EP-4735415-A1 - CALIXARENE COMPOUNDS, THEIR SYNTHESIS AND USE IN PHARMACEUTICAL COMPOSITIONS

EP4735415A1EP 4735415 A1EP4735415 A1EP 4735415A1EP-4735415-A1

Abstract

The invention relates to new compounds of general Formula (I), which can be used in delivery systems for nucleotides. The present invention further relates to pharmaceutical compositions and their use thereof.

Inventors

VANDER STRAETEN, Aurélien
BEVERNAEGIE, Robin
JABIN, IVAN
LAVENDOMME, Roy

Assignees

Phoenix Biosciences SA

Dates

Publication Date: 20260506
Application Date: 20240429

Claims (1)

CLAIMS Formula (I) or a pharmaceutically acceptable salt thereof wherein : R 1 is selected from hydrogen, halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-io haloalkyl, -CN, -OR 20 , -SR 20 , -SF 5 , -NO 2 , -N(R 20) 2 , -C(O)R 20 , - A, D, E, F, G, I, J, K, M, Q, X, and Y are each independently selected from Ci-io alkylene, C2-10 alkenylene, C2-10 alkynylene, wherein the C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene are optionally substituted with one or more substituents independently selected from halogen, C1-10 haloalkyl, - CN, -NO2, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and - S(O) 2 (R 20 ); each R 2 , R 6 , R 8 , is independently selected from C3-10 alkyl, wherein the C3-10 alkyl is substituted with one or more substituents selected from -N(R 20 )2, -N(R 20 ) 3 + , and 3- to 12-membered heterocycle, wherein the 3- to 12- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, Ci-6 alkyl, C1-10 haloalkyl, -CN, -NO2, =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); each R 7 is selected from: C1-2 alkyl, wherein the C1-2 alkyl is substituted with one or more substituents selected from -N(R 20 )2, and 3- to 12-membered heterocycle, wherein the 3- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, Ci- 6 alkyl, Ci-io haloalkyl, -CN, -N0 2 , =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); and C3-10 alkyl, wherein the C3-10 alkyl is substituted with one or more substituents selected from -N(R 20 )2, -N(R 20 )3 + , and 3- to 12-membered heterocycle, wherein the 3- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, Ci- 6 alkyl, Ci-io haloalkyl, -CN, -N0 2 , =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); R 8A is independently selected from hydrogen and C1-10 alkyl, wherein the Ci-10 alkyl is substituted with one or more substituents selected from - N(R 20 )2, -N(R 20 )3 + , and 3- to 12-membered heterocycle, wherein the 3- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, Ci-6 alkyl, C1-10 haloalkyl, -CN, -NO2, =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and - S(O) 2 (R 20 ); each R 11 is independently selected from C3-10 alkyl, wherein the C3-10 alkyl is substituted with one or more substituents selected from -N(R 21 )2, - N(R 21 ) 3 + , and 3- to 12-membered heterocycle, wherein the 3- to 12- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-10 haloalkyl, -CN, -NO2, =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); each R 12 is independently selected from C3-10 alkyl, wherein the C3-10 alkyl is substituted with one or more substituents selected from -N(R 2O )CI-IO alkyl, -N(R 20 ) 3 + , and 3- to 12-membered heterocycle, wherein the 3- to 12- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-10 haloalkyl, -CN, -NO2, =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); each R 12A is independently selected from hydrogen and C1-10 alkyl, wherein the C1-10 alkyl is substituted with one or more substituents selected from -N(R 2O )CI-IO alkyl, -N(R 20 )3 + , and 3- to 12-membered heterocycle, wherein the 3- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-10 haloalkyl, -CN, -N0 2 , =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); each R 3 is independently selected from hydrogen and C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -OR 20 , -N(R 20 )2, - C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); each R 4 is independently selected from C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with one or more substituents selected from 3- to 12-membered saturated heterocycle, wherein the 3- to 12-membered saturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-10 haloalkyl, -CN, -NO2, =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); each R 4A is independently selected from C1-10 alkyl, wherein the C1-10 alkyl is substituted with one or more substituents selected from -OH and - OCi-10 alkyl; wherein when each R 1 is -CH2-N(CH2CH2OH)2, each R 9 is independently selected from R 9A ; each R 5 , R 5A is independently selected from C1-10 alkyl, wherein the Ci- 10 alkyl is substituted with one substituent selected from -OR 