Aryl carbamate oligomers for hydrolyzable prodrugs and prodrugs comprising same

1. An activated compound having a formula:

wherein an activated moiety is attached to the hydroxyl group and wherein the activated moiety is selected from the group consisting of chloroformate, NHS carbonate, DSC para-nitrochloroformate, p-nitrochlorofomate, phosgene and paranitrophenyl carbonate, and

where

R 1 is selected from the group consisting of alkyl, —CH 2 (OC 2 H 4 )OCH 3 , and —(OC 2 H 4 )OCH 3 ;

n is 0-4;

Olig is an oligomer having a formula:

-L-O-PAG R 2 ] q

where:

L is a optional linker moiety selected from the group consisting of —CH 2 O—, —CH 2 OX—, —OX—, —C(O)—, —C(O)X, —NH—, —NHC(O)—, —XNHC(O)—, —NHC(O)X, —C(O)NH—, —C(O)NHX—, and

where:

X is alkyl 1-6 or is not present,

Y is N or O or is not present, and

R 3 is alkyl 1-6;

PAG is a linear or branched polyalkylene glycol moiety;

R 2 is an alkyl 1-22 capping moiety if X is present or alkyl 2-22 if X is not present;

q is a number from 1 to 10; and

m is 1-5.

2. The compound of claim 1 comprising an Olig coupled to carbon 4 of the phenol moiety.

3. The compound of claim 1 comprising an Olig coupled to carbon 3 of the phenol moiety, and/or an Olig coupled to carbon 5 of the phenol moiety.

4. The compound of claim 1 wherein m is 1 and the Olig is coupled to carbon 4 of the phenol moiety.

5. The compound of claim 1 wherein m is 1 and the Olig is coupled to carbon 3 or carbon 5 of the phenol moiety.

6. The compound of claim 1 wherein:

(a) m is 2, and

(b) a first Olig is coupled to carbon 3 of the phenol moiety, and

(c) a second Olig is coupled to carbon 5 of the phenol moiety.

7. The compound of claim 1 wherein L is present and X is not present.

8. The compound of claim 1 wherein L and X are both present.

9. The compound of claim 1 wherein PAG is a linear polyalkylene glycol moiety.

10. The compound of claim 1 wherein PAG is a linear polyethylene glycol moiety.

11. The compound of claim 1 wherein PAG is a branched polyalkylene glycol moiety.

12. The compound of claim 1 wherein PAG is a branched polyethylene glycol moiety.

13. The compound of claim 1 wherein q is 1 to 5.

14. The compound of claim 1 wherein q is 2.

15. The compound of claim 1 wherein R 2 is alkyl 5-12 .

16. The compound of claim 1 wherein R 2 is alkyl 1-4 .

17. The compound of claim 1 wherein X is present and R 2 is methyl.

18. The compound of claim 1 wherein R 1 is alkyl 1-22 .

19. The compound of claim 1 wherein R 1 is alkyl 1-12 .

20. The compound of claim 1 wherein R 1 is alkyl 16 .

21. The compound of claim 1 wherein R 1 is methyl and L is not amide or O.

22. The compound of claim 1 wherein R 1 is methyl.

23. The activated compound of claim 1 further comprising a protein drug moiety, wherein the protein drug moiety is insulin.

24. A compound having a formula:

wherein

X is an alkyl or is not present;

PEG is linear or branched PEG 2-50 ;

R is H or alkyl;

n is from 1 to 10; and

R 1 is alkyl.

25. A compound having a formula:

26. The compound of claim 1 , wherein the compound is a pure prodrug or partial prodrug.

27. A pharmaceutically composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.

28. A method of treating a subject in need of treatment for diabetes comprising administering an effective amount of the activated compound of claim 1 that is conjugated to insulin to the subject.