Alpha-hydroxy carboxylic acid and derivatives and other GRAS-based prodrugs of opioids and uses thereof

Abstract

The invention describes pharmaceutical compounds and compositions comprised of a ligand attached to opioids in a manner that substantially decreases or deters the potential for opioid abuse, addiction, illicit and illegal use, and overdose. When delivered at the proper dosage, the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

Claims

1. An opioid prodrug of any of the following formulae where the prodrug moiety X is attached covalently to the opioid molecule, ##STR00039## ##STR00040## or a pharmaceutically acceptable salt thereof, wherein X is an alpha-hydroxy carboxylic acid selected from the group consisting of lactic acid, tartaric acid, malic acid, citric acid, mandelic acid, pantoic acid, panthothenic, 2-hydroxy glutaric acid, 3-hydroxy glutaric acid, and other poly-hydroxy carboxylic acids derived from sugars and carbohydrates.

2. The opioid prodrug of claim 1 wherein the opioid is hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, or buprenorphine.

3. The opioid prodrug of claim 2 wherein the prodrug moiety X is chemically/covalently attached to hydrocodone or hydromorphone at their 6.sup.th position oxygen atoms as a ketone enolate ester.

4. An opioid prodrug compound of formula ##STR00041## wherein OP comprises an opioid selected from the group consisting of hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, and buprenorphine, X comprises a prodrug covalently attached to the opioid, and ##STR00042## is selected from the group consisting of ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051##

5. A pharmaceutical composition comprising one or more of the opioid prodrugs according to claim 4 and one or more pharmaceutically acceptable excipient.

6. An oral pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 4, wherein the compound is a pharmaceutically acceptable salt form.

8. A method of treating pain comprising orally administering the composition of claim 6 to a patient.

9. The opioid prodrug of claim 1, wherein X is malic acid.

10. The opioid prodrug of claim 1, wherein the opioid is hydrocodone.

11. The opioid prodrug of claim 1, wherein X is malic acid and the opioid is hydrocodone.

12. The opioid prodrug compound of claim 4, wherein the opioid prodrug compound of formula ##STR00052## is represented by any one of formulae ##STR00053##

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) A first aspect of the invention relates to changing the pharmacokinetic and pharmacological properties of opioid drugs through covalent modification of opioids using alpha-hydroxy carboxylic acid and derivatives and other generally recognized as safe (GRAS)-based moieties to produce prodrugs of opioids. Covalent attachment of a chemical moietyspecifically, a moiety derived from alpha-hydroxy carboxylic acid and derivatives, as well as other GRAS-based reagents as monomers and oligomers (homo and hetero oligomers)to opioids may change one or more of the following properties of opioids: the rate of absorption; extent of absorption and distribution within the body; metabolism and drug elimination (i.e., ADME pharmacokinetic properties). As such, the alteration of one or more of these characteristics may be designed to provide fast or slow release, depending on need for relief of chronic pain versus acute pain. Additionally, alteration of one or more of these characteristics may reduce the previously noted side-effects associated with opioids. In turn, these alterations may diminish or deter abuse potential. The oligomers formed from alpha-hydroxy carboxylic acid and derivatives can be homo- and hetero-mers and can be both linear and branched mers. The hetero mers can be cross linked with other GRAS reagents. such as other alpha-hydroxy carboxylic acid, amino acid and dicarboxylic acids including, but not limited to, fumaric acid, maleic acid and succinic acid.

(2) The opioid prodrugs may also prevent abuse by exhibiting stability under conditions that are likely to be employed by chemists who may illicitly attempt to release the opioid compound from its attached group. The opioid prodrugs may further prevent abuse by exhibiting reduced bioavailability when administered via parenteral routes, particularly by intravenous, intranasal, or inhalation (smoking) routes that are often employed in illicit use. Thus, the opioid prodrugs may reduce the desired euphoric effect associated with opioid abuse, thereby preventing, deterring, or reducing abuse potential and overdose if the opioid prodrugs were to be used in an unapproved manner (e.g., ingestion of a higher dose or by non-oral administration).

(3) Opioid prodrugs of the present invention may be depicted as the structure shown below where OP represents the opioid and X represent the prodrug component that is chemically/covalently attached to the opioid OP.

