CN117624241A - Polymorphic form preparation of TLR agonist or salt thereof - Google Patents

Polymorphic form preparation of TLR agonist or salt thereof Download PDF

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CN117624241A
CN117624241A CN202210956944.0A CN202210956944A CN117624241A CN 117624241 A CN117624241 A CN 117624241A CN 202210956944 A CN202210956944 A CN 202210956944A CN 117624241 A CN117624241 A CN 117624241A
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polymorph
compound
formula
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powder diffraction
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吕彬华
冯卫东
王润卿
王彩
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Abstract

The present invention relates to an imidazoquinolinePolymorphs of a line-substituted phosphate agonist or a salt thereof, particularly, tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4, 5-c)]Quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alanine ester, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a polymorph of a hydrate thereof, i.e., a polymorph of a compound represented by formula I or a salt thereof, or a solvate thereof. The polymorphs are suitable for use in the preparation of a pharmaceutical composition of a TLR agonist.

Description

Polymorphic form preparation of TLR agonist or salt thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a polymorph of an imidazoquinoline substituted phosphate agonist or a salt thereof, and more particularly relates to a polymorph of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propane-2-yl) oxo) (4-chlorophenoxy) phosphorus group) -L-alanine ester or a pharmaceutically acceptable salt or solvate thereof.
Background
Tert-butyl ((S) - ((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alanine ester (tert-butyl ((S) - ((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidzo [4,5-c ] quinone-1-yl) prop-2-yl) oxy) (4-chlorophenoxy) phosphinyl) -L-alaninate) having the structure shown in formula I:
The formula of the compound of the formula I is C 29 H 37 ClN 5 O 6 P, molecular weight 618.07, the compound is a TLR agonist and is suitable for preparing medicaments for treating/preventing cancers, diseases possibly caused by virus infection and other related diseases.
Since different crystal forms and salt forms of the medicine can influence the dissolution and absorption of the medicine in vivo, the clinical curative effect and safety of the medicine can be influenced to a certain extent, and particularly, the influence of the crystal forms can be larger for some insoluble oral solid or semisolid preparations. No literature reports about the polymorphic forms of the compound of formula I, and no polymorphic forms of the compound of formula I have been developed.
Therefore, it is necessary to develop polymorphs of the formula I compound.
Disclosure of Invention
The object of the present invention is to provide a polymorph of a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof.
In a first aspect the present invention provides a polymorph of a free base of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof,
in another preferred embodiment, the polymorph is selected from the group consisting of: polymorph a, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F, polymorph G, polymorph H, polymorph I.
In another preferred embodiment, the polymorph is polymorph a of a hydrochloride salt of a compound of formula I, wherein the polymorph a has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.77 + -0.2 deg., 7.11 + -0.2 deg., and 21.44 + -0.2 deg..
In another preferred embodiment, the polymorph is polymorph a of a hydrochloride salt of a compound of formula I, wherein the polymorph a has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.77.+ -. 0.2 °, 7.11.+ -. 0.2 °, 15.43.+ -. 0.2 °, 21.44.+ -. 0.2 ° and 25.55.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph a of a hydrochloride salt of a compound of formula I, wherein the polymorph a has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.77.+ -. 0.2 °, 7.11.+ -. 0.2 °, 8.43.+ -. 0.2 °, 11.04.+ -. 0.2 °, 11.63.+ -. 0.2 °, 15.43.+ -. 0.2 °, 18.49.+ -. 0.2 °, 21.44.+ -. 0.2 ° and 25.55.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph B of a hydrochloride salt of a compound represented by formula I, wherein the polymorph B has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.80 + -0.2 deg., 7.25 + -0.2 deg., and 25.39 + -0.2 deg..
In another preferred embodiment, the polymorph is polymorph B of a hydrochloride salt of a compound of formula I, wherein the polymorph B has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.80.+ -. 0.2 °, 7.25.+ -. 0.2 °, 11.00.+ -. 0.2 °, 15.43.+ -. 0.2 °, 18.55.+ -. 0.2 °, 21.88.+ -. 0.2 ° and 25.39.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph B of a hydrochloride salt of a compound of formula I, wherein the polymorph B has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.80.+ -. 0.2 °, 7.25.+ -. 0.2 °, 7.92.+ -. 0.2 °, 11.00.+ -. 0.2 °, 12.28.+ -. 0.2 °, 15.43.+ -. 0.2 °, 16.10.+ -. 0.2 °, 18.55.+ -. 0.2 °, 21.88.+ -. 0.2 °, 25.39.+ -. 0.2 ° and 26.56.+ -. 0.2 °.
In another preferred embodiment, the polymorph is a polymorph of a hydrochloride salt of a compound of formula I selected from the group consisting of: polymorph C, polymorph D, polymorph E, polymorph F;
wherein the polymorph C has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.94±0.2°,8.14±0.2° and 23.29±0.2°;
the polymorph D has an X-ray powder diffraction characteristic peak selected from the group consisting of: 7.25±0.2°,21.85±0.2° and 25.46±0.2°;
The polymorph E has X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.19±0.2°,11.04±0.2° and 25.48±0.2°;
the polymorph F has X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.17±0.2°,11.12±0.2° and 25.60 ±0.2°.
In another preferred embodiment, the polymorph is polymorph C of a hydrochloride salt of a compound represented by formula I, wherein the polymorph C has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.69.+ -. 0.2 °, 5.94.+ -. 0.2 °, 8.14.+ -. 0.2 °, 9.20.+ -. 0.2 °, 11.02.+ -. 0.2 ° and 23.29.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph C of a hydrochloride salt of a compound represented by formula I, wherein the polymorph C has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.69.+ -. 0.2 °, 5.94.+ -. 0.2 °, 7.17.+ -. 0.2 °, 8.14.+ -. 0.2 °, 9.20.+ -. 0.2 °, 11.02.+ -. 0.2 °, 15.35.+ -. 0.2 °, 15.96.+ -. 0.2 °, 19.24.+ -. 0.2 °, 21.71.+ -. 0.2 °, 23.29.+ -. 0.2 ° and 25.44.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph D of a hydrochloride salt of a compound of formula I, wherein polymorph D has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 7.25±0.2°,11.06±0.2°,15.46 ±0.2°,21.85±0.2° and 25.46±0.2°.
In another preferred embodiment, the polymorph is polymorph D of a hydrochloride salt of a compound of formula I, wherein polymorph D has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.83.+ -. 0.2 °, 7.25.+ -. 0.2 °, 11.06.+ -. 0.2 °, 15.46.+ -. 0.2 °, 18.55.+ -. 0.2 °, 21.85.+ -. 0.2 ° and 25.46.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph E of a hydrochloride salt of a compound of formula I, wherein the polymorph E has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 7.19±0.2°,11.04±0.2°,15.43±0.2°,21.69±0.2° and 25.48±0.2°.
