TWI669121B - Compound for the treatment of cancer - Google Patents

Abstract

A compound for treating cancer, and a pharmaceutically acceptable salt thereof, which has the structure represented by the following chemical formula (I) or chemical formula (II): Wherein X and Y are each independently represented or R ₁ and R ₃ each independently represent a hydrogen atom or a fluorenyl group having a carbon number of 20 or less; and R ₂ represents a hydrogen atom, a fluorenyl group having 20 or less carbon atoms, an alkyl group having 20 or less carbon atoms, and a carbon number of 20 or less. An aryl group, an aralkyl group having a carbon number of 20 or less, or a hetero atom-containing alkyl group having a carbon number of 20 or less; and R ₄ represents a hydrogen atom, an alkyl group having 20 or less carbon atoms, an aryl group having 20 or less carbon atoms, and carbon An aralkyl group having a number of 20 or less or a hetero atom-containing alkyl group having a carbon number of 20 or less; and R ₅ means an alkyl group having a carbon number of 20 or less, an aryl group having a carbon number of 20 or less, an aralkyl group having a carbon number of 20 or less, or carbon A hetero atom-containing alkyl group having a number of 20 or less.

Description

Compound for the treatment of cancer

The present invention relates to a compound for treating cancer, and a pharmaceutically acceptable salt thereof, and more particularly to a compound containing a therapeutically active ingredient for cancer isolated from bitter gourd, and a pharmaceutically acceptable salt thereof, And its derivatives.

In recent decades, in Taiwan, with the aging of the population, cancer or malignant tumors have become one of the top ten causes of death among Chinese people. Medically referred to as "tumor" includes both benign and malignant tumors, usually referred to as abnormal cell proliferation, and even invading surrounding or distant cell tissue affecting normal physiological functions. Common cancers include liver cancer, rectal cancer, colorectal cancer, esophageal cancer, gastric cancer, leukemia, malignant lymphoma, nasopharyngeal carcinoma, brain tumor, lung cancer, breast cancer, cervical cancer, blood cancer and bone cancer; among them, the most lethal It is lung cancer, stomach cancer and liver cancer, accounting for 18%, 10% and 9% of cancer deaths, respectively.

Various malignant tumors are generally referred to as "cancers". The growth and division of cancer cells are out of control, can invade normal tissues and invade surrounding tissues, and are transferred to the parts far from their origins through the circulatory system, lymphatic system or cavity. Challenge human health and life safety. The treatment of cancer can be roughly divided into surgery, chemotherapy, radiation therapy, guiding therapy, immunotherapy, hormone therapy, cryotherapy, warming therapy, angiogenesis inhibitor therapy, and Chinese medicine, Chinese herbal medicine treatment.

Among various cancer treatment methods, surgery, radiotherapy, and chemotherapy are the main means of clinical treatment, and different therapies are adopted according to the type, location, and duration of the patient's cancer. Surgical resection is mainly to remove the cell tissue of the cancer site; while radiotherapy and chemotherapy kill the tumor cells, it also damages the normal cells of the human body, has large side effects, and has poor quality of life and low survival rate. However, whether it is surgical resection, chemotherapy, or radiation therapy, it is an irreversible method of destroying human cells, tissues and even organs.

With the research on cell death and molecular mechanism, people have a new understanding of the screening of anticancer drugs, so there is no way to cause irreversible secondary harm to cancer patients, for example, using Chinese herbal medicine or its extraction. Agents for the treatment of specific signal pathways of tumor cells or specific cancer cell target sites have received increasing attention.

Bitter gourd is widely grown in tropical and subtropical regions and belongs to the cucurbitaceae plant. The scientific name is Momordica charantia L.. Due to natural evolution or artificial hybridization, there are many different varieties or strains in different places. In Taiwan, what is commonly referred to as "bitter gourd" usually refers to white lotus bitter gourd, or white bitter gourd, sold in the market as a family. As for the bitter gourd that is popular in recent years, it is also a kind of bitter gourd. The scientific name is the same as that of white lotus bitter melon but the strain is different.

The most well-known function of bitter gourd is to reduce anger. Traditional Chinese herbal medicine believes that all the bitter gourd can be used as medicine, cold and bitter taste, into the heart and spleen and stomach, clearing heat and relieving heat, clearing eyes and detoxification. However, traditional medicine in China, Japan, Southeast Asia, India, Africa, Latin America and other places also treats diabetes with bitter gourd. The varieties used are usually locally produced. In some places, bitter gourd is even called plant insulin.

In recent years, scientists have tested with modern scientific methods to confirm that bitter gourd does have the function of lowering blood sugar. Further research has found that active ingredients such as proteins, polypeptides, alkaloids, triterpenoids, and sterols in bitter gourd have antiviral, antibacterial, antioxidative, and antibacterial properties in addition to hypoglycemic effects. Inflammation, immune regulation, blood fat reduction and other effects.

Furthermore, the present inventors have found that momordicin I and its derivatives in bitter gourd have an effect of inhibiting the growth of cancer cells, and can be used as an active ingredient of a drug for treating or preventing cancer in the future.

SUMMARY OF THE INVENTION The Summary of the Disclosure is intended to provide a basic understanding of the present disclosure. This Summary is not an extensive overview of the disclosure, and is not intended to be an

As described above, the present invention is based on the unexpected discovery that specific momordicin I and its derivatives are useful for treating different cancers, and are capable of providing unexpectedly superior effects far beyond the use of general anticancer agents, including Reduces the regulation of carcinogenic activity, prevents cancer cells from proliferating or even reversing, and thus achieves the effects of treating and preventing cancer and tumor metastasis; therefore, debitterin I derivatives can be used to develop agents capable of treating or preventing inflammatory and/or tumor-related diseases. .

