WO2021072771A1 - Tegafur cocrystal - Google Patents

Abstract

Provided is a tegafur-1,2-bis(4-pyridyl)ethylene cocrystal. The present invention relates to the technical field of crystal form drug molecules. According to the tegafur cocrystal, Cu-Kα radiation is used, and an X-ray diffraction pattern represented in 2θ has characteristic peaks at 6.26+/−0.2°, 9.30+/−0.2°, 11.89+/−0.2°, 12.60+/−0.2°, 14.79+/−0.2°, 20.28+/−0.2°, 23.98+/−0.2° and 26.43+/−0.2°; the crystallographic measurement parameter is: a triclinic system with a chiral space group of P-1; and cell parameters are: a=5.1391(4) Å, b=9.7392(7) Å, c=13.9658(10) Å, α=96.008(6)°, β=92.368(7)°, γ=103.481(7)°, and unit cell volume V=674.44(9) Å ³. Also provided are a related preparation method and a use. The tegafur-1,2-bis(4-pyridyl)ethylene cocrystal is good in stability and has a high solubility and dissolution rate.

Description

Tegafur Co-Crystal Technical field

The invention belongs to the technical field of medicinal chemistry, and specifically relates to a tegafur-1,2-bis(4-pyridyl)ethylene co-crystal, a preparation method thereof, and use in preparing medicines for treating diseases.

Background technique

Tegafur (TF), whose chemical name is 1-(tetrahydro-2-furyl)-5-fluoro-2,4(1H,3H)-pyrimidinedione, is white or off-white crystalline powder , The molecular formula is C ₈ H ₉ FN ₂ O ₃ , the molecular weight is 200, and its structural formula is as follows:

.

Tegafur is a derivative of fluorouracil. In 1968, Dr. Hiller, a former Soviet scientist, successfully synthesized TF. TF works by being degraded into fluorouracil by liver drug metabolizing enzymes and cytochrome P-450 system in the body, and its effect is the same as fluorouracil. TF has the advantages of high chemotherapeutic activity (twice the 5-FU) and low toxicity (5-6 times lower than 5-FU), and is widely used in the treatment of breast cancer and gastrointestinal cancer.

Although tegafur is widely used in anti-tumor therapy, it still has serious side effects such as bone marrow suppression and damage to the human body. Therefore, researchers are still constantly studying to find ways to reduce its toxicity or improve its bioavailability. Patent No. 855121 describes the existence of 2'R and 2'S racemic isomers of tegafur, but studies have shown that the two isomers have the same biological activity and toxicity ( YasumotoM . etal. ," J. Med. Chem. ", 1977 , vol.41 , No. 9 , 1632-1635 ); Uchida T et al. studied the crystal form of tegafur and successfully obtained four crystal forms of α, β, γ, and δ ( " Chem . Pharm. Bull. " , Vol . 41 , No. 9 , 1623-1625). The above four crystal forms can be obtained by simpler methods, such as: adding tegafluoride in acetone for hot melt and cold precipitation to obtain the α crystal form; the saturated methanol solution of tegafluoride can be obtained by rotary evaporation. Obtain β crystal form; β crystal form can be transformed to obtain γ crystal form at 130°C; recrystallize tegafur in methanol solution and slowly evaporate at room temperature to obtain δ crystal form. Although four crystal forms were successfully prepared, these four crystal forms did not significantly improve the physical and chemical properties of tegafur, nor did it greatly improve its therapeutic effect.

In summary, the configuration or crystal form screening does not improve the efficacy of tegafur or reduce its toxicity. Tegafur is currently used in combination with uracil. For example, Kagawa Y. et al. confirmed that tegafur and uracil Mixing with a molar ratio of 1:4 can effectively improve the curative effect of tegafur ( " Cancer Investigation " , Vol.13, No.5, 470-474 ); Sanchiz F et al. invented a combination of tegafur, folic acid and uracil Compound ( " Jpn . Journal Clin. Oncol. " , 1994, vol. 24, No. 6, 322-326 ) to improve the bioavailability of tegafur. Due to the toxicity of uracil itself, Fujita H et al. pointed out that the toxicity of tegafur in combination with thymine, adenosine, thymidine, etc. is reduced more significantly ( Experimental and Clinical Pharmacotherapy , Issue 12 , Riga , 1983 , p.205 ) . US Patent 6,538,001 reported that when tegafur and methyluracil form a molecular complex at 1:2 or 1:1, the solubility and bioavailability of tegafur can be improved. Srinivasulu A. et al. reported on the study of co-crystals of tegafur and nicotinamide, isonicotinamide, catechol, theophylline, and p-hydroxybenzoic acid. Although the co-crystals were successfully prepared, they did not show any signs of resistance. Surprising physical and chemical properties ( Crystal Growth&Design 2014,14,12,6557-6569 ). At present, combination medication is an effective method to increase the bioavailability of tegafur. Therefore, it is necessary to develop a compound sharing program for tegafur to improve the dissolution, solubility and/or increase the bioavailability of tegafur. Utilization, in order to reduce the side effects of tegafur.

