Crystal form of carboxamide triazole salt as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a crystal form of carboxamide triazole salt, a preparation method, a pharmaceutical composition and application thereof. The carboxamide triazole salt is at least one of 1-naphthalene sulfonate, benzene sulfonate or mesylate. An X-ray powder diffraction pattern of the crystal form I of the carboxamide triazole 1-naphthalenesulfonate, which is expressed by a 2 theta angle, has the following characteristic peaks: 3.8 degrees + / -0.2 degrees, 13.1 degrees + / -0.2 degrees, 16.2 degrees + / -0.2 degrees, 17.7 degrees + / -0.2 degrees, 18.7 degrees + / -0.2 degrees and 25.8 degrees + / -0.2 degrees. An X-ray powder diffraction pattern of the crystal form I of the carboxamide triazole benzene sulfonate expressed by a 2 theta angle has the following characteristic peaks: 6.1 degrees + / -0.2 degrees, 13.7 degrees + / -0.2 degrees, 19.2 degrees + / -0.2 degrees, 19.8 degrees + / -0.2 degrees, 23.5 degrees + / -0.2 degrees and 27.5 degrees + / -0.2 degrees. An X-ray powder diffraction pattern of the crystal form II of carboxamide triazole mesylate expressed by a 2 theta angle has the following characteristic peaks: 15.9 degrees + / -0.2 degrees, 18.0 degrees + / -0.2 degrees, 19.9 degrees + / -0.2 degrees, 20.7 degrees + / -0.2 degrees, 23.4 degrees + / -0.2 degrees and 29.3 degrees + / -0.2 degrees.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and particularly to the crystal forms of carboxamide triazole salt, its preparation method, pharmaceutical composition and uses. Background Art

[0002] The development of current anti-tumor drugs has mainly gone through three stages. The first stage is the chemotherapy drug treatment stage. As cytotoxic drugs, chemotherapy drugs have the advantage of significant efficacy, but the disadvantage is that they are too toxic. For patients with advanced malignant tumors, it is difficult to maintain long-term treatment. The second stage is the targeted drug treatment stage. Targeted therapy has strong precision and low toxicity, but the population it targets is limited and it is easy to develop drug resistance. Therefore, it is necessary to continuously develop second-generation and third-generation targeted drugs to overcome drug resistance, and the limitations are obvious. The third stage is the immunotherapy stage. Especially after the listing of immune checkpoint inhibitors PD-1 / L1, it has opened a new era of anti-tumor immunotherapy. Currently, there are very many immunotherapy-related experimental studies, up to several thousand, involving more than two hundred different targets. The track is crowded and the competition is extremely fierce. Experts have reported that the adverse reactions of macromolecular immunotherapy are obvious and last for a long time.

[0003] Carboxamide triazole is the world's first small molecule immunotherapy new drug that regulates the tumor inflammatory microenvironment, and has a regulatory effect on various cytokines (such as TNF-α, IL-6, etc.) and various signaling pathways (NF-κB and MAPKs) in the inflammatory microenvironment. On the one hand, carboxamide triazole regulates the tumor microenvironment to play an anti-tumor role by down-regulating the production of cytokines such as TNF-α and IL-6 in tumor-associated macrophages (TAMs). In vitro and in vivo experiments of the applicant in the early stage have shown that carboxamide triazole has a significant inhibitory effect on dozens of solid tumors such as lung cancer, breast cancer, liver cancer, kidney cancer, ovarian cancer, etc.; and the phase III clinical trial data for 495 patients with advanced non-small cell lung cancer in the first line show that the objective response rate of the carboxamide triazole experimental group has been significantly improved; and it can effectively reduce the risk of disease progression. The clinical trial has successfully reached the preset primary endpoint, with significant efficacy, few adverse reactions and high safety. On the other hand, carboxamide triazole plays an anti-autoimmune disease role by inhibiting the activities of NF-κB and MAPKs and reducing the release of inflammatory cytokines such as TNF-α and IL-6 in inflammatory tissues, and can be used for the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease; therefore, carboxamide triazole has broad application prospects in anti-tumor and anti-autoimmune diseases.

[0004] As a new small-molecule immunological anti-tumor drug, the applicant has been committed to the development of the active pharmaceutical ingredient (API) and preparations, and has also applied for related invention patents such as CN112358451B, CN112353778B, CN112083109B, etc. In addition, a single crystal patent for carboquone, CN113620892B - Carboquone single crystal, preparation method, its composition and uses, has been applied. However, problems such as the solubility and bioavailability of the API can still be further optimized. Therefore, the research on other forms of carboquone is of great significance for the expansion of drug development.

[0005] Due to the different salt forms and crystal forms of salts of the same drug, there may be obvious differences in aspects such as stability, solubility, and bioavailability compared to the drug itself. On the one hand, it will affect the efficacy of the drug, and on the other hand, it will also affect the stability and efficacy of the drug made into different preparations. The structural formula of carboquone contains amino and amide groups, and theoretically, it is significantly basic. However, in actual research, it is found that carboquone is very weakly basic and has poor salt-forming ability. Therefore, which acid to use for salification and how to prepare the salt are the problems that need to be solved currently. Moreover, in practical applications, it is usually impossible to predict whether a specific drug can form a salt form and whether this salt form will form different crystalline forms, let alone predict the structure and properties of the crystal form of the salt itself. Therefore, it is of great significance to develop salt forms that are more conducive to the pharmaceutical use of carboquone and new salt forms of carboquone in pharmaceutical compositions and new crystal forms of their salts, so as to provide more qualitative and quantitative information for the efficacy and safety research of carboquone solid preparations. Summary of the Invention

[0006] The present invention aims to overcome at least one defect of the above-mentioned prior art, and provides salts of carboquone, wherein the salts are at least one of 1-naphthalenesulfonate, benzenesulfonate or methanesulfonate. In addition, the present invention further studies the crystal forms of the salts, and screens a dominant crystal form for each salt form to improve the solubility of carboquone and the technical effect of improving bioavailability.

[0007] Salts of carboquone, wherein the salts are at least one of 1-naphthalenesulfonate, benzenesulfonate or methanesulfonate.

[0008] A crystal form I of carboquone 1-naphthalenesulfonate, the X-ray powder diffraction pattern of the crystal form I of carboquone 1-naphthalenesulfonate represented by 2θ angle has the following characteristic peaks: 3.8°±0.2°, 13.1°±0.2°, 16.2°±0.2°, 17.7°±0.2°, 18.7°±0.2°, 25.8°±0.2°.