That is, the present invention can provide a compound for treating cancer and a pharmaceutically acceptable salt thereof, which has a structure represented by the following chemical formula (I) or chemical formula (II): Wherein X and Y are each independently represented or R ₁ is a hydrogen atom, a fluorenyl group having a carbon number of 20 or less, an alkano group having a carbon number of 20 or less, an aryl group having a carbon number of 20 or less, a sulfonyl group having a carbon number of 20 or less, or a phosphine having a carbon number of 20 or less. a group or a halogenated fluorenyl group having a carbon number of 20 or less; and R ₂ represents a hydrogen atom, a fluorenyl group having 20 or less carbon atoms, an alkyl group having 20 or less carbon atoms, an aryl group having 20 or less carbon atoms, and an aromatic group having 20 or less carbon atoms. An alkyl group or a hetero atom-containing alkyl group having a carbon number of 20 or less; and R ₃ represents a hydrogen atom, a fluorenyl group having 20 or less carbon atoms, an alkyl fluorenyl group having 20 or less carbon atoms, an aryl fluorenyl group having 20 or less carbon atoms, and a carbon number a sulfonium group of 20 or less, a phosphinium group having a carbon number of 20 or less, or a halogenated fluorenyl group having a carbon number of 20 or less; and R ₄ represents a hydrogen atom, an alkyl group having a carbon number of 20 or less, and an aryl group having a carbon number of 20 or less. An aralkyl group having a carbon number of 20 or less or a hetero atom-containing alkyl group having a carbon number of 20 or less; and R ₅ is an alkyl group having a carbon number of 20 or less, an aryl group having a carbon number of 20 or less, or an aralkyl group having a carbon number of 20 or less A hetero atom-containing alkyl group having a carbon number of 20 or less.

According to a specific embodiment of the present invention, there can be provided a compound for treating cancer and a pharmaceutically acceptable salt thereof, wherein the sulfhydryl group, the alkyl fluorenyl group, the aryl fluorenyl group, the sulfonyl group, the phosphonium group, and the halogen The substituted oxime groups each further have a substituent; wherein the substituent is halogen, hydroxy, alkyl, alkoxy, phenyl, naphthyl, isobenzofuranyl, isophenylthiophenyl, and isoquinolyl At least any one selected from the group consisting of; preferably at least one of halogen, hydroxy, alkyl, alkoxy, and phenyl; more preferably halogen, hydroxy, alkyl, and alkoxy At least any one of them; most preferably at least one of a hydroxyl group, an alkyl group, and an alkoxy group.

According to a specific embodiment of the present invention, there can be provided a compound for treating cancer and a pharmaceutically acceptable salt thereof, wherein the sulfhydryl group is generally a fluorenyl group having a carbon number of 20 or less; preferably, the carbon number is 15 or less. The fluorenyl group; more preferably a fluorenyl group having a carbon number of 10 or less; a fluorenyl group having a carbon number of 5 or less; and most preferably an acetamino group.

According to a specific embodiment of the present invention, there can be provided a compound for treating cancer and a pharmaceutically acceptable salt thereof, wherein the alkyl group is generally an alkyl group having a carbon number of 20 or less; preferably, the carbon number is 15 or less. The alkyl group; more preferably an alkyl group having a carbon number of 10 or less; particularly preferably an alkyl group having a carbon number of 5 or less; most preferably a methyl group.

According to a specific embodiment of the present invention, there can be provided a compound for treating cancer and a pharmaceutically acceptable salt thereof, wherein the alkyl group is an alkyl group further having a substituent, which is a halogen, a hydroxyl group or an alkane An oxy group, an alkoxy group, a phenyl group, a naphthyl group, an isobenzofuranyl group, an isophenylthiophenyl group, and an isoquinolyl group constitute at least one selected from the group; preferably a halogen, a hydroxyl group or an alkoxy group. a group selected from the group consisting of a hydroxy group, an alkoxy group, an alkoxy group, and a phenyl group; At least any one selected; most preferably at least one selected from the group consisting of a hydroxyl group, an alkoxy group, and an alkoxy group.

According to a specific embodiment of the present invention, there can be provided a compound for treating cancer and a pharmaceutically acceptable salt thereof, wherein the aryl group is an aryl group further having a substituent, the substituent is a halogen atom, C1-4 The alkyl group, the C1-20 alkoxy group, and the halogenated C1-20 alkoxy substituent form at least one selected from the group; preferably a halogen atom, a C1-4 alkyl group, a C1-20 alkoxy group. At least any one selected from the group consisting of: a halogen atom, and a C1-4 alkyl group are at least any one selected from the group consisting of.

According to a specific embodiment of the present invention, there is provided a compound for treating cancer and a pharmaceutically acceptable salt thereof, wherein the aralkyl group further has a substituent; wherein the substituent is a halogen, a hydroxyl group or an alkane An oxy group, an alkoxy group, a phenyl group, a naphthyl group, an isobenzofuranyl group, an isophenylthiophenyl group, and an isoquinolyl group constitute at least one selected from the group; preferably from a halogen, a hydroxyl group, or an alkane group. An oxy group, an alkoxy group, an isobenzofuranyl group, and an isophenylthiophenyl group constitute at least one selected from the group; more preferably, it is a group consisting of a halogen, a hydroxyl group, an alkoxy group, and an alkoxy group. At least any one selected; most preferably at least one selected from the group consisting of a hydroxyl group, an alkoxy group, and an alkoxy group.

According to a specific embodiment of the present invention, a compound for treating cancer and a pharmaceutically acceptable salt thereof having nitrogen, oxygen, sulfur, phosphorus, boron, chlorine, bromine, And iodine forming at least one of the selected heteroatoms in the group; preferably at least one selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, chlorine, and bromine; more preferably from nitrogen and oxygen And at least one selected from the group consisting of phosphorus; preferably at least one selected from the group consisting of nitrogen and oxygen.

