Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
  • A61K47/67—Enzyme prodrug therapy, e.g. gene directed enzyme drug therapy [GDEPT] or VDEPT
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Definitions

• a number of drugs are susceptible to misuse, abuse, or overdose. Use of and access to these drugs therefore needs to be controlled.
• the control of access to the drugs is expensive to administer and can result in denial of treatment for patients that are not able to present themselves for dosing. For example, patients suffering from acute pain may be denied treatment with a drug unless they have been admitted to a hospital. Furthermore, control of use is often ineffective, leading to substantial morbidity and deleterious social consequences.
• compositions and their methods of use, where the pharmaceutical compositions comprise a prodrug that provides enzymatically- controlled release of a drug, and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the drug from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
• the embodiments include pharmaceutical compositions which comprise a gastrointestinal (GI) enzyme-cleavable prodrug and a GI enzyme inhibitor.
• GI enzyme-cleavable prodrug is a prodrug that comprises a promoiety comprising a GI enzyme- cleavable moiety.
• a GI enzyme-cleavable moiety has a site that is susceptible to cleavage by a GI enzyme.
• compositions comprising a prodrug, wherein the prodrug comprises a drug 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 drug; and a GI enzyme inhibitor that interacts with the GI enzyme that mediates enzymatically- controlled release of the drug from the prodrug following ingestion of the composition.
• cleavage can initiate, contribute to or effect drug release.
• the embodiments include dose units comprising compositions comprising a prodrug and a GI enzyme inhibitor, where the prodrug and GI enzyme inhibitor are present in the dose unit in an amount effective to provide for a pre-selected pharmacokinetic (PK) profile following ingestion.
• the pre-selected PK profile comprises at least one PK parameter value that is less than the PK parameter value of drug released following ingestion of an equivalent dosage of prodrug in the absence of inhibitor.
• the PK parameter value is selected from a drug Cmax value, a drug exposure value, and a (1/ phenolic opioid Tmax) value.
• the dose unit provides for a pre-selected PK profile following ingestion of at least two dose units.
• the pre-selected PK profile of such dose units is modified relative to the PK profile following ingestion of an equivalent dosage of phenol-modified opioid prodrug without inhibitor.
• such a dose unit provides that ingestion of an increasing number of the dose units provides for a linear PK profile.
• such a dose unit provides that ingestion of an increasing number of the dose units provides for a nonlinear PK profile.
• the PK parameter value of the PK profile of such a dose units is selected from a drug Cmax value, a (1/ drug Tmax) value, and a drug exposure value.
• compositions comprising a container suitable for containing a composition for administration to a patient; and a dose unit as described herein disposed within the container.
• the embodiments include dose units of a prodrug and a GI enzyme inhibitor wherein the dose unit has a total weight of from 1 microgram to 2 grams.
• the embodiments include pharmaceutical compositions of a prodrug and a GI enzyme inhibitor wherein the combined weight of prodrug and GI enzyme inhibitor is from 0.1% to 99% per gram of the composition.
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
• compositions and dose units wherein the prodrug is a compound of formula PC-(IIa):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• compositions and dose units wherein the prodrug is a compound of formula PC- (lib):
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• n represents an integer from 2 to 4;
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• compositions and dose units wherein the prodrug is a compound of formula PC-(III):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• compositions and dose units wherein the prodrug is a compound of formula PC-(IV):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
• compositions and dose units wherein the prodrug is a compound of formula PC-(Va):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• compositions and dose units wherein the prodrug is a compound of formula PC-(Vb):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• n represents an integer from 2 to 4;
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• compositions and dose units wherein the prodrug is a compound of formula PC- (VI):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• compositions and dose units wherein the prodrug is a compound of formula PC-( VII):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-R 6 ;
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 6 is a trypsin-cleavable moiety.
• compositions and dose units wherein the prodrug is a compound of formula PC-( VIII): X-C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-R 6 (PC-(VIII))
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-R 6 ;
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 6 is a trypsin-cleavable moiety.
• compositions and dose units wherein the prodrug is a compound of formula PC-(IX):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; n represents 2 or 3; and
• R 6 is a trypsin-cleavable moiety.
• compositions and dose units wherein the prodrug is a compound of formula PC-(X):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 6 is a trypsin-cleavable moiety.
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 6 is a GI enzyme-cleavable moiety.
• the embodiments include compositions and dose units wherein the prodrug is a compound of formula:
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 6 is a GI enzyme-cleavable moiety.
• the embodiments include compositions and dose units wherein the prodrug is a compound of formula:
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; n represents 2 or 3; and
• R 6 is a GI enzyme-cleavable moiety.
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 6 is a GI enzyme-cleavable moiety.
• X is a phenolic opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to -C(0)-Y-(C(R 1 )(R 2 )) n -N-(R 3 )(R 6 );
• Y is -NR 5 -, -O- or -S-;
• n is an integer from 1 to 4.
• each R 1 , R2 , R 3 and R 5 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group;
• each R 4 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 4 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• p is an integer from 1 to 10;
• each W is independently -NR -, -O- or -S-;
• each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 4 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
• X is an opioid comprising a phenol wherein a hydrogen atom of the phenol is replaced by a covalent bond to -(CR 12 R 13 )-Y-Z-R U ;
• R 12 and R 1 1 3 J are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• Y is aryl, heteroaryl or arylaryl optionally substituted with one or more -F, -CI, -Br, -I, -R 14 , -O , -OR 14 , -SR 14 , -S " , -NR 14 R 15 , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 " , -S(0) 2 OH, -S(0) 2 R 14 , -OS(0 2 )0 " , -OS(0) 2 R 14 , -P(0)(0 ) 2 , -P(0)(OR 14 )(0 ),
• R 14 , R 15 , R 16 and R 17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 14 and R 15 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• Z is N(R 18 )-, -O- or -S-;
• R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or
• each W is independently -NR -, -O- or -S-;
• each R 19 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 19 and R 20 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R 20 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 20 and R 21 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 21 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• n is an integer from 0 to 5;
• each U is independently -NR -, -O- or -S-;
• each R 22 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 22 and R 23 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R 23 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23 and R 24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R is hydrogen, alkyl, substitute
• o is an integer from 1 to 100;
• Z is oriented para or ortho to X-(CR 12 R 13 )- and that both R 18 and R 11 are not hydrogen.
• X is an opioid comprising a phenol, wherein X is connected by the phenol;
• R 12 and R 1 1 3 J are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• R k 26 are each independently selected from the group consisting of one or more of -F, -CI, -Br, -I, -R 14 , -O , -OR 14 , -SR 14 , -S " , -NR 14 R 15 , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 " , -S(0) 2 OH, -S(0) 2 R 14 , -OS(0 2 )0 " , -OS(0) 2 R 14 , -P(0)(0 ) 2 , -P(0)(OR 14 )(0 ),
• R 14 , R 15 , R 16 and R 17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 4 and R 5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 18 is hydrogen or methyl
• R 22 is a side chain of an amino acid or a derivative of a side chain of an amino acid; each U is independently -NR 23 -, -O- or -S-; each R is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23 and R 24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and
• R 24 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; and o is an integer from 1 to 100.
• X is an opioid comprising a phenol wherein a hydrogen atom of the phenol is replaced by a covalent bond to -(C(R 31a )(R 32a )- Ar-Z-C(O)- Y- (C(R 31 )(R 32 )) n -N-(R 33 )(R 34 );
• R 31a and R 32a are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• Ar is aryl, heteroaryl or arylaryl optionally substituted with one or more -F, -CI, -Br, -I, - R 34a , -O , -OR 34a , -SR 34a , -S-, -NR 34a R 35a , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 ' , - S(0) 2 OH, -S(0) 2 R 34a , -OS(0 2 )0 " , -OS(0) 2 R 34a , -P(0)(0 " ) 2 , -P(0)(OR 34a )(0 " ),-
• R 34a , R 35a , R 36a and R 37a are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 34 and R 35 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• Z is O, S or NH
• Y is -NR 35 -, -O- or -S-;
• n is an integer from 1 to 10;
• each R 31 , R 32 , R 33 and R 35 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 31 and R 32 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 31 or R 32 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
• each R 36 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 36 and R 37 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 37 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• p is an integer from 1 to 5;
• each W is independently -NR 38 -, -O- or -S-;
• each R 38 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 36 and R 38 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• A represents an anion
• compositions and dose units wherein the prodrug is a compound of formula KC-(Ia):
• R a is hydrogen or hydroxyl
• R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R is independently selected from hydrogen, alkyl, substituted alkyl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl,
• R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n is an integer from 2 to 4.
