阅读说明：本技术 季铵化修饰紫杉烷衍生物、其药物组合物、其合成途径和用途 (Quaternized modified taxane derivative, pharmaceutical composition, synthetic route and application thereof ) 是由 贺玖明 再帕尔·阿不力孜 李燕 张锦 杜倩倩 孙成龙 张瑞萍 靳洪涛 宋肖炜 罗志 于 2019-03-05 设计创作，主要内容包括：本发明公开了新一类紫杉烷衍生物,其合成途径,其药物组合物及其在制备抗肿瘤方面药物的用途。该类紫杉烷衍生物是将紫杉烷与主动靶向分子—胆碱或甜菜碱通过一定的连接基团发生羟基取代反应而制得,具有良好的水溶性,具有一定的肿瘤靶向性,在肿瘤组织中可代谢为紫杉醇或多西紫杉醇,作为前药策略,用作有效的抗肿瘤药物。相对于紫杉醇,同等剂量下肿瘤抑制率相当,但不破坏免疫系统,毒性显著降低。(The invention discloses a new taxane derivative, a synthetic route thereof, a pharmaceutical composition thereof and application thereof in preparing anti-tumor medicaments. The taxane derivative is prepared by carrying out hydroxyl substitution reaction on taxane and active targeting molecule-choline or betaine through a certain connecting group, has good water solubility and certain tumor targeting property, can be metabolized into paclitaxel or docetaxel in tumor tissues, is used as a prodrug strategy, and is used as an effective antitumor drug. Compared with taxol, the tumor inhibition rate is equivalent under the same dosage, but the immune system is not destroyed, and the toxicity is obviously reduced.)

1. A class of taxane derivatives having the general formula (I) and pharmaceutically acceptable salts thereof:

in the formula (I):

R₁is benzoyl, tert-butoxy acyl, sweetA betaine acyl, a substituted betaine acyl, a choline or substituted choline linked by a carbonate bond, a phosphate bond, a diacid bond, an ether bond or a sulfonate bond;

R₂is hydrogen, methyl or acetyl;

R₃is hydrogen, methyl, acetyl, betaine acyl, substituted betaine acyl, or choline linked by carbonate, phosphate, diacid, ether or sulfonate bonds;

R₄is hydrogen, betaine acyl, substituted betaine acyl, choline or substituted choline linked by carbonate bond, phosphate bond, diacid bond, ether bond or sulfonate bond;

R₅is hydrogen, betaine acyl, substituted betaine acyl, choline or substituted choline connected by carbonate bonds, phosphate bonds, diacid bonds, ether bonds or sulfonate bonds;

the above-mentioned substituents being halogen atoms, C_1-6Alkyl radical, C_1-7Acyl radical, C_3-6Cycloalkyl, hydroxyl, amino acids of different types, such as alanine, valine, threonine, aspartic acid, serine and any one of the amino acids.

2. The taxane derivative and the pharmaceutically acceptable salt thereof according to claim 1, wherein the hydroxyl group at the C2' position is in (RS) -, (S) -, (R) -configuration, and the C1 and C2 positions of choline in the formula (I) can be in (RS) -, (S) -, (R) -configuration when they are chiral.

3. The taxane derivative and the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is selected from the group consisting of:

4. the use of taxane derivatives as claimed in any one of claims 1 to 3 and pharmaceutically acceptable salts thereof in the manufacture of anti-neoplastic medicaments.

5. The use according to claim 4, wherein the tumor is lung cancer, ovarian cancer, breast cancer, colon cancer or liver cancer.

6. A pharmaceutical composition comprising a therapeutically effective amount of a taxane derivative according to any one of claims 1-3 and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel taxane derivative, which not only has good water solubility, but also has certain tumor targeting property, has equivalent tumor inhibition rate compared with the same dose of paclitaxel, does not damage an immune system, obviously reduces toxicity, improves the drug-resistant tumor sensitivity of paclitaxel, and can be used as an anti-tumor drug with high efficiency and low toxicity.