[0009] Furthermore, the X-ray powder diffraction pattern of the crystalline form I of carboxamide triazole 1-naphthalene sulfonate in terms of 2θ angle has the following characteristic peaks: 3.8° ± 0.2°, 12.6° ± 0.2°, 13.1° ± 0.2°, 15.6° ± 0.2°, 16.2° ± 0.2°, 17.7° ± 0.2°, 18.7° ± 0.2°, 21.5° ± 0.2°, 22.6° ± 0.2°, 24.6° ± 0.2°, 25.4° ± 0.2°, 25.8° ± 0.2°.

[0010] Furthermore, the X-ray powder diffraction pattern of the crystalline form I of carboxamide triazole 1-naphthalene sulfonate in terms of 2θ angle is as Figure 2 shown.

[0011] The present invention also provides a preparation method of the crystalline form I of carboxamide triazole 1-naphthalene sulfonate. The preparation method is as follows: Weigh carboxamide triazole into a sample bottle, add solvent 1 at room temperature, and then add 1-naphthalene sulfonic acid in an amount of 1 to 1.5 times the equivalent of carboxamide triazole and stir to obtain the crystalline form I of 1-naphthalene sulfonate.

[0012] Preferably, the solvent 1 is at least one of 1,4-dioxane, acetonitrile, ethyl acetate, tetrahydrofuran, and acetone / water.

[0013] Preferably, the ratio of acetone / water is 15 to 25:1.

[0014] The present invention also provides a crystalline form I of carboxamide triazole benzenesulfonate. The X-ray powder diffraction pattern of the crystalline form I of carboxamide triazole benzenesulfonate in terms of 2θ angle has the following characteristic peaks: 6.1° ± 0.2°, 13.7° ± 0.2°, 19.2° ± 0.2°, 19.8° ± 0.2°, 23.5° ± 0.2°, 27.5° ± 0.2°.

[0015] Furthermore, the X-ray powder diffraction pattern of the crystalline form I of carboxamide triazole benzenesulfonate in terms of 2θ angle has the following characteristic peaks: 6.1° ± 0.2°, 13.7° ± 0.2°, 16.9° ± 0.2°, 19.2° ± 0.2°, 19.4° ± 0.2°, 19.8° ± 0.2°, 21.4° ± 0.2°, 23.5° ± 0.2°, 25.6° ± 0.2°, 26.5° ± 0.2°, 27.3° ± 0.2°, 27.5° ± 0.2°.

[0016] Furthermore, the X-ray powder diffraction pattern of the crystalline form I of carboxamide triazole benzenesulfonate in terms of 2θ angle is as Figure 9 shown.

[0017] Furthermore, the present invention also provides a method for preparing crystalline form I of carboxamide triazole benzenesulfonate, and the preparation method is as follows: Weigh carboxamide triazole into a sample bottle, add solvent 2 at room temperature, and then add a benzenesulfonic acid solution with 1.1 - 2.2 equivalents of carboxamide triazole, and stir to obtain it.

[0018] Preferably, the solvent 2 is at least one of ethanol, 1,4 - dioxane, acetonitrile, ethyl acetate, tetrahydrofuran, and dimethyl sulfoxide.

[0019] The present invention also provides crystalline form II of carboxamide triazole methanesulfonate. The X - ray powder diffraction pattern of crystalline form II of carboxamide triazole methanesulfonate expressed in terms of 2θ angle has the following characteristic peaks: 15.9° ± 0.2°, 18.0° ± 0.2°, 19.9° ± 0.2°, 20.7° ± 0.2°, 23.4° ± 0.2°, 29.3° ± 0.2°.

[0020] Furthermore, the X - ray powder diffraction pattern of crystalline form II of carboxamide triazole methanesulfonate expressed in terms of 2θ angle has the following characteristic peaks: 4.0° ± 0.2°, 14.0° ± 0.2°, 15.9° ± 0.2°, 18.0° ± 0.2°, 19.0° ± 0.2°, 19.9° ± 0.2°, 20.7° ± 0.2°, 23.0° ± 0.2°, 23.4° ± 0.2°, 24.9° ± 0.2°, 29.1° ± 0.2°, 29.3° ± 0.2°.

[0021] Furthermore, the X - ray powder diffraction pattern of crystalline form II of carboxamide triazole methanesulfonate expressed in terms of 2θ angle is as Figure 19 shown.

[0022] The present invention also provides a method for preparing crystalline form II of carboxamide triazole methanesulfonate: Weigh carboxamide triazole into a sample bottle, add solvent 3 at room temperature, and then add a methanesulfonic acid solution with 1.1 - 2.2 times the equivalent of carboxamide triazole, and stir to obtain it.

[0023] Furthermore, the solvent 3 is acetonitrile.

[0024] The present invention also provides a pharmaceutical composition, which comprises crystalline form I of the above - mentioned carboxamide triazole 1 - naphthalenesulfonate, or crystalline form I of the above - mentioned carboxamide triazole benzenesulfonate, or crystalline form II of the above - mentioned carboxamide triazole methanesulfonate, and a pharmaceutically acceptable inactive ingredient.

[0025] Furthermore, the pharmaceutical composition comprises 0.01% - 99.9% by mass of crystalline form I of carboxamide triazole 1 - naphthalenesulfonate, or crystalline form I of carboxamide triazole benzenesulfonate, or crystalline form II of carboxamide triazole methanesulfonate.

[0026] The present invention also provides the use of polymorph I of the above-mentioned carboxyamidotriazole 1-naphthalenesulfonate, or polymorph I of the above-mentioned carboxyamidotriazole benzenesulfonate, or polymorph II of the above-mentioned carboxyamidotriazole methanesulfonate in the treatment of solid tumors or autoimmune diseases. The solid tumors include lung cancer, liver cancer, gastric cancer, breast cancer, colorectal cancer, pancreatic cancer, cervical cancer, etc.; the autoimmune diseases include but are not limited to diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

[0027] Since it is difficult for carboxyamidotriazole to form salts, and most of the salts formed are not stable enough in crystal form, through a large number of experimental screenings, the present invention unexpectedly discovers that only polymorph I of 1-naphthalenesulfonate, polymorph I of benzenesulfonate, and polymorph II of methanesulfonate have stable crystal forms, can be scaled up for production, and have obvious drug effects, and can be developed as improved products of carboxyamidotriazole. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Superimposed XRPD pattern of polymorph I of 1-naphthalenesulfonate prepared in Examples 1 to 6.

[0029] Figure 2 XRPD pattern of polymorph I of 1-naphthalenesulfonate prepared in Example 1.

[0030] Figure 3 HNMR spectrum of polymorph I of 1-naphthalenesulfonate prepared in Example 1.