20 and 3- to 12- membered heterocycle, wherein the 3- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, Ci-6 alkyl, Ci-io haloalkyl, -CN, -NO2, =0, -OR 20 , -N(R 20 )2, - C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); each R 5B is independently selected from C1-10 alkyl, wherein the C1-10 alkyl is optionally substituted with one substituent selected from -OR 20 and 3- to 12-membered saturated heterocycle, wherein the 3- to 12-membered saturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-10 haloalkyl, -CN, -NO2, =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , and -S(O) 2 (R 20 ); wherein when R 5B is unsubstituted C1-10 alkyl, each R 9 is independently selected from R 9B ; each R 9 is independently selected from hydrogen, -(R 10 )j-C(O)OR 20 , -(R 10 ) j -C(O)N(R 20 ) 2 , -(R 10 )j-NHC(S)NHR 20 , -(R 10 )j-SR 20 , -(R 10 )j-S-S-R 20 , PEG1-200, mannose, an adjuvant, a carbohydrate, an antibody, C1-20 alkyl, C2- 20 alkenyl, and C2-20 alkynyl, wherein the C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =0, -OR 20 , -N(R 20 )2, - C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -S(O) 2 (R 20 ), C3-12 carbocycle, and 3- to 12- membered heterocycle; each R 9A is independently selected from -(R 10 )j-C(O)OR 20 , — (R 10 )j- C(O)N(R 20 ) 2 , -(R 10 )j-NHC(S)NHR 20 , -(R 10 )j-SR 20 , -(R 10 )j-S-S-R 20 , PEG1-200, mannose, an adjuvant, a carbohydrate, an antibody, C12-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl, wherein the C12-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are each optionally substituted with one or more substituents independently selected from halogen, -CN, -N0 2 , =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -S(O)2(R 20 ), C3-12 carbocycle, and 3- to 12-membered heterocycle; each R 9B is independently selected from -(R 10 )j-C(O)OR 20 , - (R 10 )j- C(O)N(R 20 ) 2 , -(R 10 )j-NHC(S)NHR 20 , -(R 10 )j-SR 20 , -(R 10 )j-S-S-R 20 , PEG3-200, mannose, an adjuvant, a carbohydrate, an antibody, C5-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl, wherein the C5-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are each optionally substituted with one or more substituents independently selected from halogen, -CN, -N0 2 , =0, -OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -S(O)2(R 20 ), C3-12 carbocycle, and 3- to 12-membered heterocycle; each R 10 is independently selected from C1-20 alkylene, C2-20 alkenylene, and C2-20 alkynylene; each R 20 is independently selected from hydrogen; and C1-20 alkyl, C2- 20 alkenyl, C2-20 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, - NHC1-6 alkyl, -NHC1-6 hydroxyalkyl, -N(CI-6 alkyl)Ci-6 hydroxyalkyl, C1-10 alkyl, -Ci-10 haloalkyl, -O-Ci-10 alkyl, oxo, =NH, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R 21 is independently selected from hydrogen; and C1-20 alkyl, C2- 20 alkenyl, C2-2o alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(Ci-6 alkyl)2, - NHC1-6 alkyl, -NHC1-6 hydroxyalkyl, C1-10 alkyl, -C1-10 haloalkyl, -O-Ci-10 alkyl, = NH, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R 22 is selected from mannose, an adjuvant, a carbohydrate, and an antibody; L is selected from a covalent linker; a, b, c, d, f, j, n, p, q, r, and s, are each independently selected from 0, 1, 2, and 3; and m is selected from 1, 3, and 5. 2. The compound or salt of claim 1, wherein each R 1 is selected from hydrogen, C1-6 alkyl, 3. The compound or salt of claims 1 or 2, wherein each R 1 is selected from 4. The compound or salt of claims 1 or 2, wherein each R 1 is selected from 5. The compound or salt of claims 1 or 2, wherein each R 1 is selected from 6. The compound or salt of claim 3, Formula (I) is represented by Formula (II) : Formula (II) or a pharmaceutically acceptable salt thereof. 7. The compound or salt of claims 1, 2, 3, or 6, wherein R 2 is selected from C3- 6 alkyl, wherein the C3-6 alkyl is substituted with one or more substituents selected from -N(R 20 )2, -N(R 20 )3 + , and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle has at least one nitrogen atom. 8. The compound or salt of claim 7, wherein each R 2 is selected from 9. The compound or salt of claim 8, wherein each R 2 is selected from 10. The compound or salt of claim 8, wherein each R 2 is selected from 11. The compound or salt of any one of claims 6 to 10, wherein each R 3 is selected from hydrogen and Ci-10 alkyl. 12. The compound or salt of claim 11, wherein each R 3 is hydrogen. 13. The compound or salt of claim 4, wherein Formula (I) is represented by Formula (III) : Formula (III) or a pharmaceutically acceptable salt thereof. 