CN115626917A

CN115626917A - Crystal forms of compound, and composition and application thereof

Info

Publication number: CN115626917A
Application number: CN202211629468.8A
Authority: CN
Inventors: 魏伟业; 杨建楠; 吴小涛; 唐纬坤; 赵涛涛; 王浩; 吴小艳
Original assignee: Nanjing Gritpharma Co ltd; Beijing Grand Johamu Pharmaceutical Co Ltd
Current assignee: Nanjing Gritpharma Co ltd; Beijing Grand Johamu Pharmaceutical Co Ltd
Priority date: 2022-06-22
Filing date: 2022-12-19
Publication date: 2023-01-20
Anticipated expiration: 2042-12-19
Also published as: CN115626917B

Abstract

The invention provides a crystal form of a compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione, which is selected from one of a crystal form A or a crystal form I, or a mixture thereof; wherein form a and form I are as defined herein. The invention also relates to a drug substance or a composition comprising the crystalline form of the compound and/or the use thereof in a medicament for the treatment or prevention of diseases caused by coronaviruses, in particular novel coronaviruses, in a subject. The compound has good crystal form stability and is suitable for medicinal use.

Description

Crystal forms of compound, and composition and application thereof

Technical Field

The present invention relates to a crystalline form of a specific compound, a drug substance or composition comprising the same and/or its use in the manufacture of a medicament for treating or preventing a coronavirus-induced disease in a subject.

Background

Coronaviruses are becoming a focus of research in the field of virology. Among them, corona Virus pneumonia (Corona Virus Disease 2019) is a new acute respiratory infectious Disease, and is caused by SARS-CoV-2 (also known as 2019-nCoV).

Compounds useful in the treatment of COVID-19 are disclosed in the prior art (Yuto Unoh et al, "Discovery of S-217622, a non homologous Oral SARS-CoV-2-CL Protease Inhibitor Clinical diagnosis for Treating COVID-19", J. Med. Chem., vol. 65, p 6499-6512). At present, effective therapeutic or prophylactic means are urgently required for coronaviruses (particularly, novel coronaviruses).

According to the published literature ("Discovery of S-217622, a Noncovel Oral SARS-CoV-2-CL Protease Inhibitor Clinical code for Treating COVID-19", CN114591302A or CN 114591303A), although solid forms of the compounds described herein can be prepared, they all suffer from poor stability, poor solubility and/or poor bioavailability.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a technical scheme for solving the problems.

In a first aspect of the invention there is provided a crystalline form of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione selected from one of form a or form I, or a mixture thereof;

wherein the content of the first and second substances,

the crystal form A is characterized in that Cu-Kalpha radiation is used, and the characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by a 2 theta value +/-0.2 degrees comprise more than any three of 4.30, 12.30, 12.87 and 24.61;

form I is characterized by an X-ray powder diffraction pattern using Cu-Kalpha radiation, wherein the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed by 2 theta values +/-0.2 degrees comprise 12.98, 13.24 and 26.11.

In a second aspect of the invention, there is provided a pharmaceutical drug substance comprising a crystalline form of a compound described herein.

In a third aspect of the invention, there is provided a composition comprising a crystalline form of a compound described herein and one or more physiologically acceptable/pharmaceutically acceptable excipients.

In a fourth aspect of the invention, there is provided a crystalline form of a compound described herein or a drug substance or composition comprising the same for use in the preparation of a medicament for the treatment or prevention of a coronavirus-induced disease in a subject.

In a fifth aspect of the invention, there is provided the use of a crystalline form of a compound described herein for the preparation of a solid form of a salt of the compound.

In the present invention, the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione has good crystal form stability (including stability under light, high temperature, high humidity conditions and accelerated stability) and is suitable for pharmaceutical use. Therefore, the pharmaceutical drug containing the crystal form of the compound can effectively prolong the storage period of the drug, and can meet the pharmaceutical requirements of production, processing, transportation and storage.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of crystalline form A of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione. Wherein the abscissa is 2 θ (degree), and the ordinate is intensity (count).

Figure 2 is a thermogravimetric analysis (TGA) profile and a Differential Scanning Calorimetry (DSC) profile of crystalline form a of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione.

FIG. 3 is an X-ray powder diffraction pattern of crystalline form F of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione. Wherein the abscissa is 2 θ (degree), and the ordinate is intensity (count).

Figure 4 is a thermogravimetric analysis (TGA) profile and a Differential Scanning Calorimetry (DSC) profile of crystalline form F of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione.

FIG. 5 is an X-ray powder diffraction pattern of crystalline form H of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione. Wherein, the abscissa is 2 theta (degree), and the ordinate is intensity (count).

Figure 6 is a thermogravimetric analysis (TGA) profile and Differential Scanning Calorimetry (DSC) profile of crystalline form H of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione.

FIG. 7 is an X-ray powder diffraction pattern of crystalline form I of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione. Wherein, the abscissa is 2 theta (degree), and the ordinate is intensity (count).

Figure 8 is a thermogravimetric analysis (TGA) profile and a Differential Scanning Calorimetry (DSC) profile of crystalline form I of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione.

FIG. 9 is a PLM image of form A of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione.

FIG. 10 is a comparison of XRPD before and after DVS testing of crystalline form A of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione.

Figure 11 is a graph of the XRPD of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione as crystalline form a compared at 10 days to at 0 days under high temperature, high humidity, light and accelerated stability experimental conditions, respectively.

Figure 12 is a graph of the XRPD of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione as crystalline form a compared at 30 days to 0 days under high temperature, high humidity, light and accelerated stability experimental conditions, respectively.

Detailed Description

As used herein, the term "crystalline form" refers to a single crystalline form or a mixture of two or more thereof (e.g., a polymorph) of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione (hereinafter referred to as "the compound described herein" in the present context).

