A pharmaceutical composition and a method for preparing the same that effectively prevent the inactivation of SN triple bond structure compounds and improve target activity.

Abstract

The present invention relates to the technical field of drugs, in particular to a pharmaceutical composition that can effectively prevent the inactivation of SN triple bond compounds and improve target activity. The pharmaceutical composition includes an SN triple bond compound, a stabilizing protective agent and a pharmaceutical additive. The pharmaceutical composition of the present invention very ingeniously solves the problems of proton deficiency, water deficiency in the environment of the SN triple bond compound, as well as the hydrophobicity, targeting, acid avoidance and reaction loss of other reactive substances of the composition, thereby laying the foundation for the subsequent successful and effective application of this kind of pharmaceutical composition in drugs such as antitumor drugs.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceuticals, and more particularly to a pharmaceutical composition that can effectively prevent the inactivation of SN triple bond structure compounds and improve their target activity. [Background technology]

[0002] SN triple bond compounds are artificially synthesized compounds containing a sulfur-nitrogen triple bond. Furthermore, SN triple bond compounds are extremely rare compounds possessing a sulfur-nitrogen triple bond functional group (S≡N), and are lipophilic low-molecular-weight compounds. The sulfur-nitrogen triple bond in these compounds is highly reactive, readily protonating and exhibiting very strong proton-capturing activity towards protons in piperidine-like compounds. Therefore, in applications where proton capture inhibits the synthesis of DNA, RNA, and proteins in proton-containing sites similar to piperidine structures within cellular chromosomes, thereby hindering the division and proliferation of rapidly growing cancer cells, SN triple bond compounds have extremely high application value and future potential. Additionally, in the case of compounds with an alkoxy group on the sulfur atom, protonation of the sulfur-nitrogen group gives these drugs a highly active alkylating group, and by binding to nucleic acids in somatic cells, they can suppress and destroy cancer cells, thus potentially enhancing autoimmune effects. The greatest characteristic of this type of compound is that, under certain conditions, the sulfur-nitrogen triple bond readily captures protons from piperidine analogs, leading to a loss of replication activity. Furthermore, by inserting alkyl groups into the base chain, it accelerates the inhibition of base replication and protein synthesis. The sulfur-nitrogen triple bond is particularly prone to protonation in acidic media. Moreover, its alkylation activity becomes very high, making it highly likely to alkylate base chains and inhibit cell proliferation. On the other hand, the greatest weakness of this type of compound is as follows: In an acidic environment, the functional group of the sulfur-nitrogen triple bond is easily destroyed, losing its protonation activity and making it impossible to inhibit replication and proliferation by capturing protons from bases such as DNA and RNA. In addition, the sulfur-nitrogen triple bond compound rapidly loses its inhibitory effect on base chains after protonation. Furthermore, the SN triple bond compound in the solvent also reacts with piperidine, making it difficult to capture protons on the molecule, significantly reducing its actual efficacy in anticancer, bacteriostatic, and cancer cell killing. The above are the main reasons why the above compounds have not yet been applied in the pharmaceutical field.Therefore, the key points to be addressed in this invention are how to effectively protect the activity of this type of compound until it reaches the target, maintain very high activity even after reaching the target to effectively generate a proton capture reaction with the piperidine analog, and further extend the residence time to enhance targeting.

[0003] To date, the applicant has conducted extensive research on the deprotonation and alkylation of piperidine-like compounds using sulfur-nitrogen triple bond compounds. As a result, it has been found that while sulfur-nitrogen triple bond compounds exhibit extremely high activity below 40 degrees Celsius, their greatest drawback is that they are easily decomposed and inactivated by acidic media, and they readily lose their protonation and alkylation activity through hydrolysis and decomposition.

[0004] As is well known, many drugs are susceptible to significant reduction or even loss of efficacy due to hydrolysis or deliquescence. Therefore, to avoid hydrolysis, drugs may be manufactured as lyophilized preparations, injections, injectable powders, tablets, capsules, or granules, depending on their properties, and administered via intravenous, oral, or perfusion routes. However, to minimize the loss of efficacy, it is also necessary to reliably guarantee the stability of the active drug using scientific methods. This remains a crucial issue that needs further resolution in specific clinical applications.

[0005] Currently, there are no reports of SN triple bond structure compounds being applied to inhibit cell proliferation or as antitumor drugs, due to factors such as susceptibility to hydrolysis, inactivation, and stability. Therefore, it is necessary to provide compositions of SN triple bond structure compounds that are less prone to deliquescence, hydrolysis, and degradation, and that exhibit high activity against target substances. This will solve the problems of hydrolysis and degradation of SN triple bond structure drugs in industrial production and processing processes, as well as the problem of maintaining high activity and stability of active drugs before reaching target cells and against target substances, thereby reducing the degradation of SN triple bond structure compounds. [Overview of the project] [Problems that the invention aims to solve]

[0006] In view of the shortcomings of the prior art described above, the object of the present invention is to provide a pharmaceutical composition that can effectively prevent the inactivation of SN triple bond structure compounds and improve target activity by very cleverly solving problems such as proton deficiency, water deficiency, and loss of reaction of hydrophobicity, targetability, acid avoidance, and other reactive substances in the environment in which SN triple bond compounds exist, thereby laying the foundation for subsequently applying this type of pharmaceutical composition to drugs such as antitumor agents in a good and effective manner. [Means for solving the problem]

[0007] To achieve the above-mentioned objectives and other related objectives, the present invention is realized by the following technical solution.

