Salts of IRAK4 degrader
The adipate and malonate salts of compound (I) address the formulation challenges of IRAK4 degraders, offering stable and effective treatments for autoimmune and autoinflammatory diseases by degrading IRAK4 protein.
Patent Information
- Application Number
- PCT/US2025/024755
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-04-16
- Filing Date
- 2025-04-15
- Publication Date
- 2025-10-23
AI Technical Summary
Existing formulations of IRAK4 degraders, such as compound (I), face challenges in being easily formulated into pharmaceutical compositions and medicaments, and there is a need for effective treatments for autoimmune and autoinflammatory diseases like atopic dermatitis and hidradenitis suppurativa.
Development of adipate and malonate salts of compound (I), which are easily crystallized and formulated into pharmaceutical compositions, providing a therapeutically effective treatment for autoimmune and autoinflammatory diseases by degrading IRAK4 protein.
The adipate and malonate salts of compound (I) demonstrate good crystallization characteristics, chemical stability, and physical stability, enabling their use in medicaments for treating autoimmune and autoinflammatory diseases effectively.
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Abstract
Description
SALTS OF IRAK4 DEGRADER
[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 634,568, filed April 16, 2024, the disclosure of which is hereby incorporated herein by reference in its entirety.
[0002] The present application relates to salt forms of an IRAK4 degrader.
[0003] Herein are provided salts of 5-((1 R, 4R)-2-oxa-5-azabicyclo [2.2.1 ]heptan-5-yl)-N-(3-( difluoromethyl)-1-((1 r, 4R)-4-((4-((3-(1 -(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 Hbenzo[d]imidazol-4-yl)prop- 2-yn-1 -yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)-1 H-pyrazol-4-yl)pyrazolo[1 ,5- a]pyrimidine-3-carboxamide, hereafter designated as salts of compound (I).
[0004] Herein are also provided processes for the preparation of salts of compound (I), and their use as a medicine, and particularly in the treatment of autoimmune and autoinflammatory diseases.
[0005] Compound (I), depicted below is an IRAK4 (lnterleukin-1 receptor-associated kinase-4 ) degrader. It may be used in particular as a pharmaceutically active agent.
[0006] IRAK4 is a cytosolic kinase involved in the innate immunity and in the inflammatory responses following activation by pathogens. Moreover, the overactivation of IRAK4 is linked to several auto immune and inflammatory diseases.
[0007] The IRAK4 protein is ubiquitously expressed across multiple different tissue types, including skin, lymphoid tissue, bone marrow, gastrointestinal (Gl) tract and lung. The function of IRAK4 is dependent both on its kinase activity and on its scaffolding properties.
[0008] IRAK4 degraders allow to both degrade the IRAK4 protein and inhibit its scaffolding function.
[0009] Compound (I) and processes for its preparation are disclosed in the application W02020 / 113233.
[0010] WO2021 / 247897 discloses several salts of compound (I) and their crystalline forms.
[0011] There is a need to provide salts of compound (I) which can be easily formulated into pharmaceutical compositions and medicaments.
[0012] Herein is provided a salt of the adipic (or hexanedioic) acid of compound (I), also called adipate salt of compound (I).
[0013] Herein are also provided crystalline forms of the adipate salt of compound (I).
[0014] Herein are further provided processes for the preparation of the adipate salt of compound (I).
[0015] Herein are also provided medicaments comprising the adipate salt of compound (I), and pharmaceutical compositions comprising the adipate salt of compound (I) and at least one pharmaceutically acceptable excipient.
[0016] Herein are further disclosed the adipate salt of compound (I) for use as a medicine, for use as a degrader of IRAK4, and for use in the treatment of various diseases wherein IRAK4 is involved, more particularly autoimmune and autoinflammatory diseases, for example atopic dermatitis and hidradenitis suppurativa.