In a particular embodiment, the crystalline form of the compound described herein is a mixture (e.g., polymorph) comprising at least form a and/or form I.

In particular, the crystalline forms of the compounds described herein are a mixture (e.g., a polymorph) consisting of form a and one or more other crystalline forms other than forms a and I, a mixture (e.g., a polymorph) consisting of form a, form I, and optionally one or more other crystalline forms other than forms a and I, or a mixture (e.g., a polymorph) consisting of form I and one or more other crystalline forms other than forms a and I.

As used herein, the term "other crystal forms different from forms a and I" refers to a different crystal form of the compound described herein, preferably a pharmaceutically acceptable crystal form of the compound described herein, different from forms a and I.

For example, a crystalline form of a compound described herein is a mixture (e.g., a polymorph) comprising a combination selected from: form a and form I; form a and form F; form a and form H; form I and form F; form I and form H; form F and form H; form a, form F and form H; form a, form F and form I; form a, form H and form I; form I, form F and form H; form a, form F, form H and form I.

In a particular embodiment, the crystalline form of the compound described herein is a single crystalline form that is form a, form F, form H, or form I, preferably form a or form I, more preferably form a.

In a particular embodiment, the crystalline form of the compound described herein may be a solvate.

As used herein, the term "solvate" refers to those forms of the crystalline forms of the compounds described herein that are used to form complexes with molecules of a solvent (e.g., water, organic solvents such as formic acid, toluene, etc.) by coordination. Hydrates are a particular form of solvate in which coordination is made with water. For example, the solvate may be a hydrate.

In particular, the crystalline form of the compound described herein can be a hydrate. Preferably, form a or form I can be a hydrate (e.g., hemihydrate, monohydrate, dihydrate, etc.).

In a specific embodiment, form a further comprises any one or more of 10.65, 13.79, 20.67 of characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° using Cu-ka radiation.

In a specific embodiment, form a has characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° using Cu-ka radiation comprising 4.30, 10.65, 12.30, 12.87, 13.79, 20.67, 24.61.

Specifically, the crystal form A uses Cu-K alpha radiation, and the characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by a 2 theta value +/-0.2 degrees further comprise any one or more of 13.19, 14.94, 18.91 and 24.95. Preferably, form a has an X-ray powder diffraction pattern expressed in 2 θ values ± 0.2 ° using Cu-ka radiation as shown in fig. 1.

In a specific embodiment, the differential scanning calorimetry spectrum of form A has endothermic peaks at 167.3 ℃ ± 2 ℃, 202.5 ℃ ± 2 ℃, 211.2 ℃ ± 2 ℃ and 239.0 ℃ ± 2 ℃. Preferably, the differential scanning calorimetry pattern of form a is as shown in figure 2.

In a specific embodiment, the thermogravimetric analysis profile of form a loses less than 6% (specifically 5.2%) by weight during heating to 150 ℃ ± 2 ℃, and decomposes at 275 ℃ ± 2 ℃. Preferably, the thermogravimetric analysis profile of form a is shown in figure 2.

In a specific embodiment, form F has characteristic diffraction peaks of an X-ray powder diffraction pattern using Cu-ka radiation expressed as 2 Θ values ± 0.2 ° including any three of 7.44, 8.16, 14.65, 21.51.

In a particular embodiment, form F further comprises any one or more of 19.70, 24.61, 26.62 using Cu-ka radiation, characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 °.

In a specific embodiment, form F has characteristic diffraction peaks in an X-ray powder diffraction pattern using Cu-ka radiation expressed as 2 Θ values ± 0.2 ° comprising 7.44, 8.16, 14.65, 19.70, 21.51, 24.61, 26.62.

Specifically, the crystal form F uses Cu-K alpha radiation, and the characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by a 2 theta value +/-0.2 degrees further comprise any one or more of 16.33, 19.35, 22.72 and 29.58. Preferably, form F has an X-ray powder diffraction pattern using Cu-ka radiation expressed as 2 θ ± 0.2 ° as shown in fig. 3.

In a specific embodiment, the differential scanning calorimetry spectrum of form F has endothermic peaks at 208.1 ℃ ± 2 ℃ and 239.1 ℃ ± 2 ℃ and exothermic peaks at 210.3 ℃ ± 2 ℃. Preferably, the differential scanning calorimetry pattern of form F is shown in figure 4.

In a specific embodiment, the thermogravimetric analysis profile of form F loses less than 10% (specifically 9.6%) of weight during heating to 150 ℃ ± 2 ℃, and decomposition occurs at 275 ℃ ± 2 ℃. Preferably, the thermogravimetric analysis pattern of form F is shown in fig. 4.

In a specific embodiment, form H further comprises any three or more of 9.16, 11.69, 19.52, 24.00 characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° using Cu-ka radiation.

In a specific embodiment, form H further comprises any one or more of 15.12, 18.61, 22.01 using Cu-ka radiation and characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in terms of 2 Θ values ± 0.2 °.

In a specific embodiment, form H uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° comprise 9.16, 11.69, 15.12, 18.61, 19.52, 22.01, 24.00.

Specifically, the crystal form H uses Cu-K alpha radiation, and the characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by a 2 theta value +/-0.2 degrees further comprise any one or more of 14.33, 17.88 and 25.78. Preferably, form H has an X-ray powder diffraction pattern using Cu-ka radiation expressed as 2 θ ± 0.2 ° as shown in fig. 5.

In a specific embodiment, the differential scanning calorimetry spectrum of form H has an endothermic peak at 145 ℃ ± 2 ℃, 227.5 ℃ ± 2 ℃, 239.4 ± 2 ℃ and an exothermic peak at 239 ℃ ± 2 ℃. Preferably, the differential scanning calorimetry pattern of form H is shown in figure 6.