Background

Cancer is the second largest disease threatening human health, and from a global perspective, nearly one sixth of deaths are caused by cancer, and the burden of cancer is increasing. According to the world cancer report issued by the World Health Organization (WHO), by 2035, the number of patients with tumors worldwide may reach 2400 million, increasing nearly five years in 20 years, affected by population growth and aging, the number of cancers in developing countries is rising, 60% of the worldwide cases occur in africa, asia, central and south america and account for 70% of the worldwide cancer deaths, while the newly increased cancer cases in china account for about 20% of the world and the cancer deaths account for about 25% of the world. Recent epidemiological investigations of cancer have shown that about 1 million people diagnose cancer per day, with an average of 7 people diagnosed per minute in china. In the face of the current increasingly severe cancer pathogenesis, tumor treatment is a worldwide problem in the current disease treatment field.

In recent years, the trend of rapid development of antitumor drugs as one of the important methods for cancer treatment is shown, and numerous antitumor drugs are developed by various organizations for different indications and different targets every year. The development of antitumor drugs with high curative effect, broad spectrum and small side effect is the focus of the research and development of new drugs in the medical field.

Paclitaxel, as a diterpenoid alkaloid compound with anticancer activity, is approved by the FDA in the united states for the treatment of advanced cancers at the end of 1992, is the most successful anticancer drug after doxorubicin and cisplatin, has novel and complex chemical structure, wide and significant biological activity, brand new and unique action mechanism, and is scarcely available in natural resources, is one of the most elegant natural anticancer drugs discovered at present, and is one of the most great discoveries in drug development in the last three decades. The paclitaxel has wide anti-tumor spectrum and obvious curative effect, and is widely used for treating non-small cell lung cancer, breast cancer, ovarian cancer, esophageal cancer, head and neck cancer, gastric cancer and the like. However, the low water solubility and high cytotoxicity of paclitaxel limit its wide clinical application. The water solubility of the taxol is poor, the solubility of the taxol in water is less than 0.004mg/mL, and the taxol injection which is clinically used at present is prepared by using polyoxyethylene castor oil: absolute ethyl alcohol (1: 1) is used as a solvent, so that severe anaphylactic reaction is easy to occur in vivo; and secondly, the taxol serving as a cytotoxic anti-tumor medicament has a plurality of adverse reactions such as bone marrow suppression, neurotoxicity, cardiovascular toxicity, liver injury and the like. Paclitaxel the above-mentioned deficiencies leave a wide space for the subsequent development of paclitaxel.

Clinical requirements are the core pursuit of new drug research and development, and a great deal of research is carried out at home and abroad on new technology and new dosage forms of paclitaxel in order to improve the solubility of the paclitaxel and reduce the toxic and side effects of the paclitaxel on patients. Research hotspots are mainly divided into two directions: firstly, synthesizing derivatives which can change the solubility of the paclitaxel and reduce the cytotoxicity of the paclitaxel; secondly, preparing a novel preparation of the paclitaxel. At present, certain achievements are achieved in the aspect of a novel paclitaxel administration system, and paclitaxel liposome is the main mainstream product occupying the marketAnd paclitaxel albumin nano preparation

The two novel preparations overcome the problem of low water solubility to a certain extent, reduce the toxicity of the medicament and improve the anti-tumor effect. However, as for paclitaxel liposome, because the solubility of paclitaxel in water phase and lipid phase is low, paclitaxel is easy to separate out from liposome or lipid nanoparticle after long-term storage, and then forms precipitate, so that liposome and nanoparticle preparation lack long-term stability, and inconvenience is brought to clinical application; for paclitaxel albumin sodiumThe rice preparation uses human albumin as a carrier, and has risks of microbial contamination, immune resistance and the like. Therefore, in order to overcome the above-mentioned obstacles, there is an urgent need in the art to develop a paclitaxel derivative having improved antitumor effect while changing its solubility and reducing cytotoxicity. Choline, a type of quaternary ammonium base, is very polar. It is reported in the literature that choline plays a crucial role in maintaining normal physiological functions of cells, and the deficiency of choline induces pathological changes in the body. It has the following physiological functions as an essential nutrient for human body: it is an important component for forming cell membrane, and is also a precursor substance of important metabolites in vivo, such as glycine, betaine, acetylcholine, platelet activating factor, etc.; participating in signal transduction and promoting brain development; regulating apoptosis; choline is a substance necessary for the liver to secrete very low-density lipoprotein, thereby being beneficial to reducing serum cholesterol, maintaining the functions of liver and gallbladder and the like. Choline, as a methyl donor, is also involved in one-carbon metabolism together with folic acid, betaine and other B vitamins, is involved in nucleic acid synthesis, and affects DNA methylation. In many reports, choline and its derivatives are used as potential biomarkers of tumors, and compared with normal tissue cells, tumor tissues have high-level distribution, and probably because tumor cells have the characteristic of rapid proliferation, the nutrient substances are always actively taken in a large amount from body fluid to meet the proliferation requirement of the tumor cells, so the choline is absorbed and utilized far more than normal cells.

