Disubstituted amino acids and methods of preparation and use thereof

Patent metadata

Field	Value
Publication number	US-9845287-B2
Application number	US-201615278824-A
Country	US
Kind code	B2
Filing date	Sep 28, 2016
Priority date	Nov 1, 2012
Publication date	Dec 19, 2017
Grant date	Dec 19, 2017

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.

First claim

What is claimed is:

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

wherein:
R 1 is C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, or C 1 -C 3 haloalkyl;
* is a stereocenter;
n is an integer from 3 to 11;
R 2 is 9-Fluorenylmethoxycarbonyl (Fmoc); and
R 3 is —H;

and wherein the crystalline composition further comprises hexane and chloroform.

2. The crystalline composition of claim 1 , wherein R 1 is C 1 -C 3 alkyl.

3. The crystalline composition claim of 1 , wherein R 1 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.

21. A crystalline compound of Formula (I):

wherein:
R 1 is C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, or C 1 -C 3 haloalkyl;
* is a stereocenter;
n is an integer from 3 to 11;
R 2 is 9-Fluorenylmethoxycarbonyl (Fmoc); and
R 3 is —H;

wherein the crystalline compound is obtained by crystallization of a compound of Formula (I) with a solvent comprising hexane and chloroform.

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.

Assignees

• Aileron Therapeutics Inc

Inventors

• Darlak Krzysztof
• Kawahata Noriyuki
• Athamneh Sameer Ahmed

Classifications

• C07K1/006

  of peptides containing derivatised side chain amino acids · CPC title

• C07C271/22 Primary

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07C269/08

  Separation; Purification; Stabilisation; Use of additives · CPC title

• C07C271/34 Primary

  with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07B2200/07

  Optical isomers · CPC title