According to a specific embodiment of the present invention, a compound for treating cancer, wherein the cancer is at least one of malignant glioma, liver cancer, colon cancer, lung cancer, blood cancer, and breast cancer.

According to a specific embodiment of the present invention, there is provided a pharmaceutical composition for treating cancer comprising at least the above-mentioned compound for treating cancer, a pharmaceutically acceptable salt, a carrier, and/or a diluent, an excipient And any of the adjuvants.

According to a specific embodiment of the present invention, there is provided a pharmaceutical composition for treating cancer, wherein the compound is present in an amount of from about 0.1% to about 99% by weight based on the total weight of the pharmaceutical composition; preferably, the compound comprises At least 1% by weight of the pharmaceutical composition; more preferably, the compound comprises at least 5% by weight of the total pharmaceutical composition; particularly preferably, the compound comprises at least 10% by weight of the total pharmaceutical composition. (% by weight); most preferably, the compound comprises at least 25% by weight of the total pharmaceutical composition.

One or more embodiments of the present disclosure will be described in detail in the following embodiments. Features of the above disclosure will be better understood from the following detailed description and the appended claims. It is to be understood that the foregoing general descriptions

In this document, the meanings of the scientific and technical terms used herein are the same as those of ordinary skill in the art to which the invention pertains. In addition, the singular noun used in this specification covers the plural of the noun in the case of no conflict with the context; the plural noun of the noun is also included in the plural noun used.

As used herein, the term "alkyl" refers to a hydrocarbon radical of from 1 to 20 carbon atoms which is straight, branched and/or cyclic ("cycloalkyl") (ie, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1 carbon atom). A structure in which an alkyl group has 1 to 4 carbon atoms is referred to as a "lower alkyl group". For example, the alkyl group comprises methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, 2-isopropyl-3-methylbutyl, pentyl, pentyl -2-yl, hexyl, isohexyl, heptyl, hept-2-yl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, decyl, decyl, Undecyl and dodecyl. The cycloalkyl structure may be monocyclic or polycyclic, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Unless otherwise defined, the monoalkyl group in each of the examples optionally contains an optional substituent, that is, an unsubstituted alkyl group or a substituted alkyl group having one or more substituents. . In a particular embodiment, the alkyl group is a C2-10 alkyl group with a substituent.

As used herein, "acyl group" refers to a group that remains after removal of a hydroxyl group (-OH) from an inorganic or organic oxyacid molecule. Examples of sulfonium groups include, but are not limited to, Formyl, Acetyl, Propionyl, Butryryl, i-Butyryl, Methylsulfonyl. ), Ethylsulfonyl, n-Propylsulfonyl, iso-Propylsulfonyl, n-Butylsulfonyl, Isobutylsulfonyl (iso) -Butylsulfonyl), tert-Butylsulfonyl, etc.

As used herein, "alkoxy" refers to a mono-O-alkyl group. Examples of alkoxy groups include, but are not limited to, -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, and -O(CH2)5CH3. The "lower number alkoxy group" means -O-(lower alkyl group); for example, -OCH3 and -OCH2CH3.

As used herein, "aryl" refers to an aromatic ring or a partial aromatic ring system consisting of carbon and hydrogen atoms. An aromatic group may comprise a plurality of rings bonded or fused to each other. Examples of the aromatic group include a naphthyl group and a phenyl group. Unless otherwise indicated, an aromatic group in each instance individually contains an optional substituent, i.e., an unsubstituted aryl group or a substituted aryl group having one or more substituents. In a particular embodiment, the aryl group is a substituted phenyl group. In another embodiment, the aryl group is a naphthyl group having a substituent.

As used herein, "heteroaryl" means that at least one carbon atom of an aromatic group carries a hetero atom (eg, nitrogen, oxygen or sulfur). For example, including, but not limited to, benzofuranyl, benzothienyl, quinolyl, benzodioxolyl, furyl, and Thienyl.

As used herein, "alkylaryl" refers to the attachment of a monoalkyl group to an aromatic group.

Unless otherwise defined in the specification, the "halogen (halo)" includes fluorine, chlorine, bromine and iodine.

Unless otherwise defined in the specification, the term "substituted" when referring to a chemical structure or chemical group refers to a derivative having one or more hydrogen atoms in its structure or group, by an atom, a chemical group. Substituted or functional group substituted; ie, but not limited to, -OH, -CHO, alkoxy, fluorenyl (eg, -OAc), alkenyl, alkyl (eg, methyl, ethyl, propyl, tert-butyl) A aryl group, an aryloxy group, a halogen or a haloalkyl group (for example, -CCl3, -CF3, -C(CF3)3).

In a particular embodiment, the "substituted" when referring to a chemical structure or chemical group refers to a derivative having one or more hydrogen atoms in one or more of its structures or groups: Alkoxy, fluorenyl, alkyl, aryl, halogen, haloalkyl or hydroxy substituted.

A "therapeutically effective amount" of a compound, unless otherwise defined in the specification, refers to an amount sufficient to provide a therapeutic effect in the treatment or management of a disease or condition, or to delay or reduce the symptoms associated with the disease or condition. A therapeutically effective amount of a compound refers to a therapeutic amount which, if used alone or in combination with other agents, provides a therapeutic effect in the treatment or management of a disease or condition. The term "therapeutically effective amount" can encompass improving the overall therapeutic effect, reducing or preventing the onset of a disease or condition-related symptom or enhancing the effectiveness of other therapeutic agents.

Unless otherwise defined in the specification, "treat, treating or treating" refers to the act of administering to a patient suffering from a particular disease or condition, wherein the behavior reduces the disease or condition of the patient, or one or more The severity of a symptom, or the process of slowing or delaying a disease or condition.

