Pharmaceutical formulations of imidazolinone compounds, methods for their preparation and uses

Abstract

FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations of imidazolinone compounds and methods for their preparation. In particular, the present invention relates to pharmaceutical formulations of compounds of formula I: [Case 1] TIFF2025539576000064.tif43164

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical formulations, in particular to pharmaceutical formulations of imidazolinone compounds, their preparation methods and their uses. [Background technology]

[0002] DNA-dependent protein kinase (DNA-PK) is an enzyme complex composed of the Ku70 / Ku80 heterodimer and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). This enzyme complex can only be activated to perform its corresponding functions involving DNA (George et al., 2019). As a serine / threonine protein kinase, DNA-PK is a member of the PIKK (phosphatidylinositol 3-kinase-related kinase) family. It not only plays an important role in intracellular DNA double-strand break (DSB) repair and intracellular DNA recombination, or antibody DNA rearrangement (V(D)J recombination), but is also involved in physiological processes such as chromosome remodeling, transcriptional regulation, and telomere maintenance.

[0003] The combined use of DNA-PK inhibitors with DNA-damaging antitumor therapies (e.g., IR and chemotherapy agents) may improve therapeutic efficacy. Although the use of DNA-PK inhibitors may inhibit the DNA repair function of normal cells to some extent, normal cells still have a variety of complementary DNA repair pathways; in addition, facing enormous DNA replication pressure and lacking effective DNA repair methods, tumor cells are therefore highly sensitive to DNA-PK inhibitors. Furthermore, inhibiting DNA-PK activity in tumor cells can enhance the killing effect of other antitumor therapies on tumor cells.

[0004] The patent (application number: PCT / CN2021 / 087912) describes a novel DNA-PK inhibitor having the structure represented by formula (A). This inhibitor has a good inhibitory effect on DNA-PK activity and may be useful for the preparation of antitumor drugs. There is a need to prepare a DNA-PK inhibitor-containing formulation with good drug dissolution rate and stability. [ka] Summary of the Invention

[0005] The present invention provides a pharmaceutical formulation of an imidazolinone compound that is easy for patients to use and has characteristics such as stable quality and good dissolution effect.

[0006] The present invention provides a pharmaceutical formulation of an imidazolinone compound, the pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, the pharmaceutical formulation containing the imidazolinone compound in a dosage of 1 to 1000 mg, the imidazolinone compound being selected from compounds of Formula I: [ka] During the ceremony, [ka] teeth [ka] and; [ka] is a single or double bond; [ka] wherein A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R0 is H, C 1-6 alkyl or cyclopropyl, 1-6 The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, wherein R1 is further selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, and C 1-6 optionally substituted with 1 or 2 substituents selected from alkoxy; R 1a is H or C 1-6 is alkyl; R 1b is H, OH, cyano, or hydroxyl substituted C 1-6 is alkyl; R2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1-6 Alkoxy, C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 alkyl, 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, or C 1-6 The alkoxy may be substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1-6 alkyl, or 3- to 5-membered cycloalkyl, 1-6 Alkyl can also be substituted with OH, D, halogen, C 1-6 Alkyl, and C 1-6 may be substituted with one or more substituents selected from alkoxy; Alternatively, R 2a and R 2btogether with the atom to which they are attached form a 5-6 membered heterocyclyl ring, which contains 1, 2, or 3 heteroatoms selected from N, O, and S, and further contains C 1-6 may be substituted with one or more substituents selected from alkyl, OH, and halogen; R3 is halogen or C 1-6 alkyl, 1-6 The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2; x and y are each independently 1, 2, or 3; however, [ka] If R0, R2, and R3 simultaneously satisfy the following conditions, then R1 is [ka] rather than; [ka] teeth [ka] wherein n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0007] Further, in one or more embodiments of the present invention, in the compound of formula I above, R1 is [ka] and; R 1a is H or C 1-6 is alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b , C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 alkyl, and the -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy may be substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1-6 alkyl, or 3- to 5-membered cycloalkyl, 1-6 The alkyl may be further substituted with one or more substituents selected from OH, D, or halogen; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, which may be further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1-6 alkyl, 1-6 The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2.

[0008] Furthermore, in one or more embodiments of the present invention, in the compound of formula I above, [ka] teeth, [ka] and; R0 is H, C 1-4 alkyl or cyclopropyl, 1-4 The alkyl may be further substituted with one or more substituents selected from halogen and D; R1 is [ka] and; R 1a is H, C 1-6 Alkyl, or -C(=O)C 1-6 is alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b , C 1-6 Alkoxy, halogen, -S(=O)2R 2a , or -C(=O)OC 1-6 alkyl, and the -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy may be substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1-6 alkyl, or 3- to 5-membered cycloalkyl, 1-6 The alkyl may be further substituted with one or more substituents selected from OH, D, and halogen; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, which may be further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1-6 alkyl, 1-6 The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2.