[0008] In one aspect, the present invention provides a pharmaceutical composition. The raw materials of the pharmaceutical composition contain, by mass percent, SN triple bond structure compound: 2-98%, stabilizing protective agent: 0.5-97%, and pharmaceutical additive: 0.1-55%.

[0009] In some embodiments of the present invention, the raw materials of the pharmaceutical composition further include a lubricant. The raw materials of the pharmaceutical composition contain, by mass percent, SN triple bond structure compound: 40-85%, stabilizing protective agent: 0.5-8%, pharmaceutical additive: 5-55%, and lubricant: 2-18%.

[0010] In some embodiments of the present invention, the pharmaceutical composition is dissolved in a solvent before use. Preferably, the solvent is selected from anhydrous ethanol.

[0011] In some embodiments of the present invention, the SN triple bond structure compound is selected from APSNRI and / or FPSNRI.

[0012] In some embodiments of the present invention, the stabilizing protective agent is selected from one or more combinations of sodium alkoxides, alcohols, alcohol-based polymers, pyridines, proton-deficient hydrophobic greases, etc. The aim is to provide a composition that provides an active proton-deficient environment for the main SN triple bond structure compound and enhances solubility and target activity. Preferably, the stabilizing protective agent is selected from one or more combinations of sodium ethoxide, 4-dimethylaminopyridine, polyethylene glycol monoalkyl ether, and anhydrous ethanol.

[0013] In some embodiments of the present invention, the pharmaceutical additive is selected from one or more combinations of microcrystalline cellulose, pregelatinized starch, and capsules.

[0014] In some embodiments of the present invention, the lubricant is selected from one or more combinations of talcum powder, magnesium stearate, and fine silica gel. Preferably, the lubricant is selected from fine silica gel.

[0015] In other aspects, the present invention provides a method for preparing a pharmaceutical composition. This method includes preparing a composition by mixing an SN triple bond structure compound, a stabilizing protective agent, and a pharmaceutical additive.

[0016] In some embodiments of the present invention, the preparation involves adding a lubricant to an SN triple bond structure compound, a stabilizing protective agent, and a pharmaceutical additive, mixing them, and then obtaining the product.

[0017] In other aspects, the present invention provides for the use of the above-mentioned pharmaceutical composition in drugs that inhibit cell proliferation and antitumor drugs. [Modes for carrying out the invention]

[0018] The following describes in detail embodiments of a pharmaceutical composition that effectively prevents the inactivation of SN triple bond structure compounds and improves target activity in the present application.

[0019] The “range” disclosed in this application is limited in the form of a lower limit and an upper limit. The defined range is limited by selecting one lower limit and one upper limit, and the boundaries of the specific range are limited by the selected lower and upper limits. The range limited in this manner may or may not include endpoint values, and may be any combination. That is, one lower limit may be combined with any upper limit to form a single range. For example, if the ranges 60~120 and 80~110 are presented for a particular parameter, it is interpreted that the ranges 60~110 and 80~120 are also considered. Also, if the minimum range values ​​are 1 and 2, and the maximum range values ​​are 3, 4 and 5, then all ranges of 1~3, 1~4, 1~5, 2~3, 2~4 and 2~5 are considered. In this application, unless otherwise explained, the numerical range “a~b” is an abbreviated representation of any combination of real numbers between a and b, and both a and b are real numbers. For example, the numerical range "0 to 5" means that all real numbers between "0 to 5" are presented in the text, while "0 to 5" is merely an abbreviated representation of combinations of these numbers. Furthermore, the statement that any parameter is an integer ≥ 2 is equivalent to disclosing that the parameter is an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0020] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0021] Unless otherwise specified, all technical features and selectable technical features of this application can be combined to form new technical solutions.

[0022] Unless otherwise specified, all steps of the present application may be carried out in order or randomly, but preferably in order. For example, when the method includes steps (1) and (2), it means that the method may include steps (1) and (2) carried out in order, or steps (2) and (1) carried out in order. Also, for example, when it is said that the method presented above may further include step (3), it means that step (3) may be added to the method in any order. For example, the method may include steps (1), (2) and (3), or steps (1), (3) and (2), or steps (3), (2) and (1), etc.

[0023] Unless otherwise specified, "comprising" and "containing" as referred to in the present application may be in an open - ended form or a closed - ended form. For example, "comprising" and "containing" may include or contain other components not listed, or may include or contain only the listed components.

[0024] Unless otherwise specified, in the present application, "or" is an inclusive term. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the conditions where A is true (or exists) and B is false (or does not exist), where A is false (or does not exist) and B is true (or exists), or where both A and B are true (or exist) satisfies the condition of "A or B".