• R is hydrogen
• 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, or optionally, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• each W is independently -NR -, -O- or -S-;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• p is an integer from one to 100;
• R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
• alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• compositions and dose units wherein the prodrug is a compound of formula KC-(Ib):
• R a is hydrogen or hydroxyl
• R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached 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, form a cycloalkyl or substituted cycloalkyl group; n is an integer from 2 to 4;
• R is hydrogen
• 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, or optionally, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• each W is independently -NR -, -O- or -S-;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• compositions and dose units wherein the prodrug is a compound of formula KC-(II):
• R a is hydrogen or hydroxyl
• R 5 is selected from (l-6C)alkyl, (1-6C) substituted alkyl, -(CH 2 ) q (C 6 H 4 )-COOH, -(CH 2 ) q (C 6 H 4 )-COOCH 3 , and -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10;
• each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached 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, form a cycloalkyl or substituted cycloalkyl group; n is 2 or 3;
• R is hydrogen
• R 4 is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or a residue of an N
• compositions and dose units wherein the prodrug is a compound of formula KC-(IIIa):
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -C(0)-NR 5 - (C(R 1 )(R 2 )) N -NR 3 R 4 ;
• R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R and R together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two 2 3
• n is an integer from 2 to 4.
• R is hydrogen
• 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, or optionally, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• each W is independently -NR -, -O- or -S-;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• p is an integer from one to 100;
• R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
• alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• compositions and dose units wherein the prodrug is a compound of formula KC-(IIIb):
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -C(0)-NR 5 - (C(R 1 )(R 2 )) n -NR 3 R 4 ;
• R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached 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, form a cycloalkyl or substituted cycloalkyl group; n is an integer from 2 to 4;
• R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• each W is independently -NR -, -O- or -S-;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• p is an integer from one to 100;
• R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
• alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• compositions and dose units wherein the prodrug is a compound of formula KC-(IV):
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -C(0)-NR 5 -
• R 5 is selected from (l-6C)alkyl, (1-6C) substituted alkyl, -(CH 2 ) q (C 6 H 4 )-COOH, -(CH 2 ) q (C 6 H 4 )-COOCH3, and -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10; each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached 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, form a cycloalkyl or substituted cycloalkyl group; n is 2 or 3;
• R is hydrogen
• R 4 is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or a residue of an N
• compositions and dose units wherein the prodrug is a compound of formula KC-(Va):
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -C(0)-NR 5 - (C(R 1 )(R 2 )) n -NR 3 R 4 ;
• R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n is an integer from 2 to 4.
• R is hydrogen
• R 4 is a trypsin-cleavable moiety
• compositions and dose units wherein the prodrug is a compound of formula KC-(Vb):
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -C(0)-NR 5 - (C(R 1 )(R 2 )) n -NR 3 R 4 ;
• R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n is an integer from 2 to 4.
• R is hydrogen
• R 4 is a GI enzyme-cleavable moiety
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -C(0)-Y- (C(R 1 )(R 2 )) n -NR 3 R 4 ;
• Y is -NR 5 -, -O- or -S-;
• n is an integer from 1 to 4.
• each R 1 , R2 , R 3 and R 5 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group;
• each R 6 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; p is an integer from 1 to 10;
• each W is independently -NR -, -O- or -S-;
• each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond -(CR 12 R 13 )- Y-Z-R 11 ;
• R 12 and R 1 1 3 J are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• Y is aryl, heteroaryl or arylaryl optionally substituted with one or more -F, -CI, -Br, -I, -R 14 , -O , -OR 14 , -SR 14 , -S " , -NR 14 R 15 , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 " , -S(0) 2 OH, -S(0) 2 R 14 , -OS(0 2 )0 " , -OS(0) 2 R 14 , -P(0)(0 ) 2 , -P(0)(OR 14 )(0 ),
• R 14 , R 15 , R 16 and R 17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 14 and R 15 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• Z is N(R 18 )-, -O- or -S-;
• R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or
• each W is independently -NR -, -O- or -S-;
• each R 19 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 19 and R 20 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R 20 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 20 and R 21 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 21 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• n is an integer from 0 to 5;
• each U is independently -NR -, -O- or -S-;
• each R 22 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 22 and R 23 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R 23 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or optionally, R 23 and R 24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,
• o is an integer from 1 to 100;
• Z is oriented para or ortho to X-(CR 12 R 13 )- and that both R 18 and R 11 are not hydrogen.
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -(CR 12 R 13 )-Y-Z-R 11 ;
• R 12 and R 1 1 3 J are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• R k 26 are each independently selected from the group consisting of one or more of -F, -CI, -Br, -I, -R 14 , -O , -OR 14 , -SR 14 , -S " , -NR 14 R 15 , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 " , -S(0) 2 OH, -S(0) 2 R 14 , -OS(0 2 )0 " , -OS(0) 2 R 14 , -P(0)(0 ) 2 , -P(0)(OR 14 )(0 ),
• R 14 , R 15 , R 16 and R 17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 4 and R 5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 18 is hydrogen or methyl
• R 22 is a side chain of an amino acid or a derivative of a side chain of an amino acid; each U is independently -NR 23 -, -O- or -S-; each R is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23 and R 24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and
• R 24 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• o is an integer from 1 to 100.
• X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group of the ketone is replaced by a covalent bond to -(C(R 31a )(R 32a )- Ar-Z- C(O)- Y- (C(R 31 )(R 32 )) n -N-(R 33 )(R 34 );
• R 31a and R 32a are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• Ar is aryl, heteroaryl or arylaryl optionally substituted with one or more -F, -CI, -Br, -I, - R 34a , -O , -OR 34a , -SR 34a , -S-, -NR 34a R 35a , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 ' , - S(0) 2 OH, -S(0) 2 R 34a , -OS(0 2 )0 " , -OS(0) 2 R 34a , -P(0)(0 " ) 2 , -P(0)(OR 34a )(0 " ), - OP(0)(OR 34a )(OR 35a ), -C(0)R 34a , -C(S)R 34a , -C(0)OR 34a , -C(0)NR 34a R 35a ,
• R 34a , R 35a , R 36a and R 37a are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 34 and R 35 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• Z is O, S or NH
• Y is -NR 35 -, -O- or -S-;
• n is an integer from 1 to 10; each R 31 , R 32 , R 33 and R 35 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 31 and R 32 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 31 or R 32 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
• each R is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 36 and R 37 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted
• R 37 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• p is an integer from 1 to 5;
• each W is independently -NR 38 -, -O- or -S-;
• each R 38 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 36 and R 38 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• A represents an anion
• X is an opioid comprising an amine, wherein a hydrogen atom of the primary or secondary amine is replaced by a covalent bond to -(CR 12 R 13 )- Y-Z-R 11 or a lone pair of electrons of a tertiary amine is replaced by a covalent bond to -(CR 12 R 13 )- Y-Z-R 11 ;
• R and R are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• Y is aryl, heteroaryl or arylaryl optionally substituted with one or more -F, -CI, -Br, -I, -R 14 , -O , -OR 14 , -SR 14 , -S " , -NR 14 R 15 , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 " , -S(0) 2 OH, -S(0) 2 R 14 , -OS(0 2 )0 " , -OS(0) 2 R 14 , -P(0)(0 ) 2 , -P(0)(OR 14 )(0 ),
• R 14 , R 15 , R 16 and R 17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 14 and R 15 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• Z is N(R 18 )-, -O- or -S-;
• R 18 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or
• each W is independently -NR -, -O- or -S-;
• each R 19 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 19 and R 20 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R 20 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 20 and R 21 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 21 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• n is an integer from 0 to 5;
• each U is independently -NR -, -O- or -S-;
• each R 22 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 22 and R 23 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R 23 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23 and R 24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 24 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• o is an integer from 1 to 100;
• Z is oriented para or ortho to X-(CR 12 R 13 )- and that both R 18 and R 11 are not hydrogen.
