A Lupane triterpenoid derivative meglumine salt amorphous substance and its preparation method and application

Abstract

The invention discloses an amorphous substance of a Lupane triterpenoid derivative meglumine salt (chemical structure is shown in the following formula) and a preparation method thereof, wherein the X-ray powder diffraction spectrum of the amorphous substance has no sharp diffraction peaks. The amorphous substance of the invention has good water solubility, suitable lgP value, stable physical and chemical properties, and meets the requirements for formulation development; the preparation method of the invention is simple, easy to operate, and the product obtained by using specific processes, parameters and solvents has good dispersibility and high yield, and can be industrialized for production.

Description

Technical Field

[0001] The invention relates to an amorphous substance of a lupane triterpenoid derivative meglumine salt and a preparation method and application thereof. Background Art

[0002] Compound 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(1-(4-chlorophenyl)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecanehydro-2H-cyclopentane -9-amino)-2,2-dimethyl-4-oxo-butyric acid (R&D code: QF-036)

[0003]

[0004] It is a Lupane triterpenoid derivative. In vitro efficacy studies have shown that QF-036 has good activity against HIV virus. It is of great significance to develop a form with high bioavailability, convenient for formulation, and a simple preparation method suitable for industrial production. Summary of the invention

[0005] The invention provides a Lupane triterpenoid derivative QF-036 meglumine salt amorphous substance and a preparation method thereof. The amorphous substance has good water solubility, a suitable lgP value, stable physical and chemical properties, and meets the requirements for formulation development. The preparation method is simple and easy to operate. The product obtained by using specific processes, parameters and solvents has good dispersibility and high yield, and can be industrialized for production.

[0006] In a first aspect, the present invention provides an amorphous substance of a triterpene derivative meglumine salt of Lupane shown in Formula I,

[0007]

[0008] Preferably, using Cu-Ka radiation, the amorphous material has no sharp diffraction peaks in its X-ray powder diffraction pattern.

[0009] Preferably, the X-ray powder diffraction pattern of the amorphous material has a broad peak at a diffraction angle 2θ between 10.0 and 25.0.

[0010] Preferably, the X-ray powder diffraction pattern of the amorphous material is as follows: Figure 1 shown.

[0011] Preferably, the DSC diagram of the amorphous material is as follows Figure 2As shown;

[0012] Preferably, the TGA diagram of the amorphous material is as follows Figure 3 shown.

[0013] In a second aspect of the present invention, there is provided a method for preparing an amorphous substance of a lupane triterpenoid derivative meglumine salt as shown in formula I, comprising the following steps: dissolving the lupane triterpenoid derivative in an alcohol solvent, adding meglumine, stirring at room temperature until dissolved, removing the solvent by concentrating under reduced pressure, adding an ester solvent, stirring, slurrying, filtering and drying.

[0014] Preferably, the alcohol solvent is selected from one or more of methanol, ethanol and isopropanol, preferably ethanol;

[0015] Preferably, the amount of meglumine is 0.90 to 2.0 eq, more preferably, the amount of meglumine is 0.90 to 1 eq, such as 0.95 eq;

[0016] Preferably, the insulation temperature is 30-80°C, preferably 50-60°C;

[0017] Preferably, the insulation time is 0.5 to 6 hours, preferably 1 to 3 hours;

[0018] Preferably, the ester solvent is selected from one or more of ethyl acetate, ethyl formate, isopropyl acetate and butyl acetate, preferably ethyl acetate and isopropyl acetate, more preferably ethyl acetate;

[0019] Preferably, the drying temperature is 30-70°C, preferably 50-60°C.

[0020] Preferably, the preparation method comprises the following steps: dissolving the Lupane triterpene derivative in an alcohol solvent, adding 0.90 to 2.0 eq of meglumine, stirring at 30 to 80°C for 0.5 to 6 hours until dissolved, removing the solvent by concentrating under reduced pressure, adding an ester solvent, stirring and slurrying, filtering, and drying at 30 to 70°C.

[0021] The third aspect of the present invention provides a pharmaceutical composition comprising the amorphous meglumine salt or the amorphous meglumine salt prepared by the method, and pharmaceutically acceptable excipients.

[0022] In a fourth aspect, the present invention provides a combined pharmaceutical composition for preventing or treating HIV infection, comprising the amorphous meglumine salt or the amorphous meglumine salt prepared by the method and at least another therapeutic drug, wherein the at least another therapeutic drug is selected from: nucleoside / nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors, and / or integrase inhibitors.