[0025] The inventors of this invention, as a result of extensive exploration and experimentation, provide a pharmaceutical composition and formulation thereof that effectively prevents hydrolysis and degradation of SN triple bond structure compounds, thereby improving their deprotonation activity and alkylation activity toward target substances. This cleverly solves problems such as proton deficiency, water deficiency, and loss of reaction of other reactive substances in the environment in which SN triple bond compounds exist, thereby laying the foundation for the subsequent successful and effective application of this type of pharmaceutical composition as an antitumor drug.

[0026] In its first aspect, the present invention provides a pharmaceutical composition. It aims to provide a composition that, for SN triple bond compounds prone to hydrolysis and decomposition, can easily remove active protons, water deficiency, and a hydrophobic environment, as well as protons from piperidine analogs, and that is easily soluble while improving target activity. The raw materials of the pharmaceutical composition include an active component, an SN triple bond structure compound, a stabilizing protective agent, and a pharmaceutical additive. Of these, the stabilizing protective agent can maintain the proton deficiency, hydrophobicity, and water deficiency of the pharmaceutical composition, and can improve the deprotonation activity and hydrophobic state of the main compound, thereby effectively preventing the inactivation of the SN triple bond structure compound and improving its target activity.

[0027] The pharmaceutical compositions provided in the present invention typically need to contain a certain proportion of SN triple bond structure compounds. The raw materials for the pharmaceutical compositions contain 2 to 98% by mass of SN triple bond structure compounds. In some examples, the mass percentage of the SN triple bond structure compounds may be 2 to 40%, 40 to 85%, 85 to 98%, 40 to 50%, 50 to 80%, 80 to 85%, 40 to 60%, 60 to 80%, 5 to 90%, 10 to 80%, 20 to 70%, 30 to 60%, or 40 to 70%, etc.

[0028] The molecular formula of an SN triple bond compound can be represented by the following general formula.

[0029] [ka]

[0030] R1 and R3 are aryl groups, preferably phenyl groups, and R2 is mainly a common type such as OCH3, OC2H5, OC3H7, or F.

[0031] In some examples, the SN triple bond structure compound can be selected from, for example, APSNRI and / or FPSNRI. For convenience of use, typically R2 is OCH3, OC2H5, OC3H7, etc., and APSNRI (Alkoxy(aryl)(phenyl)-λ) is a compound in which R1 and R3 are aryl groups. 6 These are called FPSNRI (Aryl(fluoro)(phenyl)-λ). Furthermore, when R1 and R3 are aryl groups and R2=F, they are called FPSNRI (Aryl(fluoro)(phenyl)-λ. 6 These are called -sulfanenitriles. The aryl group includes a phenyl group and various situations in which substituents are present on the phenyl group. The substituents may be, for example, alkyl groups, halogen groups, nitro groups, etc. The molecular weight of APSNRI is 231 or higher. In the specific example, if R2=OCH3 and R1 and R3 are the same phenyl group, the molecular weight of APSNRI is 231. Also, the molecular weight of FPSNRI is 219 or higher. In the specific example, if R2=F and R1 and R3 are the same phenyl group, the molecular weight of FPSNRI is 219.

[0032] The pharmaceutical compositions provided in the present invention typically require the inclusion of a certain proportion of a stabilizing protective agent. Here, "stabilizing protective agent" means an agent that can function as both a stabilizing protective agent and a protective agent. The raw materials of the pharmaceutical composition contain 0.5 to 97% of the stabilizing protective agent by mass percentage. Specifically, in some examples, the mass percentage of the stabilizing protective agent may be 0.5 to 8%, 8 to 20%, 20 to 40%, 40 to 60%, 60 to 80%, 80 to 97%, 0.5 to 1%, 1 to 6%, 6 to 8%, 1 to 5%, 5 to 8%, 1 to 95%, 5 to 90%, 10 to 85%, 20 to 75%, 30 to 65%, or 40 to 55%, etc.

[0033] In the pharmaceutical compositions provided by the present invention, a compound can be selected as a stabilizing protective agent for an SN triple bond structure compound that can impart proton deficiency to the SN triple bond structure compound, accept protons, is easily soluble, and has the ability to improve target activity. In some examples, the stabilizing protective agent can be selected from one or more combinations of, for example, sodium alkoxides, alcohols, alcohol-based polymers, pyridines, and proton-deficient hydrophobic greases. Preferably, the stabilizing protective agent is selected from one or more combinations of, sodium ethoxide, 4-dimethylaminopyridine, polyethylene glycol monoalkyl ether, and anhydrous ethanol. The molecular formula of polyethylene glycol monoalkyl ether is HO(CH2CH2O). n C 12 H 25 The molecular weight can be, for example, 1100-1300, 1100-1200, 1200-1300, etc. More preferably, the stabilizing protective agent is selected from sodium alkoxide and / or polyethylene glycol monoalkyl ether. In some examples, in addition to the proton-deficient alcohol group, the stabilizing protective agent also includes other substances such as sodium chloride.

