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EP-4740965-A1 - PHARMACEUTICAL COMPOSITION OF COMPOUND FOR INHIBITING AND DEGRADING IRAK4, AND USE THEREOF IN MEDICINE

EP4740965A1EP 4740965 A1EP4740965 A1EP 4740965A1EP-4740965-A1

Abstract

A pharmaceutical composition of a compound for inhibiting and degrading IRAK4, and the use thereof in medicine. The pharmaceutical composition comprises an active ingredient A and a pharmaceutically acceptable excipient, wherein the active ingredient A is selected from the compound as represented by general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or an eutectic crystal thereof. The pharmaceutical composition comprises 0.5-800 mg of the active ingredient A, and the content of the active ingredient A is selected from 0.5%-99.0%. The present invention also relates to the use of the pharmaceutical composition in the preparation of a relevant drug for treating tumours or autoimmune system diseases. B-L-K (I).

Inventors

  • LI, XIAOPING
  • GUAN, Lin
  • XU, Zaiyang
  • BI, Xianshuang

Assignees

  • Xizang Haisco Pharmaceutical Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240704

Claims (14)

  1. A pharmaceutical composition, characterised in that the pharmaceutical composition comprises an active ingredient A and a pharmaceutically acceptable excipient, and the active ingredient A is selected from a compound as represented by general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or an eutectic crystal thereof, B-L-K (I); wherein L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, O, -(CH 2 ) q NR L -, NR L C=O, C=ONR L , C=O, -R L C=CR L -, C=C or a bond; R L is selected from H or C 1-6 alkyl; Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, 4- to 7-membered mono-heterocyclic ring, 4- to 10-membered fused-heterocyclic ring, 5-to 12-membered spiro-heterocyclic ring, 7- to 10-membered bridged-heterocyclic ring, 3- to 7-membered monocycloalkyl, 4- to 10-membered fused cycloalkyl, 5- to 12-membered spiro cycloalkyl, 7- to 10-membered bridged cycloalkyl, 5- to 10-membered heteroaryl or 6- to 10-membered aryl, wherein the aryl, heteroaryl, cycloalkyl, mono-heterocyclic ring, fused-heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C(=O)OH, CN, NH 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy, and the heteroaryl, mono-heterocyclic ring, fused-heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, or N; B is selected from B1 and B3 are each independently selected from C 6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl, wherein the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S or N; R b1 and R b7 are each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , CN, CF 3 , C(=O)OH, CHF 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -(CH 2 ) n -R b21 , -OR b21 , -N(R b21 ) 2 , C 6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, CF 3 , C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl or R b7a , and the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, or N; R b7a is selected from C 1-4 alkyl, -C 3-6 cycloalkyl, 4- to 10-membered heterocyclyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene 4- to 10-membered heterocyclyl, -O-C 3-6 cycloalkyl, -O-4- to 10-membered heterocyclyl, -NH-C 3-6 cycloalkyl, -NH-4- to 10-membered heterocyclyl, -N(C 1-4 alkyl)-C 3-6 cycloalkyl or -N(C 1-4 alkyl)-4- to 10-membered heterocyclyl, wherein the R b7a is optionally substituted with 1 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, - N(R b21 ) 2 , CN, CF 3 , C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4- to 10-membered heterocyclyl, and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, or N; R b2 and R b6 are each independently selected from H, F, Cl, Br, I, =O, OH, - C(=O)N(R b21 ) 2 , -N(R b21 ) 2 , CN, CF 3 , C(=O)OH, CHF 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -(CH 2 ) n -R b21 , -OR b21 , C 6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl, and the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, or N; each R b21 is independently selected from H, C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , C(=O)OH, C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkoxy, and the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, or N; n is selected from 0, 1, 2, 3 or 4; K is selected from each R k1 is independently selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; R k2 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, C(=O)OH, C(=O)NH 2 , C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, or NH 2 ; or two R k3 together with the carbon atoms or ring backbones to which they are directly attached form 3- to 6-membered carbocycle or 3- to 7-membered heterocycle, wherein the carbocycle or heterocycle is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, C(=O)OH, C(=O)NH 2 , C 1-4 alkyl or C 1-4 alkoxy, and the heterocycle contains 1 to 4 heteroatoms selected from O, S or N; q is selected from 0, 1, 2, 3 or 4; n1, n2 and n6 are each independently selected from 0, 1, 2 or 3; p2 and p3 are each independently selected from 0, 1, 2, 3 or 4; optionally, 0 to 50 H of the compound as represented by general formula (I) are replaced by 0 to 50 D; the pharmaceutical composition comprises 0.5-800 mg of the active ingredient A; the content of the active ingredient A is selected from 0.5%-99.0%.
  2. The pharmaceutical composition according to claim 1, characterised in that the active ingredient A is selected from a compound as represented by general formula (II) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or an eutectic crystal thereof, wherein R 1 is selected from CF 3 , CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 OMe, CH 2 CN, or CH 2 -cyclopropyl.
  3. The pharmaceutical composition according to claim 1 or 2, characterised by comprising 1-600 mg of the active ingredient A, preferably 1-400 mg of the active ingredient A, further preferably 5-350 mg of the active ingredient A, and further preferably 10-200 mg of the active ingredient A.
  4. The pharmaceutical composition according to claim 3, characterised by comprising 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, 75 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg of the active ingredient A.
