Disubstituted amino acids and methods of preparation and use thereof

• US 10,669,230 B2
• Filed: 10/26/2017
• Issued: 06/02/2020
• 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:
  US15/794,355
• Publication Number:
  US 20180265459A1
• Time in Patent Office: 950 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 salt of a compound of Formula (I):

2. The crystalline salt of claim 1, wherein n is an integer from 3 to 11.

3. The crystalline salt of claim 1, wherein n is 3 or 6.

4. The crystalline salt of claim 1, having a chemical purity ranging from about 90% to 100%.

5. The crystalline salt of claim 1, having an optical purity ranging from about 90% to 100%.

6. The crystalline salt of claim 1, having an enantiomeric excess ranging from about 90% to 100%.

7. The crystalline salt of claim 1, wherein the compound of Formula (I) is:

8. The crystalline salt of claim 1, wherein the crystalline salt comprises an additional acid.

9. The crystalline salt of claim 8, wherein the additional acid is selected from the group consisting of nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid and hydrochloric acid.

10. The crystalline salt of claim 8, wherein the additional acid is hydrochloric acid.

11. A method of preparing the crystalline salt of claim 1, comprising precipitating the compound of Formula (I) as a HCl salt.

12. The method of claim 11, wherein the HCl salt is further crystallized with a solvent comprising acetonitrile, methyl tertiary-butyl ether, isopropyl acetate, or a mixture thereof.

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

14. The crystalline composition of claim 13, wherein R₁ is C₁-C₃ alkyl.

15. The crystalline composition of claim 13, wherein n is 3 or 6.

16. The crystalline composition of claim 13, wherein the crystalline compound has a chemical purity ranging from about 90% to 100%.

17. The crystalline composition of claim 13, wherein the crystalline compound has an optical purity ranging from about 90% to 100%.

18. The crystalline composition of claim 13, wherein the crystalline compound has an enantiomeric excess ranging from about 90% to 100%.

19. The crystalline composition of claim 13, wherein the crystalline compound is selected from the group consisting of:

20. A crystalline compound of Formula (I):