In a specific embodiment, the thermogravimetric analysis profile of form H loses less than 15% (specifically 14.4%) of weight during heating to 200 ℃ ± 2 ℃, and decomposition occurs at 275 ℃ ± 2 ℃. Preferably, the thermogravimetric analysis spectrum of form H is shown in fig. 6.

In a specific embodiment, form I further comprises any one or more of 4.35, 19.99, and 29.26 using Cu-ka radiation, and characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in terms of 2 Θ values ± 0.2 °.

In a specific embodiment, form I has characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° using Cu-ka radiation comprising 4.35, 12.98, 13.24, 19.99, 26.11, 29.26.

Specifically, the crystal form I uses Cu-Kalpha radiation, and characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by 2 theta values +/-0.2 degrees further comprise any one or more of 7.03, 10.94 and 25.61. Preferably, form I has an X-ray powder diffraction pattern using Cu-ka radiation expressed in 2 Θ values ± 0.2 ° as shown in fig. 7.

In a specific embodiment, the differential scanning calorimetry spectrum of form I has endothermic peaks at 165.4 ℃ ± 2 ℃, 209.3 ℃ ± 2 ℃ and 239.5 ℃ ± 2 ℃ and exothermic peaks at 213.8 ℃ ± 2 ℃. Preferably, the differential scanning calorimetry pattern of form I is as shown in figure 8.

In a specific embodiment, the thermogravimetric analysis profile of form I loses less than 3% (specifically 2.1%) of weight during heating to 150 ℃ ± 2 ℃, and decomposition occurs at 275 ℃ ± 2 ℃. Preferably, the thermogravimetric analysis profile of form I is shown in figure 8.

In a particular embodiment, a crystalline form of the compound described herein, which is a polymorph, is characterized in that,

using Cu-Ka radiation, characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by 2 theta values +/-0.2 degrees comprise any three, four, five, six or seven of 4.30, 12.30, 12.87, 24.61, 12.98, 13.24 and 26.11;

using Cu-ka radiation, characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° include any three, four, five, six, seven, or eight of 4.30, 12.30, 12.87, 24.61, 7.44, 8.16, 14.65, 21.51;

using Cu-ka radiation, characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° comprise any three, four, five, six, seven or eight of 4.30, 12.30, 12.87, 24.61, 9.16, 11.69, 19.52, 24.00;

using Cu-ka radiation, characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° include any three, four, five, six, or seven of 12.98, 13.24, 26.11, 7.44, 8.16, 14.65, 21.51;

or

Using Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° comprise any three, four, five, six or seven of 12.98, 13.24, 26.11, 9.16, 11.69, 19.52, 24.00.

As used herein, the term "drug substance" refers to a raw drug (especially, an active ingredient (also referred to as an active ingredient)) or a synthetic intermediate for further preparation or production of various preparations, which is a substance prepared by chemical synthesis or biotechnology, in the form of powder, crystal, or the like for pharmaceutical use, but not directly taken by a subject.

In a particular embodiment, the weight percentage of the crystalline form of the compound described herein in the drug substance is 90.0-99.9%, e.g., 90.0%,91.0%,92.0%,93.0%,94.0%,95.0%,96.0%,97.0%,98.0%,99.0%,99.1%,99.2%,99.3%,99.4%,99.5%,99.6%,99.7%,99.8%, or 99.9%. In particular, the crystalline forms of the compounds described herein are as defined above.

In a particular embodiment, the weight percentage of the crystalline form of the compound described herein in the composition is from 0.1% to 85%, preferably from 1% to 70%, more preferably from 15% to 60%, most preferably from 25% to 45%; for example, a crystalline form of a compound described herein is present in the composition at a weight percentage of 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 40.64%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or 85%. In particular, the crystalline forms of the compounds described herein are as defined above.

Alternatively, in one embodiment of the present application, when the composition of the present application is in unit dosage form (e.g., a solid formulation such as a tablet, powder, dry suspension, granule, or capsule), the composition of the present application comprises 40mg to 170mg, preferably 95mg to 130mg, of the crystalline form of the compound described herein per unit dosage of the composition; for example, crystalline forms of a compound described herein 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 62.1mg, 62.2mg, 62.3mg, 62.4mg, 62.5mg, 62.6mg, 62.7mg, 62.8mg, 62.9mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 77mg, 80mg, 60mg, 62.1mg, 62.2mg, 62.3mg, 62.7mg, or the like 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg or 170mg. In particular, the crystalline forms of the compounds described herein are as defined above.

In a specific embodiment, the compositions described herein are stable pharmaceutical compositions.

As used herein, the term "physiologically acceptable/pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the active ingredient being administered (e.g., a crystalline form of a compound described herein).

The physiologically acceptable/pharmaceutically acceptable excipients that are mixed with the crystalline forms of the compounds described herein to form a pharmaceutical composition may depend on the intended method of administering the pharmaceutical composition.

Crystalline forms of the compounds described herein may have systemic and/or local activity. For this purpose, it can be administered in a suitable manner, for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

For these routes of administration, the crystalline forms of the compounds described herein may be administered in a suitable form of administration.

For example, for oral administration, crystalline forms of the compounds described herein may be formulated into dosage forms known in the art that are delivered rapidly and/or in a modified manner, e.g., tablets (uncoated or coated tablets, e.g., with an enteric coating or a controlled release coating that is delayed in dissolving or insoluble), orally disintegrating tablets, wafers, lyophilizates, capsules (e.g., hard or soft gelatin capsules), coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions. The crystalline forms of the compounds described herein may be incorporated into the dosage form as single crystalline forms and/or as multiple crystalline forms.

For example, parenteral administration can be carried out by avoiding an absorption step (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or including an absorption step (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Administration forms suitable for parenteral administration are, in particular, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

As used herein, the term "subject" refers to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. Specifically, the subject is 0 years or older, 1 year or older, 2 years or older, 4 years or older, 5 years or older, 10 years or older, 12 years or older, 13 years or older, 15 years or older, 16 years or older, 18 years or older, 20 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, 65 years or older, 70 years or older, 75 years or older, 80 years or older, 85 years or older, 90 years or older, 95 years or older, 100 years or older, or 105 years or older.

