Controlled release from macromolecular conjugates

1. A compound of the formula

wherein m is 0 or 1;

wherein at least one, or both R 1 and R 2 is independently CN; NO 2 ;

optionally substituted aryl;

optionally substituted heteroaryl;

optionally substituted alkenyl;

optionally substituted alkynyl;

COR 3 or SOR 3 or SO 2 R 3 wherein

R 3 is H or optionally substituted alkyl;

aryl or arylalkyl, each optionally substituted;

heteroaryl or heteroarylalkyl, each optionally substituted; or

OR 9 or NR 9 2 wherein each R is independently H or optionally substituted alkyl, or both R 9 groups taken together with the nitrogen to which they are attached form a heterocyclic ring;

SR 4 wherein

R 4 is optionally substituted alkyl;

aryl or arylalkyl, each optionally substituted; or

heteroaryl or heteroarylalkyl, each optionally substituted;

wherein R 1 and R 2 may be joined to form a 3-8 membered ring; and

wherein one and only one of R 1 and R 2 may be H or alkyl, arylalkyl or heteroarylalkyl, each optionally substituted;

each R 5 is independently H or is alkyl, alkenylalkyl, alkynylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted;

Z is a residue of a drug or prodrug coupled through O, S, or non-basic N or is a nucleofuge that mediates said coupling;

B is alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted; and

wherein one of R 1 , R 2 , R 5 or B is coupled to a macromolecule or one of R 1 , R 2 or R 5 comprises a functional group for mediating said coupling.

2. The compound of claim 1 wherein one of R 1 and R 2 is CN.

3. The compound of claim 1 wherein at least of one R 1 and R 2 comprises phenyl or phenylene.

4. The compound of claim 1 wherein one of R 1 and R 2 is SO 2 R 3 and the other is H, alkyl or phenyl.

5. The compound of claim 1 wherein m is 0.

6. The compound of claim 1 which is a drug conjugate of the formula

wherein R 1 , R 2 , R 5 , m and B are defined as in claim 1 ,

D is the residue of a drug or prodrug coupled through O, S or N; and

one of R 1 , R 2 , R 5 or B is coupled to a macromolecule.

7. The drug conjugate of claim 6 wherein the macromolecule is polyethylene glycol (PEG).

8. The drug conjugate of claim 6 wherein the drug is a peptide, a nucleic acid or a small molecule.

9. The compound of claim 1 which is of the formula

wherein R 1 , R 2 , R 5 , m and B are as defined in claim 1 ;

L is a nucleofuge that mediates the coupling of a drug or prodrug coupled through O, S or non-basic N; and

at least one of R 1 , R 2 or R 5 comprises a functional group for mediating coupling to a macromolecule.

10. The compound of claim 1 which is of the formula

wherein m, R 1 , R 2 , R 5 , m, and B are as defined in claim 1 ;

wherein D is the residue of a drug or prodrug coupled through O, S or non-basic N; and

at least one of R 1 , R 2 , R 5 or B comprises a functional group for mediating coupling to a macromolecule.

11. The compound of claim 1 which is of the formula

wherein the R 1 , R 2 , R 5 , m, and B are as defined in claim 1 ;

L is a nucleofuge that mediates the coupling of a drug or prodrug through O, S, or non-basic N; and

at least one of R 1 , R 2 , R 5 or B is coupled to a macromolecule.

12. A method to prepare the compound of Formula (I) of claim 6 which method comprises reacting a compound of the formula

wherein R 1 , R 2 , R 5 , m and B are as defined in claim 1 ;

L is a nucleofuge that mediates the coupling of a drug or prodrug through O, S, or non-basic N; and

wherein one of R 1 , R 2 , R 5 and B is coupled to a macromolecule;

with a drug or prodrug under conditions whereby said prodrug is coupled to said compound of formula (IV).

13. A method to prepare the compound of Formula (III) of claim 10 which method comprises reacting a compound of the formula

wherein m, R 1 , R 2 , R 5 , m and B are as defined in claim 1 ;

L is a nucleofuge; and

at least one of R 1 , R 2 , R 5 or B comprises a functional group for mediating coupling to a macromolecule;

with a drug or prodrug under conditions whereby said drug or prodrug is coupled to said compound of formula (II).

14. A method to prepare the compound of Formula (I) of claim 6 which method comprises reacting a compound of the formula

wherein m, R 1 , R 2 , R 5 , m and B are as defined in claim 1 ;

and D is the residue of a drug or prodrug coupled through O, S or non-basic N; and

wherein at least one of R 1 , R 2 , R 5 and B comprises a functional group that couples formula (III) to a macromolecule;

with a macromolecule under conditions whereby said macromolecule is coupled to the compound of formula (III).

15. A method to prepare the compound of Formula (IV) of claim 11 which method comprises reacting a compound of the formula

wherein m, R 1 , R 2 , R 5 , m and B are as defined in claim 1 ;

L is a nucleofuge; and

wherein one of R 1 , R 2 , R 5 and B comprises a functional group that couples formula (II) to a macromolecule;

with a macromolecule under conditions whereby said macromolecule is coupled to the compound of formula (II).

16. The compound of claim 1 wherein Z is the residue of an SN-38 molecule.

17. A compound of formula (XX)

wherein R 1 , R 2 , R 5 , m and B are as defined in claim 1 .

18. The compound of claim 17 wherein m is 0.

19. The compound of claim 17 wherein m is 0; R 1 is phenylsulfonyl, substituted phenylsulfonyl, methanesulfonyl, (R 9 ) 2 N—SO 2 , or CN; R 2 is H; one R 5 is N 3 (CH 2 ) 5 and the other R 5 is H; and B is phenyl or substituted phenyl.

20. The compound of claim 17 wherein m is 0; R 1 is phenylsulfonyl, substituted phenylsulfonyl, methanesulfonyl, R 2 N—SO 2 , or CN; R 2 is H; one R 5 is optionally substituted alkyl and the other R 5 is H; and B is phenyl or substituted phenyl, and wherein one of R 1 , R 5 , and B further comprises a connection to a macromolecule.

21. The compound of claim 17 wherein R 2 and one R 5 is H and the other R 5 is N 3 + (CH 2 ) 5 , m is 0 and B is

22. The compound of claim 21 wherein R 1 is CN.