US2016002291A1PendingUtilityA1
Active Agent Prodrugs with Heterocyclic Linkers
Est. expiryMar 9, 2031(~4.6 yrs left)· nominal 20-yr term from priority
A61K 47/65C07K 5/0207A61P 25/36A61P 43/00C07K 5/06A61P 25/04A61K 45/06A61K 38/05C07K 5/06026C07K 5/08A61P 29/00A61K 38/06A61K 31/24A61K 38/00G01N 33/94C07K 5/06095
53
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Claims
Abstract
The embodiments provide prodrug compounds of Formulae I-XVII. The present disclosure also provides compositions, and their methods of use, where the compositions comprise a prodrug compound of Formulae I-XVII that provides controlled release of an active agent. Such compositions can optionally provide a trypsin inhibitor that interacts with the enzyme that mediates the controlled release of an active agent from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula I:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
2 . A compound of formula II:
wherein
X is selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing opioid, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
3 . A compound of formula IIIa:
wherein
X represents a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
4 . A compound of formula Va:
wherein
X represents a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
5 . A compound of formula VIa:
wherein
X represents a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects —C(O)—CH(R 5 )—N(R 3 )— to be a GI enzyme-cleavable moiety;
each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
6 . The compound of any of claims 2 - 4 , wherein X is selected from acetylmorphone, hydrocodone, hydromorphone, ketobemidone, methadone, naloxone, naltrexone, N-methylnaloxone, N-methylnaltrexone, oxycodone, oxymorphone, and pentamorphone.
7 . The compound of any of claims 2 - 4 , wherein X is selected from hydrocodone and oxycodone.
8 . The compound of claim 3 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
9 . The compound of claim 7 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
10 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
11 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
12 . The compound of claim 10 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, and L-ornithine.
13 . The compound of any of claims 3 - 4 , wherein R 5 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 5 is attached corresponding with that in an L-amino acid.
14 . The compound of any of claims 3 - 4 , wherein R 6 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
15 . The compound of any of claims 3 - 4 , wherein R 6 that is immediately adjacent to R 5 represents —H or —CH 3 , the configuration of the carbon atom to which R 6 is attached corresponding with that in an L-amino acid.
16 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine and b is one.
17 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of an amino acid selected from L-alanine and glycine; and b is one.
18 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of glycine; and b is one.
19 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of L-alanine; and b is one.
20 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of glycine; and b is one.
21 . The compound of any of claims 3 - 4 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of L-alanine; and b is one.
22 . A compound of formula VIIa:
wherein
X represents a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
23 . A compound of formula IXa:
wherein
X represents a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
24 . A compound of formula Xa:
wherein
X represents a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects —C(O)—CH(R 5 )—N(R 3 )— to be a GI enzyme-cleavable moiety;
each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
25 . The compound of any of claims 21 - 23 , wherein X is selected from buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone, N-methyldiprenorphine, N-methylnaloxone, N-methylnaltrexone, oripavine, oxymorphone, butorphanol, dezocine, ketobemidone, meptazinol, o-desmethyltramadol, pentazocine, phenazocine, and tapentadol.
26 . The compound of any of claims 21 - 23 , wherein X is selected from hydromorphone, morphine, oxymorphone, and tapentadol.
27 . The compound of claim 22 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
28 . The compound of claim 26 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
29 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
30 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
31 . The compound of claim 29 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, and L-ornithine.
32 . The compound of any of claims 22 - 23 , wherein R 5 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 5 is attached corresponding with that in an L-amino acid.
33 . The compound of any of claims 22 - 23 , wherein R 6 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
34 . The compound of any of claims 22 - 23 , wherein R 6 that is immediately adjacent to R 5 represents —H or —CH 3 , the configuration of the carbon atom to which R 6 is attached corresponding with that in an L-amino acid.
35 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine and b is one.
36 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of an amino acid selected from L-alanine and glycine; and b is one.
37 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of glycine; and b is one.
38 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of L-alanine and b is one.