(4) ##STR00001##

(5) Specifically, opioid prodrugs of the present invention may be depicted as structures shown as Formula A-Formula F where moiety X represents the prodrug component. Formula A is the hydrocodone prodrug in which the prodrug moiety X is chemically/covalently attached to hydrocodone at the 6.sup.th position oxygen atom of hydrocodone as its ketone enolate ester. Formula B is the hydromorphone prodrug in which the prodrug moiety X is chemically/covalently attached to hydromorphone at the 6.sup.th position oxygen atom of hydromorphone as its ketone enolate ester. Formula C is the morphine prodrug in which the prodrug moiety X is chemically/covalently attached to morphine at the 6.sup.th position oxygen atom of morphine as its alcohol ester. Formula D is the codeine prodrug in which the prodrug moiety X is chemically/covalently attached to codeine at the 6.sup.th position oxygen atom of codeine as its alcohol ester. Formula E is the dihydrocodeine prodrug in which the prodrug moiety X is chemically/covalently attached to dihydrocodeine at the 6.sup.th position oxygen atom of dihydrocodeine as its alcohol ester. Formula F is the buprenorphine prodrug in which the prodrug moiety X is chemically/covalently attached to buprenorphine at the side chain alcohol oxygen atom of buprenorphine as its alcohol ester. As shown in Formula F, the side chain is attached to position 7 of the core ring and the alcohol group is at position 17 of the side chain. The opioid prodrugs of the present invention depicted as Formula A-Formula F can also be represented as their pharmaceutically acceptable salts.

(6) ##STR00002## ##STR00003## ##STR00004##

(7) Alpha-hydroxy carboxylic acids and other GRAS-based monomers used to make the monomer-based and oligomer-based opioid prodrugs are depicted below.

(8) It should be emphasized that the following chemical moieties represent non-limiting examples of alpha-hydroxy carboxylic acids and other GRAS-based monomers used to make the monomer-based and oligomer-based opioid prodrugs of the present invention:

(9) ##STR00005##

(10) C8-C20 Fatty Acids; Palmitic Acid, Linoleic Acid, Oleic Acid as Examples

(11) Amino Acids Including Alpha, Beta, Gamma and Epsilon Amino Acids

(12) The alpha-hydroxy carboxylic acids represented here include the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and meso-isomers.

(13) The amino acids represented here include both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers.

(14) The amino acids represented here also include alpha amino acids, beta amino acids, gamma amino acids, and epsilon amino acids (i.e., amino group remote relative to the carboxyl group).

(15) The fatty acids represented here include long-chain carboxylic acids, ranging in carbon lengths between eight carbons (C8) to twenty carbons (C20). These fatty acids could be both linear and branched and both saturated and non-saturated. In the case of unsaturated fatty acids, they could be both cis- and trans-isomers (Z and E isomers).

(16) In one embodiment of the present invention, the prodrug component X may be represented as,

(17) ##STR00006##
wherein,
CZ=CH2, or CHOR1,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R=Methyl (Me), Phenyl (Ph), CH2COR2, CHOR1COR2, or COR2 (when n is not zero), where R2=OH, an ester formed by the hydroxyl group of another alpha-hydroxy acid or an amide formed by the amine group of an amino acid, and,
n is an integer selected from 0 to 2.

(18) In another embodiment of the present invention, the prodrug component X may be represented as,

(19) ##STR00007##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R and R3 can be same or different, and,
R and R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4.

(20) In another embodiment of the present invention, the prodrug component X may be represented as,

(21) ##STR00008##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R and R3 can be same or different, and,
R and R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4.

(22) In another embodiment of the present invention, the prodrug component X may be represented as,

(23) ##STR00009##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R and R3 can be same or different, and,
R and R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4.

(24) In another embodiment of the present invention, the prodrug component X may be represented as,

(25) ##STR00010##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4.

(26) In another embodiment of the present invention, the prodrug component X may be represented as,

(27) ##STR00011##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4.

(28) In another embodiment of the present invention, the prodrug component X may be represented as,

(29) ##STR00012##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4.

(30) In another embodiment of the present invention, the prodrug component X may be represented as,

(31) ##STR00013##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid and,
R and R3 can be same or different, and,
R and R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4.

(32) In another embodiment of the present invention, the prodrug component X may be represented as,

(33) ##STR00014##
wherein,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
m is an integer selected from 0 to 4

(34) In another embodiment of the present invention, the prodrug component X may be represented as,

(35) ##STR00015##
wherein,
CZ=CH2, or CHOR1;
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R and R3 can be same or different, and,
R and R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
R4 is the side chain of a natural or non-natural amino acid, including side chains of (L)-isomers, (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
m is an integer selected from 0 to 4, and,
n is an integer selected from 0 to 2, and,
p is an integer selected from 0 to 1.

