Carboxylamine triazole eutectic crystal as well as preparation method and application thereof

Abstract

The invention discloses a carboxamide triazole oxalic acid eutectic crystal form I. An X-ray powder diffraction pattern expressed by a 2 theta angle has the following characteristic peaks: 3.7 degrees + / -0.2 degrees, 18.5 degrees + / -0.2 degrees, 20.1 degrees + / -0.2 degrees, 23.9 degrees + / -0.2 degrees, 25.8 degrees + / -0.2 degrees and 28.3 degrees + / -0.2 degrees. An X-ray powder diffraction pattern of the eutectic crystal form I of carboxamide triazole malonic acid, which is represented by an angle of 2 theta, has the following characteristic peaks: 19.6 degrees + / -0.2 degrees, 24.0 degrees + / -0.2 degrees, 25.2 degrees + / -0.2 degrees, 28.6 degrees + / -0.2 degrees, 28.9 degrees + / -0.2 degrees and 29.0 degrees + / -0.2 degrees. An X-ray powder diffraction pattern of the carboxylamine triazole maleic acid eutectic crystal form I expressed by a 2 theta angle has the following characteristic peaks: 14.6 degrees + / -0.2 degrees, 17.9 degrees + / -0.2 degrees, 18.3 degrees + / -0.2 degrees, 18.7 degrees + / -0.2 degrees, 21.9 degrees + / -0.2 degrees and 23.3 degrees + / -0.2 degrees. An X-ray powder diffraction pattern of the carboxylamine triazole citric acid eutectic crystal form I expressed by a 2 theta angle has the following characteristic peaks: 3.9 degrees + / -0.2 degrees, 14.3 degrees + / -0.2 degrees, 15.2 degrees + / -0.2 degrees, 16.3 degrees + / -0.2 degrees, 19.4 degrees + / -0.2 degrees and 19.6 degrees + / -0.2 degrees. An X-ray powder diffraction pattern, represented by a 2 theta angle, of the eutectic crystal form I of carboxamide triazole saccharin has the following characteristic peaks: 11.9 degrees + / -0.2 degrees, 14.0 degrees + / -0.2 degrees, 15.9 degrees + / -0.2 degrees, 17.8 degrees + / -0.2 degrees, 19.0 degrees + / -0.2 degrees and 23.2 degrees + / -0.2 degrees.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a carboxyamide triazole cocrystal and a preparation method and application thereof. Background Art

[0002] Carboxyamide triazole is the world's first small molecule immunotherapy drug that regulates the inflammatory microenvironment of tumors. It has regulatory effects on multiple cytokines (TNF-α, IL-6, etc.) and multiple signaling pathways (NF-κB and MAPKs) in the inflammatory microenvironment. On the one hand, carboxyamide triazole regulates the tumor microenvironment to exert anti-tumor effects by downregulating the production of cytokines such as TNF-α and IL-6 in tumor-associated macrophages (TAMs). The applicant's previous in vivo and in vitro tests have shown that carboxyamide triazole has a significant inhibitory effect on dozens of solid tumors such as lung cancer, breast cancer, liver cancer, kidney cancer, and ovarian cancer; and the Phase III clinical trial data for 495 first-line advanced non-small cell lung cancer patients showed that the objective efficacy of the carboxyamide triazole test group was significantly improved; and it can effectively reduce the risk of disease progression. The clinical trial successfully achieved the preset primary endpoint, with significant efficacy, few adverse reactions, and high safety. On the other hand, carboxyamide triazole plays an anti-autoimmune role by inhibiting the activity of NF-κB and MAPKs and reducing the release of inflammatory cytokines such as TNF-α and IL-6 in inflammatory tissues. It can be used to treat autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Therefore, carboxyamide triazole has a broad-spectrum application prospect in anti-tumor and anti-autoimmune diseases.

[0003] Carboxyamide triazole is a new small molecule immunotherapy drug. The applicant has been committed to the development of APIs and formulations, and has applied for related invention patents such as CN112358451B, CN112353778B, and CN112083109B. A patent for single crystals of carboxyamide triazole, CN113620892B, has also been filed, covering carboxyamide triazole single crystals, preparation methods, compositions, and uses. However, issues such as API solubility and bioavailability can be further optimized, so research into other forms of carboxyamide triazole is of great significance for the expansion of drug development.

[0004] Existing literature has not reported on the crystal form of carboxyamide triazole, and systematic research on its crystal form is almost nonexistent. In particular, comprehensive research on carboxyamide triazole cocrystal compounds has not yet been reported. Pharmaceutical cocrystals have significant research implications in the field of drug preparation due to their potential advantages in dissolution, permeability, hygroscopicity, and stability. Summary of the Invention

[0005] The present invention aims to overcome at least one defect of the above-mentioned prior art and provides a carboxyaminetriazole cocrystal, including one of carboxyaminetriazole oxalic acid cocrystal, carboxyaminetriazole malonic acid cocrystal, carboxyaminetriazole maleic acid cocrystal, carboxyaminetriazole citric acid cocrystal, and carboxyaminetriazole saccharin cocrystal, so as to achieve the purpose of high stability and good drugability.

[0006] The carboxyamine triazole cocrystal includes one of the group consisting of carboxyamine triazole oxalic acid cocrystal, carboxyamine triazole malonic acid cocrystal, carboxyamine triazole maleic acid cocrystal, carboxyamine triazole citric acid cocrystal and carboxyamine triazole saccharin cocrystal.

