reaction stirring the mixture overnight at room temperature, After the reaction is complete, the mixture is mixed with ice water. dilution, filtration, isolation and drying of the precipitated solid, iv. The obtained crude product is processed using a hexane:ethyl acetate mixture. obtaining the target compound by crystallization It includes the steps of the process.

11. A method according to claim 10, characterized by its bromoacetyl bromide derivative intermediate. instead; chloroacetyl chloride, iodoacetyl derivatives, p-toluene sulfonate (tosylate) or Acetyl derivatives containing different leaving groups, such as methanesulfonate (mesilate) It is the use of.

12. A method according to claim 10, characterized by the use of noble halides instead of; carboxylic acid derivatives such as bromoacetic acid or chloroacetic acid It is the use of.

13. A method according to claim 10, characterized by the use of diisopropylethylamine instead of triethylamine. This involves the use of N-methylmorpholine or inorganic carbonates.

14. A method according to claim 10, characterized by the use of DMSO, acetonitrile, or instead of DMF. The use of tetrahydrofuran.

15. To be used as a chemotherapeutic agent according to either of Claims 1-2. a compound.

16. Containing a compound according to Claim 15 for use as a chemotherapeutic agent. pharmaceutical composition.

17. A drug containing a compound used as a chemotherapeutic agent according to Claim 15.

18. A compound under Claim 15 for use in the treatment of colorectal cancer. 14