  5. The pharmaceutical composition according to claim 1, characterised in that the pharmaceutical composition comprises the active ingredient A and a pharmaceutically acceptable excipient, the active ingredient A is selected from the compound as represented by general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or an eutectic crystal thereof, and the structure of the compound as represented by general formula (I) is selected from one of the structures shown in Table S-1.
  6. The pharmaceutical composition according to claim 1, characterised in that the structure of the compound as represented by general formula (I) is selected from the following structures:
  7. The pharmaceutical composition according to claim 1, characterised in that the pharmaceutically acceptable excipient contains one or both of a solubilizer or a solid dispersion carrier.
  8. The pharmaceutical composition according to claim 7, characterised in that the solid dispersion carrier is selected from polymer carriers, preferably one or more of hydroxypropyl methylcellulose derivatives, ethyl celluloses, methyl celluloses, hydroxypropyl methylcellulose acetate succinate, povidones, copovidone, polyethylene glycols with an average molecular weight of not less than 1000, hydroxypropyl cellulose, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft polymers, polyacrylic resin, hydroxypropyl methylcellulose phthalate, or polyvinyl alcohol, and more preferably one or more of copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, Eudragit, hydroxypropyl methylcellulose acetate succinate (HPMCAS), or hydroxypropyl methylcellulose phthalate (HPMCP); the solid dispersion carrier is further preferably Eudragit, hydroxypropyl methylcellulose phthalate (HPMCP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS), the weight ratio of the active ingredient A to the solid dispersion carrier is 1 : 0.01-1 : 100, preferably 1 : 0.5-1 : 10, and further preferably 1 : 1-1 : 6; optionally, the content of the solid dispersion in the pharmaceutical composition is 10%-100%, preferably 15%-65%, and further preferably 20%-60%.
  9. The pharmaceutical composition according to claim 7, characterised in that the solubilizer is selected from one or more of anionic surfactant, cationic surfactant, zwitterionic surfactant, nonionic surfactant, polymeric surfactant or cyclodextrin, the solubilizer is preferably sodium lauryl sulphate (SLS), vitamin E polyethylene glycol succinate (TPGS), polyethylene glycol and a derivative thereof, cyclodextrin or polyoxyethylene hydrogenated castor oil, and the weight ratio of the active ingredient A to the solubilizer is 1 : 0.01-1 : 100, preferably 1 : 0.05 -1 : 30, and further preferably 1 : 0.1-1 : 20.
  10. The pharmaceutical composition according to any one of claims 8-9, characterised by further comprising a pharmaceutically acceptable excipient.
  11. The pharmaceutical composition according to claim 10, characterised in that the pharmaceutically acceptable excipient further comprises one or more of a filler, a disintegrant, a binder, a suspending agent, an antioxidant, a colorant, a flavouring agent, a glidant, and a lubricant.
  12. The pharmaceutical composition according to claim 11, characterised in that : the filler is selected from one or more of lactose, microcrystalline cellulose, sucrose, glucose, powdered cellulose, calcium phosphate, dicalcium phosphate, calcium carbonate, aluminium silicate, dextrin, starch (including corn starch, potato starch or amylopectin), pregelatinized starch, sodium chloride, potassium chloride, mannitol or sorbitol, preferably one or more of lactose, microcrystalline cellulose, dicalcium phosphate, pregelatinized starch, or mannitol, and more preferably one or more of lactose, microcrystalline cellulose, dicalcium phosphate, or mannitol; the disintegrant is selected from one or more of starch, pregelatinized starch, carboxymethyl starch sodium, crospovidone, and croscarmellose sodium, preferably one or more of carboxymethyl starch sodium, crospovidone, and croscarmellose sodium, and more preferably crospovidone and croscarmellose sodium; the binder is selected from one or more of starch slurry, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, arabic gum, gelatine, guar gum or carbomer, preferably one or more of povidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose, and more preferably one or more of povidone, hydroxypropyl methylcellulose E3, or hydroxypropyl methylcellulose E5; the suspending agent is selected from one or more of arabic gum, tragacanth gum, xanthan gum, peach gum, sodium alginate, agar, starch slurry, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, povidone, dextran, aluminium monostearate, or aluminium silicate, preferably one or more of xanthan gum, sodium alginate, methyl cellulose or hydroxypropyl cellulose, more preferably xanthan gum or hydroxypropyl cellulose; the antioxidant is selected from one or more of butylated hydroxyanisole, dibutyl hydroxy toluene, propyl gallate, anhydrous sodium sulphite, sodium pyrosulphite, sodium thiosulphate, chelating agent, α-tocopherol, thioglycerol, or sodium hydrogen sulphite, preferably one or more of butylated hydroxyanisole, dibutyl hydroxy toluene, α-tocopherol, or sodium thiosulphate, and more preferably one or more of butylated hydroxyanisole, dibutyl hydroxy toluene, or α-tocopherol; the colorant is selected from one or more of iron oxide yellow, iron oxide red, pigments, and lakes, preferably one or more of iron oxide yellow, iron oxide red, lemon yellow, carminum, and blue aluminium lake, and more preferably iron oxide yellow and iron oxide red; the flavouring agent is selected from one or more of stevioside, meringue, xylitol, high fructose, sodium cyclohexyl sulphamate, aspartame, neotame or sucralose, preferably aspartame or sucralose; the glidant is selected from one or more of talc, colloidal silicon dioxide, polyethylene glycol, or magnesium lauryl sulphate, preferably colloidal silicon dioxide; and the lubricant is selected from one or more of stearic acid, magnesium stearate, or sodium stearyl fumarate, preferably magnesium stearate or sodium stearyl fumarate.
  13. The pharmaceutical composition according to claim 1, characterised in that the pharmaceutical formulation form prepared with the pharmaceutical composition is selected from a tablet, a granule, a capsule, a dry suspension, a powder, and an oral solution.
  14. Use of the pharmaceutical composition according to any one of claims 1-13 in the preparation of a relevant drug for treating tumours or autoimmune system diseases.