[0007] The invention protects a carboxyamide triazole oxalic acid cocrystal form I, and an X-ray powder diffraction pattern expressed in 2θ angles has the following characteristic peaks: 3.7°±0.2°, 18.5°±0.2°, 20.1°±0.2°, 23.9°±0.2°, 25.8°±0.2°, and 28.3°±0.2°.

[0008] Furthermore, the X-ray powder diffraction pattern of the carboxyamide triazole oxalic acid cocrystal form I expressed in 2θ angles has the following characteristic peaks: 3.7°±0.2°, 18.5°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.2°±0.2°, 23.4°±0.2°, 23.9°±0.2°, 25.8°±0.2°, 26.3°±0.2°, 28.3°±0.2°, 28.8°±0.2°, and 28.9°±0.2°.

[0009] The present invention also protects a method for preparing the carboxyaminetriazole oxalic acid cocrystal form I, which comprises taking carboxyaminetriazole free base into a sample bottle at room temperature, adding solvent 1, and then adding 1.0 to 1.2 equivalents of oxalic acid and stirring to obtain the cocrystal form I; the solvent 1 is at least one of 1,4-dioxane, acetonitrile, ethyl acetate, tetrahydrofuran, and acetone / water.

[0010] The present invention also protects a carboxyaminetriazolemalonic acid cocrystal form I, whose X-ray powder diffraction pattern expressed in 2θ angles has the following characteristic peaks: 19.6°±0.2°, 24.0°±0.2°, 25.2°±0.2°, 28.6°±0.2°, 28.9°±0.2°, and 29.0°±0.2°.

[0011] Furthermore, the carboxyamide triazole malonic acid cocrystal form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 7.2°±0.2°, 9.8°±0.2°, 19.6°±0.2°, 19.8°±0.2°, 24.0°±0.2°, 24.9°±0.2°, 25.2°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29.0°±0.2°, 37.6°±0.2°, and 38.2°±0.2°.

[0012] Furthermore, the preparation method of the carboxyaminetriazolemalonic acid cocrystal form I is: take carboxyaminetriazole free base in a sample bottle at room temperature, add solvent 2, and then add 1.0 to 1.2 equivalents of malonic acid, stir and crystallize to obtain the result; the solvent 2 is acetone / water.

[0013] The present invention also protects a carboxyamide triazole maleic acid cocrystal form I, and an X-ray powder diffraction pattern expressed in 2θ angles has the following characteristic peaks: 14.6°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 21.9°±0.2°, and 23.3°±0.2°.

[0014] Furthermore, the X-ray powder diffraction pattern of the carboxyamide triazole maleic acid cocrystal form I expressed in 2θ angles has the following characteristic peaks: 4.7°±0.2°, 14.6°±0.2°, 15.8°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 21.9°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 27.7°±0.2°, 28.2°±0.2°, and 30.7°±0.2°.

[0015] Furthermore, the preparation method of the carboxyaminetriazole maleic acid cocrystal form I is as follows: take carboxyaminetriazole free base in a sample bottle, add acetonitrile at room temperature, then add 2 to 5 equivalents of maleic acid, and stir to obtain the result.

[0016] The present invention also protects a carboxyamide triazole citric acid cocrystal form I, whose X-ray powder diffraction pattern expressed in 2θ angles has the following characteristic peaks: 3.9°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 16.3°±0.2°, 19.4°±0.2°, and 19.6°±0.2°.

[0017] Furthermore, the X-ray powder diffraction pattern of the carboxyamide triazole citric acid cocrystal form I expressed in 2θ angles has the following characteristic peaks: 3.7°±0.2°, 3.9°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 16.3°±0.2°, 19.4°±0.2°, 19.6°±0.2°, 21.4°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.3°±0.2°, and 29.3°±0.2°.

[0018] Furthermore, the preparation method of the carboxyamide triazole citric acid cocrystal form I is as follows: take carboxyamide triazole free base in a sample bottle, add tetrahydrofuran at room temperature, and then add 1.0 to 1.2 times the equivalent of citric acid and stir to obtain the obtained product.

[0019] The present invention also protects a carboxyamide triazole saccharin cocrystal form I, whose X-ray powder diffraction pattern expressed in 2θ angles has the following characteristic peaks: 11.9°±0.2°, 14.0°±0.2°, 15.9°±0.2°, 17.8°±0.2°, 19.0°±0.2°, and 23.2°±0.2°.

[0020] Furthermore, the X-ray powder diffraction pattern of the carboxyamide triazole saccharin cocrystal form I expressed in 2θ angles has the following characteristic peaks: 11.9°±0.2°, 14.0°±0.2°, 15.9°±0.2°, 16.3°±0.2°, 17.8°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 23.2°±0.2°, 25.0°±0.2°, and 25.2°±0.2°.

[0021] The preparation method of the carboxyamide triazole saccharin cocrystal form I of the present invention comprises the following steps: taking carboxyamide triazole free base into a sample bottle, adding acetone / water at room temperature, and then adding 1.0 to 1.2 times the equivalent of saccharin and stirring to obtain the cocrystal form I.

[0022] The present invention also protects a pharmaceutical composition comprising carboxyamide triazole oxalic acid cocrystal form I or carboxyamide triazole malonic acid cocrystal form I or carboxyamide triazole maleic acid cocrystal form I or carboxyamide triazole citric acid cocrystal form I or carboxyamide triazole saccharin cocrystal form I and pharmaceutically acceptable inactive ingredients.