[0031] Figure 4 Superimposed TGA and DSC patterns of polymorph I of 1-naphthalenesulfonate prepared in Example 1.

[0032] Figure 5 XRPD pattern of polymorph I of 1-naphthalenesulfonate prepared in Example 6.

[0033] Figure 6 HNMR spectrum of polymorph I of 1-naphthalenesulfonate prepared in Example 6.

[0034] Figure 7 Superimposed TGA and DSC patterns of polymorph I of 1-naphthalenesulfonate prepared in Example 6.

[0035] Figure 8 Superimposed XRPD pattern of polymorph I of benzenesulfonate prepared in Examples 7, 9 to 12.

[0036] Figure 9 XRPD pattern of polymorph I of benzenesulfonate prepared in Example 8.

[0037] Figure 10 HNMR spectrum of polymorph I of benzenesulfonate prepared in Example 8.

[0038] Figure 11 The superimposed TGA and DSC spectra of benzenesulfonate polymorph I prepared in Example 8.

[0039] Figure 12 The XRPD spectrum of benzenesulfonate polymorph I prepared in Example 13.

[0040] Figure 13 The HNMR spectrum of benzenesulfonate polymorph I prepared in Example 13.

[0041] Figure 14 The superimposed TGA and DSC spectra of benzenesulfonate polymorph I prepared in Example 13.

[0042] Figure 15 The XRPD spectrum of benzenesulfonate polymorph II prepared in Comparative Example 4.

[0043] Figure 16 The HNMR spectrum of benzenesulfonate polymorph II prepared in Comparative Example 4.

[0044] Figure 17 The superimposed TGA and DSC spectra of benzenesulfonate polymorph II prepared in Comparative Example 4.

[0045] Figure 18 The superimposed XRPD spectra of methanesulfonate polymorph II prepared in Examples 14 - 16.

[0046] Figure 19 The XRPD spectrum of methanesulfonate polymorph II prepared in Example 14.

[0047] Figure 20 The HNMR spectrum of methanesulfonate polymorph II prepared in Example 14.

[0048] Figure 21 The superimposed TGA and DSC spectra of methanesulfonate polymorph II prepared in Example 14.

[0049] Figure 22 The XRPD spectrum of methanesulfonate polymorph II prepared in Example 16.

[0050] Figure 23 The HNMR spectrum of methanesulfonate polymorph II prepared in Example 16.

[0051] Figure 24 The superimposed TGA and DSC spectra of methanesulfonate polymorph II prepared in Example 16.

[0052] Figure 25 The XRPD spectrum of methanesulfonate polymorph I prepared in Comparative Example 11.

[0053] Figure 261H NMR spectrum of mesylate crystal form I prepared in Comparative Example 11.

[0054] Figure 27 Superimposed TGA and DSC spectra of mesylate crystal form I prepared in Comparative Example 11.

[0055] Figure 28 XRPD pattern of mesylate crystal form III prepared in Comparative Example 13.

[0056] Figure 29 1H NMR spectrum of mesylate crystal form III prepared in Comparative Example 13.

[0057] Figure 30 Superimposed TGA and DSC spectra of mesylate crystal form III prepared in Comparative Example 13.

[0058] Figure 31 XRPD pattern of mesylate crystal form IV prepared in Comparative Example 14

[0059] Figure 32 DVS diagram of mesylate crystal form II in the hygroscopicity investigation experiment.

[0060] Figure 33 DVS diagram of benzenesulfonate crystal form I in the hygroscopicity investigation experiment.

[0061] Figure 34 DVS diagram of 1-naphthalenesulfonate crystal form I in the hygroscopicity investigation experiment. Detailed Description of the Invention

[0062] The accompanying drawings in the embodiments are used to describe the technical solutions in the embodiments of the present invention in more detail. In the drawings, the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The described embodiments are some, but not all, of the embodiments of the present invention. The embodiments described below with reference to the accompanying drawings are exemplary and are intended to explain the present invention and should not be construed as limiting the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention. The embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0063] It should be noted that if there are directional indications (such as up, down, left, right, front, back,...) involved in the embodiments of the present application, then the directional indications are only used to explain the relative positional relationship and movement conditions between components in a specific posture (as shown in the accompanying drawings). If the specific posture changes, the directional indications will also change accordingly.

[0064] In addition, if descriptions such as "first" and "second" are involved in the embodiments of the present application, the descriptions of "first", "second", etc. are for descriptive purposes only, and should not be construed as indicating or implying their relative importance or implicitly indicating the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include at least one such feature. In addition, the technical solutions between various embodiments may be combined with each other, but it must be based on the ability of those of ordinary skill in the art to implement. When the combination of technical solutions results in contradictions or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present application.

[0065] The crystallization of the unique crystal forms disclosed in the present application is related to the kinetics and equilibrium properties of the crystallization process under specific conditions. Thus, those skilled in the art will recognize that the resulting crystal forms depend on the kinetics and thermodynamics of the crystallization process. Under specific conditions (e.g., solvent, temperature, pressure, and the concentration of the compounds of the present application), one crystal form may be more stable (or actually more stable than any other crystal form) than another. However, a crystal form with relatively low thermodynamic stability may be kinetically favorable. Thus, factors other than kinetics, such as time, impurity distribution, agitation, the presence or absence of seeds, etc., may also affect the form of crystallization.

[0066] On the other hand, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above-mentioned carboxamide triazole crystal forms and at least one pharmaceutically acceptable inactive ingredient.

[0067] The term "therapeutically effective amount" means an amount of a compound that, when used to treat a subject, is sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or disorder, when treating the disease, disorder, or symptom. The "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the patient being treated, and / or the weight of the patient being treated, etc. In any possible case, a suitable dose may be obvious to those skilled in the art or may be determined by routine experimentation. In the case of combination therapy, the "therapeutically effective amount" means the total amount of the combination that is effective in treating the disease, disorder, or condition of the subject.

[0068] The "pharmaceutically acceptable inactive ingredients" refer to conventional pharmaceutical inactive ingredients suitable for the desired pharmaceutical preparation. For example: diluents such as water and various organic solvents; fillers such as starch and sucrose; binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. Additionally, other pharmaceutically acceptable inactive ingredients such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners, and dyes can be added to the pharmaceutical composition. Inactive ingredients suitable for the desired dosage form and desired mode of administration are preferably used.