[0009] Further, in one or more embodiments of the present invention, the compound of formula I above is selected from the following: [ka] During the ceremony, R0 is H, C 1-6 alkyl, or cyclopropyl, 1-6 The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, wherein R1 is further selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, and C 1-6 optionally substituted with 1 or 2 substituents selected from alkoxy; R 1a is H or C 1-6 is alkyl; R 1b H, OH, cyano, or hydroxyl substituted C 1-6 is alkyl; R 2c is H, cyano, halogen, or C 1-6 is alkoxy; R 2d is H, cyano, carboxyl, -C(=O)NR 2a R 2b , C 1-6 Alkyl, halogen, -S(=O)2R 2a , or -C(=O)OC 1-6 alkyl, 1-6 Alkyl and -C(=O)OC 1-6 The alkyl may be substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b is H, C 1-6 alkyl, or 3- to 5-membered cycloalkyl, 1-6 Alkyl can also be substituted with OH, D, halogen, C 1-6 Alkyl, and C 1-6 may be substituted with one or more substituents selected from alkoxy; Alternatively, R 2a and R 2btogether with the atom to which they are attached form a 5-6 membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, and further containing C 1-6 may be substituted with one or more substituents selected from alkyl, OH, and halogen; R3 is halogen or C 1-6 alkyl, 1-6 The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2; x and y are each independently 1, 2, or 3.

[0010] Further, in one or more embodiments of the present invention, the compound of formula I above is selected from: [ka] During the ceremony, R0 is H, C 1-6 alkyl, or cyclopropyl, 1-6 The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, wherein R1 is further selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, and C 1-6 optionally substituted with 1 or 2 substituents selected from alkoxy; R 1b H, OH, cyano, or hydroxyl substituted C 1-6 is alkyl; R 2a and R 2b are independently H, C 1-6 alkyl, or 3- to 5-membered cycloalkyl, 1-6 The alkyl may be further substituted with one or more substituents selected from D or halogen; Alternatively, R 2a and R 2b together with the atom to which they are attached form a 5-6 membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, and further containing C 1-6 may be substituted with one or more substituents selected from alkyl, OH, and halogen; R 2c is H, cyano, halogen, or C 1-6 is an alkoxy group, 1-6 The alkoxy may be substituted with one or more deuterium atoms; R3 is halogen or C 1-6 alkyl, 1-6 The alkyl may be further substituted with 1 to 3 substituents selected from D or halogen; m is 0 or 1; n is 0, 1, or 2; x and y are each independently 1, 2, or 3.

[0011] Further, in one or more embodiments of the present invention, the compound of formula I above is selected from: [ka] During the ceremony, R0 is H, C 1-6 alkyl, or cyclopropyl, 1-6 The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R1 is -(CH) m -4- to 7-membered carbocyclyl, -(CH) m -4- to 7-membered heterocyclyl, -(CH) m -8~12-membered bridged ring, -(CH) m -7 to 12-membered spiro ring, and the -(CH) m -4- to 7-membered carbocyclyl, -(CH) m -4- to 7-membered heterocyclyl, -(CH) m -8 to 12-membered bridged ring, or -(CH) m-7- to 12-membered spiro rings can also be substituted with hydroxy, cyano, halogen, ═O, C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy substituted C 1-6 may be substituted with one or more substituents selected from alkyl; m is 0 or 1.

[0012] Further, in one or more embodiments of the present invention, in the compound of formula I above, R0 is H, C 1-6 alkyl, or cyclopropyl, 1-6 The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] or pyridyl, wherein R1 is further selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, and C 1-6 optionally substituted with 1 or 2 substituents selected from alkoxy; R 1a is H or C 1-6 is alkyl; R 1b H, OH, cyano, or hydroxyl substituted C 1-6 is alkyl; m is 0 or 1; x and y are each independently 1, 2, or 3.

[0013] Furthermore, in one or more embodiments of the present invention, in the compound of formula I above, R0 is C 1-4 alkyl, 1-4 The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R1 is [ka] is.

[0014] Further, in one or more embodiments of the present invention, the compound of formula I above is selected from: [ka] [ka] [ka] [ka] [ka]

[0015] The present invention further provides pharmaceutical formulations of imidazolinone compounds, which in one or more embodiments may comprise a compound of Formula I in an amount of 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg , 90-100mg, 100-150mg, 150-200mg, 200-250mg, 250-300mg, 300-350mg, 350-400mg, 400-450mg, 450-500mg, 500-600mg, 600-700mg, 700-800mg, 800-900mg, or 900-1000mg.

[0016] The present invention further provides a pharmaceutical formulation of an imidazolinone compound, the pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the imidazolinone compound is selected from any one or more of the compounds of Formula I above, and the content of the imidazolinone compound in the pharmaceutical formulation is 1 to 90 parts by weight.

[0017] Furthermore, in one or more embodiments of the present invention, the content of the imidazolinone compound in the pharmaceutical formulation is 1 to 5 parts, 5 to 10 parts, 10 to 15 parts, 15 to 20 parts, 20 to 25 parts, 25 to 30 parts, 30 to 35 parts, 35 to 40 parts, 40 to 45 parts, 45 to 50 parts, 50 to 55 parts, 55 to 60 parts, 60 to 65 parts, 65 to 70 parts, 70 to 75 parts, 75 to 80 parts, 80 to 85 parts, or 85 to 90 parts; optionally further, the content of the imidazolinone compound in the pharmaceutical formulation is 27.8 parts or 41.7 parts.