[0023] Furthermore, the pharmaceutical composition contains 0.01% to 99.9% by mass of carboxyamide triazole oxalic acid cocrystal form I or carboxyamide triazole malonic acid cocrystal form I or carboxyamide triazole maleic acid cocrystal form I or carboxyamide triazole citric acid cocrystal form I or carboxyamide triazole saccharin cocrystal form I.

[0024] The present invention also protects the use of carboxyaminetriazole oxalic acid cocrystal form I or carboxyaminetriazole malonic acid cocrystal form I or carboxyaminetriazole maleic acid cocrystal form I or carboxyaminetriazole citric acid cocrystal form I or carboxyaminetriazole saccharin cocrystal form I in treating solid tumors and autoimmune diseases.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The carboxyamide triazole oxalic acid cocrystal, carboxyamide triazole malonic acid cocrystal, carboxyamide triazole maleic acid cocrystal, carboxyamide triazole citric acid cocrystal and carboxyamide triazole saccharin cocrystal obtained by screening in the present invention have good stability and high drugability, laying a foundation for the development of carboxyamide triazole series products. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the XRPD pattern of carboxyamide triazole oxalic acid cocrystal Form I.

[0028] Figure 2 Oxalic acid cocrystal form I H NMR spectrum.

[0029] Figure 3 This is the TGA and DSC overlay of oxalic acid cocrystal Form I.

[0030] Figure 4 This is the XRPD pattern of malonic acid cocrystal Form I.

[0031] Figure 5 Malonic acid cocrystal form I H NMR spectrum.

[0032] Figure 6 This is the TGA and DSC overlay of malonic acid cocrystal Form I.

[0033] Figure 7 This is the XRPD pattern of maleic acid cocrystal Form I.

[0034] Figure 8 For maleic acid cocrystal form I H NMR spectrum.

[0035] Figure 9 This is the TGA and DSC overlay of maleic acid cocrystal Form I.

[0036] Figure 10 This is the XRPD pattern of citric acid cocrystal Form I.

[0037] Figure 11 It is citric acid cocrystal form I H NMR spectrum.

[0038] Figure 12 This is the TGA and DSC overlay of citric acid cocrystal Form I.

[0039] Figure 13 This is the XRPD pattern of saccharin cocrystal Form I.

[0040] Figure 14 Saccharin cocrystal form I H NMR spectrum.

[0041] Figure 15 The TGA and DSC superimposed patterns of saccharin cocrystal Form I. DETAILED DESCRIPTION

[0042] The drawings in the embodiments provide a more detailed description of the technical solutions in the embodiments of the present invention. In the drawings, the same or similar reference numerals throughout represent the same or similar elements or elements with the same or similar functions. The described embodiments are part of the embodiments of the present invention, not all of them. The embodiments described below with reference to the drawings are exemplary and are intended to be used to explain the present invention, and should not be understood as limiting the present invention. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. The embodiments of the present invention are described in detail below with reference to the drawings.

[0043] It should be noted that if the embodiments of the present application involve directional indications (such as up, down, left, right, front, back, etc.), the directional indications are only used to explain the relative position relationship, movement status, etc. between the various components under a certain specific posture (as shown in the accompanying drawings). If the specific posture changes, the directional indications will also change accordingly.

[0044] In addition, if there are descriptions involving "first", "second", etc. in the embodiments of the present application, the descriptions of "first", "second", etc. are only for descriptive purposes and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of such features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the fact that they can be implemented by ordinary technicians in this field. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by this application.

[0045] The crystallization of the unique crystal form disclosed in the present application is related to the kinetics and equilibrium performance of the crystallization process under specific conditions. Therefore, those skilled in the art will appreciate that the crystal form obtained depends on the kinetics and thermodynamics of the crystallization process. Under specific conditions (such as, solvent, temperature, pressure and concentration of the compound of the present application), one crystal form may be more stable than another crystal form (or in fact more stable than any other crystal form). However, a crystal form with relatively low thermodynamic stability may be kinetically advantageous. Therefore, factors other than kinetics, such as time, impurity distribution, agitation, the presence or absence of seed crystals, etc., may also affect the form of crystallization.

[0046] On the other hand, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned carboxyamide triazole crystal forms and at least one pharmaceutically acceptable inactive ingredient.

[0047] The term "therapeutically effective amount" refers to an amount of a compound that, when used to treat a disease, or at least one clinical symptom of a disease or condition, is sufficient to affect such treatment of the disease, condition, or symptom in a subject. The "therapeutically effective amount" can vary depending on the compound, the disease, condition, and / or symptoms of the disease or condition, the severity of the disease, condition, and / or symptoms of the disease or condition, the age of the patient being treated, and / or the weight of the patient being treated. Wherever possible, an appropriate dosage will be apparent to those skilled in the art or can be determined by routine experimentation. In the context of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination that is effective to treat the disease, condition, or symptom.

[0048] The term "pharmaceutically acceptable inactive ingredients" refers to conventional pharmaceutical inactive ingredients suitable for the desired pharmaceutical formulation. Examples include: diluents such as water and various organic solvents; fillers such as starch and sucrose; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); humectants such as glycerol; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and bentonite; and lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. Other pharmaceutically acceptable inactive ingredients such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners, and dyes may also be added to the pharmaceutical composition. It is preferred to use inactive ingredients that are suitable for the desired dosage form and route of administration.

