CN119487014A

CN119487014A - Paclitaxel antitumor compounds

Info

Publication number: CN119487014A
Application number: CN202380050402.XA
Authority: CN
Inventors: 曲凡志; 张晓君; 白洁; 刘芳茹; 邵永; 赵媛媛; 陈东健; 王雪菲; 董玥; 刘海瑞
Original assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Current assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date: 2022-06-29
Filing date: 2023-06-28
Publication date: 2025-02-18
Also published as: WO2024002127A1

Abstract

A taxol antitumor compound is provided. Specifically, a hydrate and a crystal form of 2' -acetyl docetaxel are provided. The hydrate or the preferable crystal form A of the 2' -acetyl docetaxel is superior to other crystal forms or amorphous forms in solid stability, hygroscopicity and mechanical stability, and has better drug-forming property and clinical application value.

Description

Taxol antitumor compounds

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a taxol antitumor compound, a preparation method and application thereof.

Background

Docetaxel is a non-cytotoxic precursor 10-deacetylbaccatin III semisynthesis extracted from needle leaves of taxus chinensis, is a taxol analogue, acts on cell microtubules, can promote tubulin polymerization, simultaneously inhibits microtubule depolymerization, makes cells stagnate in G2/M phase, inhibits mitosis, and kills tumor cells, and has stronger antitumor activity than taxol. 2' -acetyl docetaxel (CAS: 151509-27-2), which was originally disclosed in journal literature (Tetrahedron (1993), 49 (30), 6533-44, authors Dubois, joelle, etc.), as a synthetic intermediate or synthetic by-product of docetaxel, has the structure shown below.

Disclosure of Invention

The present inventors have conducted a systematic study of 2' -acetyl docetaxel as a drug for the first time. Through a large number of experiments and screening, the crude drug product which has stable quality, low hygroscopicity and suitability for finished drugs is finally obtained.

Accordingly, in one aspect, the present invention provides a hydrate of 2' -acetyl docetaxel:

Wherein n is 0.5 to 3, preferably 1 to 2.

Preferably, the hydrate is a sesquihydrate.

In another aspect, the present invention provides a crystalline form a of 2' -acetyl docetaxel having characteristic peaks at 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 13.6±0.2°, 19.0±0.2° by X-ray powder diffraction expressed in 2θ degrees using cu—kα radiation.

Preferably, the crystal form a uses Cu-ka radiation, and X-ray powder diffraction expressed in terms of 2θ has characteristic peaks at 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 13.6±0.2°, 15.2±0.2°, 16.2±0.2°, 19.0±0.2°.

Also preferably, the crystal form a uses Cu-ka radiation, and X-ray powder diffraction expressed in terms of 2θ has characteristic peaks at 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 11.4±0.2°, 12.4±0.2°, 13.6±0.2°, 15.2±0.2°, 16.2±0.2°, and 19.0±0.2°.

Further preferably, the form a has an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments of the invention, the form a has a differential scanning calorimetry curve with a onset of an endotherm at 169.0 ± 5 ℃.

In some aspects of the invention, the form a has a DSC profile substantially as shown in figure 4.

In some aspects of the invention, the form a has a TGA profile substantially as shown in figure 5.

According to the present invention, form a of 2' -acetyl docetaxel is preferably a hydrate, more preferably a sesquihydrate.

In another aspect, the present invention also provides a crystalline form B of 2' -acetyl docetaxel having characteristic peaks at 5.9±0.2°, 10.0±0.2°, 10.4±0.2°, 13.6±0.2°, 18.9±0.2° by X-ray powder diffraction expressed in 2θ degrees using cu—kα radiation.

Preferably, the crystal form B uses Cu-ka radiation, and X-ray powder diffraction expressed in terms of 2θ has characteristic peaks at 5.9±0.2°, 10.0±0.2°, 10.4±0.2°, 13.6±0.2°, 16.1±0.2°, 18.9±0.2°, 19.6±0.2°.

Further preferably, the form B has an X-ray powder diffraction pattern substantially as shown in figure 8.

In yet another aspect, the present invention also provides a pharmaceutical composition comprising a crystalline form or hydrate of the aforementioned 2' -acetyl docetaxel.

Preferably, the pharmaceutical composition of the present invention comprises the aforementioned crystalline form or hydrate of 2' -acetyl docetaxel and pharmaceutically acceptable excipients.

In yet another aspect, the invention also provides the use of a crystalline form or hydrate of 2' -acetyl docetaxel in the manufacture of a medicament for treating neoplastic disease. In other embodiments, the invention provides crystalline forms or hydrates of 2' -acetyl docetaxel for use in treating neoplastic diseases. In other embodiments, the invention provides methods of treating neoplastic disease comprising administering a therapeutically effective amount of a crystalline form or hydrate of 2' -acetyl docetaxel.

Those skilled in the art will readily appreciate that administration of the compounds disclosed herein and crystalline forms thereof may be admixed with pharmaceutically acceptable excipients well known in the art. In particular, as a systemically administered drug, it may be formulated into a dosage form suitable for oral or parenteral administration.

