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US-12624002-B2 - Dimers for use in synthesis of peptidomimetics

US12624002B2US 12624002 B2US12624002 B2US 12624002B2US-12624002-B2

Abstract

Dimers for use in synthesis of peptidomimetics are described. Uses of dimers as synthons in synthesis of azapeptides and other peptidomimetics, azapeptides and other peptidomimetics synthesized from the dimers and uses of azapeptides and other peptidomimetics are also described.

Inventors

  • Yousef Al-Abed
  • Ahmad Altiti

Assignees

  • THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH

Dates

Publication Date
20260512
Application Date
20210507

Claims (19)

  1. 1 . A compound of Formula (I): and salts thereof, wherein A is N-phthalimidyl or NR 3 R 4 , wherein (i) R 3 is H and R 4 is 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl or (ii) R 3 and R 1 are connected and together form a side chain radical of proline and R 4 is tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl; A 1 is H or absent; A 2 is H or absent; X is selected from the group consisting of imidazolyl, benzotriazolyl, S-D, and O-L; D is H, Cl, an alkyl, an aryl or a heteroaryl; L is imidazolyl or benzotriazolyl; R 1 and R 2 is each independently selected from the group consisting of side chain radicals of amino acids selected from the group consisting of side chain radicals of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, threonine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine; Z 1 and Z 2 is each independently C or N; and at least one of Z 1 and Z 2 is N.
  2. 2 . A compound of Formula (I): and salts thereof, wherein A is NR 3 R 4 , wherein (i) R 3 is H and R 4 is 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl or (ii) R 3 and R 1 are connected and together form a side chain radical of proline and R 4 is tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl; A 1 is H or absent; A 2 is H or absent; X is selected from the group consisting of imidazolyl, benzotriazolyl, S-D, and O-L; D is H, Cl, an alkyl, an aryl or a heteroaryl; L is imidazolyl or benzotriazolyl; R 1 and R 2 is each independently selected from the group consisting of side chain radicals of amino acids selected from the group consisting of side chain radicals of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, threonine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, and glutamine; and Z 1 is N and Z 2 is C, or Z 1 is C and Z 2 is N.
  3. 3 . A compound according to claim 1 , wherein A is NR 3 R 4 , wherein R 3 is H and R 4 is 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl.
  4. 4 . A compound according to claim 1 , wherein A is N-phthalimidyl.
  5. 5 . A compound according to claim 1 , wherein A is NR 3 R 4 , R 3 is H, R 4 is 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl, and R 3 and R 1 are connected and together form a side chain radical of proline.
  6. 6 . A compound according to claim 1 , wherein X is benzotriazolyl.
  7. 7 . A compound according to claim 1 , wherein X is S-D; and D is an alkyl.
  8. 8 . A compound according to claim 7 , wherein the alkyl is ethyl.
  9. 9 . A compound according to claim 1 , wherein X is selected from a group consisting of S-D and O-L.
  10. 10 . A compound according to claim 2 , wherein X is selected from the group consisting of S-D and O-L.
  11. 11 . A compound according to claim 1 , wherein Z 1 and Z 2 are both N.
  12. 12 . A compound according to claim 1 , wherein Z 1 is C, and Z 2 is N.
  13. 13 . A compound according to claim 1 wherein the side chain radicals of amino acids are selected from the group consisting of side chain radicals of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, threonine, tyrosine, isoleucine, arginine, asparagine, serine, and glutamine.
  14. 14 . A compound according to claim 2 , wherein A is NR 3 R 4 , R 3 is H and R 4 is 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl) propan-2-yloxycarbonyl.
  15. 15 . A compound according to claim 14 , wherein R 4 is 9-fluorenylmethoxycarbonyl.
  16. 16 . A compound according to claim 1 , wherein X is selected from a group consisting of imidazolyl, benzotriazolyl, and S-D.
  17. 17 . A compound according to claim 1 , which is (9H-fluoren-9-yl)methyl 2-(2-benzyl-2-((ethylthio) carbonyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxylate.
  18. 18 . A compound according to claim 1 , wherein A is NR 3 R 4 , and R 3 and R 1 are connected and together form a side chain radical of proline and R 4 is 9-fluorenylmethoxycarbonyl; A 1 is absent; A 2 is absent; Z 1 is C; Z 2 is N; X is S-D or O-L; and L is an alkyl.
  19. 19 . A compound according to claim 2 , wherein A is NR 3 R 4 , and R 3 and R 1 are connected and together form a side chain radical of proline and R 4 is 9-fluorenylmethoxycarbonyl; A 1 is absent; A 2 is absent; Z 1 is C; Z 2 is N; X is S-D or O-L; and L is an alkyl.

Description

This application claims the benefit of U.S. Provisional Application No. 63/021,803, filed on May 8, 2020, hereby incorporated by reference. FIELD OF THE INVENTION The present invention is directed to dimers for use in synthesis of azapeptides and other aza-amino acid conjugates; synthesis of azapeptides and other aza-amino acid conjugates, and uses of azapeptides and other aza-amino acid conjugates in drug discovery, diagnosis, prevention, inhibition, and treatment of diseases. BACKGROUND OF THE INVENTION The in vitro and in vivo stability and in vitro and in vivo half-lives of peptides are limited, e.g., by their rate of hydrolysis and enzymatic degradation. Azapeptides are analogs of peptides. An azapeptide contains a substituted semicarbazide instead of one or more of the amino acid residue(s) of a parent peptide. In other words, one or more of α-carbon atom(s) of the parent peptide are replaced with a nitrogen atom in the azapeptide. As compared to the parent peptides, azapeptides contain a nitrogen atom instead of one or more of α-carbon atom(s). Due to the reduced reactivity of the carbonyl moiety in the aza-amino acid residue relative to a natural amino acid counterpart, an aza-peptide bond is more stable under the effect of peptidases, and consequently azapeptides are hydrolysed and degraded by peptidases at a slower rate and exhibit, e.g., an improved metabolic stability, than the parent peptides. However, the rate of formation of the aza-peptide bond is much slower than that of a typical peptide bond. Thus, there is a greater potential of formation of unwanted side products during azapeptide synthesis with aza-amino acids than with conventional amino acids. An additional obstacle in utilizing aza-amino acids in syntheses of azapeptides is the orthogonal functionalization of the two available nitrogen atoms in the hydrazine system. For these and other reasons, syntheses of azapeptides with aza-amino acids and conventional coupling agents was challenging prior to the present invention. There is a need for compounds which overcome the limitations of conventional aza-amino acids and/or allow, e.g., for a faster and/or cheaper and/or more efficient syntheses of azapeptides and other aza-amino acid conjugates. SUMMARY OF THE INVENTION It is an object of the invention to provide compounds for synthesis of azapeptides and other aza-amino acid conjugates. It is an object of the invention to provide dimers for synthesis of azapeptides and other aza-amino acid conjugates. It is a further object of the invention to provide azapeptides and other aza-amino acid conjugates that are more stable and/or more efficacious than their parent peptides. It is yet an additional object of the invention to provide azapeptide diagnostic and therapeutic agents. In connection with the above objects and others, the invention provides dimers for use as building blocks or synthons for synthesis of analogues of peptides (“peptidomimetic agents”). The dimers are stable entities and may be stored (e.g., as powder) for extended periods of time without being compromised. In some embodiments, the dimers are stable at 37° C. in an aqueous medium (e.g., an aqueous solution) with a pH of about 7 (e.g., distilled water) for at least 30 minutes, 60 minutes, 90 minutes, 1 hour, 2 hours, 3 hours, 4 hours or 5 hours. As compared to the conventional amino acids and aza-amino acids, the dimers are capable of being activated under milder conditions and at lower temperatures. At the same, peptidomimetic agents assembled from the dimers are more resistant to hydrolysis and enzymatic degradation than the original peptides, and, consequently, may be used in drug discovery, diagnosis, inhibition, prevention and treatment of diseases. The invention is directed in part to the compounds of Formula (I): and salts thereof, wherein A is N-phthalimidyl (NPhth) or NR3R4, wherein (i) R3 is H and R4 is tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) or 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) or (ii) R3 and R1 are connected and together form a side chain radical of proline and R4 is tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl;A1 is H or absent;A2 is H or absent;X is selected from the group consisting of imidazolyl, benzotriazolyl, S-D, and O-L;D is H, Cl, an alkyl, an aryl or a heteroaryl;L is an alkyl, imidazolyl or benzotriazolyl;R1 and R2 is each independently selected from the group consisting of side chain radicals of amino acids;Z1 and Z2 is each independently C or N. In these compounds, A1 is absent when Z1 is N; and A2 is absent when Z2 is N. The invention is also directed in part to the compounds of Formula (I): and salts thereof, wherein A is N-phthalimidyl or NR3R4, wherein (i) R3 is H and R4 is tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl or (ii) R3 and R1 are connected and together form a side chain radical of proline and