[0017] Herein is further disclosed the use of the adipate salt of compound (I) for the manufacture of a medicament for treating a disease involving IRAK4, more particularly autoimmune and autoinflammatory diseases, for example atopic dermatitis and hidradenitis suppurativa.
[0018] Herein is further disclosed the use of the adipate salt of compound (I) for the manufacture of a medicament for treating autoimmune and / or autoinflammatory diseases, in particular atopic dermatitis and hidradenitis suppurativa.
[0019] Herein is further disclosed a method of treating a disease involving IRAK4, more particularly autoimmune and autoinflammatory diseases, for example atopic dermatitis and hidradenitis suppurativa, comprising administering to a subject in need thereof a therapeutically effective amount of the adipate salt of compound (I).
[0020] Herein is further disclosed a method of treating autoimmune and autoinflammatory diseases, in particular atopic dermatitis and hidradenitis suppurativa, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of the adipate salt of compound (I).
[0021] Herein is also provided a salt of the malonic (or propanedioic) acid of compound (I), also called malonate salt of compound (I).
[0022] Herein is also provided a crystalline form of the malonate salt of compound (I).
[0023] Herein are further provided processes for the preparation of the malonate salt of compound (I).
[0024] Herein are also provided medicaments comprising the malonate salt of compound (I), and pharmaceutical compositions comprising the malonate salt of compound (I) and at least one pharmaceutically acceptable excipient.
[0025] Herein are further disclosed the malonate salt of compound (I) for use as a medicine, for use as a degrader of IRAK4, and for use in the treatment of various diseases wherein IRAK4 is involved, more particularly autoimmune and autoinflammatory diseases, for example atopic dermatitis and hidradenitis suppurativa.
[0026] Herein is further disclosed the use of the malonate salt of compound (I) for the manufacture of a medicament for treating a diseaseinvolving IRAK4, more particularly autoimmune and autoinflammatory diseases, for example atopic dermatitis and hidradenitis suppurativa.
[0027] Herein is further disclosed the use of the malonate salt of compound (I) for the manufacture of a medicament for treating autoimmune and / or autoinflammatory diseases, in particular atopic dermatitis and hidradenitis suppurativa.
[0028] Herein is further disclosed a method of treating a disease involving IRAK4, more particularly autoimmune and autoinflammatory diseases, for example atopic dermatitis and hidradenitis suppurativa, comprising administering to a subject in need thereof a therapeutically effective amount of the malonate salt of compound (I).
[0029] Herein is further disclosed a method of treating autoimmune and autoinflammatory diseases, in particular atopic dermatitis and hidradenitis suppurativa, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of the malonate salt of compound (I).Figures
[0030] FIG. 1 depicts an XRPD pattern of Form A of the adipate salt of compound (I).
[0031] FIG. 2 depicts a DSC thermogram of Form A of the adipate salt of compound (I).
[0032] FIG. 3 depicts a TGA spectrum of Form A of the adipate salt of compound (I).
[0033] FIG. 4 depicts an XRPD pattern of Form B of the adipate salt of compound (I).
[0034] FIG. 5 depicts a DSC thermogram of Form B of the adipate salt of compound (I).
[0035] FIG. 6 depicts a TGA spectrum of Form B of the adipate salt of compound (I).
[0036] FIG. 7 depicts an XRPD pattern of Form A of the malonate salt of compound (I).
[0037] FIG. 8 depicts an DSC thermogram of Form A the malonate salt of compound (I).
[0038] FIG. 9 depicts a TGA spectrum of Form A of the malonate salt of compound (I).
[0039] Fig 10 depicts a 1 H-NMR spectrum of the adipate salt of compound (I).
[0040] Fig 11 depicts a 1 H-NMR spectrum of the malonate salt of compound (I).Preparation
[0041] Adipate salt of compound (I) can be prepared in a salt formation reaction, by reacting the compound (I) in its free base form with adipic acid in a solvent.