[0018] The present invention further provides a pharmaceutical formulation of the imidazolinone compound, wherein the dosage form of the pharmaceutical formulation is selected from, but not limited to, granules, tablets, capsules, pills, or micropellets.

[0019] The present invention further provides a pharmaceutical formulation of an imidazolinone compound, comprising one or more of a diluent, a disintegrant, and a glidant, wherein, in parts by weight, the content of the diluent is 10-85 parts; the content of the disintegrant is 3-70 parts; and the content of the glidant is 0.1-30 parts.

[0020] Additionally, in one or more embodiments of the present invention, the pharmaceutical formulation may further contain surfactants, humectants, antioxidants, and the like.

[0021] Further, in one or more embodiments of the present invention, the content of the diluent in the pharmaceutical formulation is 10-15 parts, 15-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-65 parts, 65-70 parts, 70-75 parts, 75-80 parts, or 80-85 parts.

[0022] Further, in one or more embodiments of the present invention, the content of the disintegrant is 3 to 5 parts, 5 to 15 parts, 15 to 20 parts, 20 to 25 parts, 25 to 30 parts, 30 to 35 parts, 35 to 40 parts, 40 to 45 parts, 45 to 50 parts, 50 to 55 parts, 55 to 60 parts, 60 to 65 parts, or 65 to 70 parts.

[0023] Further, in one or more embodiments of the present invention, the content of the glidant is 0.1 to 0.5 parts, 0.5 to 1 part, 1 to 5 parts, 5 to 10 parts, 10 to 15 parts, 15 to 20 parts, 20 to 25 parts, or 25 to 30 parts.

[0024] Optionally, in one or more embodiments of the present invention, the pharmaceutical formulation contains 64.1 parts, 66.7 parts, or 50 parts of diluent; 7 parts, 4.4 parts, or 6.7 parts of disintegrant; and 1.6 parts or 1.1 parts of glidant.

[0025] Further, in one or more embodiments of the present invention, the diluent is selected from, but is not limited to, one or more of sucrose, xylitol, maltitol, lactitol, hydroxypropyl cellulose, hypromellose, sorbitol, glucose, fructose, corn starch, inorganic salts, microcrystalline cellulose, starch, mannitol, lactose, and pregelatinized starch, preferably one or more of microcrystalline cellulose, mannitol, and pregelatinized starch.

[0026] Further, in one or more examples of the present invention, the disintegrant is selected from, but is not limited to, one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, calcium carboxymethylcellulose, potato starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose.

[0027] Additionally, in one or more embodiments of the present invention, the glidant is selected from, but is not limited to, one or more of colloidal silica, silica, magnesium silicate, magnesium trisilicate, polysilicates, hydrated silica, calcium phosphate, and talc.

[0028] The present invention further provides a method for preparing a pharmaceutical formulation of an imidazolinone compound, the method mainly comprising the steps of: preparing a mixture of an imidazolinone compound, a disintegrant, and a diluent; and Blending the mixture with a glidant and then preparing it into tablets, capsules, or granules.

[0029] Further, in one or more embodiments of the present invention, after mixing the glidant and the mixture, the resulting mixture is placed in a granulator to be granulated and then prepared into tablets, capsules, or granules; Or further, in one or more embodiments of the present invention: The mixture contains 50 to 80% by weight of the prescribed amount of diluent; the mixture is mixed in a mixer and then granulated in a granulator to obtain mixed particles; a glidant and the remaining prescribed amount of the diluent are added to the mixed particles, mixed in a mixer, and then prepared into tablets, capsules, or granules.

[0030] The present invention further provides the use of a pharmaceutical formulation of an imidazolinone compound in the preparation of a medicament for treating and / or preventing cancer.

[0031] In one or more embodiments of the present invention, there is provided a use of a pharmaceutical formulation of an imidazolinone compound in the preparation of a medicament for treating and / or preventing cancer by administering the medicament comprising the pharmaceutical formulation to a subject; optionally further, the use comprises orally administering the medicament; and optionally further, the medicament is orally administered 1 to 4 times daily.

[0032] The present invention further provides a pharmaceutical formulation of an imidazolinone compound, the pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the imidazolinone compound is selected from one or more compounds of Formula I above, and the compound of Formula I is present in an amount to provide a daily dose of 1 to 1000 mg, administered in single or multiple doses.

[0033] Further, in one or more embodiments of the present invention, the imidazolinone compound is present in an amount to provide a daily dose of 1-10 mg, 10-20 mg, 20-50 mg, 50-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, or 900-1000 mg.

[0034] In one or more embodiments of the present invention, a pharmaceutical formulation of an imidazolinone compound is provided, the pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the imidazolinone compound is selected from any one or more compounds of Formula I above, and the compound of Formula I is present in an amount to provide a daily dose of 1 to 1000 mg / 60 kg.