In a particular embodiment, the subject is a human, e.g., a child (e.g., a human of 0-18 years or a human of 0-14 years), an adult (e.g., a human of 19-59 years), or an elderly human (e.g., a human of 60 years or older).

As used herein, the term "Coronavirus" belongs phylogenetically to the genus Coronaviridae (Coronaviridae) coronaviruses (Coronavirus). One variant of coronavirus is the causative agent of atypical pneumonia. Coronaviruses include, but are not limited to, 2019 novel coronaviruses (2019-nCoV or SARS-CoV-2, causing novel coronavirus pneumonia COVID-19), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (causing severe acute respiratory syndrome), and MERS-CoV (causing middle east respiratory syndrome). The disease caused by coronaviruses is mainly respiratory infection (including severe acute respiratory syndrome, SARS).

In a specific embodiment, the coronavirus is a novel coronavirus.

As used herein, the term "novel coronavirus" refers to 2019 novel coronavirus (2019-nCoV) or SARS-CoV-2 (segment acid respiratory syndrome coronavirus 2) published by the International Committee of viral classifications in 2 months 2020. SARS-CoV-2 has the same meaning as 2019-nCoV in the present application, and includes all variants of the 2019 novel coronavirus, such as all variants included in NCBI or GISAID (national shared influenza data initiative), especially important variants with strong transmission, pathogenicity or immune evasion, such as Alpha, beta, gamma, delta, eta, iota, kappa or Lambda variants designated by WHO, and important variants designated subsequently.

In a particular embodiment, the present invention provides the use of a crystalline form of a compound described herein for the preparation of a solid form of a salt of the compound. In particular, the crystalline forms of the compounds described herein are as defined above.

In particular, salts of the compounds described herein are physiologically/pharmaceutically acceptable salts of the compounds described herein, and may also be isolated or purified salts that are not themselves suitable for pharmaceutical use, but which may be used, for example, for the compounds described herein.

As used herein, the term "physiologically/pharmaceutically acceptable salt" refers to relatively non-toxic, inorganic or organic acid addition Salts of the compounds described herein, see, e.g., s.m. Berge et al, "Pharmaceutical Salts", j. Pharm. Sci. 1977, 66, 1-19.

In particular, the solid form is an amorphous form, a crystalline form (which may be a single crystalline form or a polymorph) or a mesomorphic form (mesomorph).

As used herein, the term "amorphous form" refers to a non-crystalline solid state form of a substance.

As used herein, the term "polymorph" refers to a crystalline form of the same molecule, and as a result of the arrangement or conformation of the molecules in a crystal lattice; or, refers to a crystal structure in which molecules can crystallize in different crystal packing arrangements and all have the same elemental composition.

As used herein, the term "mesogenic form" refers to a substance that exists in a state between liquid and solid states (e.g., liquid crystals). In mesomorphic forms, the same molecules of a substance may be oriented in an organized manner (e.g., crystalline), and the substance may flow like a liquid.

In another aspect, the present invention provides a method of preparing a crystalline form of a compound described herein, comprising the steps of:

(1) The compound described herein is dissolved in a first solvent, then added to a second solvent, stirred, isolated, and optionally dried to provide a crystalline form of the compound described herein.

Specifically, the first solvent is selected from one or more of acetone, isopropanol, dioxane, dimethylformamide (DMF), ethanol, ethylene glycol dimethyl ether, water, tetrahydrofuran, isopropanol, acetonitrile, dimethyl sulfoxide (DMSO).

Specifically, the second solvent is selected from one or more of water, methanol, acetonitrile, ethyl acetate, isopropyl acetate, acetone, toluene and dichloromethane.

Specifically, the first solvent and the second solvent are a fixed solvent combination selected from one or more of the following combinations: acetone and water, ethanol and water, ethylene glycol dimethyl ether and water, water and acetonitrile, dimethylformamide and methanol, dioxane and water, dimethylformamide and dichloromethane, tetrahydrofuran and toluene, isopropanol and toluene, acetone and toluene, acetonitrile and toluene, dimethylformamide and toluene, ethylene glycol dimethyl ether and toluene, dimethyl sulfoxide and toluene, isopropanol and isopropyl ether.

Specifically, the volume ratio of the first solvent to the second solvent is in the range of 1 to 10, preferably in the range of 1:5 to 5:1, more preferably in the range of 1:2 to 2:1.

Specifically, the addition is dropwise (e.g., slowly dropwise) addition or rapid addition.

Specifically, the separation is filtration, suction filtration or centrifugation (e.g., centrifugation at 10000 rpm for 4 min).

Specifically, the drying is vacuum drying.

In particular, step (1) is carried out at room temperature (20-30 ℃, e.g. 25 ℃) and/or the stirring time of step (1) is in the range of 1 hour to 2 weeks.

In particular, the crystalline form of the compound described herein is form a or form F.

Specifically, when the combination of the first solvent and the second solvent is acetone and water, ethanol and water, ethylene glycol dimethyl ether and methanol, water and acetonitrile, dimethylformamide and methanol, dioxane and water, dioxane and methanol, dioxane and ethanol, dioxane and ethyl acetate, dioxane and isopropyl acetate, or dimethyl sulfoxide and acetone, the crystalline form of the compound described herein is form a.

In another aspect, the present invention also provides another method of preparing a crystalline form of a compound described herein, comprising the steps of:

(1') adding a compound described herein to an organic solvent, leaving the mixture open, isolating, and optionally drying to obtain a crystalline form of the compound described herein.

Specifically, in step (1'), the compound described herein is added to an organic solvent to completely disperse (e.g., suspend or dissolve) the compound.