[0042] Malonate salt of compound (I) can be prepared in a salt formation reaction, by reacting the compound (I) in its free base form with malonic acid in a solvent.
[0043] The examples which follow describe the preparation of the adipate and malonate salts of the compound (I).
[0044] Compound (I) can be prepared according to one of the processes described in W02020 / 113233.Adipate salt
[0045] Into a 250-mL double-jacketed vessel was placed crude compound (I) (15g, 17.333 mmol), 8.5V tetrahydrofuran (THF) corresponding to 127.5ml. The resulting suspension was stirred, with an impeller at a P / V of 120W / m3 and heated to 30°C for a complete dissolution. A solution of adipic acid (2.786g, 19.063mmol) in 1.5V (with regards to compound (I) base) of THF (corresponding to 22.5ml) was prepared by heating at 45°C to observe the total dissolution and cooled to ambient temperature before a slow additionto the base solution at 30°C. A the end of the addition the solution is cooled to 5°C with a cooling ramp of -10°C / h and hold in isotherm during 12hours.
[0046] The final suspension obtained was then filtered on sintered porosity 4, washed with 1 .7 volumes of THF (26ml) (with regards to compound (I) base) and two times with 1 .7 volumes of Acetone (26ml) (with regards to compound (I) base). The powder was then dried in a static oven under vacuum at 50°C for one night and again for 6h at 65°C under vacuum.
[0047] Compound (I) adipate salt was obtained as a white powder.
[0048] 1 H-NMR in solution, Fig 10, shows a stoichiometry 1 / 1 between adipic acid and compound (I).
[0049] The final yield of crystallization is close to 85%.
[0050] Two different crystalline forms were identified: Form A and Form B.Malonate salt
[0051] Into a 100-mL double-jacketed vessel was placed crude compound (I) (13g, 15.022 mmol), 8V THF corresponding to 104ml. The resulting suspension was stirred, with an impeller at a P / V of 120W / m3 (551 rpm) and maintained at 20°C. A solution of malonic acid (1.72g, 16.525mmol) in 2V (with regards to the compound (I) base) of THF (corresponding to 26ml) was added at 20°C to the solution of base at a flowrate of 1 ,6g / min.
[0052] The suspension obtained, maintained at 20°C for one hour was then filtered on sintered porosity 4, washed with 2 volumes of THF (with regards to compound (I) base). The powder was then dried in a static oven under vacuum at 50°C under vacuum.
[0053] Compound (I) malonate salt was obtained as a white powder.1 H-NMR in solution, Fig 11 shows a stoichiometry 1 / 1 between malonic acid and compound (I).
[0054] The final yield of crystallization was close to 90%.
[0055] One crystalline form, Form A, was identified.TESTSDefinitions:
[0056] As used herein, “a” or “an” entity refers to one or more of that entity, e.g., “a compound” refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more,” and “at least one” are used interchangeably herein.
[0057] As used herein, the term “about” or “substantially as shown in” means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 5%.
[0058] As used herein, “Compound (I)” refers to 5-((1 R, 4R)-2-oxa-5- azabicyclo [2.2.1 ]heptan-5-yl)-N-(3-( difluoromethyl)-1-((1 R, 4R)-4-((4-((3-(1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 Hbenzo[d]imidazol-4- yl)prop-2-yn-1 -yl)oxy)piperidin-1 -yl)methyl)cyclohexyl)-1 H-pyrazol-4- yl)pyrazolo[1 ,5-a]pyrimidine-3-carboxamide.
[0059] Herein, Compound (I) may be referred to as a “drug,” “active agent,” “a therapeutically active agent,” or a “API.”
[0060] The term “crystalline” refers to any solid substance exhibiting three- dimensional order, which in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with more or less sharp peaks.
[0061] As used herein, a “pharmaceutically acceptable excipient” refers to a carrier or an excipient that is useful in preparing a pharmaceutical composition. For example, a pharmaceutically acceptable excipient is generally safe and includes carriers and excipients that are generally considered acceptable for mammalian pharmaceutical use.