Based on a prodrug modification strategy, choline, or substituted choline, or betaine, or substituted betaine is combined with a taxane compound, so that the water solubility of the compound can be improved, the active transport of the compound to tumor tissues is improved, the action time of the compound in a target tumor area is prolonged, the normal cytotoxicity is reduced, and the therapeutic index of the compound is improved. Choline and betaine have many unique advantages as modifying molecule, such as small relative molecular weight, no immunogenicity, low cost, easy obtaining, good stability, simple and easy chemical bond connection with drug molecule, wide target application range, etc.

Disclosure of Invention

The invention provides taxane derivatives shown in the following general formula (I) and pharmaceutically acceptable salts thereof:

in the formula (I):

R₁is benzoyl, or tert-butoxy acyl, or betaine acyl or substituted betaine acyl, or choline or substituted choline connected by carbonate bond, phosphate bond, diacid bond, ether bond or sulfonate bond; r₂Is hydrogen or methyl or acetyl; r₃Is hydrogen, or methyl, or acetyl, or betaine acyl or substituted betaine acyl, or choline linked by carbonate, phosphate, diacid, ether or sulfonate bonds; r₄Is hydrogen, or betaine acyl or substituted betaine acyl, or choline or substituted choline connected by carbonate bond, phosphate bond, diacid bond, ether bond or sulfonate bond; r₅Is hydrogen or betaine acyl or substituted betaine acyl, or choline or substituted choline connected by carbonate bond, phosphate bond, diacid bond, ether bond or sulfonate bond. Wherein, the hydroxyl at the C2' position is in (RS) -, (S) -, (R) -configuration, and the C1 and the C2 position of choline in the formula (I) can be in (RS) -, (S) -, (R) -, under the condition of chirality.

The invention also provides the application of the taxane derivative and the pharmaceutically acceptable salt thereof in preparing antitumor drugs. The tumor is lung cancer, ovarian cancer, breast cancer, colon cancer or liver cancer. Also comprises a pharmaceutical composition containing a therapeutically effective amount of the taxane derivative and the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In summary, the present invention provides a new class of taxane derivatives and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition and uses thereof in preparing anti-tumor drugs.

The technical problem to be solved by the invention is to overcome the defects of paclitaxel or docetaxel, and carry out structural modification on the paclitaxel or docetaxel, and the technical scheme is as follows:

the first aspect of the technical scheme of the invention provides a taxane derivative shown in the following chemical structure and pharmaceutically acceptable salt thereof:

the compound has a structural general formula as follows:

among the taxane derivatives mentioned above, there are mentioned,

is taxane compound, including paclitaxel, docetaxel, cabazitaxel, etc. The compound uses carbonate bonds, phosphate bonds and the like as connecting parts, and free hydroxyl groups of targeted molecular choline or betaine or analogues thereof and antitumor drugs taxol, docetaxel and cabazitaxel are coupled to obtain the quaternized modified taxane derivative. The quaternary ammonium modified taxane derivative provided by the invention has the advantages that the absorption and utilization of choline by tumor cells are far greater than those of normal cells, so that the derivative can be actively absorbed by the tumor cells and gathered at tumor parts, the effect of treating tumors is achieved, the toxicity is weakened, and the derivative can be prepared into antitumor drugs with lower toxicity and higher efficiency. The invention provides a cholinesterase and betaine modified taxane derivative and an anti-tumor application thereof, which are innovations of the inventor and are published for the first time.