• X is an opioid comprising an amine, wherein a hydrogen atom of the primary or secondary amine is replaced by a covalent bond to -(CR 12 R 13 )-Y-Z-R 11 or a lone pair of electrons of a tertiary amine is replaced by a covalent bond to -(CR 12 R 13 )-Y-Z-R 11 ;
• R 12 and R 1 1 3 J are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• R k are each independently selected from the group consisting of one or more of -F, -CI, -Br, -I, -R 14 , -O , -OR 14 , -SR 14 , -S " , -NR 14 R 15 , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 " , -S(0) 2 OH, -S(0) 2 R 14 , -OS(0 2 )0 " , -OS(0) 2 R 14 , -P(0)(0 ) 2 ,
• R 14 , R 15 , R 16 and R 17 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 4 and R 5 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 18 is hydrogen or methyl
• R 22 is a side chain of an amino acid or a derivative of a side chain of an amino acid; each U is independently -NR 23 -, -O- or -S-;
• each R 23 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 23 and R 24 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 24 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• o is an integer from 1 to 100.
• X is a residue of an opioid wherein the lone pair of electrons of the amino nitrogen is replaced with a bond to -(C(R 31a )(R 32a )- Ar-Z-C(O)- Y- (C(R 31 )(R 32 )) n -N-(R 33 )(R 34 );
• R 31a and R 32a are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• Ar is aryl, heteroaryl or arylaryl optionally substituted with one or more -F, -CI, -Br, -I, - R 34a , -O " , -OR 34a , -SR 34a , -S-, -NR 34a R 35a , -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 0 ' , - S(0) 2 OH, -S(0) 2 R 34a , -OS(0 2 )0 " , -OS(0) 2 R 34a , -P(0)(0 " ) 2 , -P(0)(OR 34a )(0 " ),- OP(0)(OR 34a )(OR 35a ), -C(0)R 34a , -C(S)R 34a , -C(0)OR 34a , -C(0)NR 34a R 35a ,
• R 34a , R 35a , R 36a and R 37a are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 34 and R 35 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• Z is O, S or NH
• Y is -NR 35 -, -O- or -S-;
• n is an integer from 1 to 10;
• each R 31 , R 32 , R 33 and R 35 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or R 31 and R 32 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group, or two R 31 or R 32 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group;
• each R is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 36 and R 37 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R 37 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl;
• p is an integer from 1 to 5;
• each W is independently -NR 38 -, -O- or -S-;
• each R 38 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, or optionally, each R 36 and R 38 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and A represents an anion.
• X represents a residue of an amide-containing opioid, wherein -C(0)-NR 5 -(C(R 1 )(R2 )) n -
• NR 3 R 4 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;
• R 5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n is an integer from 2 to 4.
• R is hydrogen or (l-4C)alkyl
• 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, or optionally, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• each W is independently -NR -, -O- or -S-; each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• p is an integer from one to 100;
• R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
• alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• compositions and dose units wherein the prodrug is a compound of formula:
• X represents a residue of an amide-containing opioid, wherein -C(0)-NR 5 -(C(R 1 )(R2 )) n - NR 3 R 4 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;
• R 5 is selected from (l-6C)alkyl, (1-6C) substituted alkyl, -(CH 2 ) q (C 6 H 4 )-COOH, -(CH 2 ) q (C 6 H 4 )-COOCH 3 , and -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10;
• each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 1 and R 2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n 2 or 3;
• R is hydrogen;
• R 4 is a GI enzyme-cleavable moiety;
• X represents a residue of an amide-containing opioid, wherein -CO-C(R 6 )-NR 8 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;
• 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, or optionally, R 6 and R 7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
• alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• the embodiments include methods for treating a patient comprising administering any of the compositions or dose units described herein to a patient in need thereof.
• the embodiments include methods to reduce side effects of a therapy comprising administering any of the compositions or dose units described herein to a patient in need thereof.
• the embodiments include methods of improving patient compliance with a therapy prescribed by a clinician comprising directing administration of any of the compositions or dose units described herein to a patient in need thereof.
• Such embodiments can provide for improved patient compliance with a prescribed therapy as compared to patient compliance with a prescribed therapy using drug and/or using prodrug without inhibitor as compared to prodrug with inhibitor.
• the embodiments include methods of reducing risk of unintended overdose of a drug comprising directing administration of any of the pharmaceutical compositions or dose units described herein to a patient in need of treatment.
• the embodiments include methods of making a dose unit comprising combining a prodrug and a GI enzyme inhibitor in a dose unit, wherein the prodrug and GI enzyme inhibitor are present in the dose unit in an amount effective to attenuate release of the drug from the prodrug.
• the embodiments include methods of deterring misuse or abuse of multiple dose units of a prodrug comprising combining a prodrug and a GI enzyme inhibitor in a dose unit, wherein the prodrug and GI enzyme inhibitor are present in the dose unit in an amount effective to attenuate release of the drug from the prodrug such that ingestion of multiples of dose units by a patient does not provide a proportional release of the drug.
• release of drug is decreased compared to release of drug by an equivalent dosage of prodrug in the absence of inhibitor.
• One embodiment is a method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit. Such a method can be conducted as, for example, an in vitro assay, an in vivo assay, or an ex vivo assay.
• the embodiments include methods for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit comprising combining a prodrug, a GI enzyme inhibitor, and enzyme in a reaction mixture, and detecting prodrug conversion, wherein a decrease in prodrug conversion in the presence of the GI enzyme inhibitor as compared to prodrug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
• the embodiments include methods for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit comprising administering to an animal a prodrug and a GI enzyme inhibitor and detecting prodrug conversion, wherein a decrease in drug conversion in the presence of the GI enzyme inhibitor as compared to drug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
• administering comprises administering to the animal increasing doses of inhibitor co-dosed with a selected fixed dose of prodrug.
• Detecting prodrug conversion can facilitate identification of a dose of inhibitor and a dose of prodrug that provides for a pre-selected pharmacokinetic (PK) profile.
• PK pharmacokinetic
• Such methods can be conducted as, for example, an in vivo assay or an ex vivo assay.
• the embodiments include methods for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit comprising administering to an animal tissue a prodrug and a GI enzyme inhibitor and detecting prodrug conversion, wherein a decrease in prodrug conversion in the presence of the GI enzyme inhibitor as compared to prodrug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
• Figure 1 is a schematic representing the effect of increasing the level of a GI enzyme inhibitor ("inhibitor", X axis) on a PK parameter (e.g., drug Cmax) (Y axis) for a fixed dose of prodrug.
• a GI enzyme inhibitor e.g., drug Cmax
• Y axis e.g., drug Cmax
• the effect of inhibitor upon a prodrug PK parameter can range from undetectable, to moderate, to complete inhibition (i.e., no detectable drug release).
• Figure 2 provides schematics of drug concentration in plasma (Y axis) over time (X axis).
• Panel A is a schematic of a pharmacokinetic (PK) profile following ingestion of prodrug with a GI enzyme inhibitor (dashed line) where the drug Cmax is modified relative to that of prodrug without inhibitor (solid line).
• Panel B is a schematic of a PK profile following ingestion of prodrug with inhibitor (dashed line) where drug Cmax and drug Tmax are modified relative to that of prodrug without inhibitor (solid line).
• Panel C is a schematic of a PK profile following ingestion of prodrug with inhibitor (dashed line) where drug Tmax is modified relative to that of prodrug without inhibitor (solid line).
• Figure 3 provides schematics representing differential concentration-dose PK profiles that can result from the dosing of multiples of a dose unit (X axis) of the present disclosure.
• Different PK profiles (as exemplified herein for a representative PK parameter, drug Cmax (Y axis)) can be provided by adjusting the relative amount of prodrug and GI enzyme inhibitor contained in a single dose unit or by using a different prodrug or inhibitor in the dose unit.
• Figure 4 is a graph that compares mean blood concentrations over time of hydromorphone (HM) following PO administration to rats of Compound PC-1 alone and Compound PC-1 with various amounts of trypsin inhibitor from Glycine max (soybean) (SBTI).
• HM hydromorphone
• Figure 5 is a graph that compares mean plasma concentrations over time of
• HM hydromorphone
• Figure 6 is a graph that compares individual blood concentrations over time of hydromorphone (HM) following PO administration to rats of Compound PC-1 alone and Compound PC-1 with Bowman-Birk trypsin-chymotrypsin inhibitor (BBSI).
• HM hydromorphone
• BVSI Bowman-Birk trypsin-chymotrypsin inhibitor
• Figure 7 is a graph that compares mean plasma concentrations over time of
• hydromorphone (HM) release following PO administration of Compound PC-2 alone and Compound PC-2 with SBTI to rats.
• Figure 8 is a graph that compares mean plasma concentrations over time of
• Figure 9 is a graph that compares mean plasma concentrations over time of
• hydromorphone (HM) release following PO administration of Compound PC-4 alone and Compound PC-4 with SBTI to rats.