Specifically, the organic solvent is selected from one or more of acetone, ethylene glycol dimethyl ether, ethylene glycol methyl ether, acetonitrile or dimethyl sulfoxide (DMSO).

Specifically, the open-top is left for a period of time in the range of 1 week to 2 weeks.

Specifically, the drying is vacuum drying.

Specifically, step (1') is carried out at room temperature (20-30 ℃, e.g., 25 ℃).

Specifically, the crystal form of the compound described in the application is a crystal form A or a crystal form I.

In particular, when the organic solvent is selected from ethylene glycol dimethyl ether, ethylene glycol methyl ether, acetonitrile or dimethyl sulfoxide (DMSO), the crystalline form of the compound described herein is form a.

Specifically, when the organic solvent is acetone, the crystalline form of the compound described herein is form I.

In the present application, the relative humidity is represented by RH, which indicates the percentage of the amount of water vapor (water vapor pressure) contained in a gas (usually, in air) to the amount of saturated water vapor (saturated water vapor pressure) in the same case as that of the air.

The embodiments or different preferred grades of embodiments described in this application can be combined arbitrarily, unless otherwise indicated.

The present invention is illustrated below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The compounds or reagents used in the following examples are commercially available or prepared by conventional methods known to those skilled in the art; the laboratory instruments used are commercially available. Specifically, the starting materials used in the preparation examples, i.e., the compounds described herein in solid form, were prepared according to the method described in example 1 of CN 114591303A. ¹ H NMR spectra were recorded on a Bruker Advance at 400 MHz. The data are recorded as follows: chemical shifts (in ppm with reference to tetramethylsilane), integral value, multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), and coupling constants.

Examples

Preparation examples

Preparation method of crystal form A

Example 1

15.0.0 mg solid form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione was weighed and added to 0.2 mLDMSO to completely dissolve it, followed by addition of 1.0 mL acetone to the solution, stirring at room temperature for 1 day, followed by centrifugation (10000 rpm, 4 min) and vacuum drying of the solid at room temperature to give form A of the compound described herein.

Crystallization was carried out in the same or similar manner as in example 1, as shown in the following table 1:

TABLE 1

Example 12

20.6 mg solid form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione was weighed, added to 10.0 mL ethylene glycol dimethyl ether, allowed to completely dissolve, then left open at room temperature for 2 weeks, then centrifuged (10000 rpm, 4 min) to give form A of the compound described in this application.

Crystallization was carried out in the same or similar manner as in example 12, as shown in the following Table 2:

TABLE 2

Preparation method of crystal form I

The compound of form I described herein was obtained by weighing 19.8 mg as a solid, (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione, adding to 3.0 mL acetone for complete dissolution, followed by leaving to the open at room temperature for 2 weeks.

Preparation method of crystal form F

Weighing 15.0 mg solid form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione, adding to 0.6 mL tetrahydrofuran to completely dissolve it, adding to the solution 3.0 mL toluene, stirring at room temperature for 1 hour, then after centrifugation (10000 rpm, 4 min), vacuum drying the solid at room temperature to obtain crystalline form F of the compound described herein.

The Applicant has prepared crystalline form F of the compound described in the present application according to the prior art Yuto Unoh et al, "Discovery of S-217622, a Noncovent Oral SARS-CoV-2-CL Protease Inhibitor Clinical Candidate for Treating COVID-19", the method described in J. Med. Chem., vol. 65, p6499-6512 or the method described in examples 9 to 12 of CN114591302A or the method described in example 7 of CN 114591303A.

Preparation method of crystal form H

Weighing 19.8.8 zxft 3245 solid form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione, adding 10.0 mL toluene, stirring for 7 days at room temperature in suspension, centrifuging (10000 rpm, 4 min), and then drying the solid at room temperature in vacuum to obtain the compound of the invention in the form of crystal form H.

The applicants prepared form H of the compound described herein according to the method described in examples 1-6 and 8-14 of CN 114591303A.

Atlas measurement and data for the Crystal forms of the invention

1. XRPD pattern determination condition and diffraction peak data

The solid samples obtained from the experiments were analyzed by means of an X-ray powder diffractometer PANalytical Empyrean (PANalytical, NL). The 2 theta scanning angle is from 3 degrees to 45 degrees, the scanning step is 0.013 degrees, and the testing time is 5 minutes and 8 seconds. The light tube voltage and current were 45 kV and 40 mA respectively for the test samples, the sample pan was a zero background sample pan.

XRPD patterns of form a, form F, form H, and form I of the compounds described herein are shown in fig. 1, fig. 3, fig. 5, and fig. 7, respectively.

TABLE 3 XRPD diffraction peak data for form A of the compounds described herein

Angle of diffraction [ ° 2 θ [ ]]	d value [ A]	Relative intensity [% ]]
			4.30	20.54761	81.4
5.09	17.37243	27.7
			6.89	12.84860	34.4
8.37	10.58321	21.5
			8.57	10.34167	21.2
10.65	8.33233	48.8
			12.30	7.23400	100.0
12.87	6.91449	63.2
			13.19	6.75210	36.3
13.79	6.46180	42.0
			14.29	6.24067	16.4
14.94	5.97756	38.7
			15.29	5.84216	31.2
16.37	5.46733	20.9
			16.87	5.31008	14.5
17.22	5.20396	15.4
			17.48	5.12818	13.8
18.19	4.93468	16.1
			18.91	4.75278	38.7
19.20	4.68392	27.2
			19.95	4.51498	16.7
20.67	4.36381	43.9
			21.55	4.19366	21.7
22.51	4.02381	37.7
			23.23	3.90535	12.7
24.61	3.69911	64.5
			24.95	3.65168	37.3
25.45	3.58473	31.0
			25.79	3.54047	31.4
26.81	3.41627	27.3
			27.59	3.32607	35.1
28.01	3.28014	22.6
			28.34	3.24524	27.7
28.70	3.20850	28.4
			28.96	3.18189	25.2
30.23	3.05974	18.5
			31.40	2.95688	12.1
32.35	2.87944	9.6
			33.25	2.80964	12.7
33.69	2.77769	14.8
			34.04	2.75219	11.4
35.47	2.65486	7.8
			35.96	2.62373	7.5
37.48	2.53185	7.4
			38.49	2.47528	7.0
39.37	2.42867	6.2
			41.55	2.32270	7.2
43.95	2.21965	5.3