[0049] The present application also provides a pharmaceutical composition comprising at least one carboxyamide triazole capable of treating the above-mentioned conditions in an effective amount and a pharmaceutically acceptable carrier or diluent. The composition of the present application may contain other agents known to those skilled in the art, and may be prepared according to well-known processes in the field of pharmaceutical preparations using conventional solid or liquid carriers or diluents, and a class of pharmaceutical additives suitable for the desired mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavorings, etc.).

[0050] The pharmaceutical composition of the present application containing the active ingredient may be in a form suitable for systemic, oral and / or topical use. For example, the pharmaceutical composition may be in the form of a sterile injectable aqueous solution or an oily suspension. The suspension may be formulated according to known techniques using a suitable dispersant or wetting agent and a suspending agent as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable excipients and solvents that may be used may be water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are generally used as solvents or suspending media. Any bland fixed oil may be used for this purpose, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may be applied to injectable preparations.

[0051] For rectal administration, carboxyamide triazoles can also be formulated in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperatures but liquid at rectal temperature, thereby melting in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0052] Formulations for oral administration may be tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use may be prepared according to any method known in the art for preparing pharmaceutical compositions. Tablets contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer duration of action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used.

[0053] The pharmaceutical composition of the present application can also be in the form of an oil-in-water emulsifier. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture of these. Suitable emulsifiers can be naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitol monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitol monooleate. Emulsions may also contain sweeteners and flavorings. Syrups and elixirs can be prepared together with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, flavorings and a coloring agent.

[0054] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds of Formula I may be used (for this purpose, topical application includes not only topical administration but also administration as mouthwashes and gargles). The preparation of such topical formulations is well described in the art of pharmaceutical formulations, for example, in Remington's Pharmaceutical Science, 17th ed., Mack Publishing, Easton, PA. For topical administration, the compounds may also be administered as powders or sprays, particularly in aerosol form.

[0055] Dosage levels of about 0.01 mg to about 140 mg per kilogram of body weight per day are effective for treating the above-indicated conditions, or about 0.5 mg to about 7 g per patient per day can be administered. For example, about 0.01 to 50 mg per kilogram of body weight per day, or about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day, of the present compound can be effectively used to treat inflammation. However, it will be understood that the specific dosage level for a particular patient will depend on many factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

[0056] The amount of active ingredient that is combined with the carrier materials to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. For example, a human oral formulation may contain 0.5 mg to 5 g of the active agent, mixed with an appropriate amount of carrier comprising from about 5 percent to about 95 percent of the total weight of the composition. Dosage unit forms will generally contain from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0057] Diffusion In some embodiments, suitable pharmaceutical inactive ingredients are selected from water, various organic solvents and various inert diluents or fillers. If necessary, the pharmaceutical composition may contain one or more additives such as flavorings, binders and excipients. For oral administration, the tablet may contain at least one inactive ingredient selected from, for example, citric acid; various disintegrants such as starch, alginic acid and certain complex silicates; various binders such as sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate and talc are often used as fillers for tablets. These ingredients can also be filled in soft and hard gelatin capsules. When used for oral administration and an aqueous suspension is required, the active compound therein can be mixed with at least one ingredient selected from various sweeteners or flavorings, pigments or dye combinations. If necessary, various emulsifiers or suspending agents can be used; diluents such as water, ethanol, propylene glycol, glycerol, or combinations thereof can also be used. Examples 1 to 5

[0058] About 100 mg of carboxyamide triazole free base was weighed into a sample bottle, and the corresponding solvent 1 was added at room temperature, followed by the addition of 1.1 equivalents of oxalic acid.

[0059] XRPD pattern of oxalic acid cocrystal Form I prepared in Example 2, H NMR spectrum, DSC spectrum, TGA spectrum such as Figures 1 to 3 As shown. XRPD patterns indicate a high degree of crystallinity. DSC patterns reveal two endothermic peaks at ~197°C and ~227°C, presumably due to deoxalation and melting, respectively. TGA patterns reveal a ~9.6% weight loss from 140°C to 230°C, and NMR reveals virtually no residual solvent, presumably due to deoxalation. IC results indicate the sample contains ~0.5 eq of oxalic acid. H The NMR results showed that there was basically no obvious position shift, and oxalic acid cocrystal form I was formed. Comparative Example 1

[0060] The difference between Comparative Example 1 and Example 2 is that the added solvent is ethanol in an amount of 2 ml; as a result, no eutectic is formed. Examples 6 to 8

[0061] Examples 6 to 8 describe methods for preparing carboxyamide triazole malonic acid cocrystals.

[0062] Weigh about 100 mg of carboxyamide triazole free base into a sample bottle, add the corresponding solvent at room temperature, and then add 1.1 equivalents of malonic acid and stir to obtain the product.

[0063] Malonic acid cocrystal Form I was obtained only by crystallization in acetone / water. Figures 4-6 As shown, the XRPD pattern shows that the sample has high crystallinity. The DSC spectrum shows four endothermic peaks at ~110°C, ~125°C, ~157°C, and ~229°C, presumably due to demalonation and melting, respectively. The TGA spectrum shows that the sample loses ~11.2% weight from 130°C to 200°C, and NMR shows only 0.3% residual acetone, presumably due to demalonation. H NMR results showed that a signal peak of malonic acid was visible at ~3.25 ppm. According to the integration results, the molar ratio of free base to malonic acid was calculated to be ~1:0.5, with almost no obvious position shift, forming a cocrystal. Comparative Examples 2 to 6

[0064] The difference between Comparative Examples 2 to 6 and Example 6 lies in the different types of added solvents. The specific materials are shown in the following table. Examples 7 to 9

[0065] Examples 7 to 9 are methods for preparing carboxyamide triazole maleic acid eutectic.