[0069] The present application also provides a pharmaceutical composition comprising at least one carboxyamidotriazole capable of treating the above-mentioned disorders in an effective amount and a pharmaceutically acceptable carrier or diluent. The compositions of the present application may contain other reagents well known to those skilled in the art and may be formulated according to processes well known in the pharmaceutical formulation art by using conventional solid or liquid carriers or diluents, as well as a class of pharmaceutical additives suitable for the required mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.).

[0070] The pharmaceutical compositions 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 suitable dispersing or wetting agents and suspending agents 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 can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can be applied to injectable preparations.

[0071] For drugs administered rectally, carboxyamidotriazole 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 conventional temperatures but liquid at rectal temperatures and thus melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycol.

[0072] For oral administration, the pharmaceutical composition can be in the form of tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions for oral use can be prepared by any method known in the art for the preparation of pharmaceutical compositions. Tablets contain a mixture of the active ingredient with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The 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 can be used.

[0073] The pharmaceutical composition of the present application can also be in the form of an oil-in-water emulsion. 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 emulsifying agents can be naturally occurring phospholipids such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs can be prepared with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives and flavoring and coloring agents.

[0074] For local use, creams, ointments, gels, solutions or suspensions containing the compound of formula I, etc. can be used (for this purpose of medication, local medication includes not only external administration but also the administration methods of mouthwashes and gargles). The preparation of such local preparations has been well described in pharmaceutical preparations in the art, for example, in Remington’s Pharmaceutical Science, 17th edition, Mack Publishing Co., Easton, PA. For local administration, these compounds can also be administered in powder or spray form, especially in the form of an aerosol.

[0075] Dose levels of from about 0.01 mg to about 140 mg / kg body weight per day are effective for treating the above-indicated conditions, or each patient may be administered a dose of from about 0.5 mg to about 7 g per day. For example, the compound may be administered at a dose of from about 0.01 to 50 mg per kg body weight per day, or from about 0.5 mg to about 3.5 g per patient per day, preferably from 2.5 mg to 1 g per patient per day to effectively treat inflammation. However, it will be understood that the specific dose level for a particular patient will depend on multiple factors, including age, body weight, general health status, gender, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

[0076] The amount of active ingredient combined with the carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. For example, an oral preparation for humans may contain from 0.5 mg to 5 g of the active agent, mixed with a suitable amount of carrier that comprises from about 5% to about 95% of the total composition. Dosage unit forms will generally contain from about 1 mg to about 500 mg of the active ingredient, typically containing 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0077] Diffusion In some embodiments, suitable pharmaceutically inactive ingredients are selected from water, various organic solvents, and various inert diluents or fillers. If desired, the pharmaceutical composition may contain one or more additives, such as flavorings, binders, and excipients. For oral administration, tablets 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 commonly used as fillers in making tablets. These ingredients may also be filled into soft and hard gelatin capsules. When used orally and required to be a water suspension, the active compound therein may be mixed with at least one ingredient selected from various sweeteners or flavorings, pigments or dyes. If desired, various emulsifying or suspending agents may be used; diluents such as water, ethanol, propylene glycol, glycerol, or combinations thereof may also be used. Examples 1 - 5

[0078] Examples 1 - 5 are methods for preparing carboxamide triazole 1-naphthalene sulfonate:

[0079] Weigh about 100 mg of the free base into a sample bottle, add the solvents specified in Table 1 at room temperature, stir evenly, then add 1.1 equivalents of 1-naphthalene sulfonic acid, carry out crystallization, and finally separate and dry to obtain carboxamide triazole 1-naphthalene sulfonate. The superimposed XRPD patterns of Examples 1 - 5 are as Figure 1As shown, the XRPD pattern of 1-naphthalenesulfonate crystal form I prepared in Example 1, the HNMR spectrum of 1-naphthalenesulfonate crystal form I, and the superimposed TGA and DSC spectra of 1-naphthalenesulfonate crystal form I are as Figures 2 to 4 shown.

[0080] Among them, Table 2 and Figures 1 to 5 The 1-naphthalenesulfonate crystal form I shown was obtained by reaction crystallization in acetonitrile. The XRPD pattern shows that the sample has a high crystallinity. The DSC spectrum shows that the sample has two endothermic peaks at ~34 °C and ~190 °C, presumably due to desolvation and melting respectively. The TGA spectrum shows that the sample has a weight loss of ~1.8% from room temperature to 100 °C, and NMR shows that there is basically no obvious solvent residue, presumably due to dehydration. The HNMR results show that the signal peaks of 1-naphthalenesulfonic acid can be seen at ~7.43 ppm and ~7.49 ppm, ~7.88 ppm and ~8.84 ppm. According to the integral results, the molar ratio of carboxyamidotriazole free base to 1-naphthalenesulfonic acid is ~1:1. In summary, it shows that 1-naphthalenesulfonate crystal form I is a crystal form without water. Table 1 shows the preparation of 1-naphthalenesulfonate crystal form I in Examples 1 to 5 Table 2 shows the XRPD characteristic peaks / °2θ of 1-naphthalenesulfonic acid crystal form I Example 6

[0081] This example is an amplification experiment of 1-naphthalenesulfonate crystal form I

[0082] Weigh about 1 g of carboxyamidotriazole powder into a sample bottle. After adding 35 ml of ethyl acetate, it becomes a suspension state. Then add 1.1 eq. of 1-naphthalenesulfonic acid and stir overnight (about 19 h) at room temperature. The solid sample was collected by filtration and dried in vacuo at 40 °C for about 17 h. The molar yield of 1-naphthalenesulfonate crystal form I was 75%. The XRPD pattern of the obtained 1-naphthalenesulfonate crystal form I, the HNMR spectrum of 1-naphthalenesulfonate crystal form I, and the superimposed TGA and DSC spectra of 1-naphthalenesulfonate crystal form I are as Figures 5 to 7 shown. Among them, the superimposed XRPD patterns with Examples 1 to 5 are as Figure 1 shown. Comparative Example 1

[0083] The solvent selected in Comparative Example 1 was ethanol. The specific method was: weigh about 100 mg of carboxyamidotriazole powder into a sample bottle, add 2 ml of ethanol at room temperature, and then add 1-naphthalenesulfonic acid. It was still in suspension and then stirred overnight (about 9 h) at room temperature. NMR detection showed that no salt was formed. Examples 7 to 12

[0084] Examples 7 to 12 are methods for preparing benzenesulfonate crystal form I. The specific method is as follows:

[0085] Weigh about 100 mg of carboxamide triazole powder into a sample bottle, add the corresponding solvent at room temperature, and then add 1.1 equivalents or 2.2 equivalents of benzenesulfonic acid solution (dissolve the corresponding amount of benzenesulfonic acid in 0.2 mL of the corresponding solvent). The specific information and results are summarized in Table 3. The superimposed XRD patterns of benzenesulfonate crystal form IXR in Examples 79 to 12 are as Figure 8 shown; the XRD pattern of benzenesulfonate crystal form I, the HNMR spectrum of benzenesulfonate crystal form I, and the superimposed TGA and DSC spectra of benzenesulfonate crystal form I are as Figures 9 to 11 shown.