[0035] The present invention further provides a method for preventing and / or treating cancer, the method comprising administering to a subject a therapeutically effective dose of any of the pharmaceutical formulations of the imidazolinone compounds described above.

[0036] In one or more embodiments of the present invention, the pharmaceutical formulation comprises an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the imidazolinone compound is selected from any one or more compounds of Formula I above. Further, the compound of Formula I is present in an amount to provide a daily dose of 1 to 1000 mg; and still further, the compound of Formula I is present in an amount to provide a daily dose of 1 to 1000 mg / 60 kg.

[0037] Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0038] "Pharmaceutically acceptable salt" refers to a salt that is safe, non-toxic, biologically or otherwise desirable, pharmaceutically acceptable for veterinary and human pharmaceutical use, and possesses the desired pharmacological activity.

[0039] "Prodrug" refers to a compound that is convertible in vivo by metabolism to a biologically active compound of the invention.

[0040] "Stereoisomer" refers to isomers that result from different spatial arrangements of atoms in molecules, and includes cis-trans isomers, enantiomers, and conformational isomers.

[0041] "Optional" or "optionally" or "alternatively" or "alternatively" or "further" means that the subsequently described event or condition may, but need not, occur; the description includes cases where the event or condition occurs and cases where it does not. For example, "heterocyclyl alternatively substituted with alkyl" means that alkyl may, but need not, be present; the description includes cases where the heterocyclyl is substituted with alkyl and cases where the heterocyclyl is not substituted with alkyl.

[0042] An "effective dose" refers to an amount that produces a physiological or medical response in a tissue, system, or subject, and is a desired amount that includes an amount of compound sufficient, when administered to a treated subject, to prevent the occurrence of one or more symptoms of the disease or condition being treated, or to alleviate to some extent the symptom(s).

[0043] It is understood that the numerical values ​​described and claimed in this invention are approximations, and variations in the values ​​can be attributed to instrument calibration, instrument error, purity of material, crystal size, sample size, and other factors.

[0044] It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention in light of the specification and operation of the embodiments of the present invention without departing from the scope and spirit of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0045] The implementation process and beneficial effects of the present invention are described in detail below with specific examples, which are intended to help readers better understand the essence and features of the present invention, but are not intended to limit the scope of the implementation of the present invention.

[0046] Unless otherwise specified in the examples, solutions refer to aqueous solutions.

[0047] Known starting materials of the present invention can be synthesized by or according to methods known in the art or can be purchased from Titan Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Demo Co., Ltd., Chengdu Kelong Chemical Co., Ltd., Accela ChemBio Co., Ltd., J&K Scientific Co., Ltd., etc.

[0048] The compounds of general formula (I) or specific structures thereof can be obtained by the methods of patent WO2021209055, which is incorporated herein by reference in its entirety.

[0049] The active pharmaceutical ingredient, compound 62, is prepared by the following method. [ka]

[0050] 1st step: 2-Chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (62a) 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1D (400 mg, 1.57 mmol) was dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (511 mg, 1.57 mmol) and iodoethane (293 mg, 1.88 mmol) were added. The mixture was stirred at 0 °C for 1 hour. The reaction was monitored by thin-layer chromatography (TLC) until completion. 10 mL of water was then added, followed by extraction with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the organic solvent was removed by rotary evaporation to give the title compound 2-chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 62a (white solid, 290 mg, yield: 65.32%).

[0051] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 4.50 -4.41 (m, 1H), 3.99-3.95 (m, 2H), 3.89 (q, 2H), 3.45 (t, 2H), 2.46-2.41 (m, 2H), 1.71-1.67 (m, 2H), 1.25 (t, 3H).

[0052] LC-MS m / z(ESI)=283.10 [M+1].

[0053] Second step: 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 62) 2-Chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 62a (150 mg, 0.53 mmol), 4-amino-2-fluoro-5-methylbenzamide (Intermediate 2, 350 mg, 2.12 mmol), cesium carbonate (690 mg, 2.12 mmol), and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (72 mg, 0.08 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted under nitrogen protection at 110 °C for 4 hours with stirring. The reaction was monitored by TLC until completion. The concentrated reaction solution is separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) followed by preparative high performance liquid chromatography (Pre-HPLC) to obtain the title compound 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 62, white solid, 38 mg, yield: 17.28%).

[0054] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.25 (s, 1H), 7.89 (d, 1H), 7.55 (d, 1H), 7.42 (d, 2H), 4.48-4.40 (m, 1H), 3.98 (dd, 2H), 3.85 (q, 2H), 3.43 (t, 2H), 2.58-2.54 (m, 2H), 2.30 (s, 3H) 1.71-1.68 (m, 2H), 1.25 (t, 3H).

[0055] LC-MS m / z(ESI)=415.20 [M+1].