(36) In another embodiment of the present invention, the prodrug component X may be represented as,

(37) ##STR00016##
wherein,
CZ=CH2, or CHOR1;
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, and an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R and R3 can be same or different, and,
R and R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and,
R5=H, or COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, or alkyl esters (O-alkyl, alkyl group is 1-4 carbon linear and branched, saturated and non-saturated alkyl groups), and,
the amino acids represented here depicts both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
m is an integer selected from 0 to 4, and,
n is an integer selected from 0 to 2, and,
p is an integer selected from 0 to 1, and,
v is an integer selected from 0 to 5.

(38) In another embodiment of the present invention, the prodrug components X may be represented as,

(39) ##STR00017##
wherein,
CZ=CH2, or CHOR1;
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of a amino acids or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and the amino acids represented here depicts both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
R4 is the side chain of a natural or non-natural amino acid, including side chains of (L)-isomers, (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
m is an integer selected from 0 to 4, and,
n is an integer selected from 0 to 2,

(40) In another embodiment of the present invention, the prodrug component X may be represented as,

(41) ##STR00018##
wherein,
CZ=CH2, or CHOR1;
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acids, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or i an amide formed by the amine group of an amino acid, and the amino acids represented here depicts both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
R5=H, or COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, or alkyl esters (O-alkyl, alkyl group is 1-4 carbon linear and branched, saturated and non-saturated alkyl groups), and,
the amino acids represented here depicts both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
m is an integer selected from 0 to 4, and,
n is an integer selected from 0 to 2, and,
v is an integer selected from 0 to 5.

(42) In another embodiment of the present invention, the prodrug component X may be represented as,

(43) ##STR00019##
wherein,
CW=(CH2)q, or CHCH (both E and Z isomers),
CZ=CH2, or CHOR1;
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is part of an ester formed by the hydroxyl group of another alpha-hydroxy acid or part of an amide formed by the amine group of an amino acid, and the amino acids represented here depicts both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
R6=OH or is f an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, or alkyl esters (O-alkyl, alkyl group is 1-4 carbon linear and branched, saturated and non-saturated alkyl groups), and,
the amino acids represented here depicts both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
m is an integer selected from 0 to 4, and,
n is an integer selected from 0 to 2, and,
q is an integer selected from 2 to 6.

(44) In another embodiment of the present invention, the prodrug component X may be represented as,

(45) ##STR00020##
wherein,
CW=(CH2)q, or CHCH (both E and Z isomers),
CZ=CH2, or CHOR1;
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid, and,
R and R3 can be same or different, and,
R and R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and the amino acids represented here depicts both natural and non-non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
R6=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, or alkyl esters (O-alkyl, alkyl group is 1-4 carbon linear and branched, saturated and non-non-saturated alkyl groups), and
the amino acids represented here depicts both natural and non-non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and,
m is an integer selected from 0 to 4, and,
n is an integer selected from 0 to 2, and,
q is an integer selected from 2 to 6.

(46) In another embodiment of the present invention, the prodrug components X may be represented as,

(47) ##STR00021##
wherein,
CW=(CH2)q, or CHCH, (both E and Z isomers), and,
R3=Me, Ph, CH2COR2, or CHOR1COR2, where R2=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and the amino acids represented here depicts both natural and non-non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, R5=H, COR2, where R2=OH or is part of an ester formed by the hydroxyl group of another alpha-hydroxy acid or part of an amide formed by the amine group of an amino acid, or alkyl esters (O-alkyl, alkyl group is 1-4 carbon linear and branched, saturated and non-non-saturated alkyl groups), and,
R6=OH or is an ester formed by the alcohol (OH) part of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, or alkyl esters (O-alkyl, alkyl group is 1-4 carbon linear and branched, saturated and non-non-saturated alkyl groups), and,
m is an integer selected from 0 to 4, and,
n is an integer selected from 0 to 2, and,
q is an integer selected from 2 to 6, and,
v is an integer selected from 0 to 6.

(48) In another embodiment of the present invention, the prodrug component X may be represented as,

(49) ##STR00022##
wherein,
FA is C8 to C20 saturated and unsaturated fatty acids including sorbic acid, stearic acid, oleic acid, palmitic acid, linoleic acid.
These fatty acids may be linear or branched chain acids, or a combination thereof; and in the case of unsaturated fatty acids, they may be cis- or trans-isomers (Z and E isomers).

(50) With the ketone functional group present at the 6 positions of hydrocodone and hydromorphone, the ketone can be converted to its corresponding enolate and reacted with an activated prodrug side chain to form the corresponding prodrugs as the enolate ester. Upon prodrug cleavage, these prodrugs will revert back to the original opioid molecule with the keto group present intact.

(51) In another embodiment of the present invention, with the hydroxyl functional group present at the 6 positions of morphine, codeine and dihydrocodeine, the hydroxyl group (OH group) is reacted with an activated prodrug side chain to form the corresponding prodrugs of these molecules as its alcohol esters. Upon prodrug cleavage, these prodrugs will revert back to the original opioid molecules with the hydroxyl group (OH group) present intact.

(52) In another embodiment of the present invention, with the hydroxyl group present at the 17 position of buprenorphine, the hydroxyl group (OH group) is reacted with an activated prodrug side chain to form the corresponding prodrug of buprenorphine. Upon prodrug cleavage, this prodrug will revert back to the original buprenorphine molecule with the hydroxyl group (OH group) present intact.

(53) The alpha-hydroxy carboxylic acid and its homo and hetero oligomers (with another alpha-hydroxy carboxylic acid) referred to in this invention should be understood to be covalently bound via a hydroxy group on the alpha-hydroxy carboxylic acid or on the oligomer to another carbonyl (originally part of a carboxyl group of another alpha-hydroxy carboxylic acid, or to another carbonyl of the carboxyl group of the amino acid, or to one carbonyl of the carboxyl group of a dicarboxylic acid (e.g., succinic acid, maleic acid, fumaric acid), while the carboxyl group from the initial alpha-hydroxy carboxylic acid is attached to the opioid.

(54) If the initial carboxyl group that is attached to the opioid referred to in this invention is from an amino acid, it should be understood that the amino group of the said amino acid is to be bound via a covalent bond as the amide with the carboxyl group on the alpha-hydroxy carboxylic acid or the oligomer carbonyl (originally part of a carboxyl group of the alpha-hydroxy carboxylic acids) or to one carbonyl of the carboxyl group of a dicarboxylic acid (e.g., succinic acid, maleic acid, fumaric acid), or to one carbonyl of the carboxyl group of the fatty acids.

(55) It should also be understood that if the initial carboxyl group that is attached to the opioid referred to in this invention is from alpha-hydroxy carboxylic acids and its homo and hetero oligomers (with another alpha-hydroxy carboxylic acid), the ensuing hydroxyl group may be capped as its ester by fatty acids.

(56) It should also be understood that If the initial carboxyl group that is attached to the opioid referred to in this invention is from alpha-hydroxy carboxylic acids and its homo and hetero oligomers (with another alpha-hydroxy carboxylic acid), the ensuing hydroxyl group may be capped as its ester by dicarboxylic acids (e.g., succinic acid, maleic acid, fumaric acid).

(57) In another embodiment of the present invention, when the covalently modified opioid is provided in oral dosage form (e.g., a tablet, capsule, caplet, liquid dispersion, etc.) it has increased resistance to manipulation. For instance, crushing of a tablet or disruption of a capsule does not substantially increase the rate and amount of opioid absorbed when compositions of the invention are ingested.

(58) In another embodiment of the present invention, when the opioid covalently bound to the prodrug side chain is provided in oral dosage form: for example a tablet, capsule, caplet or other formulation that is resistant to generate opioid by physical manipulation such as crushing.

(59) Another embodiment of the present invention provides opioid prodrug conjugates as a composition or method for treating pain in a patient (i.e., acute and chronic pain). It should be noted that different conjugates maybe be utilized to treat acute versus chronic pain.

(60) Another embodiment of the present invention is a composition or method for a sustained-release opioid comprising a covalently bonded opioid conjugate, wherein said conjugate provides release of opioid at a rate where the level of opioid is within the therapeutic range, but below toxic levels, over an extended period of time (e.g., 8-24 hours or greater).

(61) Another embodiment of the present invention is a composition or method for reducing variability in bioavailability, or preventing a toxic release of opioid, comprising opioid covalently bonded to the prodrug moiety, wherein said bound opioid maintains a steady-state plasma release curve, which provides therapeutically effective bioavailability but prevents spikes or sharp increases in blood concentrations compared to unbound opioid when given at doses exceeding those that are within the therapeutic range of opioid.

(62) Another embodiment of the invention is a composition or method for preventing an extreme spike in plasma C.sub.max for opioid while still providing therapeutically effective bioavailability curve for opioid that has been covalently bonded to the prodrug moiety.

(63) Another embodiment of the present invention is a method for reducing or preventing abuse related to the euphoric effect of a pharmaceutical opioid composition, comprising consuming said composition, wherein said composition comprises a prodrug moiety covalently attached to opioid, such that the pharmacological activity of opioid is substantially decreased when the composition is used in a manner inconsistent with approved instructions or in a manner that substantially increases the potential of overdose.

(64) Other embodiments of the present invention are methods wherein said pharmaceutical composition is adapted solely for oral administration, and wherein said opioid is resistant to release from said prodrug moiety when the composition is administered parenterally (e.g., intranasally. Intravenously etc.). Preferably, said opioid would be preferentially released from said chemical moiety primarily in the presence of acid and/or enzymes present in the stomach or intestinal tract, respectively.

(65) In another embodiment of the present invention, the covalently bonded opioid prodrug may also be in a pharmaceutically acceptable salt form. Pharmaceutically acceptable inorganic and organic acid addition salts are known in the art. Exemplary salts include, but are not limited to, hydrobromide, hydrochloride, hydroiodide, benzoate, bisulfate, tartrate, bitartrate, edetate, edisylate, estolate, esylate, ethanesulfonate, lactate, malate, maleate, mandelate, methanesulfonate, phosphate, 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, citrate, clavulariate, cyclopentanepropionate, digluconate, dodecylsulfate, finnarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isothionate, lactobionate, laurate, laurylsulphonate, mucate, naphthylate, napsylate, nicotinate, N-methylglucamine ammonium salt, oleate, palmitate, pamoate, pantothenate, pectinate, phosphateldiphosphate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, teoclate, tosylate, triethiodide, undecanoate, and valerate salts, and the like.

(66) The term amino acid refers to one of twenty-two amino acids used for protein biosynthesis, as well as other amino acids that can be incorporated into proteins during translation. Such amino acids can be a natural amino acid, such as glycine, alanine, valine, leucine, isoleucine, aspartic acid, glutamic acid, serine, threonine, glutamine, asparagine, arginine, lysine, proline, phenylalanine, tyrosine, tryptophan, cysteine, methionine, histidine and beta alanine, or non-natural amino acids and alpha amino acids, beta amino acids, gamma amino acids, and epsilon amino acids (e.g., the amino group is remote relative to the carboxyl group).

(67) The present invention also provides methods for providing, administering, prescribing, or consuming an opioid prodrug. The invention also provides pharmaceutical compositions comprising an opioid prodrug. The formulation of such a pharmaceutical composition can optionally enhance or achieve the desired release profile.

(68) In a further embodiment of the present invention, non-limiting examples of opioid prodrugs of the present invention are shown in Formulae 1-90. In these formulae, it should be noted that while no salt forms have been depicted, all the formulae compounds can be prepared as their pharmaceutically acceptable salts, as previously described. In these formulae, it should also be noted that OP represent the opioid and the prodrug component X, the ligand is chemically/covalently attached to the opioid OP. In these formulae, it should also be noted that the opioids represented here include non-limiting examples of hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, and buprenorphine. The point of covalent attachment of the ligands to the opioids hydrocodone and hydromorphone is the 6.sup.th position ketone enolate oxygen. For morphine, codeine, and dihydrocodeine it is the 6.sup.th position hydroxyl group oxygen and for buprenorphine it is the 17.sup.th position hydroxyl group oxygen.

(69) Non-limiting examples of opioid prodrugs include the following compounds (formulae 1-90):

(70) ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##

EXAMPLES

Processes for Preparing Opioid Conjugates

(71) Two general procedures have been used for the preparation of various opioid prodrug conjugates OPX, and more specifically:

(72) ##STR00032## ##STR00033##

(73) The procedure involves treating opioid first with a base followed by reaction with the carboxyl-activated prodrug moieties. In the case of phenolic opioids (e.g., hydroxymorphone, morphine, buprenorphine), the phenolic OH group of the starting material opioid is protected with Boc.