In the above characteristic diffraction peaks, the main characteristic diffraction peaks include any three or more of 4.30, 12.30, 12.87 and 24.61, and further may include any one or more of 10.65, 13.79 and 20.67; alternatively, 4.30, 10.65, 12.30, 12.87, 13.79, 20.67, 24.61 are included. In particular, the main characteristic diffraction peaks further comprise any one or more of 13.19, 14.94, 18.91, 24.95.

TABLE 4 XRPD diffraction peak data for form I of the compounds described herein

Angle of diffraction [ ° 2 θ [ ]]	d value [ A]	Relative intensity [% ]]
			4.35	20.30014	25.2
7.03	12.58593	12.8
			7.75	11.41982	7.4
10.94	8.11497	12.6
			12.38	7.18866	11.1
12.98	6.85948	30.3
			13.24	6.72580	48.3
13.67	6.51656	6.9
			13.99	6.37260	7.7
14.32	6.22946	11.2
			15.75	5.67581	6.7
16.47	5.43342	3.5
			17.12	5.23494	6.4
18.03	4.97635	11.0
			18.48	4.86018	9.5
18.85	4.76873	11.8
			19.16	4.69318	6.6
19.99	4.50644	20.2
			20.73	4.35323	6.4
21.12	4.27565	6.4
			21.41	4.22061	7.3
22.09	4.09640	7.8
			22.66	3.99950	5.1
23.79	3.81989	5.7
			24.70	3.68620	6.6
25.61	3.56415	12.9
			26.11	3.50068	100.0
27.33	3.35554	7.7
			27.72	3.31156	8.0
29.26	3.15191	18.9
			30.46	3.03945	3.4
31.89	2.91647	3.8
			33.12	2.81951	6.1
34.26	2.73643	4.3
			35.85	2.63038	2.8
37.26	2.54480	2.8
			37.85	2.51089	2.1
39.66	2.41387	2.0
			40.91	2.35265	2.2

In the above characteristic diffraction peaks, the main characteristic diffraction peaks include 12.98, 13.24, 26.11, and further may include any one or more of 4.35, 19.99, and 29.26; alternatively, 4.35, 12.98, 13.24, 19.99, 26.11, 29.26 are included. Specifically, the main characteristic diffraction peaks further include any one or more of 7.03, 10.94, and 25.61.

TABLE 5 XRPD diffraction peak data for form F of the compound described herein

Diffraction angle 2 theta]	d value [ A]	Relative intensity [% ]]
			7.44	11.90074	99.7
8.16	10.85376	100.0
			10.67	8.32219	21.9
12.10	7.34996	19.5
			13.86	6.43178	22.9
14.65	6.09280	54.0
			14.91	5.98785	24.8
15.11	5.91156	24.4
			16.33	5.48016	29.9
17.22	5.20396	22.6
			17.71	5.06557	25.8
17.98	4.99040	14.5
			18.74	4.79448	8.8
19.35	4.65028	26.4
			19.70	4.56983	37.0
20.46	4.40666	21.3
			21.51	4.20098	89.6
22.72	3.98855	26.4
			23.15	3.91791	23.8
23.51	3.86210	16.2
			23.71	3.83185	21.5
24.38	3.73275	17.3
			24.61	3.69911	46.6
24.90	3.65889	25.8
			25.23	3.61434	26.2
26.12	3.49905	20.5
			26.62	3.43812	42.4
27.91	3.29149	23.5
			28.80	3.19779	14.1
29.17	3.16097	13.8
			29.58	3.12132	29.0
30.36	3.04777	8.3
			30.85	3.00439	8.6
31.31	2.96467	7.4
			32.08	2.90046	9.1
32.61	2.85878	8.2
			32.99	2.82945	7.5
35.80	2.63373	5.5
			36.67	2.57992	4.7
37.10	2.55405	4.6
			38.27	2.48748	5.7

In the above characteristic diffraction peaks, the main characteristic diffraction peaks include any three or more of 7.44, 8.16, 14.65 and 21.51, and further include any one or more of 19.70, 24.61 and 26.62; alternatively, 7.44, 8.16, 14.65, 19.70, 21.51, 24.61, 26.62 are included. Specifically, the main characteristic diffraction peaks further include any one or more of 16.33, 19.35, 22.72, 29.58.

TABLE 6 XRPD diffraction peak data for form H of the compound described herein

Angle of diffraction [ ° 2 θ [ ]]	d value [ A]	Relative intensity [% ]]
			8.07	10.97657	18.0
9.16	9.67960	52.0
			11.69	7.60208	100.0
12.60	7.06329	6.4
			12.99	6.85266	6.9
13.85	6.43776	16.4
			14.33	6.22387	20.3
15.12	5.90655	23.8
			16.10	5.55406	8.9
17.08	5.24666	10.2
			17.44	5.13940	14.5
17.60	5.09483	14.3
			17.88	5.01876	21.5
18.61	4.82710	25.5
			19.11	4.70560	12.0
19.52	4.61117	43.6
			20.37	4.42569	16.4
20.83	4.33225	6.1
			21.32	4.23796	6.7
22.01	4.11033	38.0
			22.66	3.99950	11.6
23.17	3.91581	4.9
			23.46	3.87026	6.7
24.00	3.78840	63.3
			24.97	3.64988	12.7
25.78	3.54215	21.2
			26.15	3.49578	12.9
26.54	3.44758	18.1
			27.30	3.35852	10.0
27.84	3.29862	17.5
			28.32	3.24800	7.7
28.76	3.20180	4.0
			29.19	3.15837	5.8
29.75	3.10503	4.2
			30.21	3.06215	9.4
30.63	3.02414	5.8
			31.18	2.97589	7.3
31.77	2.92618	11.7
			32.44	2.87217	7.7
33.12	2.81951	3.8
			34.59	2.71365	6.0
35.14	2.67642	2.8
			36.11	2.61383	3.9
36.53	2.58789	3.4
			37.19	2.54864	4.1
38.82	2.45761	3.2
			40.34	2.37983	3.0
41.88	2.30782	2.5
			42.46	2.28227	3.2
43.27	2.24759	2.6
			44.19	2.21021	3.5