[0056] Examples 1 to 4 [Table 1] Preparation method: 1) The prescribed amounts of Compound 62, microcrystalline cellulose (PH102 and PH302), mannitol, pregelatinized starch, croscarmellose sodium, and colloidal silica were weighed and passed through a 60-mesh sieve for later use; 2) The prescribed amounts of microcrystalline cellulose PH102 (or microcrystalline cellulose PH302, mannitol, and pregelatinized starch) and croscarmellose sodium were weighed, incrementally mixed, and passed through a 60-mesh sieve twice to obtain Mixture 1; 3) The prescribed amount of compound 62 was added to mixture 1, passed through a 60 mesh sieve, and mixed until uniform to obtain mixture 2; 4) Add the prescribed amount of colloidal silica to Mixture 2, pass it through a 60 mesh sieve, and mix until uniform to obtain an intermediate powder; 5) Approximately 60 mg of the intermediate powder was filled into hollow gelatin capsules to obtain capsules with a standard of 25 mg.

[0057] Examples 5 to 8 [Table 2] Preparation method: 1) Compound 62, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and colloidal silica were weighed in the prescribed amounts and passed through a 60-mesh sieve for later use; 2) The prescribed amounts of microcrystalline cellulose and croscarmellose sodium (or crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose) were weighed out, mixed incrementally, and passed through a 60-mesh sieve twice to obtain Mixture 1; 3) A prescribed amount of compound 62 was added to mixture 1 and passed through a 60 mesh sieve; a prescribed amount of colloidal silica was added and passed through a 60 mesh sieve, and mixed until uniform, to obtain mixture 2; 4) Mixture 2 is placed in a dry granulator, and the roller speed is set to 3.00 to 8.00 Hz, the granulation speed is set to 20.00 to 30.00 Hz, and the hydraulic pressure is set to 30 to 75 kg / cm 3 granulation, thereby obtaining intermediate particles; 5) Approximately 90 mg of the intermediate particles were filled into hollow gelatin capsules to obtain capsules with a standard of 25 mg.

[0058] Examples 9 and 10 [Table 3] Preparation method: 1) The prescribed amounts of Compound 62, microcrystalline cellulose, croscarmellose sodium, and colloidal silica were weighed and passed through a 60-mesh sieve for later use; 2) A prescribed amount of compound 62, as well as 80% of the prescribed amounts of microcrystalline cellulose and croscarmellose sodium were weighed and passed through a 60 mesh sieve twice to obtain mixture 1; 3) Mixture 1 was placed in a three-dimensional mixer and mixed for 20 minutes at a mixing frequency of 40±5Hz, thereby obtaining mixture 2; 4) Mixture 2 is placed in a dry granulator, and the roller speed is set to 3.00 to 8.00 Hz, the granulation speed is set to 20.00 to 30.00 Hz, and the hydraulic pressure is set to 30 to 75 kg / cm 3 granulation at a setting of 0.05 to 1.05, thereby obtaining particles of Mixture 3; 5) About 20% of the formulation amount of microcrystalline cellulose and colloidal silica was added to the mixture 3, and the mixture was mixed in a three-dimensional mixer with a mixing frequency set to 40±5Hz for 20 minutes, thereby obtaining an intermediate; 6) Example 9: Approximately 90 mg of intermediate particles were filled into hollow gelatin capsules to obtain capsules with a 25 mg standard.

[0059] Example 10: Approximately 360 mg of intermediate particles were filled into hollow gelatin capsules to obtain capsules with a 100 mg standard.

[0060] Dissolution test 1: According to the dissolution rate test method (Chinese Pharmacopoeia 2020, Vol. IV 0931, Method 2), 900 ml of pH 6.8 phosphate buffer solution was added to each sample of Examples 1, 2, 3, and 4. The rotation speed was 75 revolutions per minute, and samples were taken at 10, 15, 20, 30, 45, 60, and 90 minutes to determine the dissolution rate. The results are shown in Table 4: [Table 4]

[0061] As can be seen from the dissolution rate results above, all capsules prepared using various types of diluents as shown in the examples had dissolution rates of over 80% after 20 minutes, and their dissolution behaviors were almost identical.

[0062] Dissolution test 2 According to the dissolution rate test method (Chinese Pharmacopoeia 2020, Vol. IV 0931, Method 2), 900 ml of pH 6.8 phosphate buffer solution was added to each sample of Examples 5, 6, 7, and 8. The rotation speed was 75 revolutions per minute, and samples were taken at 10, 15, 20, 30, 45, and 60 minutes to determine the dissolution rate. The results are shown in Table 5: [Table 5]

[0063] As can be seen from the dissolution rate results above, the dissolution behavior of the capsules was almost unaffected by the various types of disintegrants used according to the examples, and all capsules had a dissolution rate of over 70% after 30 minutes.

[0064] Dissolution test 3 According to the dissolution rate test method (Chinese Pharmacopoeia 2020, Vol. IV 0931, Method 2), 900 ml of dissolution solvents, 1) hydrochloric acid solution pH 1.0, 2) acetate buffer pH 4.5, and 3) phosphate buffer pH 6.8, were added to the sample of Example 9. The rotation speed was 75 revolutions per minute, and samples were taken at 15, 30, and 60 minutes to determine the dissolution rate. The results are shown in Table 6: [Table 6]

[0065] As can be seen from the dissolution rate results above, all of the samples of Example 9 in various pH environments exhibit good dissolution rates.