39 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of L-arginine;
R 6 is a side chain of glycine; and b is one.
40 . The compound of any of claims 22 - 23 , wherein R 5 is a side chain of L-arginine;
R 6 is a side chain of L-alanine; and b is one.
41 . A compound of formula XIa:
wherein
X represents a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
42 . A compound of formula XIIa:
wherein
X represents a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
43 . A compound of formula XIIIa:
wherein
X represents a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects —C(O)—CH(R 5 )—N(R 3 )— to be a GI enzyme-cleavable moiety;
each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
44 . The compound of any of claims 40 - 42 , wherein X is selected from alfentanil, carfentanil, fentanyl, lofentanil, loperamide, ohmefentanyl, remifentanil, and sufentanil.
45 . The compound of claim 41 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
46 . The compound of claim 44 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
47 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
48 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
49 . The compound of claim 47 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, and L-ornithine.
50 . The compound of any of claims 41 - 42 , wherein R 5 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 5 is attached corresponding with that in an L-amino acid.
51 . The compound of any of claims 41 - 42 , wherein R 6 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
52 . The compound of any of claims 41 - 42 , wherein R 6 that is immediately adjacent to R 5 represents —H or —CH 3 , the configuration of the carbon atom to which R 6 is attached corresponding with that in an L-amino acid.
53 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine and b is one.
54 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of an amino acid selected from L-alanine and glycine; and b is one.
55 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of glycine; and b is one.
56 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of L-alanine; and b is one.
57 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of glycine; and b is one.
58 . The compound of any of claims 41 - 42 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of L-alanine; and b is one.
59 . A compound of formula XIV:
wherein
X represents acetaminophen, wherein the hydrogen atom of the phenolic hydroxyl group of acetaminophen is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; or wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
60 . The compound of claim 59 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
61 . The compound of claim 60 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
62 . The compound of claim 59 , wherein R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
63 . The compound of claim 59 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
64 . The compound of claim 63 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, and L-ornithine.
65 . The compound of any of claims 60 - 61 , wherein R 5 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 5 is attached corresponding with that in an L-amino acid.
66 . The compound of claim 59 , wherein R 6 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
67 . The compound of claim 59 , wherein R 6 that is immediately adjacent to R 5 represents —H or —CH 3 , the configuration of the carbon atom to which R 6 is attached corresponding with that in an L-amino acid.
68 . The compound of claim 59 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine and b is one.
69 . The compound of claim 59 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of an amino acid selected from L-alanine and glycine; and b is one.
70 . The compound of claim 59 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of glycine; and b is one.
71 . The compound of any of claims 60 - 61 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of L-alanine; and b is one.
72 . The compound of claim 59 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of glycine; and b is one.
73 . The compound of claim 59 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of L-alanine; and b is one.
74 . A compound of formula XVa:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
A 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
A 3 is carbon or nitrogen;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
75 . A compound of formula XVIa:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
A 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
A 3 is carbon or nitrogen;
Y is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
76 . A compound of formula XVIIa:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
A 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
A 3 is carbon or nitrogen;
Y is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects —C(O)—CH(R 5 )—N(R 3 )— to be a GI enzyme-cleavable moiety;
each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
b is a number from zero to 100;
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or a salt, hydrate or solvate thereof.
77 . The compound of any of claims 74 - 76 , wherein A 1 , A 2 , A 4 , and A 5 are carbon.
78 . The compound of any of claims 74 - 76 , wherein A 3 is carbon.
79 . The compound of any of claims 74 - 76 , wherein A 3 is nitrogen.
80 . The compound of claim 75 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
81 . The compound of claim 80 , wherein R 5 is a side chain of an L-amino acid selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
82 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
83 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
84 . The compound of claim 83 , wherein R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, and L-ornithine.
85 . The compound of any of claims 75 - 76 , wherein R 5 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 5 is attached corresponding with that in an L-amino acid.