[0062] As used herein, the terms “polymorph,” “crystal form,” “crystalline form,” and “Form” interchangeably refer to a solid having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by at least onecharacterization technique including, e.g., X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of this disclosure are characterized by an X-ray powder diffractogram having at least one signal at least one specified two-theta value (e20).
[0063] Characterizations and some properties of the herein described salts are detailed below.
[0064] As used herein, the term “DSC” refers to the analytical method of differential scanning calorimetry.
[0065] As used herein, the term “TGA” refers to the analytical method of thermogravimetric analysis.
[0066] As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.
[0067] As used herein, the term “NMR” refers to the analytical method of Nuclear magnetic resonance. NMR analyses were performed using a 400 MHz NMR spectrometer (NMR6).DSC
[0068] A differential thermodynamic analysis was carried out on the crystalline forms of salts of compound (I), using a TA Instruments Q2000.
[0069] Form A of the adipate salt of compound (I) shows a melting endotherm at about 224.1 °C onset, as shown in Fig 2.
[0070] Form B of the adipate salt of compound (I) shows a melting endotherm at about 229.5°C onset, as shown in Fig 5.
[0071] Form A of the malonate salt of compound (I) shows a melting endotherm at about 182.6 °C onset, as shown in Fig 8.XRPD
[0072] Crystalline forms of both adipate and malonate salts of compound (I) were analyzed by XRPD, using a Bruker D8 Discover (Cu). The Bruker D8 Discover uses Cu a radiation of wavelength 1 .5406 A.
[0073] In Fig 1 , the XRPD pattern of adipate salt of compound (I) Form A shows peaks at 5.8, 6.1 , 11 .7 and 16,9 ±0.2 degree 2-theta. Accordingly, provided herein is an adipate salt of compound (I) Form A having an x-ray powder diffraction pattern comprising peaks at 5.8, 6.1 , 11.7 and 16,9 ±0.2 degree 2-theta as measured using an x-ray wavelength of 1 .5406 A.
[0074] In Fig 4, the XRPD pattern of adipate salt of compound (I) Form B shows peaks at 6.4, 10.7, 12.7, 15.9, 17.7 and 21.1 ±0.2 degree 2-theta. Accordingly, provided herein is an adipate salt of compound (I) Form B having an x-ray powder diffraction pattern comprising peaks at 6.4, 10.7, 12.7, 15.9, 17.7 and 21 .1 ±0.2 degree 2-theta as measured using an x-ray wavelength of 1 .5406 A.
[0075] In Fig 7, the XRPD pattern of malonate salt of compound (I) Form A shows peaks at 6.5, 11 .9 and 14.0 ±0.2 degree 2-theta. Accordingly, provided herein is a malonate salt of compound (I) Form A having an x-ray powder diffraction pattern comprising peaks at 6.5, 11 .9 and 14.0 ±0.2 degree 2-theta as measured using an x-ray wavelength of 1 .5406 A.TGA
[0076] Crystalline forms of both adipate and malonate salts of compound (I) were analyzed by TGA using a TA Istruments Q500.
[0077] Fig 3 shows that for the adipate salt of compound (I) Form A, degradation starts at around 150°C.
[0078] Fig 6 shows that for the adipate salt of compound (I) Form B, degradation starts at around 200°C.
[0079] Fig 9 shows that for the malonate salt of compound (I) Form A, degradation starts at around 100°C.Crystallization characteristics:
[0080] Several characteristics of the crystallization of the adipate and malonate salts of compound (I) in THF solvent were analyzed.
[0081] The results are described in the table below.Table 1
[0082] In the light of the results above, it is found that both adipate and malonate salts of compound (I) have good crystallization characteristics in the tested solvent.