It should be noted that if there is no stereochemistry or a part of the structure (for example, a portion indicated by a thick line or a broken line) specifying a structure, the structure or part structure should be interpreted to cover all stereoisomers. . Similarly, when a compound contains one or more asymmetric centers, but the name does not specifically define the stereochemical structure that can be covered by the asymmetric centers, the range of the compound should be interpreted to cover its pure optics. An isomer and a mixture of the optical isomers. Furthermore, any atom having an unsaturated valence is shown in the figure, assuming that it can be connected to a sufficient number of hydrogen atoms to saturate the valence.

Although numerical ranges and parameters are used to define a broad range of values for the present invention, the relevant values in the specific embodiments have been presented as precisely as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the average, depending on the considerations of those of ordinary skill in the art to which the invention pertains. Except for the experimental examples, or unless otherwise explicitly stated, all ranges, quantities, values, and percentages used herein are understood (eg, to describe the amount of material used, the length of time, the temperature, the operating conditions, the quantity ratio, and the like. Are all modified by "about". Therefore, unless otherwise indicated to the contrary, the numerical parameters disclosed in the specification and the appended claims are intended to be At a minimum, these numerical parameters should be understood as the number of significant digits indicated and the values obtained by applying the general carry method.

The compound of the present invention may comprise one or more stereocenters for the Momordicin I derivative; therefore, the compounds exist in different isomeric forms, for example, a mixture of racemic mirror image isomers and/or non-image isomers. mixture. The present invention encompasses mirror image isomers of such compounds, as well as mixtures of such mirror image isomers and/or non-image areomers. The mirror image isomers can be prepared by asymmetric synthesis or by conventional techniques, for example, by crystallization, chromatography, and separation using a resolving agent. A preferred method for separating the enantiomers from the racemic mixture is by high performance liquid chromatography (HPLC). Alternatively, the two mirror image isomers may be separated from each other from the racemic isomer by reaction with an optically active form of a resolving agent in a solvent. Depending on the optical form of the separating agent used, one of the isomers of the second image isomer can be isolated as an insoluble salt, separated from the isomer remaining in the solution. The isomers have high yields and high optical purity.

The invention further comprises a mixture of stereoisomers of the compound. Furthermore, the invention also encompasses configurational isomers of the compounds (ie, trans and cis isomers, whether or not containing double bonds), including mixtures of isomers, pure isomers or substantially It is in the form of a pure isomer.

The pharmaceutical compositions disclosed herein are suitable for use in the treatment of various cancers, for example, including, but not limited to, liver cancer, colorectal cancer, esophageal cancer, gastric cancer, leukemia, malignant lymphoma, nasopharyngeal carcinoma, malignant glioma. , lung cancer, breast cancer, cervical cancer, bone cancer, rectal cancer, liver cancer, breast cancer, or blood cancer. Preferably, it is suitable for treating liver cancer, colon cancer, esophageal cancer, gastric cancer, leukemia, malignant lymphoma, nasopharyngeal carcinoma, malignant glioma, lung cancer, breast cancer, cervical cancer, blood cancer or bone cancer.

The pharmaceutical composition disclosed in the present invention can be prepared according to a publicly accepted pharmaceutical process. According to one embodiment of the invention, the pharmaceutical compositions disclosed herein can be administered via any suitable route of administration. For example, capsules, suspensions or tablets administered orally, or systemically administered without gastrointestinal administration, for example, intramuscular, intravenous, subcutaneous or intraperitoneal injection. Additionally, in certain embodiments, the pharmaceutical compositions disclosed herein can also be administered by transdermal means, for example, topical skin application, or by, for example, intrabronchial, intranasal, intraoral inhalation, or nasal drops. Instillation; it can also be administered intrarectally.

When administered orally, the pharmaceutical compositions disclosed herein can be administered with excipients or without excipients. Further, the pharmaceutical composition of the present invention may be formulated into a tablet containing a variety of adjuvants, various disintegrating agents, particulate binders or lubricants to form a solid dosage form. Additionally, in one embodiment, lactose or high molecular weight polyethylene glycols can also be used. In addition, coatings or coatings, such as casing coatings, etc., which may be further used to improve the rate of release of any of the active ingredients of the drug, may also be used as needed. In other examples, the pharmaceutical compositions of the present invention may also be formulated as a liposome structure or a biomimetic interstitial system structure, or may be filled in a soft or hard gelatin capsule, or may be encapsulated in a biodegradable The particles in the medicine pack.

Further, in the present invention, a pharmaceutically acceptable excipient means a substance which is compatible with other ingredients in the pharmaceutical preparation and is compatible with a living body, for example, an encapsulating material or such as an absorption enhancer, an antioxidant, a binder. , buffers, coatings, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavoring agents, moisturizers, lubricants, perfumes, preservatives, propellants, release agents, fungicides, Various additives such as sweeteners, solubilizers, wetting agents, and mixtures thereof.

As the adjuvant suitable for use in the present invention, for example, microcrystalline cellulose, calcium carbonate, dicalcium phosphate or glycine may be used. Suitable disintegrants for use in the present invention are, for example, starch, alginic acid or a specific citrate. As the particulate binder suitable for use in the present invention, for example, polyvinylpyrrolidone, sucrose, gelatin, or acacia can be used. For the lubricant to be used in the present invention, for example, magnesium stearate, sodium lauryl sulfate or talc or the like can be used. Excipients suitable for use in the present invention may, for example, be lactose, sucrose, mannitol, sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth or the like.

In certain embodiments, the pharmaceutical compositions of the present invention are formulated as liquid dosage forms suitable for oral administration, for example, oral suspensions, emulsions, microemulsions, and/or special effects liquids (elixirs). In the case of such a liquid dosage form, the active ingredient of the pharmaceutical composition of the present invention may be further formulated with various sweeteners or flavors, colorants or dyes, if necessary, emulsifiers and/or suspensions, or A diluent such as water, alcohol, propylene glycol, glycerin, or a buffer that maintains the pH.