86 . The compound of any of claims 75 - 76 , wherein R 6 is a side chain of an L-amino acid independently selected from L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
87 . The compound of any of claims 75 - 76 , wherein R 6 that is immediately adjacent to R 5 represents —H or —CH 3 , the configuration of the carbon atom to which R 6 is attached corresponding with that in an L-amino acid.
88 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine and b is one.
89 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of an amino acid selected from L-alanine and glycine; and b is one.
90 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of glycine; and b is one.
91 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of L-alanine; and b is one.
92 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of glycine; and b is one.
93 . The compound of any of claims 75 - 76 , wherein R 5 is a side chain of L-arginine; R 6 is a side chain of L-alanine; and b is one.
94 . The compound of any of claims 1 - 93 , wherein A ring is a heterocyclic 5 or 6-membered ring.
95 . The compound of any of claims 1 - 93 , wherein A ring is a heterocyclic 5-membered ring and a is 2.
96 . The compound of any of claims 1 - 93 , wherein A ring is a heterocyclic 6-membered ring and a is one.
97 . The compound of any of claims 1 - 93 , wherein each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl.
98 . The compound of any of claims 1 - 93 , wherein each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl.
99 . The compound of any of claims 1 - 93 , wherein R 1 and R 2 are hydrogen.
100 . The compound of any of claims 1 - 93 , wherein R 1 and R 2 which are on the same carbon are alkyl.
101 . The compound of any of claims 1 - 93 , wherein R 1 and R 2 which are on the same carbon are methyl.
102 . The compound of any of claims 1 - 93 , wherein R 1 and R 1 which are vicinal are both alkyl and R 2 and R 2 which are vicinal are both hydrogen.
103 . The compound of any of claims 1 - 93 , wherein R 1 and R 1 which are vicinal are both methyl and R 2 and R 2 which are vicinal are both hydrogen.
104 . The compound of any of claims 1 - 93 , wherein one of R 1 and R 2 is carboxyl.
105 . The compound of any of claims 1 - 93 , wherein one of R 1 and R 2 is amino.
106 . The compound of any of claims 1 - 93 , wherein one of R 1 and R 2 is aminoacyl.
107 . The compound of any of claims 1 - 93 , wherein Y is carboxyl.
108 . The compound of any of claims 1 - 93 , wherein Y is amino.
109 . The compound of any of claims 1 - 93 , wherein Y is aminoacyl.
110 . The compound of any of claims 1 - 93 , wherein c is zero or one.
111 . The compound of any of claims 1 - 93 , wherein c is zero.
112 . The compound of any of claims 1 - 93 , wherein c is one.
113 . The compound of any of claims 1 - 93 , wherein R 3 is hydrogen or alkyl.
114 . The compound of any of claims 1 - 3 , 22 , 41 , 59 , and 74 wherein R 5 is selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, and substituted heteroarylalkyl.
115 . The compound of any of claims 1 - 3 , 22 , 41 , 59 , and 74 wherein b is a number from zero to 50.
116 . The compound of any of claims 1 - 3 , 22 , 41 , 59 , and 74 , wherein b is zero or one.
117 . The compound of any of claims 1 - 93 , wherein R 7 is hydrogen, acyl, or substituted acyl.
118 . The compound of any of claims 1 - 93 , wherein R 7 is selected from hydrogen, acetyl, benzoyl, malonyl, piperonyl and succinyl.
119 . The compound of any of claims 1 - 93 , wherein R 7 is acetyl or malonyl.
120 . A compound of the following formula:
121 . A composition comprising
a compound of any of claims 1 - 120 ; and a pharmaceutically acceptable carrier.
122 . A method of treating pain in a patient in need thereof, which comprises administering an effective amount of a compound of any of claims 1 - 120 or an effective amount of a composition of claim 121 .
123 . A method of preventing pain in a patient in need thereof, which comprises administering an effective amount of a compound of any of claims 1 - 120 or an effective amount of a composition of claim 121 .
124 . A compound of any of claims 1 - 120 or an effective amount of a composition of claim 121 for use in medical therapy.
