Controlled release of phenolic opioids
View Patent ↗A method of providing a patient with controlled release of a phenolic opioid using a prodrug capable, upon enzymatic activation, of releasing the phenolic opioid through intra-molecular cyclization leading to formation of a cyclic urea, carbamate or thiocarbamate.
1. A compound of structural Formula (I):
or a pharmaceutically acceptable salt thereof wherein:
X is a phenolic opioid, 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 2 or 3;
R 1 and R 2 are each hydrogen;
R 3 is hydrogen or (1-4C)alkyl; and
R 4 is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, lysine and valine; a residue of a dipeptide or tripeptide composed of two or three L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, lysine and valine; or a residue of an N-acyl derivative thereof.
2. The compound of claim 1 wherein X is oxymorphone, hydromorphone or morphine.
3. The compound of claim 1 , in which R 5 is methyl.
4. The compound of claim 1 , in which R 3 is hydrogen or methyl.
5. The compound of claim 1 , in which R 4 is a residue of arginine, N-acetylarginine, N-t-butanoylarginine, N-benzoylarginine, N-piperonylarginine, N-glycinylarginine, lysine, glutamic acid, aspartic acid, tyrosine, proline or N-glycinylproline.
6. The compound of claim 5 , in which R 4 is a residue of arginine, N-acetylarginine, N-t-butanoylarginine, N-benzoylarginine, N-piperonylarginine, N-glycinylarginine, lysine, glutamic acid, proline or N-glycinylproline.
7. A pharmaceutical composition, which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.
8. Hydromorphone 3-(N-methyl-N-(2-N′-acetylarginylamino))ethylcarbamate, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition, which comprises a compound as claimed in claim 8 and a pharmaceutically acceptable carrier.
10. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 , which comprises reacting a compound of formula (III)
or a protected derivative thereof, with a compound of formula (IV)
in which M represents a leaving atom or group;
followed by removing any protecting groups and, if desired, acylating a compound of formula (I) and/or forming a pharmaceutically acceptable salt.
11. Morphine 3-(N-methyl-N-(2-N′-acetylarginylamino))ethylcarbamate, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition, which comprises a compound as claimed in claim 11 and a pharmaceutically acceptable carrier.