[0066] Weigh about 100 mg of carboxyamide triazole free base into a sample bottle, add the corresponding solvent at room temperature, and then add 3.0 equivalents of maleic acid and stir to prepare the product.

[0067] Maleic acid cocrystal form I was obtained by crystallization with maleic acid in acetonitrile. Figures 7-9 As shown. The XRPD pattern showed that the sample had moderate crystallinity. The DSC spectrum showed three endothermic peaks at ~142°C, ~170°C, and ~222°C, presumably due to dehydration, demaleic acid, and melting. The TGA spectrum showed that the sample had a weight loss of ~3.2% from 140°C to 160°C and a weight loss of ~18.7% from 160°C to 210°C. NMR showed that only 0.1% acetonitrile solvent remained, presumably due to dehydration and maleic acid. H NMR results showed that a signal peak of maleic acid was visible at ~6.27 ppm. According to the integration results, the molar ratio of free base to maleic acid was calculated to be ~1:1.2, with almost no obvious position shift, forming a cocrystal. Comparative Examples 7 to 12

[0068] The difference between Comparative Examples 7 to 12 and Examples 7 to 9 is that different amounts of maleic acid were added or different solvents were used, and no eutectic was formed. Examples 10 to 12

[0069] Examples 10 to 12 are methods for preparing carboxyamide triazole citric acid eutectic.

[0070] Weigh about 100 mg of carboxyamide triazole free base into a sample bottle, add the corresponding solvent at room temperature, and then add 1.1 equivalents of citric acid and stir to obtain the product.

[0071] Citric acid cocrystal form I is obtained by crystallization in tetrahydrofuran. Figures 10-12 As shown, the XRPD pattern shows that the sample has high crystallinity. The DSC spectrum shows two endothermic peaks at ~47°C and ~130°C, presumably due to desolvation and melting. The TGA spectrum shows that the sample loses ~1.9% weight from room temperature to 100°C and ~2.6% weight from 100°C to 150°C. NMR shows no obvious residual solvent, presumably due to dehydration. H NMR results showed a signal peak of citric acid at ~2.74 ppm. According to the integration results, the molar ratio of free base to citric acid was ~1:1, with almost no obvious position shift, forming a cocrystal. Comparative Examples 13-17

[0072] The difference between Comparative Examples 13 to 17 and Example 10 lies in the different types of solvents used, and ultimately no eutectic was formed. Examples 13 to 15

[0073] Examples 13 to 15 are methods for preparing carboxyamide triazole saccharin cocrystals.

[0074] Weigh about 100 mg of carboxyamide triazole free base into a sample bottle, add the corresponding solvent at room temperature, and then add 1.1 equivalents of saccharin and stir to obtain the product.

[0075] Saccharin cocrystal Form I was obtained by reaction crystallization in acetone / water. XRPD patterns revealed a high degree of crystallinity. DSC patterns revealed three endothermic peaks at ~80°C, ~148°C, and ~182°C, presumably due to desolvation and melting, respectively. TGA patterns revealed a ~2.8% weight loss from room temperature to 120°C (theoretical weight loss for one molecule of water is 2.88%), and NMR patterns revealed virtually no significant residual solvent, presumably due to dehydration. HNMR results showed that the signal peaks of saccharin were visible at 7.96 ppm and 8.13 ppm. According to the integration results, the molar ratio of free base to saccharin was 1:1 cocrystal. Comparative Examples 18 to 26

[0076] Comparative Examples 18 to 26 differ from Examples 13 to 15 in that different crystallization solvents and crystallization methods were used, and no eutectic was formed in any of the comparative examples, as shown in the table below.

[0077] In summary, due to the difficulty in preparing carboxyamine triazole cocrystals, the selection of cocrystal solvents, the type of acid, and the addition of acid equivalents are all critical. The inventors screened dozens of acids and ultimately obtained only five cocrystals. Comparative Example 27

[0078] Comparative Example 27 is a method for preparing carboxyamide triazole nicotinic acid cocrystals. Approximately 100 mg of carboxyamide triazole free base was weighed into a sample bottle and the corresponding solvent was added at room temperature. Except for the tetrahydrofuran, acetone / water, and dimethyl sulfoxide systems, the other solvent systems were in a suspended state. Then, 1.1 equivalents of nicotinic acid were added, but no nicotinic acid cocrystal was obtained. Comparative Example 28

[0079] Comparative Example 28 is a method for preparing a carboxyamide triazole salicylic acid cocrystal. About 100 mg of carboxyamide triazole free base is weighed into a sample bottle and the corresponding solvent is added at room temperature. Except for tetrahydrofuran, acetone / water, and dimethyl sulfoxide systems, the other solvent systems are in a suspended state. Then, 1.1 equivalents of salicylic acid are added, but no salicylic acid cocrystal is obtained. Comparative Example 29

[0080] Comparative Example 29 is a method for preparing carboxyamide triazole benzoic acid cocrystal. About 100 mg of carboxyamide triazole free base is weighed into a sample bottle and the corresponding solvent is added at room temperature. Except for tetrahydrofuran, acetone / water, and dimethyl sulfoxide systems, the other solvent systems are in a suspended state. Then, 1.1 equivalents of benzoic acid are added, but no benzoic acid cocrystal is obtained. Comparative Example 30