• Figures 10A and 10B are graphs that indicate the in vitro results of exposure of a certain combination of Compound PC-4 and trypsin, in the absence of any trypsin inhibitor or in the presence of SBTI, Compound 107, Compound 108, or Compound 109.
• Figure 10A depicts the disappearance of Compound PC-4
• Figure 10B depicts the appearance of hydromorphone, over time under these conditions.
• Figure 11 is a graph that compares mean plasma concentrations over time of
• hydromorphone (HM) release following PO administration of Compound PC-3 alone and Compound PC-3 with Compound 101 to rats.
• Figure 12 is a graph that compares mean plasma concentrations over time of
• hydromorphone (HM) release following PO administration of Compound PC-4 alone and Compound PC-4 with Compound 101 to rats.
• Figure 13A and Figure 13B compare mean plasma concentrations over time of hydromorphone release following PO administration of increasing doses of prodrug Compound PC-5 to rats.
• Figure 14 compares mean plasma concentrations over time of hydromorphone release following PO administration of prodrug Compound PC-5 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to rats.
• Figure 15A and Figure 15B compare mean plasma concentrations over time of hydromorphone release following PO administration of a single dose unit and of multiple dose units of a composition comprising prodrug Compound PC-5 and trypsin inhibitor Compound 109 to rats.
• Figure 16 compares mean plasma concentrations over time of hydromorphone release following PO administration of increasing doses of prodrug Compound PC-6 to rats.
• Figure 17 compares mean plasma concentrations over time of hydromorphone release following PO administration of prodrug Compound PC-6 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to rats.
• Figure 18 compares mean plasma concentrations over time of hydromorphone release following PO administration of a single dose unit and of multiple dose units of a composition comprising prodrug Compound PC-6 and trypsin inhibitor Compound 109 to rats.
• Figure 19 shows a plasma concentration time course of the production of oxycodone following oral (PO) dosing of an oxycodone prodrug in rats.
• Figure 20 shows a plasma concentration time course of the production of oxycodone following intravenous (IV) dosing of an oxycodone prodrug in rats.
• Figure 21 shows release of oxycodone from an oxycodone prodrug exposed to a variety of readily availably household chemicals or enzyme preparations.
• Figure 22 shows disappearance of an oxycodone prodrug and appearance of oxycodone following in vitro incubation of the prodrug and trypsin, in the absence or presence of a trypsin inhibitor.
• Figure 23 compares mean plasma concentrations over time of oxycodone release following PO administration of prodrug Compound KC-2 alone and Compound KC-2 with trypsin inhibitor Compound 109 to rats.
• Figure 24 compares mean plasma concentrations over time of oxycodone release following PO administration of increasing doses of prodrug Compound KC-2 to rats.
• Figure 25 compares mean plasma concentrations over time of oxycodone release following PO administration of prodrug Compound KC-2 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to rats.
• Figure 26 compares mean plasma concentrations over time of oxycodone release following PO administration of increasing doses of Compound KC-3 to rats.
• Figure 27 shows a plasma concentration time course of the production of oxycodone following intravenous (IV) dosing of prodrug Compound KC-3 in rats.
• Figure 28 compares mean plasma concentrations over time of oxycodone release following PO administration of prodrug Compound KC-3 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to rats.
• Figure 29 demonstrates the release of oxycodone from prodrug Compound KC-3 exposed to a variety of household chemicals and enzyme preparations.
• Figure 30 shows a plasma concentration time course of the production of oxycodone following intravenous (IV) dosing of prodrug Compound KC-4 in rats.
• Figure 31 compares mean plasma concentrations over time of hydrocodone release following PO administration of prodrug Compound KC-4 with or without a co-dose of trypsin inhibitor to rats.
• Figure 32 demonstrates mean plasma concentrations over time of oxycodone release following PO administration of Compound KC-5 to rats.
• Figure 33 shows a plasma concentration time course of the production of oxycodone following intravenous (IV) dosing of prodrug Compound KC-5 in rats.
• Figure 34 demonstrates mean plasma concentrations over time of oxycodone release following PO administration of Compound KC-6 to rats.
• Figure 35 shows a plasma concentration time course of the production of oxycodone following intravenous (IV) dosing of prodrug Compound KC-6 in rats.
• alkyl by itself or as part of another substituent refers to a saturated branched or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
• Typical alkyl groups include, but are not limited to, methyl; ethyl, propyls such as propan-l-yl or propan-2-yl; and butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl or 2-methyl-propan-2-yl.
• an alkyl group comprises from 1 to 20 carbon atoms. In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms. In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms.
• alkanyl by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of an alkane.
• Typical alkanyl groups include, but are not limited to, methanyl;
• ethanyl propanyls such as propan-l-yl, propan-2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2- yl (t-butyl), cyclobutan-l-yl, etc.; and the like.
• Alkylene refers to a branched or unbranched saturated hydrocarbon chain, usually having from 1 to 40 carbon atoms, more usually 1 to 10 carbon atoms and even more usually 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene
• Alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of an alkene.
• the group may be in either the cis or trans conformation about the double bond(s).
• Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-l-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-1,3- dien-l-yl, buta-l,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
• Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of an alkyne.
• Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc.; and the like.
• Acyl by itself or as part of another substituent refers to a radical -C(0)R 30 , where R 30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein and substituted versions thereof.
• Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, succinyl, and malonyl, and the like.
• aminoacyl refers to the group -C(0)NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
• Alkoxy by itself or as part of another substituent refers to a radical -OR 31 where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.
• Alkoxycarbonyl by itself or as part of another substituent refers to a radical -C(0)OR 31 where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
• Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of an aromatic ring system.
• Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
• Arylalkyl by itself or as part of another substituent refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl group.
• Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2- naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
• an arylalkyl group is (C 7 -C 30 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 10 ) and the aryl moiety is (C 6 -C 20 ).
• an arylalkyl group is (C 7 -C 20 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci-Cs) and the aryl moiety is (C 6 -C 12 ).
• Arylaryl by itself or as part of another substituent, refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of aromatic ring systems involved.
• Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-napthyl, binaphthyl, biphenyl-napthyl, and the like. When the number of carbon atoms in an arylaryl group are specified, the numbers refer to the carbon atoms comprising each aromatic ring.
• (C 5 -C 14 ) arylaryl is an arylaryl group in which each aromatic ring comprises from 5 to 14 carbons, e.g., biphenyl, triphenyl, binaphthyl,
• each aromatic ring system of an arylaryl group is independently a (C 5 -C 14 ) aromatic. In certain embodiments, each aromatic ring system of an arylaryl group is independently a (C 5 -C 10 ) aromatic. In certain embodiments, each aromatic ring system is identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.
• Cycloalkyl by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical. Where a specific level of saturation is intended, the nomenclature
• cycloalkanyl or “cycloalkenyl” is used.
• Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
• the cycloalkyl group is (C 3 -C 10 ) cycloalkyl.
• the cycloalkyl group is (C3-C7) cycloalkyl.
• Cycloheteroalkyl or “heterocyclyl” by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
• Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
• Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like.
• Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups.
• Heteroaryl by itself or as part of another substituent, refers to a monovalent
• heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a heteroaromatic ring system.
• Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,
• the heteroaryl group is from 5-20 membered heteroaryl. In certain embodiments, the heteroaryl group is from 5-10 membered heteroaryl. In certain embodiments, heteroaryl groups are those derived from thiophene, pyrrole,
• benzothiophene benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
• Heteroarylalkyl by itself or as part of another substituent, refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is used.
• the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl.
• the heteroarylalkyl group is 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.
• aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc.
• Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as- indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta- 2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
• Heteroaromatic Ring System by itself or as part of another substituent, refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "heteroaromatic ring systems” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc.
• Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ - carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadia
• Substituted refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s).
• R 60 , R 61 , R 62 and R 63 are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 60 and R 61 together with the nitrogen atom to which they are bonded form a cyclohe
• a substituted group may bear a methylenedioxy substituent or one, two, or three substituents selected from a halogen atom, a (l-4C)alkyl group and a (l-4C)alkoxy group.
• Dose unit refers to a combination of a GI enzyme-cleavable prodrug (e.g., trypsin-cleavable prodrug) and a GI enzyme inhibitor (e.g., a trypsin inhibitor).
