Prodrugs of Peripheral Phenolic Opioid Antagonists

1 . A method of antagonising peripheral action of an opioid in a patient undergoing opioid treatment, which comprises orally administering to said patient an effective amount of a compound of formula (I)

or a salt, hydrate or solvate thereof wherein:

X is a residue of a peripheral phenolic opioid antagonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—Y—(C(R 1 )(R 2 )) n —N—(R 3 )(R 4 );

Y is —NR 5 — and R 5 is (1-4C)alkyl;

n is an integer from 1 to 10;

each R 1 , R 2 , and R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;

R 4 is hydrogen

or a derivative thereof capable of delivering the compound of formula (I) into the gut.

2 . A method as claimed in claim 1 , in which the peripheral phenolic opioid antagonist is (R)—N-methylnaltrexone, N-methylnaloxone, N-methyldiprenorphine or N-methylnalmefene.

3 . A method as claimed in claim 1 , in which the peripheral phenolic opioid antagonist is (R)—N-methylnaltrexone or N-methylnaloxone.

4 . (canceled)

5 . A method as claimed in claim 1 , in which R 5 is methyl.

6 . A method as claimed in claim 1 , in which n is 2 or 3.

7 . A method as claimed in claim 1 , in which R 1 and R 2 are each hydrogen.

8 . A method as claimed in claim 1 , in which R 3 is hydrogen or (1-4C)alkyl.

9 . A compound of structural Formula (I):

or a salt, hydrate or solvate thereof wherein:

X is (R)—N-methylnaltrexone, N-methylnaloxone, N-methyldiprenorphine or N-methylnalmefene wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—Y—(C(R 1 )(R 2 )) n —N—(R 3 )(R 4 );

Y is —NR 5 —, —O— or —S—;

n is an integer from 1 to 10;

each R 1 , R 2 , R 3 and R 5 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; and

R 4 is hydrogen.

10 . A compound as claimed in claim 9 , wherein X is (R)—N-methylnaltrexone or N-methylnaloxone.

11 . A compound as claimed in claim 9 , in which Y is NR 5 and R 5 is hydrogen or (1-4C)alkyl.

12 . A compound as claimed in claim 11 , in which R 5 is methyl.

13 . A compound as claimed in claim 9 , in which n is 2 or 3.

14 . A compound as claimed in claim 9 , in which R 1 and R 2 are each hydrogen.

15 . A compound as claimed in claim 9 , in which R 3 is hydrogen or (1-4C)alkyl.

16 . A pharmaceutical composition, which comprises a compound as claimed in claim 9 and a pharmaceutically acceptable carrier.

17 . (canceled)

18 . A compound as claimed in claim 9 , wherein X is (R)—N-methylnaltrexone.

19 . A compound as claimed in claim 9 , wherein X is N-methylnaloxone.

20 . A compound as claimed in claim 9 , wherein

X is (R)—N-methylnaltrexone, N-methylnaloxone, N-methyldiprenorphine or N-methylnalmefene wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—Y—(C(R 1 )(R 2 )) n —N—(R 3 )(R 4 );

Y is —NR 5 —;

R 5 is (1-4C)alkyl;

R 1 and R 2 are independently selected from hydrogen and (1-4C)alkyl;

n is 2 or 3;

R 3 is hydrogen or (1-4C)alkyl;

R 4 is hydrogen.

21 . A compound as claimed in claim 20 , wherein X is (R)—N-methylnaltrexone.

22 . A compound as claimed in claim 20 , wherein X is N-methylnaloxone.