[0083] In particular, the crystallization of the adipate and malonate salts of compound (I) is quick, with a good yield and the obtained product is easily filtrated.
[0084] Thus, these results demonstrate the good crystallization processability of the adipate and malonate salts of compound (I).Chemical stability
[0085] The sum of impurities > 0.05 % present in powders of the adipate and malonate salts of compound (I) was measured after two and four weeks of storage.
[0086] The results are described in the table below.*RH relative humidityTable 2
[0087] In the light of the results obtained above, it is found that the adipate and malonate salts of compound (I) are chemically stable under the effect of heat and humidity under the tested conditions.Physical stability.
[0088] The adipate and malonate salts of compound (I) were analyzed after two and four weeks of storage at: - 50° C- 50°C and under saturated humidity (75% RH),
[0089] The results are described in the table below.Table 3
[0090] In the light of the results obtained above, it is found that the adipate and malonate salts of compound (I) are physically stable under the effect of heat and humidity under the tested conditions. Test of solubility
[0091] The solubility of hydrochloride, adipate and malonate salts compound (I) was analyzed under different pH conditions.
[0092] The physicochemical properties of the above-described salts of compound (I) allow them to be easily processed and formulated.
Claims
CLAIMS.1 . Adipate salt of compound (I)Compound (I)2. The adipate salt of compound (I) according to claim 1 , wherein said salt is crystalline.
3. The adipate salt of compound (I) according to any one of claim 1 or 2, characterized by one or more peaks in its XRPD pattern selected from those at 5.8, 6.1 , 11 .7 and 16,9 ±0.2 degree 2-theta.
4. The adipate salt of compound (I) according to any one of claim 1 or 2, characterized by one or more peaks in its XRPD pattern selected from those at 6.4, 10.7, 12.7, 15.9, 17.7 and 21 .1 ±0.2 degree 2-theta.
5. Process for the preparation of the adipate salt of compound (I) as defined in anyone of claims 1 to 4 wherein the free base form compound (I) is reacted with adipic acid in a solvent.
6. A medicament, characterized in that it comprises the adipate salt of compound (I) as defined in anyone of claims 1 to 4.
7. Pharmaceutical composition comprising the adipate salt of compound (I) as defined in anyone of claims 1 to 4, and at least one pharmaceutically acceptable excipient.
8. The adipate salt of compound (I) as defined in anyone of claims 1 to 4 for use as a medicine.
9. The adipate salt of compound (I) as defined in anyone of claims 1 to 4 for use in the treatment of autoimmune or autoinflammatory diseases.10 The adipate salt of compound (I) as defined in anyone of claims 1 to 4 for use in the treatment of a disease selected from atopic dermatitis and hidradenitis suppurativa.11 . Malonate salt of compound (I)Compound (I)12. The malonate salt of compound (I) according to claim 11 , wherein said salt is crystalline.
13. The malonate salt of compound (I) according to any one of claim 11 or 12, characterized by one or more peaks in its XRPD pattern selected from those at 6.5, 11 .9 and 14.0 ±0.2 degree 2-theta.
14. Process for the preparation of the malonate salt of compound (I) as defined in anyone of claims 11 to 13, wherein the free base form compound (I) is reacted with adipic malonic acid in a solvent.
15. A medicament, characterized in that it comprises the malonate salt of compound (I) as defined in anyone of claims 11 to 13.
16. Pharmaceutical composition comprising the malonate salt of compound (I) as defined in anyone of claims 11 to 13, and at least one pharmaceutically acceptable excipient.
17. The malonate salt of compound (I) as defined in anyone of claims 11 to 13 for use as a medicine.
18. The malonate salt of compound (I) as defined in anyone of claims 11 to 13 for use in the treatment of autoimmune or autoinflammatory diseases.
19. The malonate salt of compound (I) as defined in anyone of claims 11 to 13 for use in the treatment of a disease selected from atopic dermatitis and hidradenitis suppurativa.
Citation Information
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