[0081] Comparative Example 30 is a method for preparing carboxyamide triazole xylitol cocrystal. About 100 mg of carboxyamide triazole free base is weighed into a sample bottle and the corresponding solvent is added at room temperature. Except for tetrahydrofuran, acetone / water, and dimethyl sulfoxide systems, the other solvent systems are in a suspended state. Then, 1.0 equivalent of xylitol is added, but no xylitol cocrystal is obtained. Comparative Example 31

[0082] Comparative Example 31 is a method for preparing a carboxyaminetriazole sorbitol cocrystal. About 100 mg of carboxyaminetriazole free base is weighed into a sample bottle and the corresponding solvent is added at room temperature. Except for tetrahydrofuran, acetone / water, and dimethyl sulfoxide systems, the other solvent systems are in a suspended state. Then, 1.0 equivalent of sorbitol is added, but no sorbitol cocrystal is obtained. Examples 16 to 20

[0083] Examples 16 to 20 are composition implementations of five types of cocrystals of carboxyamide triazole. Example 16

[0084] The specific composition is as follows: Example 17

[0085] The difference between Example 17 and Example 16 is that the active ingredient is replaced with carboxyamide triazole malonic acid cocrystal Form I. Example 18

[0086] The difference between Example 18 and Example 16 is that the active ingredient is replaced with carboxyamide triazole maleic acid cocrystal Form I. Example 19

[0087] The difference between Example 19 and Example 16 is that the active ingredient is replaced with carboxyamide triazole citrate cocrystal Form I. Example 20

[0088] The difference between Example 20 and Example 16 is that the active ingredient is replaced with carboxyamide triazole saccharin cocrystal Form I.

[0089] The pharmaceutical compositions prepared in Examples 16 to 20 have good drugability and are suitable for pharmaceutical production. 1. Dynamic Solubility and Stability Investigation of Candidate Cocrystals

[0090] Solubility tests were conducted on five candidate cocrystals: oxalic acid cocrystal Form I, malonic acid cocrystal Form I, maleic acid cocrystal Form I, citric acid cocrystal Form I, and saccharin cocrystal Form I, in biological media (FaSSIF, FeSSIF, and FaSSGF) and water at 37°C. 50 mg of the candidate cocrystals were weighed into a sample vial, and then 5 mL of each of the three biological media and water were added to form a suspension. All suspensions were shaken at 200 rpm at 37°C. Approximately 0.3 mL of the suspension was filtered, and the filtrate was analyzed by HPLC.

[0091] Compared with the free base, the solubility of the five cocrystals in FaSSIF, FeSSIF, FaSSGF and water was greatly improved. The results are summarized in Table 9. Table 9 Solubility test results in biological media and water

[0092] LOD = 0.056 μg / mL; solubility is based on the free base content. 3. Solid-state stability study

[0093] 50 mg of oxalic acid cocrystal form I, malonic acid cocrystal form I, maleic acid cocrystal form I, citric acid cocrystal form I, and saccharin cocrystal form I prepared in the scale-up experiment were placed under light (closed) and 60 ° C (closed) conditions for 5 days and 10 days respectively. The solid samples after placement were subjected to XRPD and HPLC tests to analyze the crystal stability and chemical stability. The results showed that the physical and chemical properties of the three candidate cocrystals were basically stable after being placed under the above conditions for 10 days, and the crystal form did not change. Compared with the free base, the stability of the carboxyamide triazole cocrystal under light and high temperature environment is significantly improved. The experimental results are shown in Table 10: Table 10 Stability evaluation results 4. Pharmacokinetic Studies

[0094] Study objective: To investigate the in vivo plasma pharmacokinetic characteristics of five candidate cocrystals (oxalic acid cocrystal form I, malonic acid cocrystal form I, maleic acid cocrystal form I, citric acid cocrystal form I, saccharin cocrystal form I) and carboxyamidotriazole free base) in rats after a single oral administration.

[0095] Female rats weighing 180-220 g were housed in plastic boxes with free access to water. The room temperature was 20-25°C, with a diurnal temperature difference of 3°C, and the humidity was 50-60%. The light cycle was 12 hours with alternating light and dark, and the ventilation rate was 10-20 times / hour.

[0096] Rats were randomly divided into six groups of five rats each. Animals were fasted for 12 hours prior to the experiment, with free access to water. Carboxyamide triazole solution, oxalic acid cocrystal Form I, malonic acid cocrystal Form I, maleic acid cocrystal Form I, citric acid cocrystal Form I, and saccharin cocrystal Form I solutions were prepared using PEG 400 and administered orally to the animals at a dose of 20 mg / kg.

[0097] The experiment used a continuous blood sampling method. 200 μL of blood was collected from the orbital venous plexus at 15, 30 minutes, and 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 minutes after gavage. The blood was placed on ice, centrifuged, and 50 μL of plasma was separated and stored at -20°C. To the anticoagulated rat plasma / tissue homogenate, 50 μL of internal standard working solution and 200 μL of acetonitrile were added. The mixture was shaken for 30 seconds and then centrifuged twice at high speed (14,000 rpm for 5 minutes). 2 μL of the supernatant was collected for LC-MS analysis.

[0098] The experimental data were analyzed using WinNonLin software (Pharsight, version 8.3) for non-compartmental model analysis and plasma pharmacokinetic parameters were calculated. Statistical analysis of the experimental data was performed using Microsoft Office Excel and Student's T-test.