technical problem

In view of the problems of the prior art, one aspect of the present invention provides a tegafur-1,2-bis(4-pyridyl)ethylene co-crystal with high stability and solubility. The co-crystal has exact crystallographic main parameters and Atomic space position; another aspect of the present invention provides a method for preparing the co-crystal.

Technical solutions

The specific technical content of the present invention is as follows:

In the first aspect, the present invention provides a tegafluoride-1,2-bis(4-pyridyl)ethylene co-crystal, in which tegafluoride and 1,2-bis(4-pyridyl) The molar ratio of ethylene is 1:1. One tegafluoride molecule and one 1,2-bis(4-pyridyl)ethylene molecule constitute the basic structural unit of the eutectic. The specific structure is shown in Formula I:

.

Preferably, the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ is at 6.26±0.2, 9.30±0.2°, 11.89±0.2°, 12.60±0.2°, 14.79±0.2°, 20.28±0.2°, 23.98±0.2° have characteristic peaks.

Preferably, the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ is at 6.26±0.2°, 9.30±0.2° , 10.59±0.2°, 11.89±0.2°, 12.60±0.2°, 14.79±0.2°, 18.74±0.2°, 19.14±0.2°, 20.28±0.2°, 21.39±0.2°, 22.32±0.2°, 23.98±0.2° , 26.43±0.2° has a characteristic peak.

Preferably, the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal uses Cu-Kα radiation, and its characteristic peaks conform to the X-ray powder diffraction pattern shown in FIG. 1.

Preferably, the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal has an endothermic peak in the differential scanning calorimetry curve (DSC), and the corresponding temperature range is 133.55~153.13°C , Preferably 142.73°C.

Preferably, the crystallographic parameters of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal are: triclinic crystal system, the chiral space group is P-1; the unit cell parameters are: a=5.1391(4)Å, b=9.7392(7)Å, c=13.9658(10)Å, α=96.008(6)°, β=92.368(7)°, γ=103.481(7)°, unit cell The volume V=674.44(9)Å ³ .

In the second aspect, the present invention provides a method for preparing tegafur-1,2-bis(4-pyridyl)ethylene co-crystal, and the specific preparation steps include:

Add tegafluoride and 1,2-bis(4-pyridyl)ethylene into organic solvent A, heat and stir to dissolve it, continue to keep the temperature reaction, the reaction is over, filter, volatilize, crystallize, filter, and dry to obtain tegafluoride- 1,2-bis(4-pyridyl)ethylene co-crystal.

Preferably, the preparation step includes: adding tegafluoride and 1,2-bis(4-pyridyl)ethylene into the organic solvent A, heating and stirring to dissolve, and then continuing the heat preservation reaction, the reaction is over, filtering, and the filtrate is slowly reduced to room temperature ; Place the filtrate in a beaker, seal with a parafilm, puncture the holes, volatilize, crystallize, filter, and dry under reduced pressure to obtain tegafluoro-1,2-bis(4-pyridyl)ethylene co-crystal.

Preferably, the molar ratio of the tegafur to 1,2-bis(4-pyridyl)ethylene is 1:1 to 1.5, preferably 1:1.1.

Preferably, the organic solvent A is one or two of acetonitrile, acetone, methanol, and ethanol, preferably methanol.

Preferably, the mass-volume ratio of the tegafur and the organic solvent A is 1:80~120, g/ml.

Preferably, the heating and dissolving temperature is 30-50°C.

Preferably, the heat preservation reaction time is 1 to 3 hours; the heat preservation reaction temperature is 30-50°C.

In a preferred embodiment, the slow cooling method of the filtrate is program cooling, and preferably, the cooling rate is 0.5° C./min.

In the third aspect, the present invention provides a pharmaceutical composition containing the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention and other pharmaceutically acceptable components.