[0086] Table 4 and Figures 8 to 11 The benzenesulfonate crystal form I shown was obtained by reaction crystallization in ethyl acetate. The XRD pattern shows that the sample has a high crystallinity. The DSC spectrum shows an endothermic peak at ~200 °C for the sample, presumably due to melting. The TGA spectrum shows a weight loss of ~1.8% for the sample from room temperature to 100 °C, and the NMR shows basically no obvious solvent residue, presumably due to dehydration. The HNMR results show signal peaks of benzenesulfonic acid at ~7.31 ppm and ~7.59 ppm. According to the integral results, the molar ratio of the free base to benzenesulfonic acid is ~1:1. In summary, it shows that benzenesulfonate crystal form I is a water-free crystal form. Table 3 is for the preparation of benzenesulfonate crystal form I in Examples 7 to 12 Table 4 is for the characteristic peaks of XRD of benzenesulfonate crystal form I / °2θ Example 13

[0087] This example is a method test for preparing benzenesulfonate crystal form I.

[0088] Weigh about 1 g of carboxamide triazole powder into a sample bottle. After adding 20 ml of ethyl acetate, it becomes a suspension state. Then add 1.1 eq. of benzenesulfonic acid system, and it becomes thick. Then add 15 mL of ethyl acetate and stir at room temperature overnight (about 19 h). Collect the solid sample by filtration and dry it under vacuum at 40 °C for about 17 h to obtain benzenesulfonate crystal form I. The molar yield of benzenesulfonate crystal form I is 89%. The XRD pattern of benzenesulfonate crystal form I, the HNMR spectrum of benzenesulfonate crystal form I, and the superimposed TGA and DSC spectra of benzenesulfonate crystal form I are as Figures 12 to 14 shown. Comparative Examples 2 to 9

[0089] Comparative Examples 2-9 mainly investigated the effects of different solvents and the reaction of different ratios of free base to acid on salt formation and crystallization.

[0090] Weigh about 100 mg of the free base into a sample bottle, add the corresponding solvent at room temperature. Referring to Table 5, then add 1.1 equivalents or 2.2 equivalents of benzenesulfonic acid solution (dissolve the corresponding amount of benzenesulfonic acid in 0.2 mL of the corresponding solvent). The specific information and results are shown in Table 5. Table 5 Salt Formation Reactions and Results of Comparative Examples 2-9

[0091] The results showed that ethanol was selected as the solvent in both Comparative Example 2 and Comparative Example 7, and no salt was formed. Dimethyl sulfoxide was selected as the solvent in both Comparative Example 6 and Comparative Example 9, and no salt was formed either. In Comparative Example 3, where acetonitrile was used as the solvent and 1.1 times the equivalent of benzenesulfonic acid was added, the crystallinity of the obtained benzenesulfonate crystal form was poor, but it generally tended to be Crystal Form II. When tetrahydrofuran was used as the solvent and 1.1 times the equivalent of benzenesulfonic acid was added, benzenesulfonate Crystal Form II was formed. However, according to Example 6, when tetrahydrofuran was used as the solvent and the addition of benzenesulfonic acid reached 2.2 times the equivalent, benzenesulfonate Crystal Form I was formed. This shows that the solvent and the amount of acid have a great influence on the salt formation state and the crystal form of the salt.

[0092] Upon further research, benzenesulfonate Crystal Form II was obtained by reaction crystallization in tetrahydrofuran. The XRPD pattern showed that the sample had a high crystallinity. The DSC spectrum showed that the sample had an endothermic peak at ~192 °C, presumably due to melting. The TGA spectrum showed that the sample had no obvious weight loss from room temperature to 150 °C. The HNMR results showed that the signal peaks of benzenesulfonic acid were visible at ~7.31 ppm and ~7.59 ppm. According to the integration results, the molar ratio of the free base to benzenesulfonic acid was ~1:1, and the NMR showed that there was basically no obvious solvent residue. Overall, it was shown that benzenesulfonate Crystal Form II was a water-free crystal form, and the identification spectra were as Figures 15 to 17 shown. Combining with Comparative Example 3, it was found that its crystallinity was unstable and could not be reproduced in subsequent scale-up preparations, so it was not selected as the preferred crystal form. Examples 14-15

[0093] Examples 14-15 are the preparation methods for methanesulfonate Crystal Form II.

[0094] Weigh about 100 mg of carboxamide triazole powder into a sample bottle, add acetonitrile at room temperature, and then add 1.1 equivalents or 2.2 equivalents of methanesulfonic acid solution (dilute the corresponding amount of methanesulfonic acid in 0.2 mL of the corresponding solvent). The specific information and results are summarized in Table 6. The superimposed XRPD patterns of Examples 14-15 are as Figure 18As shown, the XRPD pattern of the mesylate crystal form II prepared in Example 14, the HNMR spectrum of the mesylate crystal form II, and the superimposed TGA and DSC spectra of the mesylate crystal form II are as Figures 19 to 21 shown. Table 6 shows the preparation of the mesylate crystal form II in Examples 14-15 Table 7 shows the XRPD characteristic peaks of the mesylate crystal form II / °2θ

[0095] Table 7 and Figures 18 to 21 shown were obtained by reaction crystallization of the mesylate crystal form II in acetonitrile. The XRPD pattern shows that the sample has a high crystallinity. The DSC spectrum shows that the sample has an endothermic peak at ~183 °C, presumably due to melting. The TGA spectrum shows that the sample has basically no obvious weight loss from room temperature to 100 °C. The HNMR results show that the signal peak of methanesulfonic acid can be seen at ~2.39 ppm. According to the integral results, the molar ratio of the free base to methanesulfonic acid is ~1:1, and only 0.1% of the acetonitrile solvent remains. Based on the above, it is speculated that the mesylate crystal form II is a water-free crystal form. Example 16

[0096] This example is an amplification experiment of the mesylate crystal form II.