[0099] The results are shown in the following table: The rat pharmacokinetic parameters Cmax, AUC(0-t) and other parameters of oxalic acid cocrystal form I, malonic acid cocrystal form I, maleic acid cocrystal form I, citric acid cocrystal form I and saccharin cocrystal form I solutions are better than those of carboxyamide triazole solution, indicating that the cocrystal form has better bioavailability than carboxyamide triazole solution. Table 11 Plasma pharmacokinetic parameters of rats after oral administration of different crystalline carboxyamide triazole (20 mg / kg) 5. Pharmacodynamic Studies

[0100] 1. Anti-tumor efficacy experiment

[0101] The pharmacological effects of five candidate cocrystals, namely oxalic acid cocrystal form I, malonic acid cocrystal form I, maleic acid cocrystal form I, citric acid cocrystal form I, and saccharin cocrystal form I, were investigated. The results showed that these five candidate cocrystals, namely oxalic acid cocrystal form I, malonic acid cocrystal form I, maleic acid cocrystal form I, citric acid cocrystal form I, and saccharin cocrystal form I, had significant inhibitory effects on various tumor cells, and their effects were better than those of carboxyamidotriazole free base.

[0102] This experiment is a CCK8 experiment in which five candidate cocrystals, namely oxalic acid cocrystal form I, malonic acid cocrystal form I, maleic acid cocrystal form I, citric acid cocrystal form I, and saccharin cocrystal form I, inhibit the proliferation of A549 cells, A498 cells, MCF-7 cells, and HUH-7 cells.

[0103] A549 (human lung cancer cells), A498 (human renal cancer cells), MCF-7 (human breast cancer cells), and HUH-7 (human liver cancer cells) were seeded into 96-well microplates (3000-5000 cells / well) and cultured in a 37°C, 5% CO2 incubator until the cells reached 80% fusion, and then treated with drugs; 100 μL of carboxyamidotriazole single crystal DMSO solution at different concentrations (final concentrations of 20, 10, 5, 1, and 0.1 μg / mL) was added as the experimental group, and the normal control group was cultured with 100 μL of control solution; after incubation for 72 hours, 10 μL of CCK8 reagent was added, and after incubation at 37°C for 4 hours, the absorbance of each well was measured using a microplate reader.

[0104] The results are shown in the following table

[0105] The above results indicate that the cocrystals of carboxyaminotriazole exhibit different degrees of anticancer activity, which is better than that of carboxyaminotriazole free base.

[0106] 2. Research on the efficacy of drugs against autoimmune diseases

[0107] This example investigates the use of oxalic acid cocrystal Form I, malonic acid cocrystal Form I, maleic acid cocrystal Form I, citric acid cocrystal Form I, and saccharin cocrystal Form I for autoinflammatory diseases. The positive control drug is calcipotriol ointment.

[0108] Eighty quarantined animals were randomly divided according to body weight into a model group (n=10), a positive control group (n=10), an oxalic acid cocrystal Form I group (n=10), a malonic acid cocrystal Form I group (n=10), a maleic acid cocrystal Form I group (n=10), a citric acid cocrystal Form I group (n=10), a saccharin cocrystal Form I group (n=10), and a carboxyamidotriazole free base group (n=10). Modeling was performed immediately after grouping. An area approximately 5 cm × 3 cm on the back of all mice was depilated and skin prepared. Imiquimod cream was applied to the back of the animals once daily for 5 consecutive days. Drug administration was performed on the same day after modeling. Drug administration lasted for 3 days, with the corresponding test substance applied to the modeling site twice daily. One day after the last dose, the animals were euthanized, and the full-thickness skin of the modeling site was excised for ELISA analysis. Table 12 Groups and dosage design list Table 13 Experimental results statistics

[0109] Note: Compared with the model group, * indicates P < 0.05.

[0110] The results showed that carboxyamide triazole free base had a significant therapeutic effect on imiquimod-induced psoriasis mice, and could significantly reduce the expression levels of TNF-α, IL-17, and IL-23 in the skin tissues of imiquimod-induced psoriasis mice. The therapeutic effect of the cocrystal form was better than that of carboxyamide triazole free base.

[0111] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the above preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent replacements of the technical solutions of the present invention may be made without departing from the spirit and scope of the technical solutions of the present invention. Those skilled in the art may also make other changes within the spirit of the present invention and apply them to the design of the present invention, as long as they do not deviate from the technical effects of the present invention. These changes made in accordance with the spirit of the present invention should all be included in the scope of protection claimed by the present invention.

Claims

1. A carboxyamide triazole eutectic, characterized in that The invention comprises one of the following: carboxyamine triazole oxalic acid eutectic, carboxyamine triazole malonic acid eutectic, carboxyamine triazole maleic acid eutectic, carboxyamine triazole citric acid eutectic and carboxyamine triazole saccharin eutectic.

2. A carboxyamide triazole oxalic acid cocrystal form I, characterized in that: The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 3.7°±0.2°, 18.5°±0.2°, 20.1°±0.2°, 23.9°±0.2°, 25.8°±0.2°, and 28.3°±0.2°.

3. The carboxyamide triazole oxalic acid cocrystal form I according to claim 2, characterized in that The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 3.7°±0.2°, 18.5°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.2°±0.2°, 23.4°±0.2°, 23.9°±0.2°, 25.8°±0.2°, 26.3°±0.2°, 28.3°±0.2°, 28.8°±0.2°, and 28.9°±0.2°.