In another preferred embodiment, the polymorph is polymorph E of a hydrochloride salt of a compound of formula I, wherein the polymorph E has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.78.+ -. 0.2 °, 7.19.+ -. 0.2 °, 7.76.+ -. 0.2 °, 11.04.+ -. 0.2 °, 12.54.+ -. 0.2 °, 15.43.+ -. 0.2 °, 18.51.+ -. 0.2 °, 21.69.+ -. 0.2 ° and 25.48.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph F of a hydrochloride salt of a compound of formula I, wherein polymorph F has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.11.+ -. 0.2 °, 6.63.+ -. 0.2 °, 7.17.+ -. 0.2 °, 11.12.+ -. 0.2 °, 12.62.+ -. 0.2 ° and 25.60.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph F of a hydrochloride salt of a compound of formula I, wherein polymorph F has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.11.+ -. 0.2 °, 6.63.+ -. 0.2 °, 7.17.+ -. 0.2 °, 7.86.+ -. 0.2 °, 11.12.+ -. 0.2 °, 12.62.+ -. 0.2 °, 15.42.+ -. 0.2 °, 18.63.+ -. 0.2 °, 21.57.+ -. 0.2 °, 25.60.+ -. 0.2 ° and 26.45.+ -. 0.2 °.
In another preferred embodiment, the polymorph is a polymorph of a compound of formula I selected from the group consisting of: polymorph G of mandelate salt of compound of formula I, polymorph H of oxalate salt of compound of formula I, polymorph I of tartrate salt of compound of formula I;
wherein the polymorph G has an X-ray powder diffraction characteristic peak selected from the group consisting of: 8.09±0.2°,21.76±0.2° and 27.94±0.2°;
the polymorph H has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.55.+ -. 0.2 °, 7.05.+ -. 0.2 ° and 11.41.+ -. 0.2 °;
the polymorph I has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.82 + -0.2 deg., 6.85 + -0.2 deg., and 7.58 + -0.2 deg..
In another preferred embodiment, the polymorph is polymorph G of a mandelate salt of a compound of formula I, wherein polymorph G has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.28.+ -. 0.2 °, 6.65.+ -. 0.2 °, 8.09.+ -. 0.2 °, 8.51.+ -. 0.2 °, 9.10.+ -. 0.2 °, 21.76.+ -. 0.2 ° and 27.94.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph G of a mandelate salt of a compound of formula I, wherein polymorph G has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.28.+ -. 0.2 °, 6.65.+ -. 0.2 °, 8.09.+ -. 0.2 °, 8.51.+ -. 0.2 °, 9.10.+ -. 0.2 °, 12.04.+ -. 0.2 °, 18.25.+ -. 0.2 °, 21.76.+ -. 0.2 °, 25.75.+ -. 0.2 ° and 27.94.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph H of a compound oxalate of formula I, wherein polymorph H has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.55.+ -. 0.2 °, 6.65.+ -. 0.2 °, 7.05.+ -. 0.2 °, 11.41.+ -. 0.2 °, 11.80.+ -. 0.2 °, 25.08.+ -. 0.2 ° and 25.48.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph H of a compound oxalate of formula I, wherein polymorph H has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.55.+ -. 0.2 °, 6.43.+ -. 0.2 °, 6.65.+ -. 0.2 °, 7.05.+ -. 0.2 °, 11.41.+ -. 0.2 °, 11.80.+ -. 0.2 °, 15.28.+ -. 0.2 °, 16.81.+ -. 0.2 °, 21.61.+ -. 0.2 °, 25.08.+ -. 0.2 ° and 25.48.+ -. 0.2 °.
In another preferred embodiment, the polymorph is polymorph I of a tartrate salt of the compound of formula I, wherein the polymorph I has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.82 + -0.2 deg., 6.85 + -0.2 deg., 7.58 + -0.2 deg., 8.33 + -0.2 deg., and 9.15 + -0.2 deg..
In another preferred embodiment, the polymorph is polymorph I of a tartrate salt of the compound of formula I, wherein the polymorph I has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 5.82+ -0.2 °, 6.85+ -0.2 °, 7.58+ -0.2 °, 8.33+ -0.2 °, 9.15+ -0.2 °, 10.20+ -0.2 °, 11.27+ -0.2 ° and 13.26+ -0.2 °.
In a second aspect of the invention, there is provided an amorphous form J which is the free base of a compound of formula I, having X-ray powder diffraction characteristic peaks substantially as shown in figure 10 a.
In a third aspect of the invention there is provided the use of a polymorph or amorphous form according to the first and second aspects for the preparation of a pharmaceutical composition of a TLR agonist.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising:
a) The polymorphs or amorphous of the first and second aspects; and
b) A pharmaceutically acceptable carrier.
In a fifth aspect of the present invention there is provided a process for the preparation of the polymorph of the first aspect comprising the steps of: crystallizing a compound of formula I and an acid as a salt in an inert solvent, or crystallizing a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof, in an inert solvent, to give the polymorph of the first aspect.
In another preferred embodiment, the process for preparing the polymorph A, G, H, I of the compound of formula I comprises three steps: step (1) dissolving a compound shown in a formula I in a specific solvent with a specific volume; step (2) adding a specific equivalent of acid, and then stirring at a specific temperature for a specific time; and (3) filtering and drying to obtain a polymorphic substance A, G, H, I.
In another preferred embodiment, in the preparation method of the polymorphic substance A, G, H, I of the compound shown in the formula I, in the step (1), the specific volume of the solvent means that the volume of the solvent is 1 to 50 times of the weight of the compound shown in the formula I; preferably 2 to 20 times; particularly preferably 3 to 10 times.
In another preferred embodiment, the method for preparing the polymorphic form A, G, H, I of the compound of formula I, step (1), the specific solvent is selected from ethyl acetate, isopropyl acetate, ethanol, isopropanol, n-propanol, or a combination thereof.
In another preferred embodiment, in the preparation method of the polymorphic substance A, G, H, I of the compound shown in the formula I, in the step (2), the specific equivalent of acid is hydrogen chloride, mandelic acid, oxalic acid or tartaric acid, and the molar equivalent of the acid used is 0.5-10 equivalent of the compound shown in the formula I; preferably 1 to 5 equivalents; particularly preferably 1 to 3 equivalents.
In another preferred embodiment, the process for preparing the polymorph A, G, H, I of the compound of formula I, step (2), the specific temperature is from-10 to 105 ℃, preferably from-5 to 100 ℃; particularly preferably the temperature is from 10 to 50 ℃.
In another preferred embodiment, in the preparation method of the polymorphic substance A, G, H, I of the compound shown in the formula I, in the step (2), stirring for a specific time is 1-48 hours; preferably the time is 2 to 24 hours; particularly preferably the time is 3 to 10 hours.
In a sixth aspect of the present invention, there is provided a process for the preparation of polymorph a of a compound of formula I, comprising the steps of:
(S1) dissolving a polymorph of the hydrochloride salt of the compound of formula I in a specific volume of a specific solvent;
(S2) slowly adding a specific antisolvent, and then stirring at a specific temperature for a specific time; and
(S3) filtering and drying to obtain a polymorph A.