Preferably, the other pharmaceutically acceptable components include other active ingredients, excipients, fillers and the like that can be used in combination.

Preferably, the pharmaceutical composition of the present invention can be prepared using the following method: using standard and conventional techniques, the compound of the present invention is combined with a pharmacologically acceptable solid or liquid carrier, and arbitrarily combined with a pharmacologically acceptable The adjuvants and excipients are combined to prepare usable dosage forms.

Preferably, the pharmaceutical composition is spray, tablet, capsule, powder injection, liquid injection and the like.

In the fourth aspect, the present invention provides an application of tegafur-1,2-bis(4-pyridyl)ethylene co-crystal as an active ingredient in the preparation of an antitumor drug.

Confirmation of crystal structure

The X-ray crystal data was collected on a Rigaku XtaLAB Synergy model instrument at a test temperature of 293(2) K, and CuKa radiation was used to collect the data in an ω scan mode and perform L p correction. The structure is analyzed by the direct method, and the difference Fourier method is used to find all non-hydrogen atoms. All hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is refined by the least square method.

The crystallographic data obtained by testing and analyzing the tegafur crystals prepared by the present invention are (Table 1): The crystallographic parameters are: triclinic crystal system, the chiral space group is P-1; the unit cell parameters are: a=5.1391( 4) Å, b=9.7392(7)Å, c=13.9658(10)Å, α=96.008(6)°, β=92.368(7)°, γ=103.481(7)°, unit cell volume V=674.44 (9) Å ³ . The molecular formula is: C ₂₀ H ₁₉ FN ₄ O ₃ , and the molecular weight is: 382.28. The packing diagram of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention is shown in FIG. 3. The ORTEP diagram of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention (Figure 4) shows that the co-crystal of the present invention consists of a molecule of active pharmaceutical ingredient tegafur and a molecule of co-crystal ligand 1 ,2-bis(4-pyridyl)ethylene is combined under the force of NH...N hydrogen bond.

The X-ray powder diffraction test instrument and test conditions of the present invention: X-ray powder diffractometer: PANalytical E; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv, current 40mA; divergence Slit: 1/4; Anti-scattering slit: 1; Sola slit: 0.04 rad; Step length: 0.5s; Scan range: 3～50°.

According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in Figure 1 and Table 2.

The samples prepared by the scheme of the present invention have the same crystallographic parameters and X-ray powder diffraction spectrum.

The TGA/DSC thermal analysis tester and test conditions of the present invention: TGA/DSC thermal analyzer: METTLER TOLEDO TGA/DSC3+; dynamic temperature section: 30~300°C; heating rate: 10°C/min; program gas N ₂ ; Gas flow rate: 50mL/min; crucible: aluminum crucible 40μl.

The DSC/TGA chart result of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal prepared by the method of the present invention is shown in Figure 2. The differential scanning calorimetry (DSC) only contains An endothermic peak with a temperature range of 133.55~153.13°C and a peak value of 142.73°C.

Beneficial effect

The present invention provides a new tegafur-1,2-bis(4-pyridyl)ethylene co-crystal, which has certain crystallographic main parameters and exact atomic spatial positions; the present invention provides the The preparation method of the co-crystal is simple to operate, and the obtained crystal yield and purity are relatively high; the tegafluoro-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention has good stability and high Solubility and dissolution rate can increase the bioavailability of tegafur and improve the efficacy, which is suitable for large-scale promotion and application.

Description of the drawings

Figure 1 X-ray powder diffraction pattern of tegafur co-crystal.

Figure 2 Differential scanning calorimetry (DSC) and thermal analysis (TGA) diagrams of tegafur eutectic.

Figure 3 Single crystal diffraction stacking pattern of tegafur eutectic.

Figure 4 ORTEP diagram of tegafur eutectic.

Embodiments of the present invention

The following examples are used to further illustrate the present invention. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, not to limit the present invention. Therefore, the present invention is simply improved on the premise of the method of the present invention. All belong to the scope of the present invention.

The raw materials of tegafur (β crystal form, purity 99.91%) and 1,2-bis(4-pyridyl)ethylene used in the experiment of the present invention are all commercially available products. The co-crystal of tegafur-isonicotinamide is based on patents. CN104496972A was prepared by the method of Example 1 disclosed in CN104496972A.

