Camptothecin derivative compounds and their applications

Abstract

The present invention discloses a camptothecin derivative compound and its application, belonging to the field of pharmaceutical chemistry technology. The structural formula of the camptothecin derivative compound is shown in formula (1), 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. This invention, while maintaining the pharmacological skeleton of isotecan, has developed a series of isotecan derivatives. These compounds exhibit high anti-tumor activity, low toxicity and side effects, and are readily water-soluble, demonstrating potential application as single anti-tumor agents or antibody-drug conjugates. #imgabs0#.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and in particular 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 damaging normal cells, leading to a variety of adverse events in patients. To improve therapeutic efficacy and reduce side effects, the development of targeted drugs and antibody-drug conjugates (ADCs) has become a research hotspot. By combining cytotoxic drugs with specific antibodies, ADCs can deliver the drugs directly to tumor cells, thereby improving therapeutic efficacy and reducing damage to normal cells.

[0003] The design and application of ADCs currently face a series of challenges. First, the selection of cytotoxic drugs is crucial; they must possess sufficient water solubility, serum stability, conjugable functional groups, and insensitivity to degradation by lysosomal enzymes. Furthermore, the drug's lipid-water partition coefficient (LogP) and charge state also influence its ability to penetrate cell membranes, which in turn affects the efficacy of ADCs. Exatecan, a fully synthetic derivative of the natural product camptothecin, exhibits potent inhibitory activity against the topoisomerase Top1, promotes cell apoptosis, and possesses broad-spectrum antitumor activity, but its toxic side effects limit its clinical application. Therefore, the development of novel exatecan derivatives aimed at improving their water solubility, reducing their toxic side effects, and maintaining or enhancing their antitumor activity is a technical challenge that urgently needs to be addressed in the existing technology. Summary of the Invention

[0004] In response to the above-mentioned 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 is easily soluble in water.

[0005] In order 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, first undergoes a condensation reaction with chloroformate, and then undergoes urethane exchange with an amino alcohol compound. Camptothecin derivative compounds are obtained through filtration, water washing, drying and / or post-treatment.

[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 dropwise add phenyl chloroformate, stir at room temperature, add triethylamine and amino alcohol compounds, react, and filter, wash with water, dry and / or post-treat to obtain a camptothecin derivative compound.

[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)piperazin-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 is 20-30° C., and the stirring time 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 exitecan 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 its pharmacodynamic skeleton, 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-drug conjugates. 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 the embodiments.

[0038] As used herein, "ranges" are defined in terms of lower and upper limits. A given range is defined by selecting a lower limit and an upper limit, the selected lower and upper limits defining the boundaries of the particular range. Ranges defined in this manner may be inclusive or exclusive and may be combined arbitrarily, i.e., any lower limit may 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; otherwise, the percentage is weight / weight percentage.

[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] Dissolve D-prolinol (28.5 mg), triethylamine (28.5 mg), and oxalyl chloride (107.3 mg) in dichloromethane and stir at room temperature for 3 hours. Concentrate to dryness, then add dimethyl sulfoxide (DMSO) (5 mL) and exitecan mesylate (100 mg). Add triethylamine (28.5 mg) while stirring at room temperature, and stir for 5 minutes. Then, add phenyl chloroformate (45.02 mg) dropwise. Stir the reaction mixture at room temperature for 7 hours. Add triethylamine (56 mg) and D-prolinol (38.0 mg). Allow the reaction mixture to react at room temperature overnight.

[0044] Water (15 mL) was added, stirred, and the precipitate was filtered. 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] + ).1 HNMR (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 prepared in the example (compound (HG-YX-25)) and the reference substance Dxd were tested for cell proliferation inhibition:

[0046] The required number of NCI-N87 cells (1500 cells / well / 40 µL) (ATCC, CRL-5822) was seeded into a 384-well plate (Corning, 3764) and incubated overnight at 37°C. Compounds diluted in DMSO were added to the cell culture plate via IDOT (DISPENDIX) and allowed to act for 6 days. CellTiter-Glo reagent (CTG, Vazyme, DD1101-03) was equilibrated with the cell culture plate at room temperature for 30 minutes. Then, 20 µL of CTG was added and shaken for 2 minutes. The plate was incubated at room temperature for 30 minutes in the dark. Luminescence signals were read using a BMG (PHERAstar FSX).

[0047] The inhibition rate of the compound on 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 50% of the curve.

[0048] The results are shown in Table 1. Compared with Dxd, 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 has been described in detail above with reference to specific implementation methods and exemplary embodiments. However, these descriptions should not be construed as limiting the present application. Those skilled in the art will appreciate that, without departing from the spirit and scope of the present application, various equivalent substitutions, modifications, or improvements may be made to the technical solutions and implementation methods of the present application, 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 thereof, wherein: X is a carbon atom; n is 1 or 2; R1 and R2 are each independently selected from -(CH2) m -; m is 0, 1, or 2; and R1 and R2 are not simultaneously -(CH2)0- or -(CH2)2-.

2. The camptothecin derivative compound according to claim 1, characterized in that It has the following chemical formula: 。 3. Use of the camptothecin derivative compound according to claim 1, or a pharmaceutically acceptable salt thereof, as a small molecule toxin in the preparation of an antibody-drug conjugate.

4. A pharmaceutical composition, characterized in that The composition comprises a pharmaceutically acceptable excipient or carrier and the camptothecin derivative compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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