In another preferred embodiment, in the process for preparing polymorph a of a compound, step (S1), the specific volume of solvent means that the volume of solvent used is 1 to 50 times the weight of the hydrochloride salt of the compound of formula I; preferably 2 to 20 times; particularly preferably 3 to 10 times.
In another preferred embodiment, the method for preparing polymorph a of the compound of formula I, step (S1), the specific solvent is selected from ethanol, isopropanol, n-propanol, or a combination thereof.
In another preferred embodiment, the method for preparing polymorph a of the compound of formula I, step (S2), the specific antisolvent is selected from n-heptane, petroleum ether, n-hexane, methyl-n-hexane, pentane, cyclohexane, or a combination thereof.
In another preferred embodiment, the process for preparing polymorph a of a compound of formula I, step (S2), the specific temperature is a temperature of-10 to 105 ℃, preferably a temperature of-5 to 100 ℃; particularly preferably the temperature is from 10 to 50 ℃.
In another preferred embodiment, in the preparation method of the polymorph a of the compound shown in formula I, in the step (S2), stirring for a specific time is 1 to 48 hours; preferably the time is 2 to 24 hours; particularly preferably the time is 3 to 10 hours.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
Figure 1a shows the X-ray powder diffraction pattern of polymorph a.
Figure 1b shows the differential scanning calorimetry trace of polymorph a.
FIG. 1c shows polymorph A 1 H NMR chart.
Figure 2a shows the X-ray powder diffraction pattern of polymorph B.
Figure 2B shows a differential scanning calorimetry trace of polymorph B.
FIG. 2c shows polymorph B 1 H NMR chart.
Figure 3a shows the X-ray powder diffraction pattern of polymorph C.
Figure 3b shows a differential scanning calorimetry trace of polymorph C.
FIG. 3C shows polymorph C 1 H NMR chart.
Figure 4a shows the X-ray powder diffraction pattern of polymorph D.
Figure 4b shows a differential scanning calorimetry trace of polymorph D.
FIG. 4c shows polymorph D 1 H NMR chart.
Figure 5a shows the X-ray powder diffraction pattern of polymorph E.
Figure 5b shows a differential scanning calorimetry trace of polymorph E.
FIG. 5c shows polymorph E 1 H NMR chart.
Figure 6a shows the X-ray powder diffraction pattern of polymorph F.
Figure 6b shows a differential scanning calorimetry trace of polymorph F.
FIG. 6c shows polymorph F 1 H NMR chart.
Figure 7a shows the X-ray powder diffraction pattern of polymorph G.
Fig. 7b shows a differential scanning calorimetry trace of polymorph G.
FIG. 7c shows polymorph G 1 H NMR chart.
Figure 8a shows the X-ray powder diffraction pattern of polymorph H.
Figure 8b shows a differential scanning calorimetry trace of polymorph H.
FIG. 8c shows polymorph H 1 H NMR chart.
Figure 9a shows the X-ray powder diffraction pattern of polymorph I.
Figure 9b shows a differential scanning calorimetry trace of polymorph I.
FIG. 9c shows polymorph I 1 H NMR chart.
Figure 10a shows an X-ray powder diffraction pattern of amorphous J.
Figure 10b shows a differential scanning calorimetry plot of amorphous J.
FIG. 10c shows amorphous J 1 H NMR chart
Detailed Description
The present inventors have unexpectedly found, through long and intensive studies, a variety of polymorphs of a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof, which have better drug bioavailability and which are highly pure and very stable, and which are suitable for use in the preparation of a pharmaceutical composition of a TLR agonist, thereby being more advantageous for the prevention and treatment of cancer, diseases (e.g., hepatitis b, herpes, etc.) which may be caused by viral infection, and the like. In addition, the polymorphic substance is not easy to lift, collect and waste in the manufacturing process of medicines such as split charging and the like, and is beneficial to protecting the health of operators. On this basis, the inventors completed the present invention.
Terminology
Compounds of formula I
As used herein, a "compound of formula I" refers to tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate of formula I.
Inert solvents
As used herein, "inert solvent" refers to methanol, ethanol, isopropanol, N-propanol, dimethyl sulfoxide, N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, acetic acid, formic acid, benzene, toluene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, methylene chloride, chloroform, N-heptane, cyclohexane, N-hexane, methylcyclohexane, pentane, petroleum ether, dioxane, water, or a mixture of the foregoing solvents.
Salts of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alanine acid ester
Salts of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate described herein include the various salt forms of the compound of formula I.
For example, hydrochloride salts of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate; mandelic acid salts of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate; oxalate salt of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate; tartrate salt of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate.
Preferably, the hydrochloride salt of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate means the salt of the compound of formula I in a 1:1 molar ratio to hydrogen chloride.
Polymorphs
The solid is present either in amorphous form or in crystalline form. In the case of the crystalline form, the molecules are positioned within the three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it may crystallize in a different spatial lattice arrangement (this property is known as "polymorphism") to form crystals having different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, specific gravity, crystal form, mode of stacking, flowability and/or solid state stability.
Crystallization
Crystallization on a production scale can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature, and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method. The solubility of the compound of interest may be reduced by adding an anti-solvent or a mixture of such solvents in which the compound has low solubility. An alternative is to adjust the pH to reduce the solubility. For a detailed description of Crystallization see crystal, third edition, J W Mullens, butterworth-Heineman Ltd.,1993, ISBN0750611294.
If salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble in the reaction medium than the starting material, the addition of an appropriate acid or base can result in direct crystallization of the desired salt. Also, completion of the synthesis reaction may allow direct crystallization of the final product in a medium where the final desired form is less soluble than the reactants.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at an elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner to bring the system well below saturation level. At this point, the desired form of seed crystals (and maintaining the integrity of the seed crystals) may be added and the system cooled to complete crystallization.
As used herein, the term "room temperature" generally refers to 4-30 ℃, preferably 20±5 ℃.
Polymorphs of the present invention
As used herein, the term "polymorphs of the present invention" includes polymorphs of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt), or various solvates thereof.
Preferred polymorphs or amorphous forms of the present invention include (but are not limited to):
polymorph a of the hydrochloride salt of the compound of formula I;
polymorph B of the hydrochloride salt of the compound of formula I;
polymorph C of the hydrochloride salt of the compound of formula I;
polymorph D of the hydrochloride salt of the compound of formula I;
polymorph E of the hydrochloride salt of the compound of formula I;
polymorph F of the hydrochloride salt of the compound of formula I;
polymorph G of mandelic acid of the compound of formula I;
polymorph H of oxalic acid of the compound of formula I;
polymorph I of tartaric acid of the compound of formula I;
an amorphous form J of a compound of formula I;
wherein, in the polymorphs A-I, the mol ratio of the compound of the formula I to the acid is 1:1.