4. A method for preparing the carboxyamide triazole oxalic acid cocrystal form I according to any one of claims 2 to 3, characterized in that: Carboxyamide triazole free base is placed in a sample bottle at room temperature, solvent 1 is added, and then 1.0 to 1.2 times the equivalent of oxalic acid is added and stirred to obtain the product; the solvent 1 is at least one of 1,4-dioxane, acetonitrile, ethyl acetate, tetrahydrofuran, and acetone / water.

5. A carboxyamide triazole malonic acid cocrystal form I, characterized in that: The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 19.6°±0.2°, 24.0°±0.2°, 25.2°±0.2°, 28.6°±0.2°, 28.9°±0.2°, and 29.0°±0.2°.

6. The carboxyaminetriazolemalonic acid cocrystal form I according to claim 5, characterized in that The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 7.2°±0.2°, 9.8°±0.2°, 19.6°±0.2°, 19.8°±0.2°, 24.0°±0.2°, 24.9°±0.2°, 25.2°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29.0°±0.2°, 37.6°±0.2°, 38.2°±0.2°.

7. A method for preparing the carboxyamide triazole malonic acid cocrystal form I according to any one of claims 5 to 6, characterized in that: Take carboxyamine triazole free base in a sample bottle, add acetone / water at room temperature, and then add 1.0 to 1.2 equivalents of malonic acid, stir and crystallize to obtain the product.

8. A carboxyamide triazole maleic acid cocrystal form I, characterized in that: The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 14.6°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 21.9°±0.2°, and 23.3°±0.2°.

9. The carboxyamide triazole maleic acid cocrystal form I as claimed in claim 8, characterized in that The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 4.7°±0.2°, 14.6°±0.2°, 15.8°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 21.9°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 27.7°±0.2°, 28.2°±0.2°, and 30.7°±0.2°.

10. A method for preparing the carboxyamide triazole maleic acid cocrystal form I according to any one of claims 8 to 9, characterized in that: Take carboxyamine triazole free base in a sample bottle, add acetonitrile at room temperature, then add 2 to 5 equivalents of maleic acid, and stir to obtain the product.

11. A carboxyamide triazole citric acid cocrystal form I, characterized in that: The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 3.9°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 16.3°±0.2°, 19.4°±0.2°, and 19.6°±0.2°.

12. The carboxyamide triazole citric acid cocrystal form I according to claim 11, characterized in that The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 3.7°±0.2°, 3.9°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 16.3°±0.2°, 19.4°±0.2°, 19.6°±0.2°, 21.4°±0.2°, 24.1°±0.2°, 24.5°±0.2°, 25.3°±0.2°, and 29.3°±0.2°.

13. A method for preparing the carboxyamide triazole citrate cocrystal form I according to any one of claims 11 to 12, characterized in that: Take carboxyamine triazole free base in a sample bottle, add tetrahydrofuran at room temperature, and then add 1.0 to 1.2 times the equivalent of citric acid and stir to obtain the product.

14. A carboxyamide triazole saccharin cocrystal form I, characterized in that: The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 11.9°±0.2°, 14.0°±0.2°, 15.9°±0.2°, 17.8°±0.2°, 19.0°±0.2°, and 23.2°±0.2°.

15. The carboxyamide triazole saccharin cocrystal Form I according to claim 14, characterized in that: The X-ray powder diffraction pattern expressed in 2θ degrees has the following characteristic peaks: 11.9°±0.2°, 14.0°±0.2°, 15.9°±0.2°, 16.3°±0.2°, 17.8°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 23.2°±0.2°, 25.0°±0.2°, 25.2°±0.2°.

16. A method for preparing the carboxyamide triazole saccharin cocrystal Form I according to any one of claims 14 to 15, characterized in that: Take carboxyamide triazole free base in a sample bottle, add acetone / water at room temperature, and then add 1.0-1.2 equivalents of saccharin and stir to obtain the product.

17. A pharmaceutical composition, characterized in that The invention comprises the carboxyaminetriazole oxalic acid cocrystal form I according to any one of claims 2 to 3, the carboxyaminetriazole malonic acid cocrystal form I according to any one of claims 5 to 6, the carboxyaminetriazole maleic acid cocrystal form I according to any one of claims 8 to 9, the carboxyaminetriazole citric acid cocrystal form I according to any one of claims 11 to 12, or the carboxyaminetriazole saccharin cocrystal form I according to any one of claims 14 to 15, and pharmaceutically acceptable inactive ingredients.

18. The pharmaceutical composition according to claim 17, characterized in that The pharmaceutical composition comprises 0.01% to 99.9% by mass of carboxyaminetriazole oxalic acid cocrystal form I, carboxyaminetriazole malonic acid cocrystal form I, carboxyaminetriazole maleic acid cocrystal form I, carboxyaminetriazole citric acid cocrystal form I, or carboxyaminetriazole saccharin cocrystal form I.

19. Use of the carboxyaminetriazole oxalic acid cocrystal Form I according to any one of claims 2 to 3, the carboxyaminetriazole malonic acid cocrystal Form I according to any one of claims 5 to 6, the carboxyaminetriazole maleic acid cocrystal Form I according to any one of claims 8 to 9, the carboxyaminetriazole citric acid cocrystal Form I according to any one of claims 11 to 12, and the carboxyaminetriazole saccharin cocrystal Form I according to any one of claims 14 to 15 in treating solid tumors and autoimmune diseases.

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