125 . A compound of any of claims 1 - 120 or an effective amount of a composition of claim 121 for use in a method of treating a patient suffering from, or at risk of suffering from, pain.
126 . Use of a compound of any of claims 1 - 120 or an effective amount of a composition of claim 121 for treatment of a patient suffering from, or at risk of suffering from, pain.
127 . Use of a compound of any of claims 1 - 120 or a composition of claim 121 for the preparation of a medicament for treatment of a patient suffering from, or at risk of suffering from, pain.
128 . A composition comprising
a trypsin inhibitor; a compound of any of claims 1 - 120 ; and a pharmaceutically acceptable carrier.
129 . The composition of claim 128 , wherein the trypsin inhibitor is derived from soybean.
130 . The composition of claim 128 , wherein the trypsin inhibitor is an arginine mimic or a lysine mimic.
131 . The composition of claim 130 , wherein the arginine mimic or lysine mimic is a synthetic compound.
132 . The composition of claim 128 , wherein the trypsin inhibitor is Compound 109.
133 . A method for reducing drug abuse potential of a composition containing an active agent prodrug, the method comprising: combining a compound of any of claims 1 - 120 with a trypsin inhibitor, wherein the trypsin inhibitor reduces the ability of a user to release the active agent from the active agent prodrug by addition of trypsin.
134 . A method of treating pain in a patient in need thereof, which comprises administering an effective amount of a composition of any of claims 128 - 132 .
135 . A method of preventing pain in a patient in need thereof, which comprises administering an effective amount of a composition of any of claims 128 - 132 .
136 . A composition of any of claims 128 - 132 for use in medical therapy.
137 . A composition of any of claims 128 - 132 for use in a method of treating a patient suffering from, or at risk of suffering from, pain.
138 . Use of a composition of any of claims 128 - 132 for treatment of a patient suffering from, or at risk of suffering from, pain.
139 . Use of a composition of any of claims 128 - 132 for the preparation of a medicament for treatment of a patient suffering from, or at risk of suffering from, pain.
140 . A composition comprising:
an active agent prodrug comprising an active agent covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by a GI enzyme mediates release of the active agent; wherein the active agent prodrug is of formula I:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof; and
a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the active agent from the active agent prodrug following ingestion of the composition.
141 . A composition of claim 140 , wherein the GI enzyme is trypsin, and wherein the GI enzyme-cleavable moiety is a trypsin-cleavable moiety, and wherein the GI enzyme inhibitor is a trypsin inhibitor.
142 . A dose unit comprising the composition of any of claims 140 - 141 , wherein
the active agent prodrug and the inhibitor are present in the dose unit in an amount effective to provide for a pre-selected pharmacokinetic (PK) profile following ingestion.
143 . The dose unit of claim 142 , wherein the pre-selected PK profile comprises at least one PK parameter value that is less than the PK parameter value of active agent released following ingestion of an equivalent dosage of active agent prodrug in the absence of inhibitor.
144 . The dose unit of claim 142 , wherein the pre-selected PK profile comprises at least one PK parameter value that is less than the PK parameter value of opioid released following ingestion of an equivalent dosage of active agent drug.
145 . The dose unit of claim 142 , wherein the PK parameter value is selected from an active agent Cmax value, an active agent exposure value, and a (1/active agent Tmax) value.
146 . The dose unit of claim 142 , wherein the dose unit provides for a pre-selected PK profile following ingestion of at least two dose units.
147 . The dose unit of claim 146 , wherein the pre-selected PK profile is modified relative to the PK profile following ingestion of an equivalent dosage of active agent prodrug in the absence of inhibitor.
148 . The dose unit of claim 146 , wherein the pre-selected PK profile is modified relative to the PK profile following ingestion of an equivalent dosage of active agent drug.
149 . The dose unit of claim 146 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a linear PK profile.
150 . The dose unit of claim 146 , wherein the dose unit provides that ingestion of an increasing number of the dose units provides for a nonlinear PK profile.