[0034] In this invention, sodium alkoxide or DMAP, polyethylene glycol monoalkyl ether, etc., which are proton-deficient and proton-receiving, are used as stabilizing protective agents for SN triple bond structures for the following reasons. Specifically, from the pH-rate distribution, the hydrolysis of SN triple bond structures is a first-order reaction, and acid hydrolysis is relatively fast. For example, at a temperature of 25 degrees Celsius, an SN triple bond structure compound having a C2H4O group (0.035moldm -3 ) is a D2O / CD3CN solvent (phosphate buffer 8:1), pD 6.1, total buffer concentration 0.065 mol.dm³. -3 Under these conditions, 99% of the SN triple bond structure compounds are hydrolyzed within 45 minutes.

[0035] [ka]

[0036] On the other hand, when an appropriate amount of sodium alkoxide, DMAP, polyethylene glycol monoalkyl ether, etc., which are proton-deficient or deprotonated compounds that accept proton hydrogen ions, is added to the pharmaceutical composition, it becomes possible to maintain a slightly alkaline environment in some parts, which is advantageous in preventing the hydrolysis of SN triple bond structure compounds. Furthermore, the number of protons in the environment is significantly reduced, and the protonation of the SN triple bond structure is decreased, thus reducing the decomposition and inactivation effect. Therefore, in the present invention, the stabilizing protective agent is, firstly, one that reduces the hydrogen ion concentration in the environment, secondly, one that reduces the water content in the environment and absorbs water when it encounters a small amount of water in the environment, and thirdly, one that makes the pharmaceutical composition hydrophobic and easily soluble in piperidines.

[0037] The pharmaceutical compositions provided in the present invention typically need to contain a certain proportion of pharmaceutical additives. The raw materials of the pharmaceutical composition contain 0.1 to 55% by mass of pharmaceutical additives. In some examples, the mass percentage of the pharmaceutical additives may be 0.1 to 5%, 5 to 55%, 5 to 10%, 10 to 45%, 45 to 55%, 10 to 35%, 35 to 55%, 1 to 50%, 5 to 45%, 10 to 40%, or 20 to 35%, etc.

[0038] In the pharmaceutical composition provided by the present invention, in order to further ensure the stability of the drug during storage and use, pharmaceutical additives with low hygroscopicity should be selected. Lactose is an additive commonly used in drugs, but due to its high hygroscopicity, when directly tabletting, it is not only disadvantageous for the stability of the SN triple bond structure compound, but also disadvantageous for the storage of the tablets after production. On the other hand, pregelatinized starch has a certain hygroscopicity, so when tabletted alone, it is disadvantageous for the stability of the SN triple bond structure compound. However, pregelatinized starch is excellent in both compression moldability and fluidity, and more ideal effects can be achieved when used in combination with microcrystalline cellulose. Therefore, in the pharmaceutical composition of the present invention, the pharmaceutical additive is selected from one or a combination of more than one of microcrystalline cellulose, pregelatinized starch, and capsules. Preferably, the pharmaceutical additive used is microcrystalline cellulose and / or pregelatinized starch. Among these, the molecular formula of microcrystalline cellulose is (C6H 10 O5) n / 2 and the degree of polymerization is n≦350. In the experiment, microcrystalline cellulose ph103 was used. Also, the molecular formula of pregelatinized starch is (C6H 10 O5) n and the degree of polymerization is n = 300~1000.

[0039] More preferably, the pharmaceutical additive is a combination of microcrystalline cellulose and pregelatinized starch. Also, the mass ratio of microcrystalline cellulose to pregelatinized starch is 1~2:1~4, 1~2:~1~2, 1~2:2~3 or 1~2:3~4, etc.

[0040] In a specific embodiment, the raw materials of the pharmaceutical composition contain, by mass percentage, SN triple bond structure compound: 2~98%, stability protectant: 0.5~97%, pharmaceutical additive: 0.1~55%.

[0041] In the pharmaceutical composition provided by the present invention, generally, different pharmaceutical additives may be selected according to the difference in the target site. If it is a site such as the stomach, intestine, esophagus, etc., assistance such as a lubricant is required. Therefore, the pharmaceutical composition may further contain a lubricant.

[0042] The pharmaceutical composition provided in the present invention contains a lubricant in mass percentage of 2 to 18% of the pharmaceutical composition. The mass percentage of the lubricant may be 2 to 3%, 3 to 15%, 15 to 18%, 2 to 5%, 5 to 10%, 10 to 18%, or 3 to 15%, 5 to 12%, or 8 to 10%, etc.

[0043] In the pharmaceutical composition provided by the present invention, the lubricant is selected from one or more combinations of talcum powder, magnesium stearate, and fine silica gel. Fine silica gel has a high water absorption capacity and is therefore usually used as a desiccant for chemicals and medical supplies to prevent moisture in the atmosphere. Fine silica gel can also act as a purifying agent for some moisture in tablets, absorbing free water in the micropores of the tablet to reduce the interaction between water and drug molecules, thereby exhibiting a certain stabilizing effect on SN triple bond structure compounds. On the other hand, magnesium stearate is somewhat inferior and contains free metal ions, which may promote the hydrolysis of SN triple bond structure compounds. Therefore, in the present invention, it is preferable to use fine silica gel that can act not only as a lubricant but also as a stabilizing and protective agent.