[0066] Stability testing According to the requirements of the Chinese Pharmacopoeia (2015 edition, Volume IV) 9001 "Guidelines for Stability Testing of Drug Substances and Preparations", the samples of Examples 9 and 10 were investigated by influence factor tests. The experimental results are shown in Tables 7 and 8. The test conditions were as follows:

[0067] The samples were placed in a clean open watch glass and subjected to high temperature (60±2°C), high humidity (RH 92.5%), and light (4500±500Lx) conditions. Sampling was performed on the 10th and 30th days, respectively. [Table 7] [Table 8]

[0068] Conclusion: After investigation by the influence factor test, the indicators of the samples of Examples 9 and 10 did not change significantly compared with those on day 0, indicating that they were all qualified, indicating that the quality of the composition of Compound 62 involved in the present invention is stable.

Claims

1. 1. A pharmaceutical formulation of an imidazolinone compound, the pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, the pharmaceutical formulation comprising the imidazolinone compound in a dosage of 1 to 1000 mg, the imidazolinone compound being selected from compounds of Formula I: 【Chemistry 1】 During the ceremony, 【Chemistry 2】 teeth 【Transformation 3】 and 【Chemistry 4】 is a single or double bond; 【Transformation 5】 wherein A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R ０ is H, C １－６ alkyl or cyclopropyl, １－６ The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Transformation 6】 or pyridyl, and R １ may further include D, halogen, cyano, hydroxyl, C １－６ Alkyl, and C １－６ may be substituted with one or two substituents selected from alkoxy; R １ａ is H or C １－６ is alkyl; R １ｂ is H, OH, cyano, or hydroxyl substituted C １－６ is alkyl; R ２ is H, cyano, ═O, carboxyl, —C(═O)NR ２ａ R ２ｂ , C １－６ Alkoxy, C １－６ Alkyl, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １－６ alkyl, １－６ Alkyl, —C(═O)OC １－６ Alkyl, or C １－６ The alkoxy may be substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １－６ alkyl, or 3- to 5-membered cycloalkyl, １－６ Alkyl can further include OH, D, halogen, C １－６ Alkyl, and C １－６ may be substituted with one or more substituents selected from alkoxy; Or, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, and further containing C １－６ may be substituted with one or more substituents selected from alkyl, OH, and halogen; R ３ is a halogen or C １－６ alkyl, １－６ The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2; x and y are each independently 1, 2, or 3; however, 【Transformation 7】 R ０ , R ２ , and R ３ If simultaneously satisfies the following conditions, R １ teeth 【Transformation 8】 rather than: 【Chemistry 9】 teeth 【Chemistry 10】 where n is 1 and R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl.

2. In the compounds of formula I, R １ teeth 【Chemistry 11】 and R １ａ is H or C １－６ is alkyl; R ２ is H, cyano, -C(=O)NR ２ａ R ２ｂ , C １－６ Alkoxy, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １－６ alkyl, and the —C(═O)OC １－６ Alkyl or C １－６ The alkoxy may be substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １－６ alkyl, or 3- to 5-membered cycloalkyl, １－６ The alkyl may be further substituted with one or more substituents selected from OH, D, or halogen; Or, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl ring, which contains 1-3 heteroatoms selected from N, O, and S, and which may be further substituted with one or more substituents selected from OH and halogen; R ３ is a halogen or C １－６ alkyl, １－６ The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; 2. The pharmaceutical formulation of claim 1, wherein n is 0, 1, or 2.

3. In the compounds of formula I, 【Chemistry 12】 teeth 【Chemistry 13】 and R ０ is H, C １－４ alkyl or cyclopropyl, １－４ The alkyl may be further substituted with one or more substituents selected from halogen and D; R １ teeth 【Chemistry 14】 and R １ａ is H, C １－６ Alkyl, or —C(═O)C １－６ is alkyl; R ２ is H, cyano, -C(=O)NR ２ａ R ２ｂ , C １－６ Alkoxy, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １－６ alkyl, and the —C(═O)OC １－６ Alkyl or C １－６ The alkoxy may be substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １－６ alkyl, or 3- to 5-membered cycloalkyl, １－６ The alkyl may be further substituted with one or more substituents selected from OH, D, and halogen; Or, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl ring, which contains 1-3 heteroatoms selected from N, O, and S, and which may be further substituted with one or more substituents selected from OH and halogen; R ３ is a halogen or C １－６ alkyl, １－６ The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; 2. The pharmaceutical formulation of claim 1, wherein n is 0, 1, or 2.

