Pro-drugs for controlled release of biologically active compounds

1. A compound of the general formula (I):

X—C(═O)—Y—R 1 —NR 2 R 3   (i)

or a pharmaceutically acceptable salt thereof, in which:

X is a residue of a phenolic opioid selected from buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalmefene, naloxone, N-methylnaloxone, naltrexone, N-methylnaltrexone and oxymorphone in which the hydrogen atom of the phenol group is replaced by a covalent bond to C(═O)—Y—R 1 —NR 2 R 3 ;

Y is O, S or NR 4 ;

R 1 is selected from —CH(CH 2 F)CH(CH 2 F)—; —CH(CHF 2 )CH(CHF 2 )—; —CH(CF 3 )CH(CF 3 )—; —CH 2 CH(CF 3 )—; —CH 2 CH(CHF 2 )—; —CH 2 CH(CH 2 F)—; —CH 2 CH(F)CH 2 —; —CH 2 C(F 2 )CH 2 —; —CH(CH 2 F)CH 2 CH(CH 2 F)—; —CH(CHF 2 )CH 2 CH(CHF 2 )—; —CH(CF 3 )CH 2 CH(CF 3 )—; —CH 2 CH 2 CH(CF 3 )—; —CH 2 CH 2 CH(CHF 2 )—; and —CH 2 CH 2 CH(CH 2 F)—;

R 2 is hydrogen or (1-4C)alkyl;

R 3 is an L-arginine or L-lysine residue or an N-acyl derivative thereof, or is a peptide, or an N-acyl derivative of the peptide, wherein the residue of the peptide bonded to N is an L-arginine or L-lysine residue; and

R 4 is hydrogen or (1-4C)alkyl;

wherein a digestive enzyme mediates release of X when the compound is administered to a patient.

2. A compound as claimed in claim 1 , in which Y is NR 4 .

3. A compound as claimed in claim 2 , in which R 4 is methyl.

4. A compound as claimed in claim 2 , in which R 2 is hydrogen.

5. A compound as claimed in claim 2 , in which R 3 is a peptide or an N-acyl derivative thereof.

6. A compound as claimed in claim 5 , in which R 3 is a dipeptide or tripeptide.

7. A compound as claimed in claim 1 , in which R 3 is L-arginine, N-acetylarginine, N-glycinylarginine, N-acetylglycinylarginine, L-lysine, or N-acetyllysine.

8. A compound as claimed in claim 1 , in which R 3 is a residue of L-lysine or L-arginine, or an N-acetyl or N-benzoyl derivative thereof.

9. A compound as claimed in claim 1 , in which the phenolic opioid is selected from buprenorphine, dihydroetorphine, etorphine, hydromorphone, levorphanol, morphine and oxymorphone.

10. A compound as claimed in claim 1 , in which the phenolic opioid is hydromorphone, morphine or oxymorphone.

11. A pharmaceutical composition, which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

12. A method of treating pain in a patient in need of treatment, which comprises administering an effective amount of a compound as claimed in claim 9 .

13. A process for the preparation of a compound as defined in claim 1 , which comprises:

a) reacting a compound of formula (II)

X—C(═O)—Z  (II)

or a protected derivative thereof, in which Z represents a leaving atom or group, with a compound of formula (III)

H—Y—R 1 —NR 2 R 3   (III)

or a protected derivative thereof; or

b) reacting a compound of formula (IV)

X—C(═O)—Y—R 1 —NHR 2   (IV)

or a protected derivative thereof, with a compound of formula (V)

HR 3   (V)

or a protected derivative thereof, or reactive derivative of said compound of formula (V) or protected derivative thereof;

followed, if desired, by N-acylating an amino group in R 3 to afford another compound of formula (I);

removing any protecting groups and, if desired, forming a pharmaceutically acceptable salt.

14. A method of providing a patient with post administration-activated, controlled release of a phenolic opioid comprising administering to said patient a compound according to claim 1 .

15. A compound as claimed in claim 1 , in which R 4 is methyl.

16. A compound as claimed in claim 2 , in which the phenolic opioid is selected from buprenorphine, dihydroetorphine, etorphine, hydromorphone, levorphanol, morphine and oxymorphone.

17. A method of treating pain in a patient in need of treatment, which comprises administering an effective amount of a compound as claimed in claim 16 .

18. A compound as claimed in claim 2 , in which the phenolic opioid is hydromorphone, morphine or oxymorphone.

19. A pharmaceutical composition which comprises a compound as claimed in claim 2 and a pharmaceutically acceptable carrier.

20. A method as claimed in claim 14 , in which Y is NR 4 .

21. A method as claimed in claim 20 , in which R 2 is hydrogen.