Compositions comprising enzyme-cleavable phenol-modified tapentadol prodrug
View Patent ↗A method of providing a patient with controlled release of tapentadol using a prodrug capable, upon enzymatic activation and intramolecular cyclization, of releasing tapentadol is disclosed. The disclosure also provides such prodrug compounds and pharmaceutical compositions comprising such compounds. Such pharmaceutical compositions can optionally include an enzyme inhibitor that interacts with the enzyme(s) to mediate the enzymatically-controlled release of tapentadol from the prodrug so as to modify enzymatic cleavage of the prodrug. Also included are methods to use such compounds and pharmaceutical compositions.
1. A compound of formula TP-1:
or a salt, hydrate or solvate thereof.
2. The compound of claim 1 , wherein the compound is of formula TP-1 or a salt thereof.
3. A method of treating or preventing pain in a patient in need thereof, which comprises administering an effective amount of a compound of claim 2 .
4. A composition comprising a compound of claim 2 ; and
a pharmaceutically acceptable carrier.
5. The composition of claim 4 , further comprising a trypsin inhibitor.
6. The composition of claim 5 , wherein the trypsin inhibitor is a compound selected from the group consisting of:
BBSI;
SBTI;
(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-yl4-(diaminomethyleneamino)benzoate; and
4,4′-(pentane-1,5-diylbis(oxy))dibenzimidamide.
7. A compound of formula TP-3:
or a salt, hydrate or solvate thereof.
8. The compound of claim 7 , wherein the compound is of formula TP-3 or a salt thereof.
9. A method of treating or preventing pain in a patient in need thereof, which comprises administering an effective amount of a compound of claim 8 .
10. A composition comprising
a compound of claim 8 ; and
a pharmaceutically acceptable carrier.
11. The composition of claim 10 , further comprising a trypsin inhibitor.
12. The composition of claim 11 , wherein the trypsin inhibitor is a compound selected from the group consisting of:
BBSI;
SBTI;
(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.
13. A compound of formula TP-4:
or a salt, hydrate or solvate thereof.
14. The compound of claim 13 , wherein the compound is of formula TP-4 or a salt thereof.
15. A method of treating or preventing pain in a patient in need thereof, which comprises administering an effective amount of a compound of claim 14 .
16. A composition comprising
a compound of claim 14 ; and
a pharmaceutically acceptable carrier.
17. The composition of claim 16 , further comprising a trypsin inhibitor.
18. The composition of claim 17 , wherein the trypsin inhibitor is a compound selected from the group consisting of:
BBSI;
SBTI;
(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.
19. A compound of formula TC-(I):
wherein:
R 5 is methyl;
each R 1 is hydrogen or methyl;
each R 2 is hydrogen or methyl;
n is 2 or 3;
R 3 is hydrogen:
R 4 is
p is 1;
R 6 is —CH 2 CH 2 CH 2 NH(C═NH)NH 2 or —CH 2 CH 2 CH 2 CH 2 NH 2 ;
W is —NR 8 —;
R 8 is hydrogen; and
R 7 is malonyl;
or a salt, hydrate or solvate thereof.
20. The compound of claim 19 , wherein the compound is of formula TC-(I) or a salt thereof.
21. A method of treating or preventing pain in a patient in need thereof, which comprises administering an effective amount of a compound of claim 20 .
22. A composition comprising
a compound of claim 20 ; and
a pharmaceutically acceptable carrier.
23. The composition of claim 22 , further comprising a trypsin inhibitor.
24. The composition of claim 23 , wherein the trypsin inhibitor is a compound selected from the group consisting of:
BBSI;
SBTI;
(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-yl4-(diaminomethyleneamino)benzoate; and
4,4′-(pentane-1,5-diylbis(oxy))dibenzimidamide.