Description

Technical Field The present invention belongs to the field of pharmaceutical formulations, and in particular relates to a pharmaceutical composition, which comprises a therapeutically effective amount of an active ingredient A and a pharmaceutically acceptable excipient, wherein the active ingredient A is selected from a compound as represented by general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or an eutectic crystal thereof; and the pharmaceutical composition comprises 0.5-800 mg of the active ingredient A, and the content of the active ingredient A is selected from 0.5%-99.0%. The present invention also relates to the use of the pharmaceutical composition in the preparation of a relevant drug for treating tumours or autoimmune system diseases. Background Art Kinases catalyse the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites and play key roles in various aspects of physiology in eukaryotic cells. In particular, protein kinases and lipid kinases are involved in controlling the activated signal events in cells for growth, differentiation and survival in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. In general, protein kinases are divided into two classes, one that preferentially phosphorylates tyrosine residues and the other that preferentially phosphorylates serine and/or threonine residues. Interleukin-1 receptor kinase 4 (IRAK4) is a serine/threonine-specific protein kinase that belongs to the tyrosine-like kinase (TLK) family and is a key factor in the innate immune response involving interleukin-1, interleukin-18, and interleukin-33 receptors and Toll-like receptors. After extracellular signal molecules bind to interleukin receptors or Toll-like receptors, they are recruited to form a MyD88:IRAK4:IRAKl/2 multiprotein complex, leading to the phosphorylation of IRAK1/2 and mediating a series of downstream signallings, thereby activating the p38, JNK and NF-kB signalling pathways, and ultimately leading to the expression of pro-inflammatory cytokines. Clinical pathological studies have shown that individuals with IRAK4 mutations are protected against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal; individuals survive to adulthood and their risk of infection decreases with age. Therefore, IRAK4 has become an important therapeutic target and has attracted widespread research and development interest. PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind targeting proteins and E3 ubiquitin ligases. Such compounds can be recognized by proteasomes of cells, causing the degradation of targeting proteins, and can effectively reduce the content of targeting proteins in the cells. By introducing a ligand capable of binding to various targeting proteins into the PROTAC molecules, it is possible to apply the PROTAC technology to the treatment of various diseases, and this technology has attracted extensive attention in recent years. Therefore, it is necessary to develop a novel IRAK4 inhibitor and a PROTAC drug of E3 ubiquitin ligase for the treatment of IRAK4-related diseases. The patent PCT/CN2023/070367 recites compounds 19, 20, 24, and 25, which have good IRAK4 inhibitory or degrading activity. When the compound is used as a therapeutic agent for treating humans, the administration of a therapeutically effective dose becomes problematic and may lead to toxic side effects or ineffective therapy. Therefore, it is essential to develop a pharmaceutical composition or a pharmaceutical formulation with good safety, effectiveness and stability. Summary of the Invention The objective of the present invention relates to a pharmaceutical composition, which comprises an active ingredient A and a pharmaceutically acceptable excipient, wherein the active ingredient A is selected from a compound as represented by general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or an eutectic crystal thereof. The present invention also relates to the use of the pharmaceutical composition in the preparation of a relevant drug for treating tumours or autoimmune system diseases. The pharmaceutical composition of the present invention has stable quality, a high dissolution rate, good absorption, low irritation, and good safety, and is orally absorbable. The present invention relates to a pharmaceutical composition, which comprises a therapeutically effective amount of an active ingredient A and a pharmaceutically acceptable excipient. The pharmaceutical composition can be in a unit formulation form. The present invention relates to a pharmaceutical composition, which comprises an active ingredient A and a pharmaceutically acceptable excipient, wherein the activ