• a “single dose unit” is a single unit of a combination of a GI enzyme-cleavable prodrug (e.g., trypsin- cleavable prodrug) and a GI enzyme inhibitor (e.g., trypsin inhibitor), where the single dose unit provide a therapeutically effective amount of drug (i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range).
• a therapeutically effective amount of drug i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range.
• PK profile refers to a profile of drug concentration in blood or plasma. Such a profile can be a relationship of drug concentration over time (i.e., a "concentration-time PK profile”) or a relationship of drug concentration versus number of doses ingested (i.e., a "concentration-dose PK profile”).
• a PK profile is characterized by PK parameters.
• PK parameter refers to a measure of drug concentration in blood or plasma, such as: 1) “drug Cmax”, the maximum concentration of drug achieved in blood or plasma; 2) “drug Tmax”, the time elapsed following ingestion to achieve Cmax; and 3) “drug exposure”, the total concentration of drug present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a time course of drug release over a selected period of time (t). Modification of one or more PK parameters provides for a modified PK profile.
• PD profile refers to a profile of the efficacy of a drug in a patient
• PD parameters include “drug Emax” (the maximum drug efficacy), “drug EC50” (the concentration of drug at 50% of the Emax) and side effects.
• Gastrointestinal enzyme or "GI enzyme” refers to an enzyme located in the central nervous system
• GI gastrointestinal
• Trypsin is an example of a GI enzyme.
• Gastrointestinal enzyme-cleavable moiety or "GI enzyme-cleavable moiety” refers to a group comprising a site susceptible to cleavage by a GI enzyme.
• a "trypsin- cleavable moiety” refers to a group comprising a site susceptible to cleavage by trypsin.
• Gastrointestinal enzyme inhibitor or "GI enzyme inhibitor” refers to any agent capable of inhibiting the action of a gastrointestinal enzyme on a substrate.
• the term also encompasses salts of gastrointestinal enzyme inhibitors.
• a "trypsin inhibitor” refers to any agent capable of inhibiting the action of trypsin on a substrate.
• “Pharmaceutical composition” refers to at least one compound and can further comprise a pharmaceutically acceptable carrier, with which the compound is administered to a patient.
• “Pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the compound.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-
• solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g. a prodrug or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent.
• solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent.
• Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.
• “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with, or in which a compound is administered.
• Preventing or “prevention” or “prophylaxis” refers to a reduction in risk of occurrence of a condition, such as pain.
• Prodrug refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In certain embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
• Promoiety refers to a form of protecting group that when used to mask a functional group within an active agent converts the active agent into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
• Treating” or “treatment” of any condition refers, in certain embodiments, to ameliorating the condition (i.e., arresting or reducing the development of the condition). In certain embodiments “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In certain embodiments, “treating” or “treatment” refers to inhibiting the condition, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In certain embodiments, “treating” or “treatment” refers to delaying the onset of the condition.
• “Therapeutically effective amount” means the amount of a compound (e.g. prodrug) that, when administered to a patient for preventing or treating a condition such as pain, is sufficient to effect such treatment.
• the “therapeutically effective amount” will vary depending on the compound, the condition and its severity and the age, weight, etc. , of the patient.
• chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography.
• HPLC high performance liquid chromatography
• Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer- Verlag, New York, 1969.
• any of the processes for preparation of the compounds of the present disclosure it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Fourth edition, Wiley, New York 2006.
• the protecting groups can be removed at a convenient subsequent stage using methods known from the art.
• the compounds described herein can contain one or more chiral centers and/or double bonds and therefore, can exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures are included in the description of the compounds herein. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
• the compounds can also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
• the compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 0, 17 0, etc.
• Compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure. Representative Embodiments
• compositions and their methods of use, where the pharmaceutical compositions comprise a prodrug that provides enzymatically- controlled release of a drug and an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of the drug from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
• the disclosure provides pharmaceutical compositions which comprise an enzyme inhibitor and a prodrug that contains an enzyme-cleavable moiety that, when cleaved, facilitates release of the drug.
• the disclosure provides a prodrug which provides enzymatically-controlled release of an active agent.
• the disclosure provides a promoiety that is attached to an active agent through any suitable structural moiety on the drug, where the structural moiety has a reactive group.
• Any type of reactive group on an active agent can provide a handle for a point of attachment to a promoiety.
• Examples of reactive groups on an active agent include, but are not limited to, alcohol (such as phenol), ketone, amino, thiol, carboxyl, and amide.
• An alcohol (such as a phenol) on an active agent can provide a point of attachment to a promoiety by reaction to form a linkage, such as a carbamate, an ether, or an ester.
• a ketone on an active agent can provide a point of attachment to a promoiety by reaction to form a linkage, such as an enol carbamate.
• An amino group on an active agent can provide a point of attachment to a promoiety by reaction to form an amino linkage including a quaternary ammonium salt or an amide.
• a thiol on an active agent can provide a point of attachment to a promoiety by reaction to form a linkage, such as a thioester or thiocarbamate.
• An amide on an active agent can provide a point of attachment to a promoiety by reaction to form a linkage, such as an amide enol.
• active agent refers to a chemical substance that exerts a pharmacological action.
• active agents include, but are not limited to, active agents that are susceptible to misuse, abuse, or overdose.
• active agents include, but are not limited to, opioids, NSAIDs, other analgesics, GABA agonists, GABA antagonists and psychostimulants.
• Opioid Prodrugs include, but are not limited to, opioids, NSAIDs, other analgesics, GABA agonists, GABA antagonists and psychostimulants.
• the embodiments include pharmaceutical compositions, which comprise a GI enzyme-cleavable opioid prodrug and a GI enzyme inhibitor.
• a GI enzyme-cleavable opioid prodrug and a GI enzyme inhibitor. Examples of opioid prodrugs and enzyme inhibitors are described below.
• opioid refers to a chemical substance that exerts its pharmacological action by interaction at an opioid receptor.
• An opioid can be a natural product, a synthetic compound or a semi- synthetic compound.
• an opioid is a compound with a
• the disclosure provides an opioid prodrug which provides enzymatically-controlled release of an opioid.
• the disclosure provides a promoiety that is attached to an opioid through any structural moiety on the opioid, where the structural moiety has a reactive group.
• Any type of reactive group on an opioid can provide a handle for a point of attachment to a promoiety.
• Examples of reactive groups on an opioid include, but are not limited to, alcohol (such as phenol), ketone, amino, and amide.
• An alcohol (such as a phenol) on an opioid can provide a point of attachment to a promoiety by reaction to form a linkage, such as a carbamate, an ether, or an ester.
• a ketone on an opioid can provide a point of attachment to a promoiety by reaction to form a linkage, such as an enol carbamate.
• An amino group on an opioid can provide a point of attachment to a promoiety by reaction to form an amino linkage, including quaternary salts, or an amide.
• An amide on an opioid can provide a point of attachment to a promoiety by reaction to form a linkage, such as an amide enol or an N-acylated amide.
• An alcohol-containing (such as a phenol-containing) opioid refers to a subset of the opioids that contain alcohol (such as a phenol) group.
• a phenolic opioid refers to a subset of the opioids that contain a phenol group.
• the following opioids contain an alcohol (such as a phenol group) that can be a point of attachment to a promoiety: buprenorphine,
• dihydroetorphine diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalmefene, naloxone, N-methyldiprenorphine, N-methylnaloxone, naltrexone, N-methylnaltexone, oxymorphone, oripavine, ketobemidone, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, meptazinol, o-desmethyltramadol, tapentadol, and nalorphine.
• the following opioids also contain an alcohol (such as a phenol) that can be a point of attachment to a promoiety: benzylmorphine, codeine, dihydrocodeine, dihydromorphine, ethylmorphine, loperamide, methyldihydromorphine, normorphine, N-methylnalmefene, olmefentanyl, oxycodone, pentamorphone, pholcodine, and tramadol.
• alcohol such as a phenol
• a ketone-containing opioid refers to a subset of the opioids that contain a ketone group.
• the following opioids contain a ketone group that can be a point of attachment to a promoiety: acetylmorphone, hydrocodone, hydromorphone, ketobemidone, methadone, naloxone, N-methylnaloxone, naltrexone, N-methylnaltrexone, oxycodone, oxymorphone, and pentamorphone.
• amino-containing opioid refers to a subset of the opioids that contain an amino group.