14. The compound or salt of claims 1, 2, 4, or 13, wherein R 7 is selected from C3- 6 alkyl, wherein the C3-6 alkyl is substituted with one or more substituents selected from -N(R 20 )2, -N(R 20 )3 + , and 5- to 6-membered heterocycle, wherein the 5- to 6-membered heterocycle has at least one nitrogen atom. 15. The compound or salt of claim 14, wherein R 7 is selected from C3-6 alkyl, wherein the C3-6 alkyl is substituted with one -N(R 20 )2. 16. The compound or salt of claim 15, wherein each R 7 is selected from 17. The compound or salt of claim 1, wherein Formula (I) is represented by Formula (IV): Formula (IV) or a pharmaceutically acceptable salt thereof. 18. The compound or salt of claims 1, 2, 5, or 17, wherein each R 4 is selected from C1-2 alkyl. 19. The compound or salt of claims 17 or 18, wherein each R 5 is selected from C2-5 alkyl, wherein the C2-5 alkyl is substituted with one -OR 20 . 20. The compound or salt of claim 19, wherein each R 5 is selected from C2-5 alkyl, wherein the C2-5 alkyl is substituted with one -OH. 21. The compound or salt of claim 20, wherein each R 5 is selected from 22. The compound or salt of any one of claims 1 to 21, wherein each R 9 is selected from unsubstituted C1-12 alkyl. 23. A composition comprising the compound or salt of any one of claims 1 to 22 and an excipient. 24. A pharmaceutical composition comprising the compound or salt of any one of claims 1 to 22, or the composition of claim 23, and one or more nucleotides. 25. The compound or salt of any one of claims 1 to 22, for use as a delivery system. 26. The compound or salt of claim 1, wherein each R 1 is selected from 27. The compound or salt of claims 1 or 26, wherein each R 1 is selected from hydrogen. 28. The compound or salt of claims 1 or 26 to 27, wherein each R 1 is selected from hydrogen. 29. The compound or salt of claims 1, 2, 4, 13 or 26 to 28, wherein each R 7 is selected from substituted C3-5 alkyl, and substituted C2 alkyl. 30. The compound or salt of claims 1, 2, 4, 13, or 26 to 29, wherein each R 7 is selected from C3-5 alkyl substituted with one or more substituents selected from -N(R 20 ) 2 , and 4- to 6-membered heterocycle; and C 2 alkyl, which is substituted with one or more substituents selected from -N(R 20 ) 2 , and 4- to 6-membered heterocycle. 31. The compound or salt of claims 1, 2, 4, 13 or 26 to 30, wherein each R 20 is independently selected from C1-4 alkyl, which is optionally substituted with one or more -OH, 32. The compound or salt of claims 1, 2, 4, 13 or 26 to 31, wherein each R 7 is 34. The compound or salt of claims 1, 2, 4, or 33, wherein each R 1 is selected 35. The compound or salt of claims 1, 2, 4, or 33-34, wherein each R 1 is selected 36. The compound or salt of claims 1 or 26, wherein each R 1 is selected from and hydrogen. 37. The compound or salt of claims 1, or 36, wherein each R 1 is selected from and hydrogen. 38. The compound or salt of claims 1 or 37, wherein each R 1 is selected from 39. The compound or salt of claims 1 or 37, wherein each R 1 is selected from 40. The compound or salt of claims 1 or 37, wherein each R 1 is selected from 41. The compound or salt of claim 1 or 26, wherein each R 1 is selected from hydrogen. 42. The compound or salt of claim 1, wherein each R 1 is selected from hydrogen. 43. The compound or salt of claims 1 or 26, wherein each R 1 is selected from 44. The compound or salt of claims 1, 2, 6, or 43, wherein each R 3 is selected from hydrogen. 45. The compound or salt of claims 1, 2, 6, 43 or 44, wherein each R 2 is selected from C3-10 alkyl, wherein the C3-10 alkyl is substituted with one or more substituents selected from -N(R 20 )2, and -N(R 20 )3 + . 46. The compound or salt of claims 1, 2, 6, 43 to 45, wherein each R 2 is selected from 47. The compound or salt of any one of claims 1 to 21, or 26 to 46, wherein each R 9 and R 9A is selected from C12-16 alkyl, 48. The compound or salt of claims 26 to 47, wherein each R 9 is selected from C12-16 alkyl. 49. The compound or salt of claims 26 to 47, wherein each R 9A is selected from C12-16 alkyl. 50. A composition comprising the compound or salt of any one of claims 26 to 49 and an excipient. 51. A pharmaceutical composition comprising the compound or salt of any one of claims 26 to 49, or the composition of claim 50, and one or more nucleotides. 52. The compound or salt of any one of claims 26-49, for use as a delivery system. 53. Use of a compound or salt in an immunogenic composition, wherein said composition comprises an immunogenic component encapsulated in a lipid nanoparticle (LNP) comprising said compound or salt of any one of claims 1 to 22 or 26 to 49 and wherein said LNP is an adjuvant for said immunogenic composition