[0097] Weigh about 1 g of carboxamido triazole powder into a sample bottle. After adding 25 ml of ethyl acetate, it becomes a suspension state. Then, add 1.1 eq. of methanesulfonic acid, and the system becomes thick. Stir at room temperature overnight (~19 h). Collect the solid sample by filtration and dry it in vacuo at 50 °C for ~4 h to obtain the mesylate crystal form II, with a molar yield of 85%. The batch of samples was characterized by XRPD, DSC, TGA, and HNMR, and the results are as Figure 18 and Figures 22 to 24 shown. The XRPD pattern shows that the sample has a high crystallinity and is consistent with the crystal form of the mesylate crystal form II. The DSC spectrum shows that the sample has an endothermic peak at ~183 °C, presumably due to melting. The TGA spectrum shows that the sample has basically no obvious weight loss from room temperature to 100 °C. The HNMR results show that the signal peak of methanesulfonic acid can be seen at ~2.39 ppm. According to the integral results, the molar ratio of the free base to methanesulfonic acid is ~1:1, and only 0.2% of the ethyl acetate solvent remains. Comparative Examples 10-21

[0098] Comparative Examples 10-21 show the effects of different crystallization solvents or different methanesulfonic acid equivalents on the final product. Table 8 shows the salt-forming reactions and results of Comparative Examples 10-21

[0099] As shown in Table 8, when ethanol and acetone / water (19:1, 1.5 mL) are selected as solvents, it is basically impossible to form salts. However, when 1,4-dioxane is selected as the solvent, methanesulfonate crystal form I can be obtained. Figures 25 to 27 As shown, methanesulfonate crystal form I is obtained by reaction crystallization in 1,4-dioxane. The XRPD pattern shows that the sample has medium crystallinity. The DSC spectrum shows that the sample has two endothermic peaks at ~153 °C and ~179 °C, presumably due to desolvation and melting, respectively. The TGA spectrum shows that the sample has a weight loss of ~8.1% from room temperature to 110 °C and a weight loss of ~7.3% from 110 °C to 180 °C, and NMR shows that there is a residue of 14.7% of 1,4-dioxane solvent (~1.1 eq.), presumably due to the removal of the 1,4-dioxane solvent. The HNMR result shows that the signal peak of methanesulfonic acid can be seen at ~2.39 ppm. According to the integral result calculation, the molar ratio of free base to methanesulfonic acid is ~1:1. In summary, it shows that methanesulfonate crystal form I is a 1,4-dioxane solvate and has poor drugability.

[0100] However, when tetrahydrofuran is selected as the solvent, methanesulfonate crystal form III can be obtained. Methanesulfonate crystal form III is obtained by reaction crystallization in tetrahydrofuran, and the results are as Figures 28 to 30 shown. The XRPD pattern shows that the sample has high crystallinity. The DSC spectrum shows that the sample has an endothermic peak at ~151 °C, presumably due to melting. The TGA spectrum shows that the sample has basically no obvious weight loss from room temperature to 100 °C. The HNMR result shows that the signal peak of methanesulfonic acid can be seen at ~2.38 ppm. According to the integral result calculation, the molar ratio of free base to methanesulfonic acid is ~1:1, and there is basically no obvious solvent residue. In summary, it is speculated that methanesulfonate crystal form III is a non-aqueous crystal form. However, subsequent studies found that methanesulfonate crystal form III cannot form salts in the scale-up experiment, so it is not selected as the preferred crystal form.

[0101] When ethyl acetate is selected as the solvent, a mixture of methanesulfonate crystal form II and crystal form III will be obtained, which is difficult to separate and is not suitable for drug formation. When dimethyl sulfoxide is selected as the solvent, the results are as Figure 31 shown, and methanesulfonate crystal form IV is obtained. Methanesulfonate crystal form IV is easy to absorb moisture and become viscous, and no other specific characterizations have been carried out.

[0102] In summary, the advantageous salt forms of the present invention are methanesulfonate crystal form II, benzenesulfonate crystal form I, and 1-naphthalenesulfonate crystal form I. I. Hygroscopicity investigation of candidate salt forms

[0103] The three candidate salt forms, namely mesylate crystal form II, benzenesulfonate crystal form I, and 1-naphthalenesulfonate crystal form I, prepared from the scale-up experiment were subjected to DVS testing to exclude salts with strong hygroscopicity. The test results are shown in Figures 32 to 34 the following. The DVS test results showed that the weight gain of mesylate crystal form II was 70.97% at 95% RH and 1.92% at 80% RH, indicating that mesylate crystal form II had slightly hygroscopic properties. The DVS test results showed that the weight gain of benzenesulfonate crystal form I was 1.30% at 95% RH and 0.48% at 80% RH, indicating that benzenesulfonate crystal form I had slightly hygroscopic properties. The DVS test results showed that the weight gain of 1-naphthalenesulfonate crystal form I was 1.81% at 95% RH and 0.81% at 80% RH, indicating that 1-naphthalenesulfonate crystal form I had slightly hygroscopic properties. II. Investigation of the dynamic solubility and stability of the candidate salt forms

[0104] The solubility tests of mesylate crystal form II, benzenesulfonate crystal form I, and 1-naphthalenesulfonate crystal form I were carried out by shaking in biological media (FaSSIF, FeSSIF, and FaSSGF) and water at 37 °C. Weighed 50 mg of the candidate salt form samples into sample bottles, and then added 5 mL of the three biological media and water respectively to form suspensions. All the suspensions were shaken at 200 rpm at 37 °C, and about 0.3 mL of the suspension was filtered, and the filtrate was subjected to HPLC testing.

[0105] Compared with the free base, the solubility of the three salt forms was significantly improved in FaSSIF, FeSSIF, FaSSGF, and water, and the solubility improvement of 1-naphthalenesulfonate crystal form I was more significant. The results were summarized in Table 9. Table 9 Solubility test results in biological media and water

[0106] LOD = 0.056 μg / mL; the solubility was calculated based on the content of the free base. III. Solid-state stability study

[0107] Took 50 mg of benzenesulfonate crystal form I, mesylate crystal form II, and 1-naphthalenesulfonate crystal form I prepared from the scale-up experiment and placed them in the light (closed) and at 60 °C (closed) for 5 days and 10 days respectively. The solid samples after placement were subjected to XRPD and HPLC testing to analyze the crystal form stability and chemical stability. The results showed that the physical and chemical properties of the three candidate salt forms were basically stable after being placed under the above conditions for 10 days, and the crystal forms did not change. Compared with the free base, the crystal forms of the three salts of carboxamide triazole had significantly improved stability in the light and high-temperature environments. The experimental results are shown in Table 10: Table 10 Stability evaluation results IV. Pharmacokinetic Study

[0108] Purpose of the study: To study the in vivo plasma pharmacokinetic characteristics of three candidate salt forms, namely benzenesulfonate polymorph I, mesylate polymorph II, and 1-naphthalenesulfonate polymorph I, and carboxyamidotriazole solid (free base) in rats after single oral administration.