Further, in other embodiments, the liquid formulation containing the pharmaceutical composition of the present invention is formulated into a sterile injectable solution or suspension; for example, it is formulated to be suitable for intravenous, intramuscular, subcutaneous or intraperitoneal injection. The solution applied.

Suitable diluents for use in the above sterile injectable solutions or suspensions, for example, may include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer's solution, isotonic chlorination A sodium solution; a fatty acid such as oleic acid, a glyceride derivative, or a pharmaceutically acceptable natural fat such as olive oil or rapeseed oil may also be used.

Further, in some embodiments, an alcohol, a carboxymethylcellulose dispersant, a surfactant, an emulsifier, or the like may be further added.

Further, in some embodiments, a liquid formulation containing the pharmaceutical composition of the present invention may be filled in a soft capsule for use.

Further, in one embodiment, the above-mentioned pharmaceutical or pharmaceutical composition of the present invention may be formulated together with a pharmaceutically acceptable polymeric adjuvant into a plurality of dosage forms suitable for mucosal application, such as buccal. And/or sublingual pharmaceutical dosage forms. In general, the above polymeric adjuvant comprises a hydrophilic polymer, for example, which may be used, for example, but not limited to, acrylic acid polymers, hydrolyzed polyvinyl alcohol, polyethylene oxidation. Polyethylene oxides, polyacrylates, vinyl polymers, polyvinylpyrrolidine, dextran, guar gum, pectins, starch, or cellulose polymerization Cellulosic polymers, etc.

In certain embodiments, the pharmaceutical compositions disclosed herein can be used as another adjunctive therapeutic agent to enhance the therapeutic effects of major cancer treatment methods such as surgery, radiation therapy or chemotherapy. The administration of the pharmaceutical composition disclosed in the present invention may be administered alone or in combination with a conventional pharmaceutically acceptable adjuvant, for example, the pharmaceutical composition disclosed in the present invention may be administered orally, or together with food. The substance is administered to the individual.

In certain embodiments, the methods of the invention further comprise additionally administering to the individual, prior to, concurrently with, or after the administration of the pharmaceutical composition of the invention, additional primary cancer treatments such as surgery, radiation therapy or chemotherapy. Means to improve the therapeutic effect of cancer on the individual.

In order to make the description of the present disclosure more detailed and complete, the following description of the embodiments of the present invention is intended to The features of various specific embodiments, as well as the method steps and sequences thereof, are constructed and manipulated in the embodiments. However, other specific embodiments may be utilized to achieve the same or equivalent function and sequence of steps.

First, the standard operation method of each test in the examples of the present invention will be described.

Cell Cell Sustainability Test Method

The cells used in this time are human blood cancer cell U937, human lung cancer cell A549, African green monkey kidney cell Vero, human malignant glioma cell line U87-MG, human liver cancer cell Mahlavu, human colon cancer cell SW-480, human breast cancer cell. MDA-MB-231, and human breast cancer cell line MDA-MB-468.

U937 and A549 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and 100 U/ml penicillin and 10 μg/ml streptomycin.

Vero, U87-MG, MDA-MB-231, MDA-MB-468, Mahlavu and SW480 cells were cultured in DMEM containing 10% fetal calf serum and 100 U/ml penicillin and 10 μg/ml streptomycin. in.

Vero, U87-MG, MDA-MB-231, MDA-MB-468, A549 and Mahlavu cells were seeded on 96-well plates in cell culture medium containing 10% fetal bovine serum, each well containing 1 × 104 cells The cells were cultured for 16 hours in a constant temperature incubator until the cells were attached. After washing twice with Phosphate-buffered saline (PBS), the cell culture medium containing 0.1% fetal bovine serum was added and cultured in a constant temperature incubator. After hours. Wash once with phosphate buffer, add cell culture medium containing drug and 0.1% fetal bovine serum (final concentration of drug is 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125, 0 μM, respectively). The chamber was incubated for 48 hours and cell viability was measured with Resazurin (final concentration 25 μg/mL).

SW480 cells were planted on a 96-well plate in a cell culture medium containing 10% fetal bovine serum. Each well contained 1 × 104 cells, and cultured in a constant temperature incubator for 36 hours until the cells were attached intact, and the cells were washed with phosphate buffer. After that, add the cell culture medium containing the drug and 0.1% fetal bovine serum (the final concentration of the drug is 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125, 0 μM, respectively) and incubate in a constant temperature incubator for 48 hours. Cell viability was measured with Resazurin (final concentration 25 μg/mL).

U937 cells were cultured in a constant temperature incubator for 24 hours in a cell culture medium containing 0.1% fetal bovine serum. After washing twice with phosphate buffer, the cell culture medium containing 0.1% fetal bovine serum was re-added and U937 cells were seeded at 96. In the well plate (containing 1 × 104 cells per well), add the cell culture medium containing the drug and 0.1% fetal bovine serum (the final concentration of the drug is 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, respectively). 0.78125, 0 μM) was cultured in a constant temperature incubator for 48 hours, and cell viability was measured with Resazurin (final concentration 25 μg/mL).

Next, the preferred embodiments of the present invention will be described in detail with reference to the drawings.

Preparation Example 1

1 to 3, FIG. 1 to FIG. 3 are flow charts for separating the compounds 1 to 23. First, the dried bitter gourd vine (dry weight 1.0 kg) was powdered by a powder mill and extracted three times with 10 liters of methanol (MeOH) each time. The extract was combined and filtered, and concentrated under reduced pressure. The ester/water (EtOAc/H 2 O) was separated from the liquid layer, and the ethyl acetate layer of the upper layer was taken and concentrated under reduced pressure to give a pale green crude extract of 35 g.

