Pharmaceutical compositions with attenuated release of phenolic opioids
View Patent ↗Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise a phenolic opioid prodrug that provides enzymatically-controlled release of a phenolic opioid, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the phenolic opioid from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
1. A pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general formula (II):
X—C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 ) (II)
or a pharmaceutically acceptable salt thereof, in which:
X represents a residue of a phenolic opioid selected from the group consisting of buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalmefene, naloxone, N-methylnaloxone, naltrexone, N-methylnaltrexone, oxymorphone, oripavine, ketobemidone, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, meptazinol, O-desmethyltramadol, tapentadol, and nalorphine, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—NR 1 —(C(R 2 )(R 3 )) n —NH—C(O)—CH(R 4 )—NH(R 5 );
R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
each R 3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
or R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
n represents an integer from 2 to 4;
R 4 represents —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 , the configuration of the carbon atom to which R 4 is attached corresponding with that in an L-amino acid; and
R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
2. The pharmaceutical composition of claim 1 , wherein R 1 represents a (1-4C)alkyl group.
3. The pharmaceutical composition of claim 1 , wherein R 1 represents a methyl or ethyl group.
4. The pharmaceutical composition of claim 1 , wherein R 1 represents a methyl group.
5. The pharmaceutical composition of claim 1 , wherein each of R 2 and R 3 each independently represents a hydrogen atom or a (1-4C)alkyl group.
6. The pharmaceutical composition of claim 1 , wherein R 5 is acetyl, benzoyl, malonyl, piperonyl, succinyl, N-acetylarginine or N-acetyllysine.
7. The pharmaceutical composition of claim 1 , wherein R 2 and R 3 are hydrogen.
8. The pharmaceutical composition of claim 1 , wherein R 2 and R 3 which are on the same carbon are alkyl.
9. The pharmaceutical composition of claim 1 , wherein R 2 and R 3 which are on the same carbon form a spirocycle.
10. The pharmaceutical composition of claim 1 , wherein R 2 and R 3 which are on the same carbon are methyl.
11. The pharmaceutical composition of claim 1 , wherein R 2 and R 3 can modulate a rate of intramolecular cyclization.
12. The pharmaceutical composition of claim 1 , wherein R 2 and R 3 comprise an electron-withdrawing group or an electron-donating group.
13. The pharmaceutical composition of claim 1 , wherein—[C(R 2 )(R 3 )] n — is selected from; —CH(CF 3 )CH(CF 3 )—; —CH 2 CH(F)CH 2 —; —CH 2 C(F 2 )CH 2 —; —CH 2 CH(C(O)NR 20 R 21 )—; —CH 2 CH(C(O)OR 22 )—; —CH 2 CH(C(O)OH)—; —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(C(O)NR 23 R 24 )—; —CH 2 CH 2 CH(C(O)OR 25 )—; and —CH 2 CH 2 CH(C(O)OH)—, in which R 20 , R 21 , R 22 and R 23 each independently represents hydrogen or (1-6C)alkyl, and R 24 and R 25 each independently represents (1-6C)alkyl.
14. The pharmaceutical composition of claim 1 , wherein one of R 2 and R 3 is aminoacyl.
15. The pharmaceutical composition of claim 1 , wherein one of R 2 and R 3 is
wherein each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, and acyl, and R 11 is alkyl or substituted alkyl.
16. The pharmaceutical composition of claim 1 , wherein n represents 2 or 3.
17. The pharmaceutical composition of claim 1 , wherein n represents 2.
18. The pharmaceutical composition of claim 1 , wherein R 4 represents —CH 2 CH 2 CH 2 NHC(═NH)(NH 2 ).
19. The pharmaceutical composition of claim 1 , wherein R 5 represents an N-acyl group.
20. The pharmaceutical composition of claim 19 , wherein the N-acyl group is an N-(1-4C)alkanoyl, N-benzoyl or N-piperonyl group.
21. The pharmaceutical composition of claim 19 , wherein R 5 is acetyl, benzoyl, malonyl, piperonyl, succinyl, N-acetylarginine or N-acetyllysine.
22. The pharmaceutical composition of claim 1 , wherein R 5 is an acetyl, glycinyl or N-acetylglycinyl group.
23. The pharmaceutical composition of claim 22 , wherein R 5 is an acetyl group.
24. The pharmaceutical composition of claim 1 , wherein the group —C(O)—CH(R 4 )—NH(R 5 ) is N-acetylarginine.
25. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is derived from soybean.
26. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is an arginine mimic or a lysine mimic.
27. The pharmaceutical composition of claim 22 , wherein the arginine mimic or lysine mimic is a synthetic compound.
28. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is a compound of formula:
wherein:
Q 1 is selected from —O-Q 4 or -Q 4 —COOH, where Q 4 is C 1 -C 4 alkyl;
Q 2 is N or CH; and
Q 3 is aryl or substituted aryl.
29. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is a compound of formula:
wherein:
Q 5 is —C(O)—COOH or —NH-Q 6 -Q 7 -SO 2 —C 6 H 5 , where
Q 6 is —(CH 2 ) p —COOH;
Q 7 is —(CH 2 )—C 6 H 5 ; and
p is an integer from one to three; and
r is an integer from one to three.
30. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is selected from
(S)-ethyl 4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazine-1-carboxylate;
(S)-ethyl 4-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperazine-1-carboxylate;
(S)-ethyl 1-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperidine-4-carboxylate;
(S)-ethyl 1-(5-guanidino-2-(2,4,6-triisopropylphenylsulfonamido)pentanoyl)piperidine-4-carboxylate;
(S)-6-(4-(5-guanidino-2-(naphthalene-2-sulfonamido)pentanoyl)piperazin-1-yl)-6-oxohexanoic acid;
4-aminobenzimidamide;
3-(4-carbamimidoylphenyl)-2-oxopropanoic acid;
(S)-5-(4-carbamimidoylbenzylamino)-5-oxo-4-((R)-4-phenyl-2-(phenylmethylsulfonamido)butanamido)pentanoic acid;
6-carbamimidoylnaphthalen-2-yl 4-(diaminomethyleneamino)benzoate; and
4,4′-(pentane-1,5-diylbis(oxy))dibenzimidamide.
31. The pharmaceutical composition of claim 1 , wherein the trypsin inhibitor is 6-carbamimidoylnaphthalen-2-yl 4-(diaminomethyleneamino)benzoate.