Camptothecin derivative compound and application thereof

Abstract

The invention discloses a camptothecin derivative compound and application thereof, and belongs to the technical field of medicinal chemistry. The structural formula of the camptothecin derivative compound is as shown in formula (1), wherein X is oxygen, nitrogen, a nitrogen atom with alkyl, a sulfur atom, a carbon atom and-SO2-; n is 1 or 2; r1 and R2 are each independently selected from-(CH2) m-; m is 0, 1, 2 or-(CH2) y-CO-; and y is 0, 1 or 2. On the basis of maintaining the pharmacological skeleton of the etixetecan, a series of derivations are performed on the etixetecan to form a series of etixetecan derivatives, and the compounds have the characteristics of high anti-tumor activity, low toxic and side effects and easiness in water dissolution, and have potential application value as anti-tumor single drugs or antibody coupling drugs. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to camptothecin derivative compounds and applications thereof. Background Art

[0002] In the field of cancer treatment, traditional chemotherapy drugs, due to their non-selectivity and high systemic toxicity, often inhibit tumor cell proliferation while also causing damage to normal cells, leading to a variety of adverse events in patients. In order to improve the therapeutic effect and reduce side effects, the research and development of targeted drugs and antibody-drug conjugates (ADCs) have become a research hotspot. ADCs can deliver drugs directly to tumor cells by combining cytotoxic drugs with specific antibodies, thereby improving the therapeutic effect and reducing damage to normal cells.

[0003] In the prior art, the design and application of ADCs face a series of challenges. First, the selection of cytotoxic drugs is crucial. They need to have sufficient water solubility, serum stability, conjugated functional groups, and insensitivity to lysosomal enzyme degradation. In addition, the drug's lipid-water partition coefficient (LogP) and charge state also affect its ability to penetrate the cell membrane, thereby affecting the efficacy of ADC. Exatecan is a fully synthetic derivative of the natural product camptothecin. It has a strong inhibitory activity on the topoisomerase Top1, can promote cell apoptosis, and has a broad spectrum of anti-tumor activity, but its toxic side effects limit its clinical application. Therefore, the development of new exatecan derivatives, aimed at improving its water solubility, reducing toxic side effects, and maintaining or enhancing its anti-tumor activity, is a technical problem that needs to be solved in the prior art. Summary of the invention

[0004] In view of the above problems existing in the prior art, the present application provides a camptothecin derivative compound and its application, which has the characteristics of high anti-tumor activity, low toxicity and side effects, and easy solubility in water.

[0005] To solve the above problems, the present invention provides the following technical solutions:

[0006] In a first aspect, the present application provides a camptothecin derivative compound as shown in formula (1),

[0007]

[0008] or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer or crystal form thereof, wherein:

[0009] X is oxygen, nitrogen, a nitrogen atom with an alkyl group, a sulfur atom, a carbon atom, and -SO2-;

[0010] n is 1 or 2;

[0011] R1 and R2 are each independently selected from -(CH2) m -; m is 0, 1, 2 or -(CH2) y -CO-; y is 0, 1 or 2.

[0012] In one embodiment of the present application, the carbon at the position marked with * is a carbon atom having a chiral center, and its chiral configuration is R or S alone.

[0013] In one embodiment of the present application, when X is a nitrogen atom carrying an alkyl group, the alkyl group is selected from a C1-C3 alkyl group.

[0014] In one embodiment of the present application, the camptothecin derivative compound has one of the following chemical formulas:

[0015]

[0016] In a second aspect, the present application provides a method for preparing a camptothecin derivative compound, comprising the following steps:

[0017] Exitecan mesylate is dissolved in a solvent, firstly reacted with chloroformate for condensation reaction, then reacted with amino alcohol compound for amine ester exchange, and then filtered, washed, dried and / or post-treated to obtain camptothecin derivative compounds.

[0018] In one embodiment of the present application, the preparation method of camptothecin derivative compounds specifically comprises the following steps:

[0019] Dissolve exitecan mesylate in a solvent, add triethylamine under stirring, then drop phenyl chloroformate, stir at room temperature, add triethylamine and amino alcohol compounds, react, and obtain camptothecin derivative compounds through filtering, washing, drying and / or post-treatment.

[0020] In one embodiment of the present application, the solvent is selected from one of dimethyl sulfoxide, toluene, xylene, and N,N-dimethylformamide.

[0021] In one embodiment of the present application, the solvent is selected from dimethyl sulfoxide.

[0022] In one embodiment of the present application, the amino alcohol compound can be selected from but is not limited to D-prolinol, L-prolinol, (S)-2-piperidinemethanol, (R)-2-piperidinemethanol, (R)-3-hydroxymethylmorpholine, (S)-3-hydroxymethylmorpholine, (R)-2-(pyrrolidin-2-yl)ethan-1-ol, (S)-3-(hydroxymethyl)piperazine-2-one, (R)-2-hydroxymethylazetidine, and (S)-1-Boc-3-hydroxymethylpiperazine.

[0023] In one embodiment of the present application, the molar ratio of exitecan mesylate to the amino alcohol compound is 1:1.5-2.5.

[0024] In one embodiment of the present application, the molar ratio of exitecan mesylate to the amino alcohol compound is 1:2.0.

[0025] In one embodiment of the present application, the molar ratio of exitecan mesylate to phenyl chloroformate is 1:1.0-2.0.

[0026] In one embodiment of the present application, the molar ratio of exitecan mesylate to phenyl chloroformate is 1:1.5.

[0027] In one embodiment of the present application, the molar ratio of exitecan mesylate to triethylamine is 1:4-8.

[0028] In one embodiment of the present application, the molar ratio of exitecan mesylate to triethylamine is 1:5-7.