The crude extract was initially separated by column chromatography using silica gel (Silica gel 60, 70−230 mesh) with different ratios of organic solvent n-hexane/ethyl acetate/methanol (n-hexane/ The gradient was washed with EtOAc/MeOH. First use n-hexane as the initial solvent, and gradually increase the ratio of ethyl acetate (EtOAc) to increase the polarity of the embankment to ethyl acetate (EtOAc) to 100%, then ethyl acetate (EtOAc) is a dyke solution, and gradually increase the ratio of methanol (MeOH) to increase the polarity of the dyke solution to methanol (MeOH) to 100%, and by fractionation with ¹ H-NMR and TLC tablets, A total of 29 fractions were obtained, which were MC-1 to MC-29, and the separation flowchart is shown in Figure 1.

1. Purification and separation of compounds 1 and 2

Referring to Figure 1, the MC-19 (5 g) obtained by using the dyke solution as n-hexane/ethyl acetate (1:8) was subjected to reverse phase enthalpy with methanol/water (80:20) as a banknote. Column chromatography (RP-18, 230−400 mesh), divided into 2 divisions, MC-19-R1 and MC-19-R2; then, MC-19-R1 (4 g), using methanol/ Water (60:40 to 100:0) is a reverse phase tantalum rubber column chromatography (RP-18, 230−400 mesh) for the levee liquid, divided into 5 divisions, respectively MC-19-R1-R1 to MC -19-R1-R5; then, take MC-19-R1-R4 (3.3 g) for reverse phase high performance liquid chromatography HPLC (RP-18, 5 μm, 250 × 25 mm, Merck, UV-vis detector) Separation and purification were carried out with methanol/water (80:20) as a banknote to obtain Compound 1 (30 mg) and Compound 2 (40 mg).

2. Purification and separation of compound 3-10

Referring to Figure 2, 270 mg of MC-19-R1-R4 (3.3 g) was dissolved in acridine (2 ml), and 4 drops of acetic anhydride were added for three hours, then the reaction was terminated with water, followed by Ethyl acetate was separated into liquid and liquid, and the ethyl acetate layer of the upper layer was taken out and concentrated under reduced pressure, and then purified by a reverse phase high performance liquid chromatography (HPLC) column and reverse phase high performance liquid chromatography (HPLC) to obtain compound 3 (7 mg), 4 (3.2 mg), 5 (5.2 mg), 6 (9 mg), 7 (26.2 mg), 8 (3.5 mg), 9 (10.6 mg) and 10 (24 mg).

3. Purification and separation of compound 11

Referring to Figure 1, MC-18 (2 g) obtained using hexane solution as n-hexane/ethyl acetate (1:6) was pulverized with n-hexane/ethyl acetate (1:1−0:1). The levee liquid is subjected to a positive phase 矽 柱 冲 ( (Silica gel 60, 230−400 mesh), divided into 11 divisions, respectively MC-18-N1 to MC-18-N11; then, the dyke liquid will be used again MC-18-N4 (750 mg) obtained by n-hexane/ethyl acetate (1:3) was subjected to reverse phase tantalum column chromatography (RP-18, methanol/water (70:30−100:0) ratio. 230−400 mesh), divided into 11 divisions, MC-18-N4-R1 to MC-18-N4-R11; then, MC-18-N4-R3 (119.3 mg) was used for reverse phase high performance liquid phase Chromatography HPLC (RP-18, 5 μm, 250 × 25 nm, Merck, UV-vis detector) was isolated and purified using methanol/water (75:25) as a solvent to give compound 11 (26 mg).

4. Purification and separation of compound 12-14

Referring to Figure 1, the MC-27 (6.3 g) obtained using the embankment liquid as ethyl acetate/methanol (2:1) was subjected to a reverse phase tube at a ratio of methanol/water (60:40−100:0). Column chromatography (MCI), divided into 10 divisions, MC-27-M1 to MC-27-M10; MC-27-M2 (using the dyke solution for methanol/water (80:20)) 1 g) Reverse phase tantalum column chromatography (RP-18, 230−400 mesh) with methanol/water (60:40−100:0), divided into 8 divisions, respectively MC-27-M2-R1 To MC-27-M2-R8; take MC-27-M2-R5 (568.3 mg) for reverse phase high performance liquid chromatography HPLC (RP-18, 5 μm, 250 × 25 mm, Merck, UV-vis detector) Separation and purification were carried out with methanol/water (77:23) as a dyke, to give Compound 12 (32 mg), Compound 13 (30 mg), and Compound 14 (5 mg).

5. Purification and separation of compound 15-23

Referring to Figure 3, 300 mg of MC-19-R1-R4 (3.3 g) was dissolved in methanol (10 ml), and reacted with hydrochloric acid (0.1 M, 1 ml) at room temperature for 3.5 hours, then The reaction was terminated with water, followed by liquid-liquid layering using ethyl acetate and water, and the ethyl acetate layer of the upper layer was taken out and concentrated under reduced pressure, and then separated and purified using a reverse phase gel column and reverse phase high performance liquid chromatography HPLC. Compound 15 (14 mg), 16 (6 mg), 17 (14 mg), 18 (3 mg), 19 (3 mg), 20 (3 mg), 21 (2.9 mg), 22 (2 mg), 23 (12.2 mg),.

Then, with respect to the above-obtained Compound 1 to Compound 23, the chemical structural characteristics, functional groups, molecular weight, and spectral data are further identified or measured by nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry or the like. The identification or measurement results of the aforementioned Compound 1 to Compound 23 are shown in Table 1.

Table 1

<<Examples 1-23>>

With respect to the above-obtained Compound 1 to Compound 23, the cancer cell survival rate test was carried out by the above-mentioned "Cell Cancer Survival Rate Test Method", and the results obtained are shown in Figs. 4 to 26 .