In the above characteristic diffraction peaks, the main characteristic diffraction peaks include any three or more of 9.16, 11.69, 19.52 and 24.00, and may further include any one or more of 15.12, 18.61 and 22.01; alternatively, 9.16, 11.69, 15.12, 18.61, 19.52, 22.01, 24.00 are included. In particular, the main characteristic diffraction peaks further comprise any one or more of 14.33, 17.88, 25.78.

And (4) conclusion: by comparing XRPD patterns of the four crystal forms, the four crystal forms have obviously distinguished characteristic diffraction peaks and can be determined as four different crystal forms.

2. Differential scanning calorimetry mapping conditions and data

DSC spectra for form a, form F, form H, and form I of the compounds described herein were obtained as follows:

the model of the differential scanning calorimetry analyzer is TA Discovery 2500 (TA, US). The 1-2 mg samples were accurately weighed and placed in a perforated DSC Tzero sample pan and heated to the final temperature at a rate of 10 ℃/min with a nitrogen purge rate in the furnace of 50 mL/min.

As a result: DSC profiles for form a, form F, form H, and form I of the compounds described herein are shown in figure 2, figure 4, figure 6, and figure 8, respectively. Specifically, the crystal form A has endothermic peaks at 167.3 ℃ +/-2 ℃, 202.5 ℃ +/-2 ℃, 211.2 ℃ +/-2 ℃ and 239.0 ℃ +/-2 ℃; the crystal form F has endothermic peaks at 208.1 +/-2 ℃ and 239.1 +/-2 ℃ and exothermic peaks at 210.3 +/-2 ℃; the crystal form H has endothermic peaks at 145 +/-2 ℃, 227.5 +/-2 ℃ and 239.4 +/-2 ℃ and exothermic peaks at 239 +/-2 ℃; crystal form I has endothermic peaks at 165.4 ℃. + -. 2 ℃, 209.3 ℃. + -. 2 ℃ and 239.5 ℃. + -. 2 ℃ and exothermic peaks at 213.8 ℃. + -. 2 ℃.

3. Thermogravimetric analysis atlas determination conditions and data

The thermogravimetric analyzer is model number TA Discovery 55 (TA, US). The 2-5 mg samples were placed in an equilibrated open aluminum sample pan and automatically weighed in a TGA furnace. The samples were heated to the final temperature at a rate of 10 ℃ per minute with a nitrogen purge at the sample of 60 mL per minute and a nitrogen purge at the balance of 40 mL per minute.

As a result: thermogravimetric analysis spectra of form a, form F, form H, and form I of the compounds described herein are shown in fig. 2, fig. 4, fig. 6, and fig. 8, respectively. Specifically, the weight loss of the crystal form A is less than 6 percent (specifically 5.2 percent) in the process of being heated to 150 +/-2 ℃, and the crystal form A is decomposed at 275 +/-2 ℃; the weight loss of the crystal form F is less than 10 percent (specifically 9.6 percent) in the process of heating to 150 +/-2 ℃, and the crystal form F is decomposed at 275 +/-2 ℃; the weight loss of the crystal form H is less than 15 percent (specifically 14.4 percent) in the process of heating to 200 +/-2 ℃, and the crystal form H is decomposed at 275 +/-2 ℃; form I loses less than 3% (specifically 2.1%) weight during heating to 150 ℃, and decomposes at 275 ℃ ± 2 ℃.

4. Offline heat table experiment and online variable-temperature XRPD (X-ray fluorescence Spectroscopy) measuring condition and data

Off-line hot bench test:

using an Instec HCS424GXY hot stage (Instec inc., US), the 6-8 mg samples were placed on a glass slide, heated to a target temperature (in the range of 120-220 ℃) at a rate of 20 ℃/min, thermostatted for 10 min, then naturally cooled to room temperature before XRPD testing of the solid.

On-line temperature change XRPD experiments:

the test was performed using an X-ray powder diffractometer Malvern PANalytical Aeris (Malvern PANalytical, UK) with a 2 θ scan angle from 8 ° to 40 °, a scan step of 0.02 ° and a test time of 15 min. The light pipe voltage and current were 40 kV and 7.5 mA, respectively, for the test samples, and the sample disks were zero background sample disks. An amount of the sample was placed in a BTS500 hot stage (Anton Paar, AT) and XRPD measurements were performed AT room temperature, followed by heating to a target temperature (120 ℃) AT 20 ℃/min, and after 10 min of constant temperature XRPD measurements were performed AT the corresponding temperature.

As a result:

in an off-line hot-stage experiment, crystal form a and crystal form I of the compound described herein do not undergo crystal transformation after being heated to a high temperature and then cooled to room temperature, while crystal form F and crystal form H of the compound described herein are heated to a high temperature (160 ℃ -170 ℃) and then cooled to room temperature and then undergo crystal transformation.

Furthermore, taking into account the parameters of form a, form I, form F and form H of the compounds described herein (including XRPD, DSC, TGA and results of off-line hot-bench testing and/or on-line variable temperature XRPD testing), the following conclusions can be drawn: form a and form I of the compounds described herein are hydrates, and form F and form H are solvates.