For the treatment of neoplastic diseases, crystalline forms of 2' -acetyl docetaxel may be co-administered with other therapeutic agents. Accordingly, in another aspect the present invention provides a combination pharmaceutical composition for use in the treatment of a neoplastic disease comprising a therapeutically effective amount of a crystalline form of 2' -acetyl docetaxel and one or more additional therapeutic agents. For the treatment of neoplastic diseases, crystalline forms of 2' -acetyl docetaxel may be co-treated in combination with other therapeutic means, including but not limited to radiation therapy.

Advantageous effects

The present invention provides hydrates and crystalline forms of 2' -acetyl docetaxel. The inventors have unexpectedly found that the hydrate or preferably crystalline form a of 2' -acetyl docetaxel has excellent properties such as stable physicochemical stability, extremely low hygroscopicity, excellent mechanical force stability, etc. Especially, the preparation is superior to other crystal forms or amorphous forms in terms of hygroscopicity and stability, and has better drug-forming property and clinical application value.

Drawings

FIG. 1 is an XRPD pattern for an amorphous form of 2' -acetyl docetaxel.

FIG. 2 is a DVS plot of an amorphous form of 2' -acetyl docetaxel.

FIG. 3 is an XRPD pattern for form A of 2' -acetyl docetaxel.

Fig. 4 is a DSC profile of 2' -acetyl docetaxel form a.

Fig. 5 is a TGA profile of 2' -acetyl docetaxel form a.

FIG. 6 is a schematic diagram of an asymmetric unit of the single crystal structure of crystalline form A of 2' -acetyl docetaxel.

Fig. 7 is an XRPD pattern of single crystal structure XRPD versus compound starting material form a.

Fig. 8 is an XRPD pattern of 2' -acetyl docetaxel form B.

Fig. 9 is a DVS diagram of form a.

Fig. 10 is an XRPD pattern of form a before and after DVS testing.

Fig. 11 is an XRPD pattern of form a before and after tabletting and manual milling.

Detailed Description

The technical scheme of the invention will be further described in detail below with reference to specific embodiments. The following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.

Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.

DSC, TGA test project instrument name and model TA Discovery 5500 TGA thermogravimetric analyzer and TA Discovery 2500 DSC differential scanning calorimeter. The measurement parameters were as follows:

XRPD detection item instrument name and model numbers panaceae X' Pert3 and Empyrean X-ray powder diffraction analyzer. The test parameters were as follows:

Dynamic moisture sorption (DVS) curves were collected at DVS INTRINSIC of SMS (Surface Measurement Systems). The relative humidity at 25 ℃ was corrected with deliquescence points of LiCl, mg (NO ₃)₂ and KCl:

single crystal diffractometer name and model Bruker D8 VENTURE single crystal diffractometer, test conditions are as follows:

Example 1.2 preparation of acetyl docetaxel

2' -Acetyl docetaxel was obtained according to the procedure of steps 1-3 of example 1 of prior art patent CN102050804 a.

¹H-NMR 600MHz(CDCl₃)：δ1.119(s,3H),1.227(s,3H),1.332(s,9H),1.744(s,3H),1.831-1.874(m,1H),1.935(s,3H),2.078(s,3H),2.152-2.328(m,2H),2.433(s,3H),2.550-2.600(m,1H),3.919-3.929(m,1H),4.190-4.204(m,1H),4.252-4.281(m,1H),4.312-4.327(m,1H),4.955-4.970(m,1H),5.219(s,1H),5.366(s,1H),5.477-5.490(m,2H),5.676-5.687(m,1H),6.242(s,1H),7.281-7.324(m,3H),7.380-7.404(m,2H),7.490-7.514(m,2H),7.593-7.617(m,1H),8.102-8.115(m,2H);MS m/z 850.45([M+H]+).

The 2' -acetyl docetaxel obtained was detected as amorphous form and XRPD detection results are shown in fig. 1. Fig. 2 shows a DVS diagram of this amorphous form. As shown in FIG. 2, the amorphous sample has moisture absorption and weight increase of 4.0% -4.6% under the condition of 25 ℃ and 80% RH, so that the amorphous sample has moisture absorption, and the XRPD result after DVS test shows that a weak diffraction peak (which is matched with the crystal form A) can be observed, so that the amorphous sample has a tendency of converting to the crystal form A.

Examples 2 to 5.2' -preparation of crystalline form A of acetyl docetaxel

About 20mg of each 2' -acetyl docetaxel was weighed into a 3mL vial, 1.0 to 2.0mL of the solvent shown below was added, stirred at 50℃overnight, then filtered (PTFE filter membrane with a pore size of 0.45 μm) to obtain a filtrate, the obtained filtrate was placed in a biochemical incubator, cooled from 50℃to 5℃at a cooling rate of 0.1℃per minute, and after slow cooling, a form A was obtained by XRPD, TGA and DSC detection.

The XRPD detection result of the crystal form a is shown in fig. 3, the diffraction peak data of the XRPD is shown in table 1, and the DSC and TGA detection results are shown in fig. 4 and 5. As shown by DSC results of this crystal form, there was an endothermic peak at 169.0 ℃.