[0044] In specific examples, the raw materials of the pharmaceutical composition contain, by mass percent, SN triple bond structure compound: 40-85%, stabilizing protective agent: 0.5-8%, pharmaceutical additive: 5-55%, and lubricant: 2-18%.

[0045] In a preferred specific embodiment, the raw materials of the pharmaceutical composition contain, by mass percent, SN triple bond structure compound: 50-80%, stabilizing protective agent: 1-6%, pharmaceutical additive: 10-45%, and lubricant: 3-15%.

[0046] In a more preferred specific embodiment, the raw materials of the pharmaceutical composition contain, by mass percent, SN triple bond structure compound: 60-80%, stabilizing protective agent: 1-5%, pharmaceutical additive: 10-35%, and lubricant: 5-10%.

[0047] The pharmaceutical composition provided in the present invention can be dissolved in a solvent. Preferably, the solvent is selected from anhydrous ethanol. The amount of anhydrous ethanol used should be sufficient to dissolve the pharmaceutical composition, and may be, for example, a mass ratio of 1-8:5-30. In some examples, the mass ratio may be 1-3:5-30, 3-5:5-30, 5-8:5-30, 1-8:5-10, 1-8:10-20, or 1-8:20-30, etc.

[0048] Anhydrous ethanol allows for the direct dissolution of SN triple bond compounds, stabilizing agents, and pharmaceutical additives in a pharmaceutical composition, followed by direct injection into a piperidine-containing solution (mimicking a biological environment). This effectively protects the activity of these compounds until they reach the target, and upon reaching the vicinity of the target, maintains an environment deficient in active protons or hydrogen ions, hydrophobicity, and water, resulting in a hydrophobic state. This facilitates approach and dissolution of piperidine analogs, and enables highly efficient proton capture reactions with piperidine analogs due to their extremely high activity. Furthermore, it increases residence time and enhances targetability.

[0049] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition described in the first aspect of the present invention. This method includes mixing an SN triple bond structure compound, a stabilizing protective agent, and a pharmaceutical additive, and then preparing the mixture to obtain the pharmaceutical composition.

[0050] If the pharmaceutical composition is to be used in areas such as the stomach, intestines, or esophagus, further additives such as lubricants will be necessary. Therefore, the specific examples include further adding a lubricant to an SN triple bond structure compound, a stabilizing protective agent, and a pharmaceutical additive, mixing them, and then preparing the pharmaceutical composition.

[0051] In the method for preparing a pharmaceutical composition provided in the present invention, the pharmaceutical composition may be manufactured in the form of a tablet, capsule, or other formulation. When using the whole powder direct compression method, the drying process in wet granulation can be omitted, thus reducing the possibility of hydrolysis of the SN triple bond structure compound during the production process.

[0052] Furthermore, regarding the packaging of pharmaceutical products, the packaging material is also an important part of improving the stability of the drug. Wrapping the outside in aluminum foil and individually sealing it to better isolate it from air can help prevent hydrolysis. Experiments have shown that using aluminum foil significantly improves the stability of SN triple bond structure compounds.

[0053] In other aspects, the present invention provides the use of pharmaceutical compositions in drugs that inhibit cell proliferation and antitumor agents. By applying pharmaceutical compositions to drugs that inhibit cell proliferation and antitumor agents, it becomes possible to reduce the degradation of SN triple bond structure compounds by solving the problem of stability of high activity of the active drug before it reaches the target cells and against the target.

[0054] Compared to conventional technologies, the pharmaceutical compositions and formulations of the present invention can effectively prevent the hydrolysis of SN triple bond structure compounds. The stabilizing protective agent can maintain the pharmaceutical composition in a state of environmental active proton deficiency, hydrophobicity, and water deficiency, and can also improve the target activity of the main compound, thereby effectively improving and maintaining deprotonation, alkylation, and other activities toward the target. By cleverly utilizing the time difference in dissolution between similar substances, an interesting effect is observed in which deprotonation activity can be significantly improved over time. This not only extends the activity time of the drug but also improves the deprotonation and alkylation activities. This provides a solid foundation for subsequent clinical trials.

[0055] Embodiments of the present invention will be described below through specific examples. Those skilled in the art will readily understand other advantages and effects of the present invention from the disclosures herein. Furthermore, the present invention can be implemented or applied by other different specific embodiments. Also, various additions or modifications can be made to each detail herein, based on different perspectives and applications, without departing from the spirit of the invention.

[0056] Unless otherwise specified, the reagents, materials, and instruments used in the examples described later may all be obtained by purchase.