• the following opioids contain an amino group that can be a point of attachment to a promoiety as a quaternary ammonium salt: acetylmorphine, alfentanil, benzylmorphine, buprenorphine, butorphanol, carfentanil, codeine, dextropropoxyphene,
• methyldihydromorphine methyldihydromorphine, morphine, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone, nicocodeine, nicomorpine, normorphine, olmefentanyl, oripavin, oxycodone, oxymorphone, pentamorphone, pentazocine, phenazocine, pholcodine, remifentanil, sufentanil, tapentadol, thebaine, tilidine, tramadol, and o-desmethyltramadol.
• the following opioid contains an amino group that can be a point of attachment to a promoiety: dezozine.
• An amide-containing opioid refers to a subset of the opioids that contain an amide group.
• the following opioids contain an amide group that can be a point of attachment to a promoiety: alfentanil, carfentanil, fentanyl, lofentanil, loperamide, olmefentanyl, remifentanil, and sufentanil.
• opioids bearing at least some of the functionalities described herein will be developed; such opioids are included as part of the scope of this disclosure.
• a promoiety can be attached to an alcoholic (such as phenolic) opioid via modification of the alcohol (such as phenol) moiety. Release of the opioid is mediated by enzymatic cleavage of the promoiety from the alcoholic (such as phenolic) opioid.
• a promoiety can be attached to a ketone-containing opioid through the enolic oxygen atom of the ketone moiety. Release of the opioid is mediated by enzymatic cleavage of the promoiety from the ketone-containing opioid.
• a promoiety can be attached to an amino-containing opioid through the amino moiety. Release of the opioid is mediated by enzymatic cleavage of the promoiety from the amino-containing opioid.
• a promoiety can be attached to an amide-containing opioid through the enolic oxygen of the amide moiety or the imine tautomer. Release of the opioid is mediated by enzymatic cleavage of the promoiety from the amide-containing opioid.
• the promoiety comprises an enzyme-cleavable moiety that is susceptible to cleavage by a GI enzyme. Such cleavage can initiate, contribute to or effect drug release.
• the disclosure provides an alcohol-modified opioid prodrug which provides
• a promoiety is attached to the alcohol-containing opioid via modification of the alcohol moiety.
• the hydrogen atom of the hydroxyl group of the alcohol-containing opioid is replaced by a covalent bond to a promoiety.
• the promoiety of an alcohol-modified opioid prodrug can be attached to an alcohol-containing opioid through the alcohol moiety, which alcohol moiety can be a phenol or can be an alcohol moiety other than phenol, including primary, secondary, and tertiary alcohol moieties.
• Release of the opioid is mediated by enzymatic cleavage of the promoiety from the alcohol-containing opioid.
• the disclosure provides for release of the opioid through GI enzymatic cleavage (e.g, trypsin cleavage) of the promoiety from the alcohol-containing opioid. Cleavage can initiate, contribute to or effect drug release.
• X represents a residue of an alcohol- containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )-NH(R 5 ).
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-R 6 .
• X is an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to -C(0)-Y-(C(R 1 )(R 2 )) n -N-(R 3 )(R 4 ).
• X is an opioid comprising a hydroxyl group wherein a hydrogen atom of the hydroxyl group is replaced by a covalent bond to -(CR 12 R 13 )-Y-Z-R 11.
• X is an opioid comprising a hydroxyl group, wherein X is connected to the promoiety via modification of the hydroxyl group.
• X is an opioid comprising a hydroxyl group wherein a hydrogen atom of the hydroxyl group is replaced by a covalent bond to - (C(R 31a )(R 32a )- Ar-Z-C(O)- Y- (C(R 31 )(R 32 )) n -N-(R 33 )(R 34 ).
• AA can represent a side chain of an amino acid.
• Amino acids, including amino acid variants, are discussed in a section herein.
• a certain example is a compound of Formula CC-(I): CC-(I)
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to -C(0)-CH(AA)-NR ccl R cc2 ;
• AA is a side chain of an amino acid
• R ccl and R cc2 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl.
• a certain example is a compound of formula CC-(II):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to -C(0)-N(R cc3 )-CH(AA)-C(0)-Z;
• R cc3 is selected from selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl;
• AA is a side chain of an amino acid
• Z is selected from NH-R cc4 , 0-R cc4 , OH, and NH 2 ;
• R cc4 is selected from selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl.
• a certain example is a compound of formula CC-(III):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to -C(0)-0-R cc5 ;
• R cc5 is selected from
• a certain example is a compound of formula CC-(IV):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the benzoyl group;
• Z is amidino or guanidino.
• a certain example is a compound of formula CC-(V):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc6 and R cc7 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• n is a number from zero to 2;
• Z is O or NH
• AA is a side chain of an amino acid
• R cc8 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl.
• a certain example is a compound of formula CC-(VI):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc9 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• Z is O or NH
• AA is a side chain of an amino acid
• R ccl ° is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl.
• a certain example is a compound of formula CC-(VII):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R ccU and R cc12 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• R cc13 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl;
• Z is O or NH
• AA is a side chain of an amino acid.
• a certain example is a compound of formula CC-(VIII):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc14 and R cc15 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• n is a number from zero to 2;
• AA is a side chain of an amino acid
• Z is O or N
• R cc16 and R cc17 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl, wherein if Z is O, then R cc17 is not present.
• a certain example is a compound of formula CC-(IX):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• gcc2o arg i n( j e p en( j en tiy selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl.
• a certain example is a compound of formula CC-(X):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc and R cc are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• R cc23 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl;
• AA is a side chain of an amino acid.
• a certain example is a compound of formula CC-(XI):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc24 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl;
• AA is a side chain of an amino acid.
• a certain example is a compound of formula CC-(XII):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc25 and R cc26 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• R cc27 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl;
• AA is a side chain of an amino acid.
• Formula CC-(XIII) A certain example is a compound of formula CC-(XIII):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc28 and R cc29 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• R cc3 ° is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl;
• AA is a side chain of an amino acid.
• a certain example is a compound of formula CC-(XIV):
• X represents a residue of an alcohol-containing opioid, wherein the hydrogen atom of the hydroxyl group is replaced by a covalent bond to the carbonyl group;
• R cc31 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
• Z is O or NH
• R cc32 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, arylalkyl, and substituted arylalkyl;
• AA is a side chain of an amino acid.
• the disclosure provides a phenol-modified opioid prodrug which provides enzymatically- controlled release of a phenolic opioid.
• a promoiety is attached to the phenolic opioid via modification of the phenol moiety.
• a phenol-modified opioid prodrug can also be referred to as a phenolic opioid prodrug.
• the hydrogen atom of the phenolic hydroxyl group of the phenolic opioid is replaced by a covalent bond to a promoiety.
• a gastrointestinal (GI) enzyme-cleavable phenol-modified opioid prodrug is a phenol-modified opioid prodrug that comprises a promoiety comprising a GI enzyme-cleavable moiety having a site susceptible to cleavage by a GI enzyme.
• a prodrug comprises a phenolic opioid 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 drug. Cleavage can initiate, contribute to or effect drug release.
• Phenol-modified opioid prodrugs with promoiety comprising cyclizable spacer leaving group and cleavable moiety
• a phenol-modified opioid prodrug which provides enzymatically-controlled release of a phenolic opioid.
• the disclosure provides for a phenol-modified opioid prodrug in which the promoiety comprises a cyclizable spacer leaving group and a cleavable moiety.
• the phenol-modified opioid prodrug is a corresponding compound in which the phenolic hydrogen atom has been substituted with a spacer leaving group bearing a nitrogen nucleophile that is protected with an
• the configuration of the spacer leaving group and nitrogen nucleophile being such that, upon enzymatic cleavage of the cleavable moiety, the nitrogen nucleophile is capable of forming a cyclic urea, liberating the compound from the spacer leaving group so as to provide a phenolic opioid.
• the enzyme capable of cleaving the enzymatically-cleavable moiety may be a peptidase, also referred to as a protease - the promoiety comprising the enzymatically-cleavable moiety being linked to the nucleophilic nitrogen through an amide (e.g. a peptide: -NHC(O)-) bond.
• the enzyme is a digestive enzyme of a protein.
• the corresponding prodrug provides post administration-activated, controlled release of the phenolic opioid.
• the prodrug requires enzymatic cleavage to initiate release of the phenolic opioid and thus the rate of release of the phenolic opioid depends upon both the rate of enzymatic cleavage and the rate of cyclization. Accordingly, the prodrug has reduced susceptibility to accidental overdosing or abuse, whether by deliberate overdosing, administration through an inappropriate route, such as by injection, or by chemical modification using readily available household chemicals.