Further, the cell growth inhibitory concentration IC50 (μM) of the aforementioned Compound 1 to Compound 23 was calculated according to the cancer cell survival rate test shown in FIGS. 4 to 26 (that is, the cell growth activity which inhibits 50% of the cell growth activity by the compound). Minimum concentration). The cell growth inhibitory concentration (IC50) of the above Compounds 1 to 23 was as shown in Table 2 below.

Table 2 ** means that the inhibitory concentration (IC50) of the cell growth activity of the compound is much larger than 256 μM, and has no inhibitory effect.

Table 2 (continued) ** means that the inhibitory concentration (IC50) of the cell growth activity of the compound is much larger than 256 μM, and has no inhibitory effect.

Table 2 (continued) ** means that the inhibitory concentration (IC50) of the cell growth activity of the compound is much larger than 256 μM, and has no inhibitory effect.

Next, with respect to the above-obtained Compound 1 to Compound 23, the data of the above Table 2 was used, and the ability of the compound to inhibit cell growth activity was evaluated based on the evaluation criteria described later.

That is, when the cell growth inhibitory concentration (IC50) of the compound described in the above Table 2 is more than 256 μM, the cell growth inhibitory ability of the compound is evaluated as extremely poor (XX); when the cell growth activity inhibitory concentration (IC50) When it is between 64 and 256 μM, the cell growth activity inhibiting ability of the compound is evaluated as inferior (X); when the compound has a cell growth inhibitory concentration (IC50) of between 16 and 64 μM, The cell growth activity inhibiting ability of the compound was evaluated as (△); when the compound had an inhibitory concentration (IC50) of 8 to 16 μM, the inhibitory ability of the compound was evaluated as good (○) when the compound When the cell growth inhibitory concentration (IC50) was less than 8 μM, the cell growth activity inhibiting ability of the compound was evaluated as excellent (?). The individual evaluation results of these compounds are shown in Table 3, respectively.

table 3

Table 3 (continued)

Table 3 (continued)

From the evaluation results of the cell growth activity inhibiting ability (IC50) described in the above Table 3, it is apparent that Compounds 4, 5, 7, 9, 10, and 20 are effective for inhibiting the effect of human neuroblastoma cell line U87-MG. It has "good (○)" human glioma cell growth inhibition ability, while compounds 2, 3, 8, and 23 have "excellent (◎)" human glioma cell growth inhibition ability; in other words, according to this The bitter melon and the derivative thereof obtained by the invention are effective ingredients for medicinal anti-neuronal brain tumor or for treating neuroencephaloma.

Compounds 2, 7, 8, and 23 have "good (○)" human hepatocarcinoma cell growth inhibitory ability, while Compound 9 has "excellent (?)" human hepatoma cell growth for the effect of inhibiting human liver cancer cell Mahlavu. Inhibition ability growth inhibiting ability; in other words, the bitter melon and the derivative thereof obtained according to the present invention are effective components for medicinal anti-liver cancer or for treating liver cancer.

Compounds 2, 4, 6, 7, 8, and 20 have "good (○)" colorectal cancer cell growth inhibitory ability, while Compound 23 has "excellent (◎) for the effect of inhibiting human colorectal cancer cell SW480. The human colorectal cancer cell growth inhibiting ability; in other words, the momordicin and its derivative obtained according to the present invention are effective components for medicinal anti-rectal colon cancer or for treating colorectal cancer.

Compounds 3, 4, 5, 10, and 23 have "good (○)" human lung cancer cell growth inhibitory ability for inhibiting human lung cancer cell A549, and compounds 2, 6, 7, and 8 have "excellent ( ◎)" lung cancer cell growth inhibiting ability; in other words, the bitter melon and its derivative obtained according to the present invention are effective ingredients for medicinal anti-lung cancer or for treating lung cancer.

Compounds 4, 9, 17, and 19 have "good (○)" blood cell growth inhibition ability for compounds that inhibit human blood cancer cell line U937, and compounds 2, 3, 5, 6, 7, 8, 10, 15, And 20-23 have "excellent (?)" blood cancer cell growth inhibiting ability; in other words, the momordicin and its derivative obtained according to the present invention are effective ingredients for medicinal anti-blood cancer or for treating blood cancer.

Compounds 4, 5, 10, and 20 have "good (○)" growth inhibition ability of breast cancer cell line MDA-MB-231, while compounds 2, 3, and 7 have effects on inhibition of human breast cancer cell line MDA-MB-231. , 8, and 23 have "excellent (◎)" breast cancer cell line MDA-MB-231 growth inhibition ability; in addition, for inhibition of the effect of human breast cancer cell line MDA-MB-468, compound 3, 6, 7, 8, And 17 have "good (○)" breast cancer cell line MDA-MB-468 growth inhibiting ability, while compounds 2, 20, and 23 have "excellent (◎)" breast cancer cell line MDA-MB-468 growth inhibiting ability; in other words, The Momordicin and its derivatives obtained according to the present invention are effective ingredients for medicinal anti-breast cancer or for treating breast cancer.

From the exemplification of the above-mentioned Example 1 - Example 23, it is apparent that the pharmaceutical compound for treating cancer of the present invention has a chemical structure represented by the chemical formula (I) or the chemical formula (II), and is applicable to various human cancer cells. All of them have excellent cell growth activity inhibiting ability, and thus the compound of the present invention is an effective active ingredient for the treatment of cancer, and can be formulated into a pharmaceutical compound or a pharmaceutical composition for treating cancer.

Although the embodiments of the present invention are disclosed in the above embodiments, the present invention is not intended to limit the invention, and the present invention may be practiced without departing from the spirit and scope of the invention. Various changes and modifications may be made thereto, and the scope of the invention is defined by the scope of the appended claims.