[0057] The experimental materials used in the following experiments included APSNRI, FPSNRI, sodium ethoxide, DMAP, polyethylene glycol monoalkyl ether, finely powdered silica gel, microcrystalline cellulose, pregelatinized starch, and anhydrous ethanol. The equipment used mainly consisted of the same tablet press (19-tablet press) and an electric thermostat.

[0058] Tablets and solvent: The tablets were dissolved in anhydrous ethanol at the time of use and injected into piperidine to exert their effect.

[0059] The solvent used was anhydrous ethanol. During use, it exerted its effect by being directly injected into piperidine.

[0060] The stability, deprotonation activity, and other effects of the pharmaceutical composition containing the SN triple bond structure compound of the present invention are as follows: 1 Analysis and measurement were performed based on changes in the 1H NMR area ratio. This was a commonly used method. Furthermore, the reaction product of piperidine could be synthesized by other known methods or compared and analyzed against commercially available corresponding reaction products (e.g., the reaction product of Scheme 2).

[0061] [ka]

[0062] APSNRI was obtained by the reaction of FPSNRI. The raw materials were purchased from Sinopharmaceutical Group Chemical Reagents Co., Ltd. The following literature was consulted regarding the synthesis and preparation.

[0063] 1)Bull.Chem.Soc.Jpn.71,1629-1637(1998),Yoshimura,T;Ohkubo,M.;Fujii,T.;Kita,H.;Wakai,Y.;Ono,S.;etc.

[0064] FPSNRI was obtained by a multi-step reaction involving phenyl sulfide, chloramine T, etc. The raw materials were purchased from Sinopharmaceutical Chemicals Ltd. The following literature was consulted for details on the synthesis and preparation.

[0065] 1) Tetrahedron Lett, 30, 6339-6340 (1989), Yoshimura, T; Tsukurimichi, E.; Kita, H.; Fujii, H.; Shimasaki, C. 2)a.Chem.Lett.1433-1436(1992), Yoshimura, T.etc. b.Chem.Lett.2213-2216(1992), Yoshimura, T.etc. cJOrg.Chem.62.3802-3803(1997), Yoshimura, T.etc.

[0066] The finely powdered silica gel was purchased from Lianshuo Biotechnology Co., Ltd. The specifications were 200-300 mesh.

[0067] Microcrystalline cellulose was purchased from Xueji Food Distribution Company and produced by Huzhou Lingxinwang Chemical Co., Ltd. in accordance with GB1886.103.

[0068] Pregelatinized starch was purchased from Shanghai Qianwei Food Additives Co., Ltd.

[0069] Polyethylene glycol monoalkyl ether was purchased from a scientific research reagents and consumables store (Brij-35).

[0070] Comparative Example 1 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: APSNRI 100mg

[0071] Specific manufacturing method The aforementioned SN triple bond structure compounds were uniformly mixed using a direct compression method to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0072] Comparative Example 2 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: APSNRI 100mg Sodium ethoxide 5mg DMAP 20mg Polyethylene glycol monoalkyl ether 10 mg

[0073] Specific manufacturing method The aforementioned SN triple bond structure compound, sodium ethoxide, DMAP, and polyethylene glycol monoalkyl ether were homogeneously mixed. Furthermore, using a direct tableting method, the mixture was homogeneously combined to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0074] Comparative Example 3 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: APSNRI 100mg DMAP 20mg Polyethylene glycol monoalkyl ether 10 mg

[0075] Specific manufacturing method The aforementioned SN triple bond structure compound, DMAP, and polyethylene glycol monoalkyl ether were homogeneously mixed. Furthermore, using a direct compression method, the mixture was homogeneously combined to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0076] Comparative Example 4 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: APSNRI 100mg Polyethylene glycol monoalkyl ether 10 mg

[0077] Specific manufacturing method The aforementioned SN triple bond structure compound and polyethylene glycol monoalkyl ether were homogeneously mixed. Furthermore, using a direct tableting method, the mixture was homogeneously combined to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0078] Comparative Example 5 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: APSNRI 100mg DMAP 20mg

[0079] Specific manufacturing method The aforementioned SN triple bond structure compound and DMAP were homogeneously mixed. Furthermore, using a direct compression method, the mixture was homogeneously mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0080] Comparative Example 6 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: APSNRI 100mg Sodium ethoxide 5mg

[0081] Specific manufacturing method The aforementioned SN triple bond structure compound and sodium ethoxide were homogeneously mixed. Furthermore, using a direct compression method, the mixture was homogeneously mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0082] Example 1 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured using the same method as in Comparative Example 1. The composition of the pharmaceutical composition used in this formulation was as follows. APSNRI 100mg Sodium ethoxide 8mg DMAP 10mg Polyethylene glycol monoalkyl ether 20 mg Microcrystalline cellulose 20 mg Pregelatinized starch 40mg

[0083] Specific manufacturing method Tablet Compression and Manufacturing: The above-mentioned SN triple bond structure compound, sodium ethoxide, DMAP, polyethylene glycol monoalkyl ether, microcrystalline cellulose, and pregelatinized starch were uniformly mixed. Alternatively, using a direct tableting method, the mixture was uniformly mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0084] Example 2 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured using the same method as in Comparative Example 1. The composition of the pharmaceutical composition used in this formulation was as follows. APSNRI 100mg Sodium ethoxide 5mg DMAP 5mg Polyethylene glycol monoalkyl ether 20 mg Microcrystalline cellulose 20 mg