[0023] The fifth aspect of the present invention provides the use of the amorphous meglumine salt or the amorphous meglumine salt prepared by the method, the pharmaceutical composition or the combined pharmaceutical composition in the preparation of drugs for preventing or treating HIV infection.

[0024] Preferably, the HIV is HIV-1.

[0025] Beneficial technical effects of the present invention:

[0026] (1) The amorphous meglumine salt of the present invention has good water solubility, suitable lgP value, stable physicochemical properties, and meets the requirements for formulation development.

[0027] (2) The preparation method of the amorphous meglumine salt of the present invention is simple and easy to operate. The product obtained by using specific processes, parameters and solvents has good dispersibility, high yield and high purity, can be industrialized and has good economic and social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 : XRD pattern of amorphous substance of Lupane triterpenoid derivative meglumine salt QF036;

[0029] Figure 2 : DSC diagram of amorphous substance of meglumine salt QF036, a triterpenoid derivative of Lupane;

[0030] Figure 3 : TGA diagram of the amorphous substance of the meglumine salt of Lupane triterpenoid derivative QF036. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with specific examples. The operating parameters in the examples are only for illustration and are not intended to limit the entire scope of the present invention.

[0032] Experimental Example Group 1: Preparation of Lupane Triterpenoid Derivative QF-036 Meglumine Salt Amorphous

[0033] Example 1

[0034] 1.05 kg of Lupane triterpene derivative No. 98-1 compound (i.e., QF-036) prepared in the implementation of CN103242413A was added to 4.06 kg of ethanol, and 256 g of meglumine was added under stirring. The temperature was raised to 50°C, and after stirring for 3 hours, the reaction liquid became clear. The solvent was concentrated to dryness under reduced pressure, 10 kg of ethyl acetate was added, the temperature was controlled at 25-30°C, and after stirring for 1 hour, it was filtered, and the filter cake was vacuum dried at 50°C for 36 hours to obtain 1.03 kg of powder.

[0035] Using Cu-Ka radiation, the X-ray powder diffraction spectrum expressed by 2theta value has no sharp diffraction peaks, but a broad peak between 10.0 and 25.0. Therefore, it is judged to be an amorphous form. Its XRD chromatogram is as follows: Figure 1 As shown in the DSC diagram Figure 2 As shown in the TGA diagram Figure 3 shown.

[0036] Example 2

[0037] 1.00 kg of Lupane triterpene derivative No. 98-1 compound (i.e., QF-036) prepared in the implementation of CN103242413A was added to 4.06 kg of methanol, and 244 g of meglumine was added under stirring. The temperature was raised to 60° C. and stirred for 2 hours. The reaction liquid became clear. The solvent was concentrated to dryness under reduced pressure, 10 kg of ethyl acetate was added, the temperature was controlled at 25-30° C., and after stirring for 1 hour, it was filtered, and the filter cake was vacuum dried at 40° C. for 36 hours to obtain 0.96 kg of powder.

[0038] Example 3

[0039] 1.00 kg of Lupane triterpene derivative No. 98-1 compound (i.e., QF-036) prepared in the implementation of CN103242413A was added to 4.06 kg of isopropanol, and 244 g of meglumine was added under stirring. The temperature was raised to 80° C., and after stirring for 0.5 h, the reaction liquid became clear. The solvent was concentrated to dryness under reduced pressure, 10 kg of ethyl formate was added, the temperature was controlled at 25-30° C., and after stirring for 1 h, it was filtered, and the filter cake was vacuum dried at 40° C. for 36 h to obtain 0.99 kg of powder.

[0040] Example 4

[0041] 1.00 kg of Lupane triterpene derivative No. 98-1 compound (i.e., QF-036) prepared in the implementation of CN103242413A was added to 4.06 kg of ethanol, and 244 g of meglumine was added under stirring. The temperature was raised to 30° C., and after stirring for 6 hours, the reaction liquid became clear. The solvent was concentrated to dryness under reduced pressure, 10 kg of isopropyl acetate was added, the temperature was controlled at 25-30° C., and after stirring for 1 hour, it was filtered, and the filter cake was vacuum dried at 70° C. for 24 hours to obtain 0.95 kg of powder.