The position of the free hydroxyl of the taxane compound (I)) combined by choline or betaine is not limited to 2 ' position, and can also react with 7-position hydroxyl of taxane, and the technical personnel in the field know that 2 ' position and 7-position hydroxyl have certain nucleophilicity, can realize substitution reaction with acyl chloride obtained after one-step reaction, and find that 2 ' position hydroxyl has very good regioselectivity in experiments, which is consistent with the literature report. If the 7-position is combined with choline, the 2' -hydroxyl can be protected by a silicon etherifying reagent, and then subsequent substitution reaction is carried out.

The taxane compound is not limited to paclitaxel, docetaxel and cabazitaxel, and the skilled person in the art knows that the taxane compound has a common parent-nucleus skeleton structure and similar anti-tumor effects, and has 2' -hydroxyl and 7-hydroxyl which react with choline or betaine, so that corresponding reaction conditions and results are provided.

The linking group of the compound of the present invention is not limited to a carbonate bond, and may be a saturated carbon chain, an aromatic ring, a sulfonyl group, a phosphate, a diester, an ether bond, or the like. Carbonate and acyl ester bonds are the best choices from a chemical standpoint-ease of connection and disconnection.

Among the taxane derivatives of the above formula (I), preferably, the choline and betaine-modified paclitaxel derivative, docetaxel derivative have the following structures:

the second aspect of the technical problem to be solved by the present invention is to provide a process for the preparation of this novel taxane derivative.

The compounds of the present invention are prepared by the following reaction scheme

A third aspect of the technical problem underlying the present invention is to provide a pharmaceutical composition comprising compound A, B, C, D, E or other choline-modified taxanes, and pharmaceutically acceptable salts thereof, as an active ingredient, together with a pharmaceutically acceptable carrier or excipient.

Part of the compounds of the present invention contain basic groups in the molecule, which can be converted to pharmaceutically acceptable salts by acid treatment, as is recognized in the art. Examples of such salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate or bisulfate, nitrate, phosphate or bisulfate, and the like, and organic acid salts such as formate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like.

The compound can be prepared into different parenteral administration dosage forms according to the known method in the field, and is suitable for human or animals. For example, the compounds of the present invention may be formulated into injectable preparations such as solutions, suspensions, emulsions, lyophilized powders, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, preservatives, surfactants, solubilizers, buffers, pH adjusters. These adjuvants are all commonly used in the art. For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The compound or composition of the present invention can be administered alone or in combination with other therapeutic agents or symptomatic agents, and when the compound of the present invention acts synergistically with other therapeutic agents, its dosage should be adjusted as appropriate.

The fourth aspect of the present invention is to provide the use of the quaternized modified taxane derivative and the composition thereof in the preparation of antitumor drugs, wherein the tumors of the present invention are preferably selected from lung cancer, breast cancer, ovarian cancer, liver cancer, colon cancer, stomach cancer, but not limited to the above tumors.

Drawings

FIG. 1 growth inhibition of paclitaxel derivative A on colon cancer in mouse C26

FIG. 2 Effect of paclitaxel derivative A on the immune System of C26 Colon cancer mice

FIG. 3 growth inhibitory Effect of paclitaxel derivative A on mouse EMT6 Breast cancer

FIG. 4 Effect of paclitaxel derivative A on the immune System of EMT6 Breast cancer mice

FIG. 5 growth inhibition of paclitaxel derivative A on mouse Lewis lung carcinoma

Detailed Description

Abbreviations:

TEA: triethylamine

DCM: methylene dichloride

The invention discloses a quaternized modified taxane derivative, and application of a salt, a solvate, a prodrug and a pharmaceutical composition containing the quaternized modified taxane derivative. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The invention will be further illustrated with reference to specific embodiments: