Disubstituted amino acids and methods of preparation and use thereof

• US 9,845,287 B2
• Filed: 09/28/2016
• Issued: 12/19/2017
• Est. Priority Date: 11/01/2012
• Status: Active Grant

• Current Assignee: Aileron Therapeutics Inc.
• Original Assignee: Aileron Therapeutics Inc.
• Inventors: Darlak, Krzysztof, Kawahata, Noriyuki, Athamneh, Sameer Ahmed
• Primary Examiner(s): BROOKS, CLINTON A
• Application Number:
  US15/278,824
• Publication Number:
  US 20170066714A1
• Time in Patent Office: 447 Days
• Field of Search: None
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 269/08 Separation; Purification; Stabilisation; Use of additives
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/34 with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07K 1/006 of peptides containing derivatised side chain amino acids
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Provided are crystalline α, α-disubstituted amino acids and their crystalline salts containing a terminal alkene on one of their side chains, as well as optionally crystalline halogenated and deuterated analogs of the α, α-disubstituted amino acids and their salts; methods of making these, and methods of using these.

Claims

1. A crystalline composition comprising a crystalline compound of Formula (I):

2. The crystalline composition of claim 1, wherein R₁ is C₁-C₃ alkyl.

3. The crystalline composition claim of 1, wherein R₁ is methyl.

4. The crystalline composition of claim 1, wherein n is selected from the group consisting of:

3 and 6.

5. The crystalline composition of claim 1, wherein the stereocenter * is (S).

6. The crystalline composition of claim 1, wherein the stereocenter * is (R).

7. The crystalline composition of claim 1, wherein the crystalline compound has a chemical purity ranging from about 90% to 100%.

8. The crystalline composition of claim 1, wherein the crystalline compound has an optical purity ranging from about 90% to 100%.

9. The crystalline composition of claim 1, wherein the crystalline compound has an optical purity ranging from about 95% to 100%.

10. The crystalline composition of claim 1, wherein the crystalline compound has an enantiomeric excess ranging from about 90% to 100%.

11. The crystalline composition of claim 1, wherein the crystalline compound has an enantiomeric excess ranging from about 95% to 100%.

12. The crystalline composition of claim 1, wherein the crystalline compound has a Formula (IIa):

13. The crystalline composition of claim 1, wherein the crystalline compound has a Formula (IIb):

14. The crystalline composition of claim 1, wherein the crystalline compound has a Formula (IIIa):

15. The crystalline composition of claim 1, wherein the crystalline compound has a Formula (IIIb):

16. The crystalline composition of claim 12, wherein the crystalline compound has an enantiomeric excess ranging from about 95% to 100%.

17. The crystalline composition of claim 13, wherein the crystalline compound has an enantiomeric excess ranging from about 95% to 100%.

18. The crystalline composition of claim 14, wherein the crystalline compound has an enantiomeric excess ranging from about 95% to 100%.

19. The crystalline composition of claim 15, wherein the compound or its crystalline salt has an enantiomeric excess ranging from about 95% to 100%.

20. The crystalline composition of claim 1, wherein n is 3.

22. A method of making a peptide, the method comprising reacting the crystalline composition of claim 1 with an amino acid building block in presence of a coupling agent, thereby forming a peptide bond.

23. The method of claim 1, wherein the peptide comprises an α

-helix.

24. The method of claim 1, further comprising crosslinking a pair of terminal alkene side chains of at least two amino acids of the peptide.

25. The method of claim 24, wherein the crosslinking comprises a metal-catalyzed olefin metathesis reaction.

21. A crystalline compound of Formula (I):