151 . The dose unit of claim 146 , wherein the PK parameter value is selected from an active agent Cmax value, a (1/active agent Tmax) value, and an active agent exposure value.
152 . A method to treat a patient comprising administering a composition of claim 140 or claim 141 or dose unit of any of claims 142 - 151 to a patient in need thereof.
153 . A method of making a dose unit, the method comprising:
combining in a dose unit:
an active agent prodrug comprising an active agent covalently bound to a promoiety cleavable by a GI enzyme, wherein cleavage of the promoiety by the GI enzyme mediates release of the active agent from the active agent prodrug;
wherein the active agent prodrug is of formula I:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof; and
a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically-controlled release of the active agent from the active agent prodrug;
wherein the active agent prodrug and the GI enzyme inhibitor are present in the dose unit in an amount effective to attenuate release of the active agent from the active agent prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of active agent.
154 . A method of claim 153 , wherein said release of drug is decreased compared to release of drug by an equivalent dosage of prodrug in the absence of inhibitor.
155 . A method for identifying an active agent prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
combining an active agent prodrug, a GI enzyme inhibitor, and a GI enzyme in a reaction mixture, wherein the active agent prodrug comprises an active agent covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the GI enzyme mediates release of the active agent;
wherein the active agent prodrug is of formula I:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof; and
detecting active agent prodrug conversion,
wherein a decrease in active agent prodrug conversion in the presence of the GI enzyme inhibitor as compared to active agent prodrug conversion in the absence of the GI enzyme inhibitor indicates the active agent prodrug and the GI enzyme inhibitor are suitable for formulation in a dose unit.
156 . A method for identifying an active agent prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
administering to an animal an active agent prodrug and a GI enzyme inhibitor, wherein the active agent prodrug comprises an active agent covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the GI enzyme mediates release of the active agent;
wherein the active agent prodrug is of formula I:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof; and
detecting active agent prodrug conversion, wherein a decrease in active agent conversion in the presence of the GI enzyme inhibitor as compared to active agent conversion in the absence of the GI enzyme inhibitor indicates the active agent prodrug and the GI enzyme inhibitor are suitable for formulation in a dose unit.
157 . The method of claim 156 , wherein said administering comprises administering to the animal increasing doses of inhibitor co-dosed with a selected fixed dose of active agent prodrug.
158 . The method of claim 157 , wherein said detecting facilitates identification of a dose of inhibitor and a dose of active agent prodrug that provides for a pre-selected pharmacokinetic (PK) profile.
159 . The method of claim 156 , wherein said method comprises an in vivo assay.
160 . The method of claim 156 , wherein said method comprises an ex vivo assay.
161 . A method for identifying an active agent prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit, the method comprising:
administering to an animal tissue an active agent prodrug and a GI enzyme inhibitor, wherein the active agent prodrug comprises an active agent covalently bound to a promoiety comprising a GI enzyme-cleavable moiety, wherein cleavage of the GI enzyme-cleavable moiety by the GI enzyme mediates release of the active agent;
wherein the active agent prodrug is of formula I:
wherein
X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—[(A ring)-Y c ]—(CR 1 R 2 ) a NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 ; and a residue of an amide-containing active agent, wherein —C(O)—N[(A ring)-Y c ]—(CR 1 R 2 ) a —NH—C(O)—CH(R 5 )—N(R 3 )—[C(O)—CH(R 6 )—N(R 3 )] b —R 7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
the A ring is a heterocyclic 5 to 12-membered ring;
each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
c is a number from zero to 3;
each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
each R 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
R 1 and R 2 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group;
a is an integer from one to 8;
provided that when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
each R 3 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
b is a number from zero to 100; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof; and
detecting active agent prodrug conversion, wherein a decrease in active agent prodrug conversion in the presence of the GI enzyme inhibitor as compared to active agent prodrug conversion in the absence of the GI enzyme inhibitor indicates the active agent prodrug and the GI enzyme inhibitor are suitable for formulation in a dose unit.Join the waitlist — get patent alerts
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