[0109] Female rats, weighing 180 - 220 g. The animals were housed in plastic cages, with free access to water, at a room temperature of 20 - 25°C, a daily temperature difference of 3°C, a humidity of 50 - 60%, a 12-hour light-dark cycle, and a ventilation rate of 10 - 20 times per hour.

[0110] The rats were randomly divided into 4 groups, with 5 rats in each group. Before the experiment, the animals were fasted for 12 h with free access to water. Before the experiment, carboxyamidotriazole solution, benzenesulfonate polymorph I, mesylate polymorph II, and 1-naphthalenesulfonate polymorph I solutions were prepared with PEG400 for gavage administration to the animals. The dosing dose for rats was 20 mg / kg, and the dosing volume was 10 mL / kg.

[0111] The continuous blood sampling method was used in the experiment. After gavage, 200 μL of blood was taken from the orbital venous plexus of the rats at 15, 30 min, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 h, placed on ice, and after centrifugation, 50 μL of plasma was separated and stored at -20°C. 50 μL of anticoagulated rat plasma / tissue homogenate sample was taken, 50 μL of internal standard working solution and 200 μL of acetonitrile were added, and after shaking and mixing for 30 s, it was centrifuged twice at high speed (14,000 rpm × 5 min), and 2 μL of the supernatant was taken for LC-MS analysis.

[0112] The measured experimental data were analyzed using WinNonLin software (Pharsight, version 8.3) for non-compartmental model analysis to calculate plasma pharmacokinetic parameters. Microsoft Office Excel and Student’s T-test were used for statistical analysis of the experimental data.

[0113] Experimental Results

[0114] The above experimental results showed that the plasma pharmacokinetic parameters Cmax, AUC (0-t) , AUC (0-∞) of benzenesulfonate polymorph I, mesylate polymorph II, and 1-naphthalenesulfonate polymorph I of carboxyamidotriazole in female rats were all higher than those of carboxyamidotriazole free base. It indicated that the absorption utilization of benzenesulfonate polymorph I, mesylate polymorph II, and 1-naphthalenesulfonate polymorph I of carboxyamidotriazole in rats was higher than that of carboxyamidotriazole free base. V. Pharmacodynamic Study

[0115] 1. Antitumor Pharmacodynamic Experiment

[0116] The pharmacodynamic effects of three candidate salt forms, namely benzenesulfonate polymorph I, methanesulfonate polymorph II, and 1-naphthalenesulfonate polymorph I, were investigated. It was shown that these three candidate salt forms had significant inhibitory effects on a variety of tumor cells, and the effect was superior to that of the free base of carboxamide triazole.

[0117] This experiment was a CCK8 experiment on the inhibition of the proliferation of A549 cells, A498 cells, MCF-7 cells, and HUH-7 cells by three candidate salt forms of carboxamide triazole benzenesulfonate polymorph I, methanesulfonate polymorph II, and 1-naphthalenesulfonate polymorph I.

[0118] A549 (human lung cancer cells), A498 (human renal cancer cells), MCF-7 (human breast cancer cells), and HUH-7 (human liver cancer cells) were respectively inoculated into 96-well microplates (3000 - 5000 cells / well) and cultured in an incubator at 37°C and 5% CO2 until the cell confluence reached 80%, and then drug treatment was carried out; 100 μL of DMSO solutions of carboxamide triazole single crystals with different concentrations (final concentrations of 20, 10, 5, 1, and 0.1 μg / mL) were added as the experimental group, and the normal control group was cultured with 100 μL of the control solution; after incubation for 72 hours, 10 μL of CCK8 reagent was added, and after incubation at 37°C for 4 h, the absorbance of each well was measured using an enzyme-linked immunosorbent assay (ELISA) reader. GraphPad Prism 5.0 software was used to analyze the data, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated therefrom.

[0119] Experimental Results

[0120] The above experimental results showed that benzenesulfonate polymorph I, methanesulfonate polymorph II, and 1-naphthalenesulfonate polymorph I, as well as the free base group of carboxamide triazole, all had significant ability to inhibit the growth of tumor cells in A549 cells, A498 cells, MCF-7 cells, and HUH-7 cells, and the ability of benzenesulfonate polymorph I, methanesulfonate polymorph II, and 1-naphthalenesulfonate polymorph I to inhibit the growth of tumor cells was equivalent to that of the free base group of carboxamide triazole.

[0121] 2. Pharmacodynamic Study on Anti-Autoimmune Diseases

[0122] This example investigated the use of benzenesulfonate polymorph I, methanesulfonate polymorph II, and 1-naphthalenesulfonate polymorph I in autoinflammatory diseases. The positive control drug was methotrexate.

[0123] Sixty quarantined animals were randomly divided into a model group (n = 10), a positive control group (n = 10), a benzenesulfonate polymorph I group (n = 10), a mesylate polymorph II group (n = 10), a 1-naphthalenesulfonate polymorph I group (n = 10), and a carboxamide triazole free base group (n = 10) according to their body weights. After grouping, modeling was carried out immediately. The back of all mice with an area of about 5 cm × 3 cm was depilated and prepared for skin. Once a day for 5 consecutive days, imiquimod cream was applied to the back of the animals. On the day after the end of modeling, administration was carried out. The administration period was 3 days, and the corresponding test substances were applied to the modeling site twice a day continuously. One day after the last administration, the animals were euthanized, and the full-thickness skin of the modeling site was separated for ELISA detection. Table 11 List of groups and dose designs Table 12 Statistical results of the experiment

[0124] The above experimental results showed that the carboxamide triazole free base group, the benzenesulfonate polymorph I, the mesylate polymorph II, and the 1-naphthalenesulfonate polymorph I groups could all reduce the inflammatory response of imiquimod-induced psoriatic skin tissue in mice. Among them, the 1-naphthalenesulfonate polymorph I had the largest reduction in TNF-a, IL-12, and IL-23. The effects of the benzenesulfonate polymorph I and the mesylate polymorph II groups on TNF-a, IL-12, and IL-23 were similar to those of methotrexate. The above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the above preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention. Those skilled in the art can also make other changes within the spirit of the present invention for use in the design of the present invention, as long as they do not deviate from the technical effects of the present invention. These changes made according to the spirit of the present invention should all be included within the scope claimed by the present invention.

Claims

1. Crystal form of carboxyamidotriazole salt, characterized in that, The salt is at least one of 1-naphthalenesulfonate, benzenesulfonate or methanesulfonate.