5. Polarizing microscope analysis (PLM)

The polarizing microscope is model Nikon Ci-POL (Nikon, JP). A small amount of sample crystal form A is placed on a glass slide, and a proper lens is selected to observe the appearance of the sample.

As a result:

as shown in fig. 9, PLM images show that form a is mostly rod-shaped particles, generally less than 25 μm in particle size. In the field of pharmacy, rod-shaped crystals are suitable for patent medicine because of large specific surface area and good fluidity.

6. Dynamic moisture sorption desorption analysis (DVS) assay conditions and data

Dynamic water sorption desorption analysis was determined using DVS Intrinsic (SMS, UK). The test adopts a gradient mode, the humidity change is 50% -95% -0% -50%, the humidity change amount of each gradient in the range of 0% to 90% is 10%, the gradient end point is judged in a dm/dt mode, and the gradient end point is determined by maintaining the dm/dt value to be less than 0.002% for 10 minutes. After the test is finished, XRPD analysis is carried out on the crystal form A and the crystal form I of the sample to confirm whether the solid form is changed.

As a result:

the XRPD pattern of form a of the sample did not change form before and after DVS testing, as shown in figure 10.

Stability determination

1. Experiment of influence factor

20mg of the compound described herein, form a, form F, form H and form I, were uniformly spread into an open petri dish, approximately 5mm thick, placed under high temperature (60 ℃), high humidity (92.5% RH, 25 ℃) and light (4500 lx ± 500lx, 25 ℃) conditions, respectively, for 10 days and 30 days, sampled, observed for appearance, checked for purity, XRPD characterized, and compared to the results for 0 days.

As a result: the compound of the present application, crystal form a and crystal form I, have good stability at high temperature, high humidity and under illumination, and maintain stable appearance and purity within 30 days. The compound of the present application, form F and form H, is relatively less stable, especially when agglomerated at high humidity and darkens under light.

Wherein, the influencing factors experimental results of the crystal form A are shown in the table 7 and figures 11 to 12.

TABLE 7

The results show that the crystal form A keeps stable appearance and purity within 30 days under the influence factor experiment condition, and no crystal form transformation occurs.

2. Accelerated stability test

Crystal form a, crystal form F, crystal form H and crystal form I of the compounds described herein were placed in a stability testing box at 40 ℃ and 75% Relative Humidity (RH), placed for 30 days, sampled at 10 and 30 days, observed for appearance, detected for purity, subjected to XRPD characterization, and compared to the results for 0 day.

As a result: the compound of the present application has good stability in crystal form a and crystal form I at 40 ℃ and 75% Relative Humidity (RH), and is more excellent than the compound of the present application in crystal form F and crystal form H. The stability of form F and form H of the compounds described herein is relatively poor, especially with respect to caking under accelerated stability testing conditions.

Wherein, the results of the accelerated stability test of the crystal form A are shown in the table 8 and the figures 11 to 12.

TABLE 8

The results show that form a maintains stable appearance and purity within 30 days under accelerated stability test conditions, and no crystal form transformation occurs.

Therefore, the crystal form A and the crystal form I (especially the crystal form A) of the compound disclosed by the application have better stability than the crystal form F and the crystal form H of the compound disclosed by the application, are more suitable for medicinal use, are favorable for preparation, transportation and storage of medicines, and ensure the effectiveness and safety of medicine use.

The above-mentioned embodiments are further described in detail for the purpose of illustrating the invention, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the invention and are not intended to limit the scope of the invention, and any modification, equivalent replacement, improvement, etc. made within the spirit and spirit of the invention should be included in the scope of the invention.

Claims

1. A crystalline form of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione selected from one of form a or form I, or a mixture thereof;

wherein the content of the first and second substances,

the crystal form A is characterized in that Cu-Kalpha radiation is used, and the characteristic diffraction peaks of an X-ray powder diffraction pattern expressed by 2 theta values +/-0.2 degrees comprise more than any three of 4.30, 12.30, 12.87 and 24.61;

2. The crystalline form according to claim 1, characterized in that form a further comprises any one or more of 10.65, 13.79, 20.67 of the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° using Cu-ka radiation.

3. Form A according to claim 1 or 2, characterized in that form A has an X-ray powder diffraction pattern with characteristic diffraction peaks expressed in terms of 2 θ values ± 0.2 ° using Cu-Ka radiation comprising 4.30, 10.65, 12.30, 12.87, 13.79, 20.67, 24.61.

4. The crystalline form according to claim 1, characterized in that form I further comprises any one or more of 4.35, 19.99, 29.26 characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2 Θ values ± 0.2 ° using Cu-ka radiation.

5. The crystalline form according to claim 1 or 4, characterized in that form I has an X-ray powder diffraction pattern with characteristic diffraction peaks comprising 4.35, 12.98, 13.24, 19.99, 26.11, 29.26 expressed in 2 θ values ± 0.2 ° using Cu-Ka radiation.

6. A drug substance comprising a crystalline form of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione as claimed in any one of claims 1-5.

7. The bulk drug of claim 6, wherein the weight percentage of the crystalline form in the bulk drug is 90.0-99.9%.

8. A composition comprising a crystalline form of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione according to any one of claims 1-5, and one or more physiologically acceptable/pharmaceutically acceptable excipients.

9. The composition according to claim 8, wherein the weight percentage of the crystalline form in the composition is 0.1-85%.

10. Use of the compound of any one of claims 1-5 (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione in the manufacture of a medicament for the treatment or prevention of a disease caused by a coronavirus in a subject.

11. Use of a crystalline form of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1,2,4-triazol-3-yl) methyl ] -1- (2,4,5-trifluorobenzyl) -1,3,5-triazinane-2,4-dione as described in any of claims 1-5 in the preparation of a solid form of a salt of the compound.