Identification and Properties of polymorphs
The present invention, after preparing amorphous polymorphs of a compound of formula I or a salt thereof, has been studied for its properties in a number of ways and instruments as follows.
Powder diffraction by X-rays
The solid samples obtained from the experiments were analyzed by means of an X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2 theta scanning angle is from 3 degrees to 60 degrees, the scanning step length is 0.02 degrees, and the exposure time is 0.12 seconds. The voltage and current of the light pipe are 40kV and 40mA respectively when the sample is tested, and the sample disk is a zero background sample disk.
Polymorphs of a salt of a compound of formula I of the present invention, having specific crystalline forms, have specific characteristic peaks in the X-ray powder diffraction (XRPD) pattern. The following are preferred:
(1) Polymorph A
The polymorph a has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.77 + -0.2 deg., 7.11 + -0.2 deg., and 21.44 + -0.2 deg..
In another preferred embodiment, the polymorph a has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.77.+ -. 0.2 °, 7.11.+ -. 0.2 °, 15.43.+ -. 0.2 °, 21.44.+ -. 0.2 ° and 25.55.+ -. 0.2 °.
In another preferred embodiment, the polymorph a has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.77.+ -. 0.2 °, 7.11.+ -. 0.2 °, 8.43.+ -. 0.2 °, 11.04.+ -. 0.2 °, 11.63.+ -. 0.2 °, 15.43.+ -. 0.2 °, 18.49.+ -. 0.2 °, 21.44.+ -. 0.2 ° and 25.55.+ -. 0.2 °.
In another preferred embodiment, the polymorph a has an X-ray powder diffraction pattern substantially as shown in figure 1 a.
(2) Polymorph B
The polymorph B has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.80 + -0.2 deg., 7.25 + -0.2 deg., and 25.39 + -0.2 deg..
In another preferred embodiment, the polymorph B has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.80.+ -. 0.2 °, 7.25.+ -. 0.2 °, 11.00.+ -. 0.2 °, 15.43.+ -. 0.2 °, 18.55.+ -. 0.2 °, 21.88.+ -. 0.2 ° and 25.39.+ -. 0.2 °.
In another preferred embodiment, the polymorph B has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.80.+ -. 0.2 °, 7.25.+ -. 0.2 °, 7.92.+ -. 0.2 °, 11.00.+ -. 0.2 °, 12.28.+ -. 0.2 °, 15.43.+ -. 0.2 °, 16.10.+ -. 0.2 °, 18.55.+ -. 0.2 °, 21.88.+ -. 0.2 °, 25.39.+ -. 0.2 ° and 26.56.+ -. 0.2 °.
In another preferred embodiment, the polymorph B has an X-ray powder diffraction pattern substantially as shown in figure 2 a.
(3) Polymorph C
The polymorph C has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.94.+ -. 0.2 °, 8.14.+ -. 0.2 ° and 23.29.+ -. 0.2 °.
In another preferred embodiment, the polymorph C has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.69.+ -. 0.2 °, 5.94.+ -. 0.2 °, 8.14.+ -. 0.2 °, 9.20.+ -. 0.2 °, 11.02.+ -. 0.2 ° and 23.29.+ -. 0.2 °.
In another preferred embodiment, the polymorph C has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.69.+ -. 0.2 °, 5.94.+ -. 0.2 °, 7.17.+ -. 0.2 °, 8.14.+ -. 0.2 °, 9.20.+ -. 0.2 °, 11.02.+ -. 0.2 °, 15.35.+ -. 0.2 °, 15.96.+ -. 0.2 °, 19.24.+ -. 0.2 °, 21.71.+ -. 0.2 °, 23.29.+ -. 0.2 ° and 25.44.+ -. 0.2 °.
In another preferred embodiment, polymorph C has an X-ray powder diffraction pattern substantially as shown in figure 3 a.
(4) Polymorph D
The polymorph D has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.25±0.2°,21.85±0.2° and 25.46±0.2°.
In another preferred embodiment, the polymorph D has an X-ray powder diffraction characteristic peak selected from the group consisting of: 7.25±0.2°,11.06±0.2°,15.46 ±0.2°,21.85±0.2° and 25.46±0.2°.
In another preferred embodiment, the polymorph D has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.83.+ -. 0.2 °, 7.25.+ -. 0.2 °, 11.06.+ -. 0.2 °, 15.46.+ -. 0.2 °, 18.55.+ -. 0.2 °, 21.85.+ -. 0.2 ° and 25.46.+ -. 0.2 °.
In another preferred embodiment, the polymorph D has an X-ray powder diffraction pattern substantially as shown in figure 4 a.
(5) Polymorph E
The polymorph E has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.19±0.2°,11.04±0.2° and 25.48±0.2°.
In another preferred embodiment, the polymorph E has an X-ray powder diffraction characteristic peak selected from the group consisting of: 7.19±0.2°,11.04±0.2°,15.43±0.2°,21.69±0.2° and 25.48±0.2°.
In another preferred embodiment, the polymorph E has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.78.+ -. 0.2 °, 7.19.+ -. 0.2 °, 7.76.+ -. 0.2 °, 11.04.+ -. 0.2 °, 12.54.+ -. 0.2 °, 15.43.+ -. 0.2 °, 18.51.+ -. 0.2 °, 21.69.+ -. 0.2 ° and 25.48.+ -. 0.2 °.
In another preferred embodiment, the polymorph E has an X-ray powder diffraction pattern substantially as shown in figure 5 a.
(6) Polymorph F
The polymorph F has 3 or more characteristic X-ray powder diffraction peaks selected from the group consisting of: 7.17±0.2°,11.12±0.2° and 25.60 ±0.2°.
In another preferred embodiment, the polymorph F has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.11.+ -. 0.2 °, 6.63.+ -. 0.2 °, 7.17.+ -. 0.2 °, 11.12.+ -. 0.2 °, 12.62.+ -. 0.2 ° and 25.60.+ -. 0.2 °.
In another preferred embodiment, the polymorph F has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.11.+ -. 0.2 °, 6.63.+ -. 0.2 °, 7.17.+ -. 0.2 °, 7.86.+ -. 0.2 °, 11.12.+ -. 0.2 °, 12.62.+ -. 0.2 °, 15.42.+ -. 0.2 °, 18.63.+ -. 0.2 °, 21.57.+ -. 0.2 °, 25.60.+ -. 0.2 ° and 26.45.+ -. 0.2 °.
In another preferred embodiment, the polymorph F has an X-ray powder diffraction pattern substantially as shown in figure 6 a.
(7) Polymorph G
The polymorph G has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 8.09 + -0.2 deg., 21.76 + -0.2 deg., and 27.94 + -0.2 deg..
In another preferred embodiment, the polymorph G has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.28.+ -. 0.2 °, 6.65.+ -. 0.2 °, 8.09.+ -. 0.2 °, 8.51.+ -. 0.2 °, 9.10.+ -. 0.2 °, 21.76.+ -. 0.2 ° and 27.94.+ -. 0.2 °.