4. The compound of formula I is selected from: 【Chemistry 15】 During the ceremony, R ０ is H, C １－６ alkyl, or cyclopropyl, １－６ The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 16】 or pyridyl, and R １ may further include D, halogen, cyano, hydroxyl, C １－６ Alkyl, and C １－６ may be substituted with one or two substituents selected from alkoxy; R １ａ is H or C １－６ is alkyl; R １ｂ is H, OH, cyano, or hydroxyl substituted C １－６ is alkyl; R ２ｃ is H, cyano, halogen, or C １－６ is alkoxy; R ２ｄ is H, cyano, carboxyl, -C(=O)NR ２ａ R ２ｂ , C １－６ Alkyl, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １－６ alkyl, １－６ Alkyl and —C(═O)OC １－６ The alkyl may be substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ is H, C １－６ alkyl, or 3- to 5-membered cycloalkyl, １－６ Alkyl can further include OH, D, halogen, C １－６ Alkyl, and C １－６ may be substituted with one or more substituents selected from alkoxy; Or, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, and further containing C １－６ may be substituted with one or more substituents selected from alkyl, OH, and halogen; R ３ is a halogen or C １－６ alkyl, １－６ The alkyl may be further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2; 2. The pharmaceutical formulation of claim 1, wherein x and y are each independently 1, 2, or 3.

5. The compound of formula I is selected from: 【Chemistry 17】 During the ceremony, R ０ is H, C １－６ alkyl, or cyclopropyl, １－６ The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, [Chemistry 18] or pyridyl, and R １ may further include D, halogen, cyano, hydroxyl, C １－６ Alkyl, and C １－６ may be substituted with one or two substituents selected from alkoxy; R １ｂ is H, OH, cyano, or hydroxyl substituted C １－６ is alkyl; R ２ａ and R ２ｂ are each independently H, C １－６ alkyl, or 3- to 5-membered cycloalkyl, １－６ The alkyl may be further substituted with one or more substituents selected from D or halogen; Or, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O, and S, and further containing C １－６ may be substituted with one or more substituents selected from alkyl, OH, and halogen; R ２ｃ is H, cyano, halogen, or C １－６ is an alkoxy, １－６ The alkoxy may be substituted with one or more deuterium atoms; R ３ is halogen or C １－６ alkyl, １－６ The alkyl may be further substituted with 1 to 3 substituents selected from D or halogen; m is 0 or 1; n is 0, 1, or 2; 2. The pharmaceutical formulation of claim 1, wherein x and y are each independently 1, 2, or 3.

6. The compound of formula I is selected from: 【Chemistry 19】 During the ceremony, R ０ is H, C １－６ alkyl, or cyclopropyl, １－６ The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R １ is -(CH) ｍ -4- to 7-membered carbocyclyl, -(CH) ｍ -4- to 7-membered heterocyclyl, -(CH) ｍ -8- to 12-membered bridged ring, -(CH) ｍ -7 to 12-membered spiro ring, and the -(CH) ｍ -4- to 7-membered carbocyclyl, -(CH) ｍ -4- to 7-membered heterocyclyl, -(CH) ｍ -8 to 12-membered bridged ring, or -(CH) ｍ The 7- to 12-membered spiro ring may further include hydroxy, cyano, halogen, ═O, C １－６ Alkyl, C １－６ Alkoxy and hydroxy substituted C １－６ may be substituted with one or more substituents selected from alkyl; 2. The pharmaceutical formulation of claim 1, wherein m is 0 or 1.

7. In the compounds of formula I, R ０ is H, C １－６ alkyl, or cyclopropyl, １－６ The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 20】 or pyridyl, and R １ may further include D, halogen, cyano, hydroxyl, C １－６ Alkyl, and C １－６ may be substituted with one or two substituents selected from alkoxy; R １ａ is H or C １－６ is alkyl; R １ｂ is H, OH, cyano, or hydroxyl substituted C １－６ is alkyl; m is 0 or 1; 7. The pharmaceutical formulation of claim 6, wherein x and y are each independently 1, 2, or 3.

8. In the compounds of formula I, R ０ is C １－４ alkyl, １－４ The alkyl may be further substituted with one or more substituents selected from halogen and deuterium; R １ teeth 【Chemistry 21】 8. The pharmaceutical formulation of claim 7, wherein:

9. The compounds of formula I are as follows: 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 【Chemistry 22-4】 【Chemistry 22-5】 2. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is selected from the group consisting of:

10. 10. The pharmaceutical formulation of any one of claims 1 to 9, comprising the compound of formula I in the following dosages: 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, or 900-1000 mg.

11. 10. A pharmaceutical formulation of an imidazolinone compound, the pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the imidazolinone compound is selected from the compounds of formula I defined in any one of claims 1 to 9, and the content of the imidazolinone compound in the pharmaceutical formulation is 1 to 90 parts by weight.

12. 12. The pharmaceutical formulation of claim 11, wherein the content of the imidazolinone compound in the pharmaceutical formulation is 1 to 5 parts, 5 to 10 parts, 10 to 15 parts, 15 to 20 parts, 20 to 25 parts, 25 to 30 parts, 30 to 35 parts, 35 to 40 parts, 40 to 45 parts, 45 to 50 parts, 50 to 55 parts, 55 to 60 parts, 60 to 65 parts, 65 to 70 parts, 70 to 75 parts, 75 to 80 parts, 80 to 85 parts, or 85 to 90 parts; optionally further, the content of the imidazolinone compound in the pharmaceutical formulation is 27.8 parts or 41.7 parts.

