Bifunctional energy-reversible acyl-compositions

1. A compound of the formula:

wherein:

R 1 and R 2 are individually selected from the group consisting of H, CH 3 , C 2 –C 10 alkyls, C 2 –C 10 alkenyls or C 2 –C 10 alkynyls, straight or branched, C 2 –C 10 heteroalkyls, C 2 –C 10 heteroalkenyls or C 2 –C 10 heteroalkynyls and —(CR 15 R 16 ) p —D;

wherein: R 15 and R 16 are individually selected from the group consisting of H, CH 3 , C 2 –C 10 alkyls, C 2 –C 10 alkenyls or C 2 –C 10 alkynyls, straight or branched; and C 2 –C 10 heteroalkyls, C 2 –C 10 heteroalkenyls or C 2 –C 10 heteroalkynyls;

p is a positive integer from 1 to about 12;

D is selected from among —SH, —OH, X 2 , —CN, —OR 19 , NHR 20 ,

wherein:

R 17 is H, CH 3 or X 3 ;

R 18 is H, a C 1-4 alkyl or benzyl;

R 19 is H, a C 1-4 alkyl, X 2 or benzyl;

R 20 is H, a C 1-10 alkyl or —C(O)R 21 ,

wherein R 21 is H, a C 1-4 alkyl or alkoxy, t-butoxy or benzyloxy;

X 2 and X 3 are independently selected halogens;

R 3 is H, CH 3 , or —C(═O)(CR 15 R 16 ) w —D,

where w is 0 or an integer from 1 to about 12, and D is H or as described for R 1 and R 2 J is O, NH or S;

R 4 , R 5 , and R 6 are independently selected from the group consisting of H, CH 3 , C 2 –C 10 alkyls, C 2 –C 10 alkenyls or C 2 –C 10 alkynyls, straight or branched; C 2 –C 10 heteroalkyls, heteroalkenyls or heteroalkynyls and halogens;

Z is NR 7 R 8 or

wherein R 7 is selected from among H, CH 3 , C 2 –C 10 alkyls, alkenyls or alkynyls straight or branched; C 2 –C 10 heteroalkyls, heteroalkenyls or heteroalkynyls, or —(CR 23 R 24 ) q -alyl, or R 8 ,

wherein R 23 and R 24 are independently selected from the group consisting of H and C 1 –C 10 alkyls;

q is an integer from 1 to about 6;

R 8 is selected from the group consisting of (CR 9 R 10 ) n —NR 22 —R 11 , (CR 9 R 10 ) n —CH 2 —NHC(O)R 26 and (CR 9 R 10 ) n —CH 2 —E;

wherein R 9 and R 10 are independently selected from the group consisting of H, CH 3 , C 2 –C 10 alkyls, C 2 –C 10 alkenyls or C 2 –C 10 alkynyls, straight or branched; C 2 –C 10 heteroalkyls, C 2 –C 10 heteroalkenyls or C 2 –C 10 heteroalkynyls and halogens;

R 26 is H, CH 3 , O-t-butyl, O-benzyl;

E is OH, SH or O—C(O)R 27 ,

wherein R 27 is a C 1 –C 6 alkyl, benzyl or phenyl;

R 22 is H or CH 3 ;

n is a positive integer from 1 to about 10;

R 11 is H or —L—B,

wherein L—B are maleimides, N-hydroxysuccinimidyl compounds, immidoesters,

2-iminothiolane, hydrazides and maleic anhydride;

R 25 is H, —C(O)—R 28 or —C(O)—O—R 29 ,

wherein R 28 is a C 1 –C 6 alkyl or benzyl; and R 29 is CH 3 , t-butyl or benzyl;

X 1 is O, NH, or S; and

A is H, or A 1 wherein X 1 A 1 is

wherein R 12 and R 13 are independently H or electron donating or electron withdrawing groups and W is CH or N.

2. The compound of claim 1 , wherein Z is NR 7 R 8 .

3. The compound of claim 2 , wherein R 8 is —CH 2 —CH 2 —NH 2 .

4. The compound of claim 2 , wherein R 8 is (CR 9 R 10 ) n —NR 22 —R 11 .

5. The compound of claim 4 , wherein R 11 is a polyalkylene oxide residue.

6. The compound of claim 5 , wherein said polyalkylene oxide residue is a polyethylene glycol.

7. The compound of claim 6 , wherein said polyethylene glycol has a number average molecular weight of from about 2,000 to about 200,000 daltons.