In another preferred embodiment, the polymorph G has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.28.+ -. 0.2 °, 6.65.+ -. 0.2 °, 8.09.+ -. 0.2 °, 8.51.+ -. 0.2 °, 9.10.+ -. 0.2 °, 12.04.+ -. 0.2 °, 18.25.+ -. 0.2 °, 21.76.+ -. 0.2 °, 25.75.+ -. 0.2 ° and 27.94.+ -. 0.2 °.
In another preferred embodiment, the polymorph G has an X-ray powder diffraction pattern substantially as shown in figure 7 a.
(8) Polymorph H
The polymorph H has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.55.+ -. 0.2 °, 7.05.+ -. 0.2 ° and 11.41.+ -. 0.2 °.
In another preferred embodiment, the polymorph H has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.55.+ -. 0.2 °, 6.65.+ -. 0.2 °, 7.05.+ -. 0.2 °, 11.41.+ -. 0.2 °, 11.80.+ -. 0.2 °, 25.08.+ -. 0.2 ° and 25.48.+ -. 0.2 °.
In another preferred embodiment, the polymorph H has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.55.+ -. 0.2 °, 6.43.+ -. 0.2 °, 6.65.+ -. 0.2 °, 7.05.+ -. 0.2 °, 11.41.+ -. 0.2 °, 11.80.+ -. 0.2 °, 15.28.+ -. 0.2 °, 16.81.+ -. 0.2 °, 21.61.+ -. 0.2 °, 25.08.+ -. 0.2 ° and 25.48.+ -. 0.2 °.
In another preferred embodiment, the polymorph H has an X-ray powder diffraction pattern substantially as shown in figure 8 a.
(9) Polymorph I
The polymorph I has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.82 + -0.2 deg., 6.85 + -0.2 deg., and 7.58 + -0.2 deg..
In another preferred embodiment, the polymorph I has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.82 + -0.2 deg., 6.85 + -0.2 deg., 7.58 + -0.2 deg., 8.33 + -0.2 deg., and 9.15 + -0.2 deg..
In another preferred embodiment, the polymorph I has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.82.+ -. 0.2 °, 6.85.+ -. 0.2 °, 7.58.+ -. 0.2 °, 8.33.+ -. 0.2 °, 9.15.+ -. 0.2 °, 10.20.+ -. 0.2 °, 11.27.+ -. 0.2 ° and 13.26.+ -. 0.2 °
In another preferred embodiment, the polymorph I has an X-ray powder diffraction pattern substantially as shown in figure 9 a.
Differential scanning calorimeter analysis
Also known as "differential thermal scanning analysis" (DSC), is a technique that measures the relationship between the energy difference between a substance being measured and a reference substance and temperature during heating. The position, shape and number of peaks on a DSC profile are related to the nature of the substance and can therefore be used qualitatively to identify the substance. The method is commonly used in the art to detect various parameters such as the phase transition temperature, the glass transition temperature, the reaction heat and the like of a substance.
DSC measurement methods are known in the art. For example, a DSC scanning profile of the crystalline form may be obtained using a DSC Q2000V 24.10 Build122 differential scanning calorimeter at a temperature ramp rate of 10℃per minute from 30℃to 300 ℃.
The amorphous form of the compound of formula I of the present invention, or its salt polymorph, has specific characteristic peaks in the differential thermal scanning analysis (DSC) diagram.
(1) Polymorph A
The differential scanning calorimetry pattern of polymorph a has a maximum peak at 200.63 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph a has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 1 b.
(2) Polymorph B
The differential scanning calorimetry pattern of polymorph B has a maximum peak at 201.55 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph B has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 2B.
(3) Polymorph C
The differential scanning calorimetry pattern of polymorph C has a maximum peak at 200.81 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph C has a differential scanning calorimetry pattern substantially as shown in figure 3 b.
(4) Polymorph D
The differential scanning calorimetry pattern of polymorph D has a maximum peak at 202.24 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph D has a differential scanning calorimetry pattern substantially as shown in figure 4 b.
(5) Polymorph E
The differential scanning calorimetry pattern of polymorph E has a maximum peak at 201.34 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph E has a differential scanning calorimetry pattern substantially as shown in figure 5 b.
(6) Polymorph F
The differential scanning calorimetry pattern of polymorph F has a maximum peak at 202.04 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃) or 187.°c±2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph F has a differential scanning calorimetry pattern substantially as shown in figure 6 b.
(7) Polymorph G
The differential scanning calorimetry pattern of polymorph G has a maximum peak at 158.09 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph G has a differential scanning calorimetry pattern substantially as shown in figure 7 b.
(8) Polymorph H
The differential scanning calorimetry pattern of polymorph H has a maximum peak at 133.84 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph H has a differential scanning calorimetry pattern substantially as shown in figure 8 b.
(9) Polymorph I
The differential scanning calorimetry pattern of polymorph I has a maximum peak at 98.59 ℃ ± 2 ℃ (or ±1 ℃, or ±0.5 ℃).
In another preferred embodiment, the polymorph I has a differential scanning calorimetry pattern substantially as shown in figure 9 b.
(10) Amorphous J
The differential scanning calorimetry pattern of amorphous J has a maximum peak at 98.59 ℃ + -2deg.C (or+ -1deg.C, or+ -0.5deg.C).
In another preferred embodiment, the amorphous J has a differential scanning calorimetry pattern substantially as shown in figure 10 b.
Nuclear Magnetic Resonance (NMR) can also be used to assist in determining the crystal structure, and determination methods are known in the art. The present invention preferably employs Bruker Avance III plus-400MHz.
Active ingredient
As used herein, the term "active ingredient" or "active compound" refers to the polymorphs of the present invention, i.e., the polymorphs of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., its hydrochloride salt), or a solvate thereof, or a hydrate thereof.
Pharmaceutical compositions and methods of administration
Because the polymorphs of the present invention have TLR agonist activity, the polymorphs of the present invention and pharmaceutical compositions containing the polymorphs of the present invention as the primary active ingredient are useful in the treatment, prevention and alleviation of TLR target mediated diseases. According to the prior art, the polymorphs of the present invention can be used for preventing or treating cancers, diseases possibly caused by viral infection (such as hepatitis B, herpes and the like) and the like.
The pharmaceutical compositions of the present invention comprise the polymorphs of the present invention in a safe and effective amount within the scope of a pharmaceutically acceptable excipient or carrier.
Wherein, "safe and effective amount" means: the amount of the compound (or polymorph) is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain from 0.01 to 2000mg of the polymorph/agent of the invention, more preferably from 0.1 to 500mg of the polymorph/agent of the invention. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the polymorphs or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, crospovidone, croscarmellose sodium; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of polymorphs of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
Polymorphs of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When pharmaceutical compositions are used, a safe and effective amount of the polymorph of the invention is suitable for use in a mammal (e.g., a human) in need of treatment, wherein the dosage at which administration is pharmaceutically effective is typically from 0.01 to 2000mg, preferably from 0.1 to 500mg, per day for a human of 60kg body weight. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the invention include:
1. a series of novel polymorphs and amorphous forms of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate or a pharmaceutically acceptable salt thereof, or a solvate thereof, are provided. Polymorphs of the present invention include polymorphs A-I, including amorphous form J.