[0042] Comparative Example 1

[0043] 10.0 g of Lupane triterpene derivative No. 98-1 compound (i.e., QF-036) prepared in the implementation of CN103242413A was added to 100 ml of dichloromethane, stirred until dissolved, and then 2.44 g of meglumine was added. The temperature was raised to 30° C., stirred for 5 hours, and the solvent was concentrated to dryness under reduced pressure. 100 ml of ethyl acetate was added, and the solid was sticky and could not be dispersed.

[0044] Comparative Example 2

[0045] 10.0 g of Lupane triterpene derivative No. 98-1 compound (i.e., QF-036) prepared in the implementation of CN103242413A was added to 100 ml of ethanol, stirred until dissolved, and then 2.44 g of meglumine was added. The temperature was controlled at 15°C and stirred. After stirring for 5 hours, there was still a large amount of solid, indicating that the salt was not fully formed. The stirring was continued for 20 hours, and there was still solid that did not dissolve, that is, the stirring temperature was ≤30°C, and the salt was not fully formed.

[0046] It can be seen from the above data that the preparation method of the amorphous meglumine salt of the present invention is simple and easy to operate. The product obtained by using specific processes, parameters and solvents has good dispersibility, high yield and high purity, and can be industrially produced.

[0047] Experimental group 2: sample testing

[0048] 2.1. Solubility (μg / mL)

[0049] Inspection method: shaking method, 37℃, 24 hours.

[0050] Sample addition amount: 10 mg to 50 ml solution. Calculate the content based on the free form.

[0051]

[0052]

[0053] From the above data, it can be seen that the solubility of QF-036 meglumine salt amorphous is significantly higher than that of QF-036 free form. In later studies, it was found that the solubility of QF-036.NMG in water increased with the increase of sample addition, and the maximum solubility in water that has been investigated is 35.59 mg / mL.

[0054] 2.2, lgP

[0055] When oral drugs penetrate by passive diffusion, the lgP range of 0-4 is optimal. High lgP compounds have poor water solubility, and low lgP compounds have poor lipid permeability.

[0056]

[0057] From the above data, it can be seen that the lgP value of QF-036 free type cannot be determined, while the lgP value of meglumine salt is within the ideal range.

[0058] 2.3 Solid Stability

[0059] The properties, content (based on dry product), and changes in related substances of QF-036 meglumine salt were investigated under the influencing factors experimental conditions (high temperature 60°C, light 4500lx±500lx, high humidity RH75%). The results of the solid stability test are as follows:

[0060]

[0061] The experimental results show that under high temperature, light and high humidity conditions, meglumine salt has good stability.

[0062] 2.4 Solution stability

[0063] The peak area and retention time RSD values ​​of QF-036 meglumine salt solution prepared with 0.5% SLS solution were less than 2% within 48 hours, and the surface solution was stable within the measurement time.

[0064]

[0065] Based on the above data, the amorphous meglumine salt of the present invention has good water solubility, suitable lgP value, stable physical and chemical properties, and meets the requirements for formulation development.

[0066] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and the embodiments. It can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily realized. Therefore, without departing from the general concept defined by the claims and equivalent scope, the present invention is not limited to the specific details and the illustrations shown and described here.

Claims

1. A method for preparing an amorphous substance of a meglumine salt of a triterpenoid derivative of Lupane as shown in Formula I, characterized in that: The steps include: Dissolve the Lupane triterpenoid derivative in an alcohol solvent, add 0.90-2.0eq of meglumine, stir at 30-80°C for 0.5-6h until dissolved, remove the solvent by decompression and concentration, add an ester solvent, stir and slurry, filter, and dry at 30-70°C. The alcohol solvent is selected from one or more of methanol, ethanol and isopropanol, The ester solvent is selected from one or more of ethyl acetate, ethyl formate and isopropyl acetate. Using Cu-Ka radiation, the amorphous material has no sharp diffraction peaks in its X-ray powder diffraction pattern.

2. A preparation method according to claim 1, characterized in that: The X-ray powder diffraction pattern of the amorphous material has a broad peak at a diffraction angle 2θ between 10.0 and 25.

0.

3. A preparation method according to claim 1, characterized in that: The X-ray powder diffraction pattern of the amorphous material is shown in FIG1 , and / or the DSC pattern is shown in FIG2 , and / or the TGA pattern is shown in FIG3 .

4. A preparation method according to claim 1, characterized in that: Dissolve the Lupane triterpene derivative in ethanol, add 0.90-1.0eq of meglumine, keep stirring at 50-60°C for 1h-3h until dissolved, remove the solvent by decompression concentration, add ethyl acetate solvent, stir and slurry, filter, and dry at 50-60°C.

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