2. A polymorphic form I of carboxamide triazole 1-naphthalenesulfonate, characterized in that, The X-ray powder diffraction pattern of crystalline form I of carboxyamidotriazole 1-naphthalenesulfonate represented by 2θ angle has the following characteristic peaks: 3.8°±0.2°, 13.1°±0.2°, 16.2°±0.2°, 17.7°±0.2°, 18.7°±0.2°, 25.8°±0.2°.

3. The crystalline form I of carboxamide triazole 1-naphthalenesulfonate according to claim 2, characterized in that The X-ray powder diffraction pattern of crystalline form I of carboxyamidotriazole 1-naphthalenesulfonate represented by 2θ angle has the following characteristic peaks: 3.8°±0.2°, 12.6°±0.2°, 13.1°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 17.7°±0.2°, 18.7°±0.2°, 21.5°±0.2°, 22.6°±0.2°, 24.6°±0.2°, 25.4°±0.2°, 25.8°±0.2°.

4. The crystalline form I of carboxyamidotriazole 1-naphthalenesulfonate according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystalline form I of carboxyamidotriazole 1-naphthalenesulfonate represented by 2θ angle is shown in Figure 2.

5. A method for preparing crystalline form I of carboxyamidotriazole 1-naphthalenesulfonate according to any one of claims 2 to 4, characterized in that, The preparation method is as follows: Weigh carboxyamidotriazole into a sample bottle, add solvent 1 at room temperature, and then add 1 - 1.5 times the equivalent amount of 1-naphthalenesulfonic acid of carboxyamidotriazole and stir to obtain crystalline form I of 1-naphthalenesulfonate.

6. The preparation method according to claim 5, characterized in that, The solvent 1 is at least one of 1,4-dioxane, acetonitrile, ethyl acetate, tetrahydrofuran, acetone / water.

7. The preparation method according to claim 6, characterized in that, The ratio of acetone / water is 15 - 25:

1.

8. A polymorphic form I of carboxyamidotriazole benzenesulfonate, characterized in that, The X-ray powder diffraction pattern of crystalline form I of carboxyamidotriazole benzenesulfonate represented by 2θ angle has the following characteristic peaks: 6.1°±0.2°, 13.7°±0.2°, 16.9°±0.2°, 19.8°±0.2°, 25.7°±0.2°, 27.5°±0.2°.

9. The crystalline form I of carboxyamidotriazole benzenesulfonate according to claim 8, characterized in that, The X-ray powder diffraction pattern of crystalline form I of carboxyamidotriazole benzenesulfonate represented by 2θ angle has the following characteristic peaks: 6.1°±0.2°, 13.7°±0.2°, 16.9°±0.2°, 19.2°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.4°±0.2°, 23.5°±0.2°, 25.6°±0.2°, 26.5°±0.2°, 27.3°±0.2°, 27.5°±0.2°.

10. The crystalline form I of carboxyamidotriazole benzenesulfonate according to claim 8, characterized in that, The X-ray powder diffraction pattern of crystalline form I of carboxyamidotriazole benzenesulfonate represented by 2θ angle is shown in Figure 9.

11. A method for preparing crystalline form I of carboxyamidotriazole benzenesulfonate according to any one of claims 8 to 10, characterized in that, The preparation method is as follows: Weigh carboxyamidotriazole into a sample bottle, add solvent 2 at room temperature, and then add 1.1 - 2.2 times the equivalent amount of benzenesulfonic acid solution of carboxyamidotriazole and stir to obtain it.

12. The preparation method of crystalline form I of carboxyamidotriazole benzenesulfonate according to claim 11, characterized in that, The solvent 2 is at least one of ethanol, 1,4-dioxane, acetonitrile, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide.

13. A polymorphic form II of carboxyamidotriazole mesylate, characterized in that, The X-ray powder diffraction pattern of crystalline form II of carboxyamidotriazole methanesulfonate represented by 2θ angle has the following characteristic peaks: 15.9°±0.2°, 18.0°±0.2°, 19.9°±0.2°, 20.7°±0.2°, 23.4°±0.2°, 29.3°±0.2°.

14. The crystalline form II of carboxamide triazole mesylate according to claim 13, characterized in that, The X-ray powder diffraction pattern of the crystalline form II of the carboxyamidotriazole mesylate, expressed in 2θ angle, has the following characteristic peaks: 4.0° ± 0.2°, 14.0° ± 0.2°, 15.9° ± 0.2°, 18.0° ± 0.2°, 19.0° ± 0.2°, 19.9° ± 0.2°, 20.7° ± 0.2°, 23.0° ± 0.2°, 23.4° ± 0.2°, 24.9° ± 0.2°, 29.1° ± 0.2°, 29.3° ± 0.2°.

15. The polymorphic form II of carboxyamidotriazole mesylate according to claim 13, characterized in that, The X-ray powder diffraction pattern of the crystalline form II of the carboxyamidotriazole mesylate, expressed in 2θ angle, is shown in Figure 19.

16. A method for preparing crystalline form II of carboxamide triazole mesylate according to any one of claims 13 to 15, characterized in that, Weigh carboxyamidotriazole into a sample bottle, add Solvent 3 at room temperature, and then add a methanesulfonic acid solution in an amount of 1.1 to 2.2 times the equivalent of carboxyamidotriazole, and stir to prepare it.

17. The preparation method of polymorph II of carboxyamidotriazole mesylate according to claim 16, characterized in that, The Solvent 3 is acetonitrile.

18. A pharmaceutical composition, characterized in that, It contains the crystalline form I of the carboxyamidotriazole 1-naphthalenesulfonate according to any one of claims 2 to 4, or the crystalline form I of the carboxyamidotriazole benzenesulfonate according to any one of claims 8 to 10, or the crystalline form II of the carboxyamidotriazole mesylate according to any one of claims 13 to 15, and a pharmaceutically acceptable inactive ingredient.

19. The pharmaceutical composition according to claim 18, wherein, The pharmaceutical composition contains 0.01% to 99.9% by mass of the crystalline form I of the carboxyamidotriazole 1-naphthalenesulfonate, or the crystalline form I of the carboxyamidotriazole benzenesulfonate, or the crystalline form II of the carboxyamidotriazole mesylate.

20. Use of the crystalline form I of the carboxyamidotriazole 1-naphthalenesulfonate according to any one of claims 2 to 4, or the crystalline form I of the carboxyamidotriazole benzenesulfonate according to any one of claims 8 to 10, or the crystalline form II of the carboxyamidotriazole mesylate according to any one of claims 13 to 15 for the treatment of solid tumors or autoimmune diseases.

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