2. The polymorphs A-I and the amorphous J of the invention have the advantages of good solubility, stability, difficult moisture absorption and the like, easy operation, split charging and the like.
3. The invention also provides the application of various polymorphs or amorphous substances, which can be used for preparing a pharmaceutical composition of a TLR agonist, thereby preventing and treating diseases (such as hepatitis B, herpes and the like) possibly caused by cancers and virus infection.
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated. Unless otherwise indicated, all numbers including amounts, percentages, fractions, and ratios are understood to be modified by the word "about," and amounts are not intended to represent significant digits.
EXAMPLE 1 preparation of polymorph A of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
The compound of formula I (1.0 eq) was dissolved in ethyl acetate, and a 4mol/L solution of hydrogen chloride (1.1 eq) in ethyl acetate was added dropwise at 20-30℃and stirred for 1-2 hours. Filtration, washing with ethyl acetate, and vacuum drying of the solid to constant weight at 40.+ -. 5 ℃ gave a white solid (yield 85%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:14.44(s,1H),9.34,8.52(br,2H),8.29(t,J＝12Hz,1H),7.75(d,J＝12Hz,1H),7.69(t,J＝11.4Hz,1H),7.51(t,J＝11.4Hz,1H),7.12(d,J＝12.6Hz,2H),6.59(d,J＝8.4Hz,2H),5.87(t,J＝17.4Hz 1H),4.64-4.96(m,5H),3.53-3.60(m,2H),3.40-3.47(m,1H),1.58(d,J＝9Hz,3H),1.37(s,9H),1.18(t,J＝10.2Hz,3H),1.02(d,J＝10.8Hz,3H).
The X-ray powder diffraction pattern is shown in figure 1a, the parameters of each peak are shown in table 1, the Differential Scanning Calorimetry (DSC) is shown in figure 1b, 1 the H NMR spectrum is shown in FIG. 1c.
TABLE 1
EXAMPLE 2 preparation of polymorph A of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
Dissolving hydrochloride of the compound shown in the formula I in isopropanol, slowly adding n-heptane, and stirring for 3-10 hours at the temperature of 10-30 ℃. The mixture was filtered, washed with n-heptane and the solid was dried under vacuum at 40.+ -. 5 ℃ to constant weight to give a white solid (yield 85%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:14.44(s,1H),9.34,8.52(br,2H),8.29(t,J＝12Hz,1H),7.75(d,J＝12Hz,1H),7.69(t,J＝11.4Hz,1H),7.51(t,J＝11.4Hz,1H),7.12(d,J＝12.6Hz,2H),6.59(d,J＝8.4Hz,2H),5.87(t,J＝17.4Hz 1H),4.64-4.96(m,5H),3.53-3.60(m,2H),3.40-3.47(m,1H),1.58(d,J＝9Hz,3H),1.37(s,9H),1.18(t,J＝10.2Hz,3H),1.02(d,J＝10.8Hz,3H).
The X-ray powder diffraction pattern is shown in figure 1a, the parameters of each peak are shown in table 1, the Differential Scanning Calorimetry (DSC) is shown in figure 1b, 1 the H NMR spectrum is shown in FIG. 1c.
TABLE 1
EXAMPLE 3 preparation of polymorph B of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
The polymorphic form A of the compound of the formula I is taken and dissolved in methylene dichloride, isopropyl ether is added dropwise at the temperature of 30-35 ℃ and stirred for 16 hours. Filtered, washed with isopropyl ether and the solid dried under vacuum at 40.+ -. 5 ℃ to constant weight to give a white solid (yield 75%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:14.44(s,1H),9.34,8.52(br,2H),8.29(t,J＝12Hz,1H),7.75(d,J＝12Hz,1H),7.69(t,J＝11.4Hz,1H),7.51(t,J＝11.4Hz,1H),7.12(d,J＝12.6Hz,2H),6.59(d,J＝8.4Hz,2H),5.87(t,J＝17.4Hz 1H),4.64-4.96(m,5H),3.53-3.60(m,2H),3.40-3.47(m,1H),1.58(d,J＝9Hz,3H),1.37(s,9H),1.18(t,J＝10.2Hz,3H),1.02(d,J＝10.8Hz,3H).
The X-ray powder diffraction pattern is shown in figure 2a, the parameters of each peak are shown in table 2, the Differential Scanning Calorimetry (DSC) is shown in figure 2b, 1 the H NMR spectrum is shown in FIG. 2c.
TABLE 2
EXAMPLE 4 preparation of polymorph C of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-C ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
The polymorphic form A of the compound of the formula I is taken and dissolved in methylene dichloride, methyl tertiary butyl ether is added dropwise at the temperature of 30-35 ℃ and stirred for 16 hours. Filtration, washing with methyl tert-butyl ether and drying of the solid at 40.+ -. 5 ℃ under vacuum to constant weight gives a white solid (yield 75%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:14.44(s,1H),9.34,8.52(br,2H),8.29(t,J＝12Hz,1H),7.75(d,J＝12Hz,1H),7.69(t,J＝11.4Hz,1H),7.51(t,J＝11.4Hz,1H),7.12(d,J＝12.6Hz,2H),6.59(d,J＝8.4Hz,2H),5.87(t,J＝17.4Hz 1H),4.64-4.96(m,5H),3.53-3.60(m,2H),3.40-3.47(m,1H),1.58(d,J＝9Hz,3H),1.37(s,9H),1.18(t,J＝10.2Hz,3H),1.02(d,J＝10.8Hz,3H).
The X-ray powder diffraction pattern is shown in figure 3a, the parameters of each peak are shown in table 3, the Differential Scanning Calorimetry (DSC) is shown in figure 3b, 1 the spectrum of H NMR is shown in 3c.
TABLE 3 Table 3
EXAMPLE 5 preparation of polymorph D of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
Dissolving the polymorphic form A of the compound shown in the formula I in dichloromethane, dropwise adding ethyl acetate at 30-35 ℃, and stirring for 16 hours. Filtration, washing with ethyl acetate, and vacuum drying of the solid at 40.+ -. 5 ℃ to constant weight gives a white solid (yield 70%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:14.44(s,1H),9.34,8.52(br,2H),8.29(t,J＝12Hz,1H),7.75(d,J＝12Hz,1H),7.69(t,J＝11.4Hz,1H),7.51(t,J＝11.4Hz,1H),7.12(d,J＝12.6Hz,2H),6.59(d,J＝8.4Hz,2H),5.87(t,J＝17.4Hz 1H),4.64-4.96(m,5H),3.53-3.60(m,2H),3.40-3.47(m,1H),1.58(d,J＝9Hz,3H),1.37(s,9H),1.18(t,J＝10.2Hz,3H),1.02(d,J＝10.8Hz,3H).
