ENZYME-CLEAVABLE METHADONE PRODRUGS AND METHODS OF USE THEREOF
The present disclosure provides methadone prodrugs, pharmaceutical compositions, and their methods of use, where the pharmaceutical compositions comprise a methadone prodrug that provides enzymatically-controlled release of methadone, and an optional enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of methadone from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
1 - 351 . (canceled)
352 . Compound MD-110, shown below:
or a salt, hydrate or solvate thereof.
353 . A composition comprising:
Compound MD-110, shown below:
or a salt, hydrate or solvate thereof.
354 . A method comprising administering to a subject in need thereof a composition of claim 353 .
355 . A composition comprising:
Compound MD-110, shown below:
or a salt, hydrate or solvate thereof; and
a GI enzyme inhibitor.
356 . The composition of claim 355 , wherein the GI enzyme inhibitor is a trypsin inhibitor.
357 . The composition of claim 356 , wherein the trypsin inhibitor is a compound of
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.
358 . The composition of claim 356 , 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 ) r —C 6 H 5 ;
Q 8 is NH;
n is a number from zero to two;
o is zero or one;
p is an integer from one to three; and
r is an integer from one to three.
359 . The composition of claim 356 , 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 ) r —C 6 H 5 ; and
p is an integer from one to three; and
r is an integer from one to three.
360 . The composition of claim 356 , wherein the trypsin inhibitor is a compound of formula:
wherein
X is NH;
n is zero or one; and
R t1 is selected from hydrogen, halogen, nitro, alkyl, substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, aminoacyl, guanidine, amidino, carbamide, amino, substituted amino, hydroxyl, cyano and —(CH 2 ) m —C(O)—O—(CH 2 ) m —C(O)—N—R n1 R n2 , wherein each m is independently zero to 2; and R n1 and R n2 are independently selected from hydrogen and C 1-4 alkyl.
361 . The composition of claim 356 , wherein the trypsin inhibitor is a compound of formula:
wherein
X is NH;
n is zero or one;
L t1 is selected from —C(O)—O—; —O—C(O)—; —O—(CH 2 ) m —O—; —OCH 2 —Ar t2 —CH 2 O—; —C(O)—NR t3 ; and —NR t3 —C(O)—;
R 3 is selected from hydrogen, C 1-6 alkyl, and substituted C 1-6 alkyl;
Ar t1 and Ar t2 are independently a substituted or unsubstituted aryl group;
m is a number from 1 to 3; and
R t2 is selected from hydrogen, halogen, nitro, alkyl, substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, aminoacyl, guanidine, amidino, carbamide, amino, substituted amino, hydroxyl, cyano and —(CH 2 ) m -C(O)—O—(CH 2 ) m -C(O)—N—R n1 R n2 , wherein each m is independently zero to 2; and R n1 and R n2 are independently selected from hydrogen and C 1-4 alkyl.
362 . The composition of claim 356 , wherein the trypsin inhibitor is a compound of formula:
wherein
each X is NH;
each n is independently zero or one;
L t1 is selected from —C(O)—O—; —O—C(O)—; —O—(CH 2 ) m -O—; —OCH 2 —Ar t2 —CH 2 O—; —C(O)—NR t3 —; and —NR t3 —C(O)—;
R t3 is selected from hydrogen, C 1-6 alkyl, and substituted C 1-6 alkyl;
Ar t1 and Ar t2 are independently a substituted or unsubstituted aryl group; and
m is a number from 1 to 3.
363 . The composition of claim 356 , 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.
364 . The composition of claim 363 , wherein the trypsin inhibitor is 6-carbamimidoylnaphthalen-2-yl 4-(diaminomethyleneamino)benzoate (Compound 109).