[0085] Specific manufacturing method Tablet Compression and Manufacturing: The above-mentioned SN triple bond structure compound, sodium ethoxide, DMAP, polyethylene glycol monoalkyl ether, and microcrystalline cellulose were homogeneously mixed. Alternatively, using a direct tableting method, the mixture was homogeneously combined to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0086] Example 3 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured using the same method as in Comparative Example 1. The composition of the pharmaceutical composition used in this formulation was as follows. APSNRI 100mg Sodium ethoxide 5mg DMAP 5mg Polyethylene glycol monoalkyl ether 20 mg Pregelatinized starch 40mg

[0087] Specific manufacturing method Tablet Compression and Manufacturing: The above-mentioned SN triple bond structure compound, sodium ethoxide, DMAP, polyethylene glycol monoalkyl ether, microcrystalline cellulose, and pregelatinized starch were uniformly mixed. Alternatively, using a direct tableting method, the mixture was uniformly mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0088] Example 4 A formulation containing 100 mg of the active ingredient APSNRI per tablet was manufactured using the same method as in Comparative Example 1. The composition of the pharmaceutical composition used in this formulation was as follows. APSNRI 100mg Sodium ethoxide 5mg DMAP 5mg Polyethylene glycol monoalkyl ether 20 mg Pregelatinized starch 40mg Finely powdered silica gel 10mg

[0089] Specific manufacturing method Tablet Compression and Manufacturing: The above-mentioned SN triple bond structure compound, sodium ethoxide, DMAP, polyethylene glycol monoalkyl ether, pregelatinized starch, and finely powdered silica gel were uniformly mixed. Alternatively, using a direct tableting method, the mixture was uniformly mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0090] Comparative Example 7 A formulation containing 100 mg of the active ingredient, an FPSNRI SN triple bond structure compound, per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: FPSNRI 200mg

[0091] Specific manufacturing method Tableting and Manufacturing: The SN triple bond structure compound described above was uniformly mixed using a direct tableting method to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0092] Example 5 A formulation containing 100 mg of the active ingredient, an FPSNRI SN triple bond structure compound, per tablet was manufactured. The composition of the pharmaceutical composition used in this formulation was as follows: FPSNRI 100mg DMAP 10mg Polyethylene glycol monoalkyl ether 20 mg Microcrystalline cellulose 20 mg Pregelatinized starch 40mg

[0093] Specific manufacturing method Tablet Compression and Manufacturing: The above-mentioned SN triple bond structure compound, DMAP, polyethylene glycol monoalkyl ether, microcrystalline cellulose, and pregelatinized starch were uniformly mixed. Alternatively, using a direct tableting method, the mixture was uniformly mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0094] Example 6 A formulation containing 100 mg of the active ingredient, an FPSNRI SN triple bond structure compound, per tablet was prepared using the same method as in Comparative Example 1. The composition of the pharmaceutical composition used in this formulation was as follows. FPSNRI 100mg Polyethylene glycol monoalkyl ether 20 mg Microcrystalline cellulose 10 mg Pregelatinized starch 10mg

[0095] Specific manufacturing method Tablet Compression and Manufacturing: The aforementioned SN triple bond structure compound, polyethylene glycol monoalkyl ether, microcrystalline cellulose, and pregelatinized starch were uniformly mixed. Alternatively, using a direct tableting method, the mixture was uniformly mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0096] Example 7 A formulation containing 100 mg of the active ingredient, an FPSNRI SN triple bond structure compound, per tablet was prepared using the same method as in Comparative Example 1. The composition of the pharmaceutical composition used in this formulation was as follows. FPSNRI 100mg Polyethylene glycol monoalkyl ether 20 mg Microcrystalline cellulose 10 mg Pregelatinized starch 10mg Finely powdered silica gel 10mg

[0097] Specific manufacturing method Tablet Compression and Manufacturing: The aforementioned SN triple bond structure compound, polyethylene glycol monoalkyl ether, microcrystalline cellulose, pregelatinized starch, and finely powdered silica gel were uniformly mixed. Alternatively, using a direct tableting method, the mixture was uniformly mixed to produce tablets containing 100 mg of the SN triple bond structure compound per tablet.

[0098] The compositions of the above-mentioned examples and comparative examples were tested. 1) Stability was determined by measuring the amount of the active compound remaining. 2) The deprotonation activity of the active product could be determined from the degree of reaction with piperidine present in different environments. Specifically, it could be determined from the degree of reaction over time in a) direct reaction, b) neutral environment, and c) acidic environment.

[0099] For relevant experimental data related to the case study, please refer to Tables 1 and 2.