The X-ray powder diffraction pattern is shown in FIG. 4a, the parameters of each peak are shown in Table 4, the Differential Scanning Calorimeter (DSC) is shown in FIG. 4b, 1 The spectrum of H NMR is shown in 4c.
TABLE 4 Table 4
EXAMPLE 6 preparation of polymorph E of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
The polymorphic form A of the compound of formula I was taken and dissolved in ethanol and methyl tert-butyl ether was added dropwise at 60℃and stirred for 16 hours. Filtration, washing with methyl tert-butyl ether and vacuum drying of the solid to constant weight at 40.+ -. 5 ℃ gives a white solid (yield 65%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:14.44(s,1H),9.34,8.52(br,2H),8.29(t,J＝12Hz,1H),7.75(d,J＝12Hz,1H),7.69(t,J＝11.4Hz,1H),7.51(t,J＝11.4Hz,1H),7.12(d,J＝12.6Hz,2H),6.59(d,J＝8.4Hz,2H),5.87(t,J＝17.4Hz 1H),4.64-4.96(m,5H),3.53-3.60(m,2H),3.40-3.47(m,1H),1.58(d,J＝9Hz,3H),1.37(s,9H),1.18(t,J＝10.2Hz,3H),1.02(d,J＝10.8Hz,3H).
The X-ray powder diffraction pattern is shown in FIG. 5a, the parameters of each peak are shown in Table 5, the Differential Scanning Calorimeter (DSC) is shown in FIG. 5b, 1 the H NMR spectrum is shown in FIG. 5c.
TABLE 5
EXAMPLE 7 preparation of polymorph F of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
Taking the polymorphic form A of the compound of the formula I, respectively suspending in ethyl acetate, tetrahydrofuran, acetone, acetonitrile or n-heptane, and stirring at 20-30 ℃ for 20 hours. Filtering, washing, and vacuum drying the solid at 40+/-5 ℃ to constant weight to obtain white solid (yield 65-85%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:14.44(s,1H),9.34,8.52(br,2H),8.29(t,J＝12Hz,1H),7.75(d,J＝12Hz,1H),7.69(t,J＝11.4Hz,1H),7.51(t,J＝11.4Hz,1H),7.12(d,J＝12.6Hz,2H),6.59(d,J＝8.4Hz,2H),5.87(t,J＝17.4Hz 1H),4.64-4.96(m,5H),3.53-3.60(m,2H),3.40-3.47(m,1H),1.58(d,J＝9Hz,3H),1.37(s,9H),1.18(t,J＝10.2Hz,3H),1.02(d,J＝10.8Hz,3H).
The X-ray powder diffraction pattern is shown in FIG. 6a, the parameters of each peak are shown in Table 6, the Differential Scanning Calorimeter (DSC) is shown in FIG. 6b, 1 the H NMR spectrum is shown in 6c.
TABLE 6
EXAMPLE 8 preparation of polymorph G of mandelate salt of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alanine ester
Dissolving a compound (1.0 eq) of the formula I in ethyl acetate, adding mandelic acid (1.1 eq), stirring for 1 hour at 20-50 ℃, and slowly cooling to 15-30 ℃. The mixture was filtered, washed, and the solid was dried under vacuum at 40.+ -. 5 ℃ to constant weight to give a white solid (yield 70%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:8.13(d,J＝8Hz,1H),7.68-7.67(m,3H),7.52(t,J＝7.6Hz,1H),7.45(d,J＝7.2Hz,2H),7.34-7.31(m,3H),7.27-7.24(m,1H),7.14(d,J＝8.8Hz,2H),6.62(d,J＝8.8Hz,2H),5.85-5.79(m,1H),4.95-4.79(m,5H),4.63(d,J＝12.8Hz,1H),3.56-3.43(m,3H),1.52(d,J＝6Hz,3H),1.37(s,9H),1.15(t,J＝7.2Hz,3H),1.00(d,J＝6.8Hz,3H).
The X-ray powder diffraction pattern is shown in FIG. 7a, the parameters of each peak are shown in Table 7, the Differential Scanning Calorimeter (DSC) is shown in FIG. 7b, 1 the H NMR spectrum is shown in 7c.
TABLE 7
EXAMPLE 9 preparation of polymorph H of oxalate of tert-butyl ((S) - ((((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
The compound of formula H (1.0 eq) was dissolved in ethyl acetate, oxalic acid (1.1 eq) was added, stirred at 20-50℃for 1 hour, and cooled slowly to 15-30 ℃. The mixture was filtered, washed, and the solid was dried under vacuum at 40.+ -. 5 ℃ to constant weight to give a white solid (yield 70%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:9.20(br,2H),8.25(d,J＝8.4Hz,1H),7.77(d,J＝8.4Hz,1H),7.67(t,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.12(d,J＝8.8Hz,2H),6.61(d,J＝8.8Hz,2H),5.86-5.81(m,1H),4.95-4.83(m,4H),4.70(d,J＝13.2Hz,1H),3.58-3.41(m,3H),2.55(s,2H),1.56(d,J＝6Hz,3H),1.37(s,9H),1.18(t,J＝6.8Hz,3H),1.03(d,J＝7.2Hz,3H).
The X-ray powder diffraction pattern is shown in FIG. 8a, the parameters of each peak are shown in Table 8, the Differential Scanning Calorimeter (DSC) is shown in FIG. 8b, 1 the H NMR spectrum is shown in 8c.
TABLE 8
EXAMPLE 10 preparation of polymorph I of tartrate salt of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
Dissolving a compound (1.0 eq) of formula I in ethyl acetate, adding tartaric acid (1.1 eq), stirring for 1 hour at 20-50 ℃, and slowly cooling to 15-30 ℃. The mixture was filtered, washed, and the solid was dried under vacuum at 40.+ -. 5 ℃ to constant weight to give a white solid (yield 65%).
Sampling warp 1 The title compound was confirmed by detection by H NMR, X-ray powder diffraction, DSC, etc.
1 H NMR(400MHz,DMSO-d6)δ:9.09(br,2H),8.24(d,J＝8Hz,1H),7.88-7.85(m,1H),7.79(d,J＝8Hz,1H),7.69(t,J＝7.2Hz,1H),7.47(t,J＝7.6Hz,1H),7.34-7.30(m,1H),7.11(d,J＝8.8Hz,2H),6.82-6.77(m,2H),6.61(d,J＝8.4Hz,2H),5.87-5.81(m,1H),4.96-4.83(m,4H),4.66(d,J＝13.2Hz,1H),3.59-3.42(m,3H),1.56(d,J＝6Hz,3H),1.37(s,9H),1.18(t,J＝6.8Hz,3H),1.03(d,J＝6.8Hz,3H).
