Amino acid derivatives

Patent metadata

Field	Value
Publication number	US-9981908-B2
Application number	US-201414910107-A
Country	US
Kind code	B2
Filing date	Aug 4, 2014
Priority date	Aug 5, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

There are provided pyrrolysine analogs of the formulae (X), (I), (II), (V), (VI), (VII) and (VIII), in which the a, b, d, X, Y, Z, FG, R, R 1 , R 2 and R 3 are as defined in the claims, which are useful in bioconjugation processes and mutant proteins containing them.

First claim

The invention claimed is:

1. A pyrrolysine analogue of formula X:

wherein
X=O or S;
Y=CH 2 , NH, O or S;
Z=CH 2 , CH—NH 2 , CH—OH, NH, O or S;
FG azide, alkene, alkyne, ketone, ester, or cycloalkyne;
a=an integer 1-7;
b=an integer 1-7 save that when Z is NH, O or S then b is an integer 2-7;
provided that a+h is in the range 2-8;
and d=an integer 1-4.

2. A pyrrolysine analogue according to claim 1 which is a pyrrolysine analogue of formula III:

wherein a, b, Z, d and FG are as defined in claim 1 .

3. A pyrrolysine analogue according to claim 2 selected from

4. A pyrrolysine analogue according to claim 1 which is a pyrrolysine analogue of
Formula IV:

wherein a, b, Y, Z, d and FG are as defined in claim 1 .

5. A pyrrolysine analogue according to claim 4 selected from

6. A pyrrolysine analogue of formula I:

wherein
Z=bond, CH 2 , CH—NH 2 , CH—OH, NH, O, S or CH—NH 2 ;
a is an integer 3-7;
b is 0 or an integer 1-7; and
FG=azide, alkene, alkyne, ketone, ester, or cycloalkyne;
with the provisos that:
when a represents 4 and Z represents O, —(CH 2 ) b -FG does not represent —CH 2 —C≡CH, —CH 2 CH 2 —N 3 , —CH 2 —CH═CH 2 or —CH 2 -Ph;
when a represents 4 and Z represents O, —(CH 2 ) b -FG does not represent —CH 2 CH 2 CH 2 —C(═O)CH 3 or —CH 2 CH 2 CH 2 —CH═CH 2 ;
when a represents 4, Z represents a bond and b represents 0, —(CH 2 ) b -FG does not represent —C(═O)Bn or —C(═O)Me; and
when a represents 4 and Z represents a bond, —(CH 2 ) b -FG does not represent —CH 2 CH 2 —C≡CH.

7. A pyrrolysine analogue according to claim 6 selected from

8. A pyrrolysine analogue according to claim 6 selected from

9. A pyrrolysine analogue of formula II:

wherein
Z=CH 2 , CH—NH 2 , CH—OH, NH, O or S;
FG=azide, alkene, alkyne, ketone, ester, aryl or cycloalkyne;
a=an integer 3 or 5-7; and
b=an integer 1-4.

10. A pyrrolysine analogue of formula V:

wherein
R=the side chain of one of the 20 natural amino acids;
Z=CH 2 , CH—NH 2 , CH—OH, NH, O or S;
FG=azide, alkene, alkyne, ketone, ester, aryl or cycloalkyne;
a=1; and
b=an integer 1 to 4.

11. A pyrrolysine analogue according to claim 10 selected from

12. A pyrrolysine analogue of formula VI:

wherein
Z=CH 2 , CH—NH 2 , CH—OH, NH, O or S;
PG=azide, alkene, alkyne, ketone, ester, or cycloalkyne;
a=4 or 5; and
b=an integer 1 to 4.

13. A pyrrolysine analogue according to claim 12 selected from

14. A pyrrolysine analogue of formula VII:

wherein
R=alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
a=an integer 1 to 7; and
b=an integer 1 to 3.

15. A pyrrolysine analogue according to claim 14 which is:

16. A pyrrolysine analogue of formula VIII:

wherein
Z=CH 2 , CH—NH 2 , CH—OH, NH, O or S;
R 1 =H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl;
R 2 =alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl;
R 3 =H, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl; and
a=1.

17. A pyrrolysine analogue according to claim 16 selected from

18. A pyrrolysine analogue according to 3 wherein the pyrrolysine analogue is

19. A pyrrolysine analogue according to 3 , wherein the pyrrolysine analogue is

20. A pyrrolysine analogue according to 3 , wherein the pyrrolysine analogue is

21. A pyrrolysine analogue according to 3 , wherein the pyrrolysine analogue is

22. A pyrrolysine analogue according to 3 , wherein the pyrrolysine analogue is

23. A pyrrolysine analogue according to 7 , wherein the pyrrolysine analogue is

24. A pyrrolysine analogue according to 11 , wherein the pyrrolysine analogue is

25. A pyrrolysine analogue according to 11 , wherein the pyrrolysine analogue is

26. A pyrrolysine analogue according to 17 , wherein the pyrrolysine analogue is

Assignees

• Medimmune Ltd

Inventors

• Marelli Marcello
• Van Brunt Michael
• Grabstein Kenneth H

Classifications

• C07C271/22

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

• C07K2317/40

  characterized by post-translational modification · CPC title

• C07C271/12

  to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals · CPC title

• C07C275/20

  of an unsaturated carbon skeleton · CPC title

• C07C271/16

  to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms · CPC title