Example 1

Add tegafur (2.02 g) and 1,2-bis(4-pyridyl)ethylene (2.01 g) to methanol (200 ml). After heating and stirring at 40°C to dissolve, continue to react at 40°C for 1 hour. Finish, filter, and the filtrate drops to room temperature at a rate of 0.5°C/min; place the filtrate in a beaker, seal with a parafilm, puncture, volatilize, crystallize for 1 day, filter, and dry under reduced pressure to obtain tegafur-1,2- Bis(4-pyridyl)ethylene co-crystal, yield 95%, purity: 99.94%.

Example 2

Add tegafur (2.04 g) and 1,2-bis(4-pyridyl)ethylene (1.82 g) into methanol (200 ml), heat and stir at 40°C to dissolve, and continue to react at 40°C for 1 hour. Finish, filter, and the filtrate drops to room temperature at a rate of 0.5°C/min; put the filtrate in a beaker, seal with a parafilm, puncture, volatilize, crystallize for 1 day, filter, and dry under reduced pressure to obtain tegafur-1,2- Bis(4-pyridyl)ethylene co-crystal, yield 87%, purity: 99.86%.

Example 3:

Add tegafur (2.05 g) and 1,2-bis(4-pyridyl)ethylene (2.73 g) into methanol (240 ml). After heating and stirring at 40°C to dissolve, the reaction is continued at 40°C for 1 hour. Finish, filter, and the filtrate drops to room temperature at a rate of 0.5°C/min; put the filtrate in a beaker, seal with a parafilm, puncture, volatilize, crystallize for 1 day, filter, and dry under reduced pressure to obtain tegafur-1,2- Bis(4-pyridyl)ethylene co-crystal, yield 90%, purity: 99.88%.

Example 4

Add tegafur (2.03 g) and 1,2-bis(4-pyridyl)ethylene (2.01 g) into acetone (160 ml), heat and stir at 30°C to dissolve, and continue to react at 30°C for 1 hour. Finish, filter, and the filtrate drops to room temperature at a rate of 0.5°C/min; put the filtrate in a beaker, seal with a parafilm, puncture, volatilize, crystallize for 1 day, filter, and dry under reduced pressure to obtain tegafur-1,2- Bis(4-pyridyl)ethylene co-crystal, yield 92%, purity: 99.91%.

Example 5

Add tegafur (2.02 g) and 1,2-bis(4-pyridyl)ethylene (2.02 g) into ethanol (220 ml), heat and stir at 45°C to dissolve, and continue to react at 45°C for 2 hours. Finish, filter, and the filtrate drops to room temperature at a rate of 0.5°C/min; put the filtrate in a beaker, seal with a parafilm, puncture, volatilize, crystallize for 2 days, filter, and dry under reduced pressure to obtain tegafur-1,2- Bis(4-pyridyl)ethylene co-crystal, yield 91%, purity: 99.92%.

Example 6

Add tegafur (2.04 g) and 1,2-bis(4-pyridyl)ethylene (2.03 g) to acetonitrile (240 ml), heat and stir at 50°C to dissolve, and continue to react at 50°C for 3 hours. Finish, filter, and the filtrate drops to room temperature at a rate of 0.5°C/min; place the filtrate in a beaker, seal with a parafilm, puncture, volatilize, crystallize for 3 days, filter, and dry under reduced pressure to obtain tegafur-1,2- Bis(4-pyridyl)ethylene co-crystal, yield 89%, purity: 99.90%.

Industrial applicability

Stability experiment

The specific stability test method is carried out with reference to the guidance method for stability investigation specified in the fourth part of the Chinese Pharmacopoeia 2015 edition. The specific experimental conditions and results are shown in Table 3.

It can be seen from the experimental results that the purity and appearance of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal prepared by the present invention are not obvious under the conditions of light, high temperature and high humidity. Change, showing better stability; while the prior art β crystal form and tegafur-isonicotinamide co-crystal under the same experimental conditions have a relatively large reduction in purity, and their impurity content is more obvious The rise. Examples 1 to 6 of the present invention have similar stability test results.

Solubility test

The specific solubility test method is as follows: separately measure 10ml of medium (water, 0.01mol/L HCl solution and pH=6.8 phosphate buffer) into a vial, add excess sample to be tested, and seal the vial at 25 Stir in a constant temperature water bath at ℃ for 1 hour, filter through a 0.45μm filter membrane, and take the filtrate; measure the absorbance at a wavelength of 271nm, and calculate the solubility by measuring the absorbance of the standard reference substance by HPLC. The results are shown in Table 4.