The X-ray powder diffraction pattern is shown in FIG. 9a, the parameters of each peak are shown in Table 9, the Differential Scanning Calorimeter (DSC) is shown in FIG. 9b, 1 The spectrum of H NMR is shown in 9c.
TABLE 9
EXAMPLE 11 amorphous J of tert-butyl ((S) - ((((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phospho) -L-alaninate
Dissolving the compound of the formula I in acetonitrile and water, and freeze-drying to obtain powdery white solid.
Sampling warp 1 Detection by H NMR, X-ray powder diffraction, DSC, etc., demonstrated the title amorphous J.
1 H NMR(400MHz,DMSO-d6)δ:8.12(d,J＝8Hz,1H),7.68-7.65(m,1H),7.49(t,J＝7.2Hz,1H),7.28(t,J＝6.8Hz,1H),7.21(d,J＝8.8Hz,1H),6.68(d,J＝8.8Hz,2H),6.67(s,2H),5.91-5.85(m,1H),4.96-4.82(m,4H),4.66(d,J＝12.8Hz,1H),3.59-3.48(m,3H),1.55(d,J＝6Hz,3H),1.42(s,9H),1.18(t,J＝6.8Hz,3H),1.03(d,J＝6.8Hz,3H).
The X-ray powder diffraction diagram is shown in figure 10a, the Differential Scanning Calorimetry (DSC) diagram is shown in figure 10b, 1 the H NMR spectrum is shown in 10c.
EXAMPLE 12 stability of polymorph A of hydrochloride salt of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate
After 6 months of acceleration test (test conditions 40±2 ℃, 75% ±5% rh), the results showed that: the crystalline form of polymorph a was very stable and the impurities of polymorph a did not change significantly at 6 months compared to the freshly prepared (0 month) polymorph a. The results of the study are as follows:
EXAMPLE 13 stability of polymorphs B-F of hydrochloride of tert-butyl ((S) - (((R) -1- (4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c ] quinolin-1-yl) propan-2-yl) oxo) (4-chlorophenoxy) phosphoryl) -L-alaninate
After 3 months of acceleration test (test conditions 40±2 ℃, 75% ±5% rh), the results showed that: the crystalline form of polymorph B, C, D, E, F is quite stable and the impurity of polymorph B, C, D, E, F is not significantly altered at 3 months compared to the newly prepared (0 month) polymorph B, C, D, E, F.
EXAMPLE 14 solubility of polymorphs
Weighing a proper amount of polymorphic substance A, H or G, placing the polymorphic substance A, H or G into a 10ml centrifuge tube, adding 1.5ml of water, shaking uniformly to prepare a supersaturated solution, centrifuging the solution for 20 minutes at 10000 revolutions per minute, removing supernatant, and using acetonitrile: the saturated solubility was obtained by HPLC measurement after dilution with water (7:3) at the appropriate magnification.
Name of the name Lot number Solubility in water (mg/mL)
Polymorphic form A 000296-29 28.46
Polymorphic form of drug H 1060-044A 6.21
Polymorphic form of drug G 1060-044C 1.15
From the solubility detection results of each polymorph, the polymorphs prepared by the method have good solubility in water, and particularly the solubility of the polymorphic medicine A is the best.
Example 15 hygroscopicity test of polymorphs
According to the guiding principle of drug hygroscopicity test (guiding principle 9103 of four parts of Chinese pharmacopoeia). As a result, it was found that the various polymorphs A-I and amorphous J of the present invention were all very stable, with substantially no or little hygroscopicity.
Therefore, the polymorphs described herein are well suited for use in pharmaceutical compositions. In addition, the polymorphic substance is not easy to lift and collect in the manufacturing process of medicines such as split charging and the like, is not easy to waste, and is beneficial to protecting the health of operators.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A polymorph, characterized in that the polymorph is a polymorph of a compound shown in formula I or a pharmaceutically acceptable salt or solvate thereof,
2. the polymorph of claim 1, wherein the polymorph is polymorph a of a hydrochloride salt of a compound represented by formula I, wherein the polymorph a has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.77 + -0.2 deg., 7.11 + -0.2 deg., and 21.44 + -0.2 deg..
3. The polymorph of claim 1, wherein the polymorph is polymorph B of a hydrochloride salt of a compound represented by formula I, wherein the polymorph B has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.80 + -0.2 deg., 7.25 + -0.2 deg., and 25.39 + -0.2 deg..
4. The polymorph of claim 1, wherein the polymorph is a polymorph of a hydrochloride salt of a compound of formula I selected from the group consisting of: polymorph C, polymorph D, polymorph E, polymorph F;
wherein the polymorph C has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.94±0.2°,8.14±0.2° and 23.29±0.2°;
the polymorph D has an X-ray powder diffraction characteristic peak selected from the group consisting of: 7.25±0.2°,21.85±0.2° and 25.46±0.2°;
the polymorph E has X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.19±0.2°,11.04±0.2° and 25.48±0.2°;
the polymorph F has X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.17±0.2°,11.12±0.2° and 25.60 ±0.2°.
5. The polymorph of claim 1, wherein the polymorph is a polymorph of a compound of formula I selected from the group consisting of: polymorph G of mandelate salt of compound of formula I, polymorph H of oxalate salt of compound of formula I, polymorph I of tartrate salt of compound of formula I;
wherein the polymorph G has an X-ray powder diffraction characteristic peak selected from the group consisting of: 8.09±0.2°,21.76±0.2° and 27.94±0.2°;
The polymorph H has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.55.+ -. 0.2 °, 7.05.+ -. 0.2 ° and 11.41.+ -. 0.2 °;
the polymorph I has an X-ray powder diffraction characteristic peak selected from the group consisting of: 5.82 + -0.2 deg., 6.85 + -0.2 deg., and 7.58 + -0.2 deg..
6. An amorphous form, wherein said amorphous form is amorphous form J of the free base of the compound of formula I having an X-ray powder diffraction characteristic peak substantially as shown in figure 10 a.
7. Use of a polymorph or amorphous form according to any one of claims 1 to 6 for the preparation of a pharmaceutical composition of a TLR agonist.
8. A pharmaceutical composition comprising:
a) A polymorph or amorphous form according to any one of claims 1 to 6; and
b) A pharmaceutically acceptable carrier.
9. A process for the preparation of the polymorph of any one of claims 1 to 5, comprising the steps of: crystallizing a compound of formula I and an acid in an inert solvent, or crystallizing a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof in an inert solvent, to give the polymorph of any one of claims 1 to 5.
10. A process for the preparation of polymorph a of a compound of formula I according to claim 9, comprising three steps:
(S1) dissolving a polymorph of the hydrochloride salt of the compound of formula I in a specific volume of a specific solvent;
(S2) slowly adding a specific antisolvent, and then stirring at a specific temperature for a specific time; and
(S3) filtering and drying to obtain a polymorph A.
CN202210956944.0A 2022-08-10 2022-08-10 Polymorphic form preparation of TLR agonist or salt thereof Pending CN117624241A (en)

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