• the prodrug is configured so that it will not provide excessively high plasma levels of the active drug if it is administered inappropriately, and cannot readily be decomposed to afford the active drug other than by enzymatic cleavage followed by controlled cyclization.
• the enzyme-cleavable moiety linked to the nitrogen nucleophile through an amide bond can be, for example, a residue of an amino acid or a peptide, or an (alpha) N-acyl derivative of an amino acid or peptide (for example an N-acyl derivative of a pharmaceutically acceptable carboxylic acid).
• the peptide can contain, for example, up to about 100 amino acid residues.
• Each amino acid can advantageously be a naturally occurring amino acid, such as an L-amino acid.
• Naturally occurring amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
• examples of enzyme-cleavable moieties include residues of the L-amino acids listed hereinabove and N-acyl derivatives thereof, and peptides formed from at least two of the L-amino acids listed hereinabove, and the N-acyl derivatives thereof.
• the cyclic group formed when the phenolic opioid is released is conveniently
• cyclic urea is generally very stable and have low toxicity.
• the embodiments include pharmaceutical compositions, which comprise a compound of general formula PC-(I):
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
• Examples of values for the phenolic opioid as provided in X are oxymorphone, hydromorphone, and morphine.
• R 1 examples of values for R 1 are methyl and ethyl groups.
• Examples of values for each of R 2 and R 3 are hydrogen atoms.
• n 2
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
• amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
• a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
• An amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
• R 5 examples of particular values for R 5 are:
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
• R 5 represents N-acetyl, N-glycinyl or N-acetylglycinyl, such as N- acetyl.
• An example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-acetylarginyl.
• the compound of formula PC-(I) is hydromorphone 3-(N- methyl-N-(2-N'-acetylarginylamino)) ethylcarbamate, or a pharmaceutically acceptable salt thereof. This compound is described in Example 3 of WO 2007/140272.
• compositions which comprises a compound of general formula PC-(IIa):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• compositions which comprises a compound of general formula PC-(IIb):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• n represents an integer from 2 to 4;
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• Reference to formula PC-(II) is meant to include compounds of formula PC-(IIa) and PC-
• examples of values for the phenolic opioid as provided in X are oxymorphone, hydromorphone, and morphine.
• R 1 can be selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl. In certain instances, R 1 is (l-6C)alkyl. In other instances, R 1 is (l-4C)alkyl. In other instances, R 1 is methyl or ethyl. In other instances, R 1 is methyl. In some instances, R 1 is ethyl.
• R 1 is substituted alkyl.
• R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
• R 1 is -(CH 2 ) n -COOH, -(CH 2 ) n -COOCH 3 , or -(CH 2 ) n - COOCH 2 CH 3 , wherein n is a number from one to 10.
• R 1 is -(CH 2 )5-COOH, -(CH 2 ) 5 -COOCH 3 , or -(CH 2 ) 5 -COOCH 2 CH 3 .
• R 1 is arylalkyl or substituted arylalkyl. In certain instances, R 1 is arylalkyl. In certain instances, R 1 is substituted arylalkyl. In certain instances, R 1 is an arylalkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(CH 2 ) q (C 6 H 4 )-COOH, -(CH 2 ) q (C 6 H 4 )- COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10. In certain instances, R 1 is -CH 2 (C 6 H 4 )-COOH, -CH 2 (C 6 H 4 )-COOCH 3 , or -CH 2 (C 6 H 4 )-COOCH 2 CH 3 .
• R 1 is aryl. In certain instances, R 1 is substituted aryl. In certain instances, R 1 is an aryl group with ortho, meta or para-substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(C 6 H 4 )-COOH, -(C 6 H 4 )-COOCH 3 , or -(C 6 H 4 )-COOCH 2 CH 3 .
• each R can be independently selected from hydrogen, alkyl,
• R is hydrogen
• R is hydrogen. In certain instances, R is alkyl. In certain instances, R is hydrogen. In certain instances, R is alkyl. In certain
• R is acyl. In certain instances, R is aminoacyl.
• each R can be independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl.
• R is hydrogen or alkyl.
• R 3 is hydrogen.
• R 3 is alkyl.
• R 3 is acyl.
• R 3 is aminoacyl.
• R 2 and R 3 are hydrogen. In certain instances, R 2 and R 3 on the same carbon are both alkyl. In certain instances, R 2 and R 3 on the same carbon are methyl. In certain instances, R 2 and R 3 on the same carbon are ethyl.
• R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen.
• R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 and
• R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl.
• one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is substituted alkyl. In certain instances, one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
• one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is -(CH 2 ) q (C 6 H4)-COOH, -(CH 2 ) q (C 6 H4)-COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10.
• one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is carboxamide.
• R 2 and R 3 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group.
• R 2 and R 3 together with the carbon to which they are attached can form a cycloalkyl group.
• R 2 and R 3 on the same carbon form a spirocycle.
• R 2 and R 3 together with the carbon to which they are attached can form a substituted cycloalkyl group.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a cycloalkyl group.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a substituted cycloalkyl group.
• R 2 and R 3 together with the carbon to which they are attached can form an aryl or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form an aryl or substituted aryl group.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a phenyl ring.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a substituted phenyl ring.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a naphthyl ring.
• one of R 2 and R 3 is aminoacyl.
• one of R 2 and R 3 is aminoacyl comprising phenylenediamine.
• R 2 and R 3 is ; wherein each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, and acyl and R 11 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is acyl. In certain instances, at least one of R 10 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is hydrogen. In certain instances, both of R 10 are hydrogen.
• one of is hydrogen, alkyl, substituted alkyl, or acyl.
• R 10 is acyl.
• R 10 is alkyl or substituted alkyl.
• R 10 is hydrogen.
• one of R 2 and R 3 is O ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5.
• O R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5.
• R and R is R O ; wherein each R is independently hydrogen, alkyl, substituted alkyl, or acyl.
• R 2" and R 3 J is ; wherein R 10a is alkyl and each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
• R 2 and R 3 are . wherein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In certain instances,
• R 2 and R 3 are R O ; wherein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
• one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein each R 10a and R 10b is independently selected from hydrogen, alkyl, substituted alkyl, and acyl.
• one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is substituted alkyl.
• one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is alkyl substituted with a carboxylic acid or carboxyl ester.
• one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is methyl and R 10b is alkyl substituted with a carboxylic acid or carboxyl ester.
• R 2 or R 3 can modulate a rate of intramolecular cyclization.
• R 2 or R 3 can speed up a rate of intramolecular cyclization, when compared to the corresponding molecule where R 2 and R 3 are both hydrogen.
• R 2 or R 3 comprise an electron- withdrawing group or an electron-donating group.
• R 2 or R 3 comprise an electron- withdrawing group.
• R 2 or R 3 comprise an electron-donating group.
• Atoms and groups capable of functioning as electron withdrawing substituents are well known in the field of organic chemistry. They include electronegative atoms and groups containing electronegative atoms. Such groups function to lower the basicity or protonation state of a nucleophilic nitrogen in the beta position via inductive withdrawal of electron density. Such groups can also be positioned on other positions along the alkylene chain.
• halogen atoms for example, a fluorine atom
• acyl groups for example an alkanoyl group, an aroyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aminocarbonyl group (such as a carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl or arylaminocarbonyl group)
• ether groups for example an alkoxy group
• each of the electron withdrawing substituents can be selected independently from these.
• -[C(R 2 )(R 3 )] n - is selected from -CH(CH 2 F)CH(CH 2 F)-;
• R 20 , R 21 , R 22 and R 23 each independently represents hydrogen or (l-6C)alkyl, and R 24 and R 25 each independently represents (l-6C)alkyl.
• n represents an integer from 2 to 4.
• An example of a value for n is 2.
• An example of a value for n is 3.
• An example of a value for n is 4.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
• amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
• R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
• an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
• R 5 represents substituted acyl.
• R 5 can be malonyl or succinyl.
• the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
• compositions which comprises a compound of general formula PC-(III):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
• R 1 represents a (l-4C)alkyl group
• R and R each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• examples of values for the phenolic opioid as provided in X are oxymorphone, hydromorphone, and morphine.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
• amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
• a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
• amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
• R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
• an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
• R 5 represents substituted acyl.
• R 5 can be malonyl or succinyl.
• the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
• compositions which comprises a compound of general formula PC-(IV):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 5 represents a hydrogen atom, an N-acyl group, or a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
• R a is hydrogen.
• R a is hydroxyl.