[0029] In one embodiment of the present application, the molar ratio of exitecan mesylate to triethylamine is 1:6.

[0030] In one embodiment of the present application, the stirring temperature at room temperature is 20-30° C., and the stirring time at room temperature is 6-8 h.

[0031] In one embodiment of the present application, the reaction temperature is 20-30° C., and the reaction time is 1-24 h.

[0032] In one embodiment of the present application, the preparation of compound HG-YX-25 further includes a pretreatment step before dissolving exotecan mesylate in a solvent. The pretreatment step is specifically as follows: dissolving part of the amino alcohol compound, triethylamine and oxalyl chloride in dichloromethane and stirring.

[0033] In a third aspect, the present application provides the use of camptothecin derivative compounds, or pharmaceutically acceptable salts, hydrates, solvates, optical isomers or crystal forms thereof as small molecule toxins for use in the preparation of antibody-drug conjugates.

[0034] In a fourth aspect, the present application provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a camptothecin derivative compound, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer or crystal form thereof.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] The present invention performs a series of derivatizations on isotecan on the basis of maintaining the pharmacodynamic skeleton of isotecan, thereby forming a series of isotecan derivatives. These compounds have the characteristics of high anti-tumor activity, low toxic side effects, and easy solubility in water, and have potential application value as anti-tumor single drugs or antibody-coupled drugs. DETAILED DESCRIPTION

[0037] The following is a clear and complete description of the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all of the embodiments.

[0038] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range.

[0039] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0040] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0041] Example 1: Preparation of compound (HG-YX-25)

[0042]

[0043] D-prolinol (28.5 mg), triethylamine (28.5 mg) and oxalyl chloride (107.3 mg) were dissolved in dichloromethane and stirred at room temperature for 3 hours. The mixture was concentrated to dryness, and dimethyl sulfoxide (DMSO) (5 mL) and exotecan mesylate (100 mg) were added. Triethylamine (28.5 mg) was added under stirring at room temperature and stirred for 5 minutes. Phenyl chloroformate (45.02 mg) was then added dropwise. The reaction solution was stirred at room temperature for 7 hours. Triethylamine (56 mg) and D-prolinol (38.0 mg) were added. The reaction solution was reacted at room temperature overnight.

[0044] Add water (15 mL), stir, and filter the precipitate. The filter cake was rinsed with water (10 mL) and dried to obtain compound (HG-YX-25) (38.9 mg), with a yield of 35.0%. MS m / z: 591.307 ([M+H] + ). 1HNMR (400MHz, DMSO): 9.30, 7.79, 7.30, 6.54, 5.60, 5.41, 5.19, 4.73-4.90, 3.45-3.79, 3.06-3.25, 2.39, 2.21, 1.78-1.97, 0.88.

[0045] The compound (compound (HG-YX-25) prepared in the example and the reference substance Dxd were tested for cell proliferation inhibition:

[0046] Take the required number of NCI-N87 cells (1500 cells / well / 40μL) (ATCC, CRL-5822) and inoculate them in a 384-well plate (Corning, 3764) and incubate them in a 37°C incubator overnight. The DMSO-diluted compound is added to the cell culture plate through IDOT (DISPENDIX) and the compound is allowed to act for 6 days. The CellTiter-Glo reagent (CTG, Vazyme, DD1101-03) and the cell culture plate are balanced at room temperature for 30 minutes, 20μL CTG is added and shaken for 2 minutes, and incubated at room temperature in the dark for 30 minutes, and the luminescence signal value is read using BMG (PHERAstar FSX).

[0047] The inhibition rate of the compound on the cells was standardized between the High control and the Low control. The wells containing cell culture medium were used as the Low control. The wells containing cells and the same proportion of DMSO were used as the High control. Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L), where Inhibition% is the inhibition rate, Ave_H represents the average signal value of the High control group, Ave_L represents the average signal value of the Low control group, and Sample is the signal value of the experimental group. IC was calculated by fitting a four-parameter logistic model or Excel 50 Value, IC 50 The value is the concentration that inhibits the curve by 50%.

[0048] The results are shown in Table 1. Compared with Dxd, the compound (HG-YX-25) is more sensitive to the cytotoxicity of NCI-N87 cells.

[0049] Table 1 Toxicity of each compound to NCI-N87 cells

[0050]

[0051] The present application is described in detail above in conjunction with specific implementation methods and exemplary embodiments, but these descriptions cannot be understood as limiting the present application. Those skilled in the art understand that, without departing from the spirit and scope of the present application, the technical solution of the present application and its implementation methods may be subjected to a variety of equivalent substitutions, modifications or improvements, all of which fall within the scope of the present application.

Claims

1. A camptothecin derivative compound, characterized in that: The structural formula of the camptothecin derivative compound is shown in formula (1): or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer or crystal form thereof, wherein: X is oxygen, nitrogen, a nitrogen atom with an alkyl group, a sulfur atom, a carbon atom, and -SO2-; n is 1 or 2; R1 and R2 are each independently selected from -(CH2) m -; m is 0, 1, 2 or -(CH2) y -CO-; y is 0, 1 or 2.

2. The camptothecin derivative compound according to claim 1, characterized in that: When X is a nitrogen atom carrying an alkyl group, the alkyl group is selected from C1-C3 alkyl groups.

3. The camptothecin derivative compound according to claim 1, characterized in that: It has one of the following chemical formulas:

4. Use of the camptothecin derivative compound according to claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer or crystal form thereof as a small molecule toxin for the preparation of an antibody-drug conjugate.

5. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically acceptable excipient or carrier and the camptothecin derivative compound as claimed in claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer or crystal form thereof.

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