It can be seen from the solubility test results that the solubility of the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal of the present invention is significantly better than that of tegafur β crystal form and tegafur-isonicotinamide co-crystal. Examples 1 to 6 of the present invention have similar solubility test results.

Dissolution rate test

This experiment was carried out in a VK7010 (Varian Company, USA) dissolution apparatus equipped with a VK750D heating circulator. Approximately 500 mg of the sample was compressed into a 0.5cm ² disc, and the US Pharmacopoeia-certified electric rotating disc was used to melt the mold. , Work for 5 minutes on a hydraulic press with a pressure of 5 tons. During the entire experiment, only one side of the disk was exposed to the solvent, and the surface of the disk was constant. Put the sample into a tank containing 900 mL of phosphate buffer (pH 6.8), preheat at 37°C, and stir at 50 rpm. At regular intervals, manually draw 2 mL samples. The collected samples were filtered through 0.4μm nylon membrane, and the calibration curve of each product was analyzed by HPLC. The absorbance was measured at a wavelength of 271nm in a phosphate buffer of pH=6.8.

It can be seen from the dissolution rate test experiment that the tegafur-1,2-bis(4-pyridyl)ethylene eutectic prepared by the present invention is compared with the tegafur β crystal form and tegafur-prepared in the prior art. The isonicotinamide co-crystal dissolves quickly. Examples 1 to 6 of the present invention have similar dissolution rate test results.

In summary, the tegafur-1,2-bis(4-pyridyl)ethylene co-crystal provided by the present invention effectively improves the physicochemical properties of tegafur, provides for reducing the toxic and side effects of tegafur and improving its biological activity. It's possible.

Claims (10)

1. A tegafur eutectic, which is characterized in that the eutectic is composed of the active pharmaceutical ingredient tegafur and the eutectic ligand 1,2-bis(4-pyridyl)ethylene.
2. The tegafur eutectic of claim 1, wherein the basic unit of the eutectic is composed of a tegafur molecule and a 1,2-bis(4-pyridyl)ethylene molecule, and its crystallographic parameters Yes: triclinic system, chiral space group is P-1; unit cell parameters are: a=5.1391(4)Å, b=9.7392(7)Å, c=13.9658(10)Å, α=96.008(6 )°, β=92.368(7)°, γ=103.481(7)°, unit cell volume V=674.44(9)Å ³ , the structure is as follows:

   

   .
3. The tegafur eutectic of claim 1, wherein the eutectic uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ is at 6.26±0.2°, 9.30±0.2°, 11.89±0.2 °, 12.60±0.2°, 14.79±0.2°, 20.28±0.2°, 23.98±0.2° have characteristic peaks.
4. The tegafur eutectic of claim 1, wherein the eutectic uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ is at 6.26±0.2°, 9.30±0.2°, 10.59±0.2 °, 11.89±0.2°, 12.60±0.2°, 14.79±0.2°, 18.74±0.2°, 19.14±0.2°, 20.28±0.2°, 21.39±0.2°, 22.32±0.2°, 23.98±0.2°, 26.43±0.2 °There are characteristic peaks.
5. The tegafur eutectic of claim 1, wherein the eutectic has an X-ray powder diffraction pattern as shown in FIG. 1.
6. A method for preparing the tegafur co-crystal according to any one of claims 1 to 5, characterized in that, the method comprises the following steps: combining tegafur, 1,2-bis(4-pyridyl)ethylene Add to the organic solvent A, heat and stir to dissolve, continue to keep the temperature reaction, the reaction is over, filter, the filtrate volatilizes and crystallizes, filter, and dry to obtain tegafluoro-1,2-bis(4-pyridyl)ethylene co-crystal.
7. The method for preparing tegafluoro co-crystal according to claim 6, wherein the molar ratio of the tegafluoro to 1,2-bis(4-pyridyl)ethylene is 1:1 to 1.5.
8. The preparation method of tegafur eutectic according to claim 6, wherein the organic solvent A is one or two of acetonitrile, acetone, methanol, and ethanol; the tegafur and organic solvent A The mass-to-volume ratio is 1:80~120, g/ml.
9. The preparation method of tegafur eutectic according to claim 6, characterized in that the heating and dissolving temperature is 30-50°C; and the holding reaction temperature is 30-50°C.
10. The use of the tegafur co-crystal according to any one of claims 1 to 5 as an active ingredient to prepare an anti-tumor drug.