13. 12. The pharmaceutical formulation of claim 11, wherein the dosage form of the pharmaceutical formulation is selected from granules, tablets, capsules, pills, or micropellets.

14. 12. The pharmaceutical formulation of claim 11, further comprising one or more of a diluent, a disintegrant, and a glidant, wherein, in parts by weight, the content of the diluent in the pharmaceutical formulation is 10-85 parts; the content of the disintegrant is 3-70 parts; and the content of the glidant is 0.1-30 parts.

15. In the pharmaceutical preparation, the content of the diluent is 10 to 15 parts, 15 to 20 parts, 20 to 25 parts, 25 to 30 parts, 30 to 35 parts, 35 to 40 parts, 40 to 45 parts, 45 to 50 parts, 50 to 55 parts, 55 to 60 parts, 60 to 65 parts, 65 to 70 parts, 70 to 75 parts, 75 to 80 parts, or 80 to 85 parts; the content of the disintegrant is 3 to 5 parts, 5 to 15 parts, 15 to 20 parts, 20 to 25 parts, 25 to 30 parts, 30 to 35 parts, 35 to 40 parts, 40 to 45 parts, 45 to 50 parts, 50 to 55 parts, 55 to 60 parts, 60 to 65 parts, or 65 to 70 parts; the amount of the glidant is 0.1 to 0.5 parts, 0.5 to 1 part, 1 to 5 parts, 5 to 10 parts, 10 to 15 parts, 15 to 20 parts, 20 to 25 parts, or 25 to 30 parts; Optionally, further, in the pharmaceutical formulation, the content of the diluent is 64.1 parts, 66.7 parts, or 50 parts; the content of the disintegrant is 7 parts, 4.4 parts, or 6.7 parts; and the content of the glidant is 1.6 parts or 1.1 parts.

16. the diluent is selected from one or more of sucrose, xylitol, maltitol, lactitol, hydroxypropyl cellulose, hypromellose, sorbitol, glucose, fructose, corn starch, inorganic salts, microcrystalline cellulose, starch, mannitol, lactose, and pregelatinized starch, preferably one or more of microcrystalline cellulose, mannitol, and pregelatinized starch; the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, carboxymethylcellulose calcium, potato starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose; 15. The pharmaceutical formulation of claim 14, wherein the glidant is selected from one or more of colloidal silica, silica, magnesium silicate, magnesium trisilicate, polysilicates, hydrated silica, calcium phosphate, and talc.

17. A process for preparing a pharmaceutical formulation of an imidazolinone compound according to any one of claims 1 to 16, comprising the steps of: preparing a mixture of an imidazolinone compound, a disintegrant, and a diluent; and mixing a glidant with the mixture, and then formulating it into tablets, capsules, or granules.

18. The preparation method, After mixing the glidant with the mixture, the resulting mixture is placed in a granulator to be granulated and then prepared into tablets, capsules, or granules; or, The method according to claim 17, wherein the mixture contains 50 to 80% by weight of the diluent in a prescribed amount; the mixture is mixed in a mixer and then granulated in a granulator to obtain mixed particles; a glidant and the remaining prescribed amount of the diluent are added to the mixed particles, mixed in a mixer, and then prepared into tablets, capsules, or granules.

19. Use of a pharmaceutical formulation of an imidazolinone compound according to any one of claims 1 to 16 in the preparation of a medicament for treating and / or preventing cancer.

20. 17. Use of a pharmaceutical formulation in the preparation of a medicament for treating and / or preventing cancer, said use being carried out by administering to a subject a medicament comprising the pharmaceutical formulation of any one of claims 1 to 16; optionally further comprising orally administering the medicament; and optionally further comprising orally administering the medicament 1 to 4 times daily.

21. 10. A pharmaceutical formulation of an imidazolinone compound, said pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein said imidazolinone compound is selected from a compound of Formula I as defined in any one of claims 1 to 9, and wherein said compound of Formula I is present in an amount to provide a daily dose of 1 to 1000 mg, said daily dose being administered in single or multiple doses.

22. 22. The pharmaceutical formulation of claim 21, wherein the imidazolinone compound is present in an amount to provide a daily dose of 1 to 10 mg, 10 to 20 mg, 20 to 50 mg, 50 to 100 mg, 100 to 150 mg, 150 to 200 mg, 200 to 250 mg, 250 to 300 mg, 300 to 350 mg, 350 to 400 mg, 400 to 450 mg, 450 to 500 mg, 500 to 600 mg, 600 to 700 mg, 700 to 800 mg, 800 to 900 mg, or 900 to 1000 mg.

23. 10. A pharmaceutical formulation of an imidazolinone compound, the pharmaceutical formulation comprising an imidazolinone compound, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the imidazolinone compound is selected from a compound of formula I as defined in any one of claims 1 to 9, and the compound of formula I is present in an amount to provide a daily dose of 1 to 1000 mg / 60 kg.

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