• R b is hydroxyl.
• PC-(rV) a certain example of the dashed line is a single bond.
• examples of values for R 1 are methyl and ethyl groups.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
• amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
• a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
• amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
• R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
• R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
• an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl.
• the embodiments provide a pharmaceutical composition, which comprises a compound of general formula PC-(Va):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• the embodiments provide a pharmaceutical composition, which comprises a compound of general formula PC-(Vb):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• n represents an integer from 2 to 4;
• Reference to formula PC-(V) is meant to include compounds of formula PC-(Va) and
• R a is hydrogen.
• R a is hydroxyl.
• R b is hydroxyl.
• a certain example of the dashed line is a double bond.
• a certain example of the dashed line is a single bond.
• R 1 can be selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl. In certain instances, R 1 is (l-6C)alkyl. In other instances, R 1 is (l-4C)alkyl. In other instances, R 1 is methyl or ethyl. In other instances, R 1 is methyl. In some instances, R 1 is ethyl.
• R 1 is substituted alkyl.
• R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
• R 1 is -(CH 2 ) n -COOH, -(CH 2 ) n -COOCH 3 , or -(CH 2 ) n - COOCH 2 CH 3 , wherein n is a number from one to 10.
• R 1 is -(CH 2 )5-COOH, -(CH 2 ) 5 -COOCH 3 , or -(CH 2 ) 5 -COOCH 2 CH 3 .
• R 1 is arylalkyl or substituted arylalkyl. In certain instances, R 1 is arylalkyl. In certain instances, R 1 is substituted arylalkyl. In certain instances, R 1 is an arylalkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(CH 2 ) q (C 6 H 4 )-COOH, -(CH 2 ) q (C 6 H 4 )- COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10. In certain instances, R 1 is -CH 2 (C 6 H 4 )-COOH, -CH 2 (C 6 H 4 )-COOCH 3 , or -CH 2 (C 6 H 4 )-COOCH 2 CH 3 .
• R 1 is aryl. In certain instances, R 1 is substituted aryl. In certain instances, R 1 is an aryl group ortho, meta or para-substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(C 6 H 4 )-COOH, -(C 6 H 4 )-COOCH 3 , or -(C 6 H 4 )-COOCH 2 CH 3 . 2
• each R can be independently selected from hydrogen, alkyl,
• R is hydrogen
• R is hydrogen. In certain instances, R is alkyl. In certain instances, R is hydrogen. In certain instances, R is alkyl. In certain
• R is acyl. In certain instances, R is aminoacyl.
• each R can be independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl.
• R is hydrogen or alkyl.
• R 3 is hydrogen.
• R 3 is alkyl.
• R 3 is acyl.
• R 3 is aminoacyl.
• R 2 and R 3 are hydrogen. In certain instances, R 2 and R 3 on the same carbon are both alkyl. In certain instances, R 2 and R 3 on the same carbon are methyl. In certain instances, R 2 and R 3 on the same carbon are ethyl.
• R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen.
• R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 and
• R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl.
• one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is substituted alkyl. In certain instances, one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
• one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is -(CH 2 ) q (C 6 H4)-COOH, -(CH 2 ) q (C 6 H4)-COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10.
• one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is carboxamide.
• R 2 and R 3 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group.
• R 2 and R 3 together with the carbon to which they are attached can form a cycloalkyl group.
• R 2 and R 3 on the same carbon form a spirocycle.
• R 2 and R 3 together with the carbon to which they are attached can form a substituted cycloalkyl group.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a cycloalkyl group.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a substituted cycloalkyl group.
• R 2 and R 3 together with the carbon to which they are attached can form an aryl or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form an aryl or substituted aryl group.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a phenyl ring.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a substituted phenyl ring.
• two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a naphthyl ring.
• one of R 2 and R 3 is aminoacyl.
• one of R 2 and R 3 is aminoacyl comprising phenylenediamine.
• R 2 and R 3 is wherein each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, and acyl and R 11 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is acyl. In certain instances, at least one of R 10 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is hydrogen. In certain instances, both of R 10 are hydrogen. In certain instances, one of R 2 and R 3 is ; wherein R 1U is hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, R 10 is acyl. In certain instances, R 10 is alkyl or substituted alkyl. In certain instances, R 10 is hydrogen.
• one of R 2 and R 3 is
• R 10 certain instances, one of R 2 and R 3 is R 10 O ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, one of R 2" and R 3 J is ; wherein R a is alkyl and each R is independently hydrogen, alkyl, substituted alkyl, or acyl
• one of R 2 and R 3 is ; wherein R is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In certain instances,
• one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein each R 10a and R 10b is independently selected from hydrogen, alkyl, substituted alkyl, and acyl.
• one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is substituted alkyl.
• one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is alkyl substituted with a carboxylic acid or carboxyl ester.
• one of R 2 and R 3 is an aminoacyl group, such as -C(0)NR R , wherein R lua is methyl and R lue is alkyl substituted with a carboxylic acid or carboxyl ester.
• R 2 or R 3 can modulate a rate of intramolecular cyclization.
• R 2 or R 3 can speed up a rate of intramolecular cyclization, when compared to the corresponding molecule where R 2 and R 3 are both hydrogen.
• R 2 or R 3 comprise an electron- withdrawing group or an electron-donating group.
• R 2 or R 3 comprise an electron-withdrawing group.
• R 2 or R 3 comprise an electron-donating group.
• Atoms and groups capable of functioning as electron withdrawing substituents are well known in the field of organic chemistry. They include electronegative atoms and groups containing electronegative atoms. Such groups function to lower the basicity or protonation state of a nucleophilic nitrogen in the beta position via inductive withdrawal of electron density. Such groups can also be positioned on other positions along the alkylene chain.
• halogen atoms for example, a fluorine atom
• acyl groups for example an alkanoyl group, an aroyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aminocarbonyl group (such as a carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl or arylaminocarbonyl group)
• ether groups for example an alkoxy group
• each of the electron withdrawing substituents can be selected independently from these.
• -[C(R 2 )(R 3 )] n - is selected from -CH(CH 2 F)CH(CH 2 F)-;
• R 20 , R 21 , R 22 and R 23 each independently represents hydrogen or (l-6C)alkyl, and R 24 and R 25 each independently represents (l-6C)alkyl.
• n represents an integer from 2 to 4.
• An example of a value for n is 2.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
• amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
• a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
• amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
• R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
• an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
• R 5 represents substituted acyl.
• R 5 can be malonyl or succinyl.
• the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
• compositions which comprises a compound of general formula PC-(VI):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
• n 2 or 3;
• R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• a certain example of R a is hydrogen.
• a certain example of R a is hydroxyl.
• R b is hydroxyl.
• a certain example of the dashed line is a double bond.
• a certain example of the dashed line is a single bond.
• examples of values for R 1 are methyl and ethyl groups.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
• amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
• a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
• amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
• N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N-benzoyl, or an N-piperonyl group; and
• R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
• an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
• R 5 represents substituted acyl.
• R 5 can be malonyl or succinyl.
• the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
• Formula PC-(I) describes compounds of Formula PC-(II), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; and R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
• Formula PC-(III) describes compounds of Formula PC-(II), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; and R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• Formula PC-(IV) describes compounds of Formula PC-(I), wherein "X" is replaced structurally with certain phenolic opioids.
• Formula PC-(IV) describes compounds of Formula PC-(V), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; and R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
• Formula PC-(VI) describes compounds of Formula PC-(V), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; and R 5 represents a hydrogen atom, an N-acyl group (including N-substituted acyl), a residue of an amino acid, a dipeptide, or an N-acyl derivative (including N-substituted acyl derivative) of an amino acid or dipeptide.
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 - (C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )-NH(R 5 ).
• compositions which comprise a compound of general formula PC- (VII):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NHR 6 ;
• R 1 represents a (l-4C)alkyl group
• R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; n represents 2 or 3; and
• R 6 is a trypsin-cleavable moiety.
• the embodiments provide a pharmaceutical composition, which comprises a compound of general formula PC-(VIII):
• X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-NR 1 -(C(R 2 )(R 3 )) n -NHR 6 ;
• R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
• R 2 and R 3 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group, or two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group;
• n an integer from 2 to 4.
• R 6 is a trypsin-cleavable moiety.
• compositions which comprises a compound of general formula PC-(IX):
• R a is hydrogen or hydroxyl
• the dashed line is a double bond or single bond
• R 1 represents a (l-4C)alkyl group

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