[0100] Table 1: Tabletization of each example and comparative example was carried out in a 100 ml sealed container. Furthermore, "active substance in aqueous solution" means that the weight ratio of water to the active substance was 1:1. Furthermore, "active substance in acetic acid / weak acid aqueous solution" means that one drop of acetic acid solution was added to a liquid-to-active substance ratio of 1:1 to adjust the pH to 4.8. Furthermore, "active substance in protein / amino acid aqueous solution" means that 2 eq of alanine was added to a liquid-to-active substance ratio of 1:1. The active substance refers to the SN triple bond compound corresponding to each example and comparative example.

[0101] [Table 1]

[0102] Based on the good stability observed in Table 1, the tests in Table 2 were conducted with particular emphasis.

[0103] Table 2 a. Reaction in piperidine means that 5 mg of the active compound, which has a C3H6O group and an SN triple bond structure, was added to 0.5 ml of piperidine and reacted in a 40°C water bath for 24 hours. b. Reaction of piperidine in anhydrous ethanol means that 5 mg of the active compound, which has a C3H6O group and an SN triple bond structure, was dissolved in a small amount of approximately 0.2 ml of anhydrous ethanol, then 0.5 ml of piperidine was added and reacted in a 40°C water bath for 24 hours. c. Reaction of piperidine in a neutral protein / amino acid aqueous solution (pharmaceutical composition dissolved in anhydrous ethanol) means that 5 mg of the active compound, which has a C3H6O group and an SN triple bond structure, was dissolved in a small amount of approximately 0.2 ml of anhydrous ethanol, then 0.5 ml of piperidine was added, followed by 3.5 mg of alanine, and then 0.5 ml of distilled water was added and reacted in a 40°C water bath for 24 hours. Furthermore, d. The reaction of piperidine in a weakly acidic protein / amino acid aqueous solution (a pharmaceutical composition dissolved in anhydrous ethanol) means that 5 mg of the active compound, which has an SN triple bond structure with a C3H6O group, was dissolved in a small amount of anhydrous ethanol, approximately 0.2 ml, then 0.5 ml of piperidine was added, followed by 3.5 mg of alanine (2 eq of the active compound), then 0.5 ml of distilled water was added, followed by 2 drops of acetic acid solution, and the mixture was reacted in a 40-degree Celsius water bath for 24 hours.

[0104] [Table 2]

[0105] These test examples revealed that, through effective pharmaceutical combinations, the stability, deprotonation activity, alkylation activity, and targeting activity of SN triple bond compounds in different environments are significantly improved. This provides a foundation for the effective application of this type of pharmaceutical composition to drugs such as antitumor agents.

[0106] Where numerical ranges are presented in the examples, unless otherwise described in the present invention, it should be interpreted that any two endpoints of each numerical range and any number between those endpoints are selectable. Furthermore, unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art. In addition to the specific methods, equipment, and materials used in the examples, the present invention may also be realized using any prior art methods, equipment, and materials similar to or equivalent to those described in the examples of the present invention, based on the understanding of the prior art by those skilled in the art and the description of the present invention.

Claims

1. A pharmaceutical composition, The raw materials of the aforementioned pharmaceutical composition are, in mass percentage, SN triple bond structure compound: 2-98%, Stabilizing and protective agent: 0.5-97%, Pharmaceutical additives: 0.1-55%, It contains, The SN triple bond structure compound is selected from APSNRI and / or FPSNRI. The aforementioned stabilizing protective agent is a pharmaceutical composition selected from one or more combinations of sodium ethoxide, 4-dimethylaminopyridine, and polyethylene glycol monoalkyl ether.

2. The raw materials of the aforementioned pharmaceutical composition further include a lubricant. The raw materials of the aforementioned pharmaceutical composition are, in mass percentage, SN triple bond structure compound: 40-85%, Stabilizing and protective agent: 0.5-8%, Pharmaceutical additives: 5-55%, Lubricant: 2-18% The pharmaceutical composition according to claim 1, characterized by containing the following:

3. The pharmaceutical composition according to claim 1, characterized in that it is dissolved in a solvent when used.

4. The pharmaceutical composition according to claim 3, characterized in that the solvent is selected from anhydrous ethanol.

5. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical additive is selected from one or more combinations of microcrystalline cellulose, pregelatinized starch, and capsules.

6. The pharmaceutical composition according to claim 2, characterized in that the lubricant is selected from one or more combinations of talcum powder, magnesium stearate, and finely powdered silica gel.

7. The pharmaceutical composition according to claim 6, characterized in that the lubricant is selected from fine silica gel powder.

8. A method for preparing a pharmaceutical composition according to any one of claims 1 to 7, A method for preparing a pharmaceutical composition, comprising mixing an SN triple bond structure compound, a stabilizing protective agent, and a pharmaceutical additive, and then preparing the mixture to obtain the composition.

9. Furthermore, the method for preparing the pharmaceutical composition according to claim 8 is characterized by further comprising adding a lubricant to an SN triple bond structure compound, a stabilizing protective agent, and a pharmaceutical additive, mixing them, and then preparing and obtaining the result.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 in drugs that inhibit cell proliferation and antitumor drugs.

Images