TABLE 1 XRPD diffraction peak data for form A

Notably, when the same procedure as in examples 2-5 was used, only the solvent was changed to methyl t-butyl ether or tetrahydrofuran/water (volume ratio 1:1), but the amorphous form of 2' -acetyl docetaxel was obtained.

From the flaky crystal sample obtained by the culture of the crystal form A obtained in the above example, a single crystal with proper diffraction quality is cut and selected, and single crystal X-ray diffraction characterization and crystal structure analysis are carried out on the single crystal. The single crystal X-ray diffraction characterization result shows that the crystal belongs to an orthorhombic system, and the single cell parameter of the crystal is { and P2 ₁2₁2₁ space group α=90°,β=90°,γ=90°,}. Fig. 6 is a schematic diagram of an asymmetric unit of a single crystal structure of form a, which contains one molecule and a total of about 1.5 crystal water molecules, indicating that the single crystal is in the form of a hydrate crystal. FIG. 7 is an XRPD pattern for single crystal structure calculation XRPD in agreement with that of compound starting material form A.

EXAMPLE 6 preparation of 2' -acetyl docetaxel form B

Form a obtained in example 2 was heated to 150 ℃ under N ₂ protection to obtain form B. The XRPD detection results of form B are shown in fig. 8. And (3) keeping N ₂ for protection and cooling to 30 ℃, keeping the crystal form B unchanged, and exposing the crystal form B to room temperature humidity (20%RH), and immediately after testing, finding that the crystal form B is converted back to the crystal form A. The obtained crystal form B is converted into the crystal form A by water absorption under the room humidity condition, and cannot exist stably.

Test example 1 solid State stability

An appropriate amount of form a samples were weighed and set for stability experiments at 60 ℃ per closed/1 day, 25 ℃ per 60% rh per open/1 week and 40 ℃ per 75% rh per open/1 week. Solid samples under different conditions were evaluated for physical stability by XRPD test crystalline forms and chemical stability by UPLC test purity, respectively. The results of the physical stability evaluation of form a are summarized in table 2, and the results of the chemical stability evaluation are summarized in table 3. The solid stability results show that the crystal form A does not undergo crystal form transformation or obvious reduction of UPLC purity after being placed under the evaluation condition, and the crystal form A has better physical and chemical stability under the evaluation condition.

Table 2 summary of solid state stability assessment results for form a

Table 3 results of UPLC for solid state stability assessment of form a

Test example 2 moisture permeability

The hygroscopicity of form a was evaluated by a dynamic moisture sorption test (DVS) at 25 ℃ between 0% rh and 95% rh. The DVS results and XRPD comparison results of the samples after testing are shown in fig. 9 and 10. The evaluation result shows that the moisture absorption weight of the crystal form A is increased by 1.8% under the condition of 25 ℃ and 80% RH, and the moisture absorption of the crystal form A is only slightly lower than that of an amorphous form (4.0% -4.6%) measured under the same conditions in the example 1. Furthermore, no significant plateau of water uptake change was observed during adsorption and desorption. XRPD results showed that form a did not undergo conversion before and after DVS testing.

Test example 3 mechanical force stability

To evaluate the mechanical force stability of form a, form a was tabletted (350 MPa pressure) and manually ground, and XRPD testing was performed on the tabletted and manually ground samples. As a result, as shown in fig. 11, after tabletting at a pressure of 350MPa and after manual grinding for 3 minutes, the crystal form a was not subjected to the crystal form transformation.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

A hydrate of 2'-acetyldocetaxel:

Here, n is 0.5-3, preferably 1-2.

The hydrate of 2'-acetyl docetaxel according to claim 1, wherein the hydrate is a sesquihydrate.

A crystalline form A of 2'-acetyldocetaxel, wherein, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 13.6±0.2°, and 19.0±0.2°.

The crystalline form according to claim 3, wherein the crystalline form uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 13.6±0.2°, 15.2±0.2°, 16.2±0.2°, and 19.0±0.2°.

The crystalline form according to claim 3, wherein the crystalline form uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.0±0.2°, 9.8±0.2°, 10.4±0.2°, 11.4±0.2°, 12.4±0.2°, 13.6±0.2°, 15.2±0.2°, 16.2±0.2°, and 19.0±0.2°.

The crystalline form according to any one of claims 3 to 5, wherein the crystalline form has an X-ray powder diffraction spectrum substantially as shown in Figure 3.

The crystalline form according to any one of claims 3 to 6, wherein the differential scanning calorimetry curve of the crystalline form has a starting point of an endothermic peak at 169.0±5°C.

The crystalline form according to any one of claims 3 to 7, wherein the crystalline form has a DSC spectrum substantially as shown in Figure 4.

The crystalline form according to any one of claims 3 to 8, wherein the crystalline form has a TGA spectrum substantially as shown in Figure 5.

The crystalline form according to any one of claims 3 to 9, wherein the crystalline form is a hydrate, preferably a sesquihydrate.

A pharmaceutical composition comprising the hydrate according to any one of claims 1 to 2 or the crystal form according to any one of claims 3 to 10.