Description

CALIXARENE COMPOUNDS, THEIR SYNTHESIS AND USE IN PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to a pharmaceutical composition and use thereof. BACKGROUND The ability to safely and efficiently transfer foreign DNA into cells is a fundamental goal in biotechnology. Toward this end, rapid advances have recently been made in our understanding of mechanisms for DNA stability and transport within cells. Current synthetic DNA delivery systems are versatile and safe, but substantially less efficient than viruses. Indeed, most current systems address only one of the obstacles to DNA delivery by enhancing DNA uptake. In fact, the effectiveness of gene expression is also dependent on several additional factors, including the release of intracellular DNA, stability of DNA in the cytoplasm, unpackaging of the DNA- vector complex, and the targeting of DNA to the nucleus. Furthermore, recent advances in the generation, purification and cellular delivery of RNA have enabled development of RNA-based therapeutics for a broad array of applications. RNA therapeutics comprise a rapidly expanding category of drugs that will change the standard of care for many diseases and actualize personalized medicine. These drugs are cost effective, relatively simple to manufacture, and can target previously undruggable pathways. It is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized RNA constructs. However, employing nucleic acids as therapeutics is challenging because they are susceptible to degradation by nucleases, contribute to immune activation and have unfavorable physicochemical characteristics that prevent facile transfection into cells. Safe and effective nucleic acid therapeutics therefore require sophisticated delivery platform technologies. A big challenge in the field of mRNA vaccines for instance relies on the development of efficient delivery vectors that can (i) compact mRNA, (ii) protect it from nuclease degradation, (iii) target the adequate organs and cells, and (iv) ensure its intracellular delivery. Appropriate carriers can help to avoid degradation and enhance immune responses, effector presentation, biocompatibility and biosafety. Among all non-viral carriers, lipid nanoparticles (LNPs) are by far the most studied and advanced into clinical development. However, these systems remain perfectible, particularly in terms of biodistribution (off-target effects), (thermo)stability and reactogenicity. Therefore, next-generation compounds and systems for RIMA delivery are still under development. The invention thereto aims to provide compounds having improved characteristics for use in nucleotide delivery systems. SUMMARY OF THE INVENTION The present invention and embodiments thereof serve to provide a solution to one or more of above-mentioned disadvantages. To this end, the present invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1. Preferred embodiments of this compound are shown in any of the claims 2 to 22. In a second aspect, the present invention relates to a composition comprising above mentioned compound according to claim 23. In a further aspect, the invention relates to a pharmaceutical composition comprising above mentioned compound or salt, or above mentioned composition, and one or more nucleotides according to claim 24. In a further aspect, the invention relates to above mentioned compound or salt, for use as a delivery system according to claim 25. DESCRIPTION OF FIGURES Figure 1 shows a synthesis scheme of compounds according to an embodiment of the present invention. Figure 2 shows a visualization of the estimated model (average + 95% confidence interval) of in vivo luminescence as a function of the (lipid+CX)/RNA mass ratio, the helper mass ratio and the PEG lipid mass ratio in a delivery system according to an embodiment of the current invention. Figure 3 shows the in vivo protein expression at 3h, 6h and 9h after the intramuscular injection of 1 pg of Flue mRNA into both left and right hindlimb of mice (geometric mean signal with 95% confidence intervals) using various delivery systems according to embodiments of the current invention. Figure 4 shows saRNA-FLuc encapsulation in nanoparticles according to an embodiment of the invention having a different CX/RNA mass ratio and the resulting in vitro protein expression after transfection of these nanoparticles. Figure 5 shows in vivo saRNA-Fluc delivery efficiency of a delivery system according to an embodiment of the current invention compared to a reference delivery system without a calixarene. Figure 6 shows virus neutralizing titers (VNT) in serum measured after 15, 35 and 64/65 days in mice which were vaccinated using a delivery system according to an embodi