8. The compound of claim 4 , wherein R 11 is a member of the group consisting of collagen, glycosaminoglycan, poly(-aspartic acid), poly(-L-lysine), poly(-lactic acid), poly-N-vinylpyrolidone and copolymers of poly(-lactic acid) and poly(-glycolic acid).

9. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H, CH 3 and CH 3 CH 2 .

10. The compound of claim 4 , wherein R 7 is CH 3 CH 2 ; R 8 is —(CR 9 R 10 ) n —NR 22 —R 11 ; and R 9 and R 10 are H; n is 2; and X 1 is O, S or NH.

11. The compound of claim 4 , wherein R 7 is CH 3 CH 2 ; R 8 is —(CR 9 R 10 ) n —NR 22 —R 11 and R 9 and R 10 are H.

12. The compound of claim 1 , wherein X 1 A is

13. The compound of claim 12 , wherein J is O, R 2 is H, R 7 is CH 3 CH 2 ; R 8 is —(CR 9 R 10 ) n —NR 22 —R 11 , R 9 and R 10 are H, and n is 2.

14. A compound of claim 1 selected from the group consisting of:

wherein

PEG is a polyethylene glycol having a molecular weight of from about 2,000 to about 200,000.

15. A pharmaceutically acceptable salt of the compound of claim 1 .

16. A method of preparing a conjugate, comprising:

reacting a compound of Formula (IV)

wherein:

R 1 and R 2 are individually selected from the group consisting of H, CH 3 , C 2 –C 10 alkyls, C 2 –C 10 alkenyls or C 2 –C 10 alkynyls, straight or branched, C 2 –C 10 heteroalkyls, C 2 –C 10 heteroalkenyls or C 2 –C 10 heteroalkynyls and —(CR 15 R 16 ) p —D

wherein: R 15 and R 16 are individually selected from the group consisting of H, CH 3 , C 2 C 10 alkyls, C 2 –C 10 alkenyls and C 2 –C 10 alkynyls, straight or branched; and C 2 –C 10 heteroalkyls, C 2 –C 10 heteroalkenyls or C 2 –C 10 heteroalkynyls;

p is a positive integer from 1 to about 12;

D is selected from among —SH, —OH, X 2 , —CN, —OR 19 , NHR 20 ,

wherein:

R 17 is H, a CH 3 or X 3 ,

R 18 is H, a C 1-4 alkyl or benzyl;

R 19 is H, a C 1-4 alkyl, X 2 or benzyl;

R 20 is H, a C 1-10 alkyl or —C(O)R 21

wherein R 21 is H, a C 1-4 alkyl or alkoxy, t-butoxy or benzyloxy;

X 2 and X 3 are independently selected halogens;

R 3 is H, CH 3 , or —C(═O)(CR 15 R 16 ) w —D,

where w is 0 or an integer from 1 to about 12, and D is H or as described for R 1 and R 2 ,

J is O, NH or S;

R 4 , R 5 and R 6 independently selected from the group consisting of H, CH 3 ,

C 2 –C 10 alkyls, C 2 –C 10 alkenyls or C 2 C 10 alkynyls, straight or branched; C 2 –C 10 heteroalkyls, heteroalkenyls or heteroalkynyls and halogens;

R 7 is selected from among H, CH 3 and C 2 –C 10 alkyls;

X 1 is O, NH, or S;

R 22 is H or CH 3 ; and

A is H or A 1 wherein X 1 A 1 is

wherein R 12 and R 13 are independently H or electron donating or electron withdrawing groups and W is CH or N;

with a linking reagent selected from the group consisting of succinimides, maleimides, imidoesters, 2-iminothiolane, hydrazides, maleic anhydride, azides, citraconic anhydride, glutaraldehyde.

17. The method of claim 16 , wherein the linking reagent is selected from the group consisting of heterobifunctional reagents having N-hydroxysuccinimide and maleimide, bifunctional maleimide and bifunctional PEG's.

18. The method of claim 17 , wherein the heterobifunctional reagent is (Succinimidyl-6-[((βmaleimidopropionamido)hexanoate]).