Fig. 1 is a flow chart showing the separation of the compound 1, 2 and the compound 11 to the compound 14 in Preparation Example 1 of the present invention. Fig. 2 is a flow chart showing the separation of the compound 3 to the compound 10 in Preparation Example 1 of the present invention. Fig. 3 is a flow chart showing the separation of the compound 15 to the compound 23 in Preparation Example 1 of the present invention. Fig. 4 is a graph showing the results of cell survival test of Compound 1 in Example 1 of the present invention. Fig. 5 is a graph showing the results of cell viability test of Compound 2 in Example 2 of the present invention. Fig. 6 is a graph showing the results of cell viability test of Compound 3 in Example 3 of the present invention. Fig. 7 is a graph showing the results of cell viability test of Compound 4 in Example 4 of the present invention. Fig. 8 is a graph showing the results of cell survival test of Compound 5 in Example 5 of the present invention. Fig. 9 is a graph showing the results of cell viability test of Compound 6 in Example 6 of the present invention. Fig. 10 is a graph showing the results of cell survival test of Compound 7 in Example 7 of the present invention. Figure 11 is a graph showing the results of cell viability test of Compound 8 in Example 8 of the present invention. Figure 12 is a graph showing the results of cell viability test of Compound 9 in Example 9 of the present invention. Figure 13 is a graph showing the results of cell viability test of Compound 10 in Example 10 of the present invention. Figure 14 is a graph showing the results of cell viability test of Compound 11 in Example 11 of the present invention. Figure 15 is a graph showing the results of cell viability test of Compound 12 in Example 12 of the present invention. Figure 16 is a graph showing the results of cell viability test of Compound 13 in Example 13 of the present invention. Figure 17 is a graph showing the results of cell survival test of Compound 14 in Example 14 of the present invention. Figure 18 is a graph showing the results of cell viability test of Compound 15 in Example 15 of the present invention. Figure 19 is a graph showing the results of cell viability test of Compound 16 in Example 16 of the present invention. Figure 20 is a graph showing the results of cell survival test of Compound 17 in Example 17 of the present invention. Figure 21 is a graph showing the results of cell viability test of Compound 18 in Example 18 of the present invention. Figure 22 is a graph showing the results of cell survival test of Compound 19 in Example 19 of the present invention. Figure 23 is a graph showing the results of cell viability test of Compound 20 in Example 20 of the present invention. Figure 24 is a graph showing the results of cell viability test of Compound 21 in Example 21 of the present invention. Figure 25 is a graph showing the results of cell survival test of Compound 22 in Example 22 of the present invention. Figure 26 is a graph showing the results of cell viability test of Compound 23 in Example 23 of the present invention.

Claims (8)

A compound for treating cancer and a pharmaceutically acceptable salt thereof having the structure represented by the following chemical formula (I): The X system indicates: R ₁ represents a hydrogen atom or a fluorenyl group having 10 or less carbon atoms; R ₂ represents a hydrogen atom or a fluorenyl group having 10 or less carbon atoms; and R ₃ represents a hydrogen atom or a fluorenyl group having 10 or less carbon atoms; R ₄ Represents a hydrogen atom; when X is expressed as At least one of R ₁ , R ₂ , and R ₃ is a fluorenyl group having 10 or less carbon atoms; and when X is represented as At least one of R ₁ and R ₂ is a fluorenyl group having 10 or less carbon atoms. The compound for treating cancer and the pharmaceutically acceptable salt thereof according to claim 1, wherein the thiol group is an ethyl hydrazide group. The compound for treating cancer and a pharmaceutically acceptable salt thereof according to claim 1, wherein the cancer is at least one of malignant glioma, liver cancer, colon cancer, lung cancer, blood cancer, and breast cancer. A pharmaceutical composition for treating a cancer, comprising at least the compound according to any one of claims 1 to 3, and a pharmaceutically acceptable salt, and a carrier, a diluent, an excipient, and/or an adjuvant Any of them. The pharmaceutical composition for cancer treatment according to claim 4, wherein the carrier is a liposome, a liposome, a brown alga, a leaf algae, a Fucus, a seaweed, or a wakame. The pharmaceutical composition for cancer treatment according to claim 4, which is further prepared to form a tablet, a capsule, a powder, a granule, a patch, a liquid, or other pharmaceutically acceptable dosage form. The invention relates to a use of a bitter gourd extract for preparing a pharmaceutical composition for treating cancer, wherein the bitter gourd extract is a compound having the structure represented by the following formula (I) or formula (II) and a pharmaceutically acceptable salt: Wherein X and Y are each independently represented: R ₁ represents a hydrogen atom or a fluorenyl group having 10 or less carbon atoms; R ₂ represents a hydrogen atom, a fluorenyl group having 10 or less carbon atoms, or a glucosyl group; and R ₃ represents a hydrogen atom and a fluorenyl group having 10 or less carbon atoms; An alkyl group having a carbon number of 10 or less, or a glucosyl group; R ₄ represents a hydrogen atom or an alkyl group having 10 or less carbon atoms; and R ₅ represents an alkyl group having 10 or less carbon atoms; when the bitter gourd extract has the chemical formula (I) In the structure shown, wherein R ₁ is a hydrogen atom and R ₂ is a glucosyl group, R ₃ and R ₄ are a hydrogen atom; and when the bitter gourd extract has a structure represented by the formula (I), and R ₃ is a glucosyl group. When R ₁ and R ₂ are a hydrogen atom. The use of the bitter gourd extract according to claim 7 for the preparation of a pharmaceutical composition for cancer treatment, wherein the bitter gourd extract can inhibit human blood cancer cell U937, human lung cancer cell A549, human malignant glioma cell line U87-MG, Cancer cell growth of at least one of human liver cancer cell Mahlavu, human colon cancer cell SW-480, human breast cancer cell line MDA-MB-231, and human breast cancer cell line MDA-MB-468.