(74) General Procedure 1Opioid Coupling with the Activated Prodrug Side Chain (KO.sup.tBu Procedure)

(75) To a solution of opioid (1.05 g, 3.2 mmol) in THF (10 mL) is added KO.sup.tBu (1M solution in THF, 1.05 eq.) at 0 C., then stirred at ambient temperature for 30 min. The brown solution is cooled down to 78 C. and a solution of Boc-hydroxyl protected Osu-active ester of alpha-hydroxy acid (1.05 g, 3.4 mmol) in THF (20 mL) is added over a period of 5 mins. After stirring the reaction at 78 C. for 30 minutes, it is allowed to warm to RT over a period of 3 hrs. The turbid reaction mixture is poured into saturated (satd) NH.sub.4Cl solution (150 mL), stirred for 5 mins and extracted with EtOAc (250 mL). The organic part is washed with aqueous (aq) NH.sub.4Cl, aq. NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and evaporated to dryness to give the product (1.5 g, purity 96.5%).

(76) In some cases the crude product may require further purification by standard column chromatography. The product may be further characterized by nuclear magnetic resonance (NMR) spectroscopy, mass spectroscopy (MS), and elemental analysis.

(77) General Procedure 2Opioid Coupling with the Activated Prodrug Side Chain (LHMDS [Lithium Hexamethyl Disilaside] Procedure)

(78) To a solution of opioid (1.05 g, 3.2 mmol) in THF (10 mL) is added LHMDS (LiN(TMS).sub.2) (1M solution in THF, 1.05 eq.) at 0 C., then stirred at ambient temperature for 30 min. The brown solution is cooled down to 78 C. and a solution of Boc-hydroxyl protected Osu-active ester of alpha-hydroxy acid (1.05 g, 3.4 mmol) in THF (20 mL) is added over a period of 5 mins. After stirring the reaction at 78 C. for 30 minutes, it is allowed to warm to room temperature (RT) over a period of 3 hrs. The turbid reaction mixture is poured into satd NH.sub.4Cl solution (150 mL), stirred for 5 mins and extracted with EtOAc (250 mL). The organic part is washed with aqueous (aq) NH.sub.4Cl, aq. NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, and evaporated to dryness to yield the product (1.4 g, purity 95%).

(79) In some cases the crude product may require further purification by standard column chromatography. The product may be further characterized by NMR, MS and elemental analysis.

(80) Boc Group Deprotection from the Coupled Enol-Ester Prodrug or Alcohol-Ester Product

(81) Boc group protection is used to protect the hydroxyl group(s) of the alpha-hydroxy carboxylic acids. After the oxycodone coupling, the Boc group is removed by the following general procedure. To a solution of the hydroxyl Boc-protected coupled product (1.5 g) in IPAc (15 mL) is added 4N HCl/dioxane (15 mL) and the reaction mixture is stirred at RT for 3 h (white ppt formation takes place after 10-15 mins). The solution is diluted with IPAc 50 mL), stirred for 10 mins. The precipitate is filtered, washed with IPAc and dried to give the deprotected product (quantitative yield). In this case the product is isolated as the HCl salt. HPLC purity 95%. The product may be further characterized by NMR, MS and elemental analysis.

(82) Boc Group Deprotection from the Coupled Enol-Ester Prodrug Product (Alternative General Procedure)

(83) A third general procedure may also be used to remove the Boc group from the coupled enol-ester prodrug product. To a solution of the above, hydroxyl Boc-protected coupled product (1.5 g) in dichloromethane (15 mL) was added trifluoro acetic acid (15 mL) and the reaction mixture was stirred at RT for 3 hrs. The reaction mixture was concentrated to a dry powder on a rotavap and the residue was further purified by either trituration or chromatography as a TFA salt of the enol ester prodrug product. In this case the product is isolated as the TFA salt. HPLC purity 95%. The product was further characterized by NMR, MS and elemental analysis.

(84) Synthesis of the Activated Side ChainOSu Ester for Opioid Coupling

(85) Generally, N-hydroxy succinimide ester activated carboxylic acid of the alpha-hydroxy carboxylic acid is used for oxycodone coupling. To a solution of the hydroxyl Boc-protected alpha-hydroxy carboxylic acid (1 g, 1.1 mmol) and NHS (N-hydroxy succinimide) (1.05 eq) in THF (10 mL) is added a solution of DCC (1.05 eq) in THF (5 mL) at 0 C. The reaction mixture is slowly brought to RT and left overnight at RT. The turbid solution is filtered and the filtrate is used as such for the next step coupling process.

(86) Depending on the specific stability of the compound being synthesized, the OSu ester also can be precipitated and crystallized.

EMBODIMENTS

(87) Various embodiments are listed below. It will be understood that the embodiments listed below may be combined with all aspects and other embodiments in accordance with the scope of the invention.

Embodiment 1

(88) Opiod prodrugs of the following formulae where the prodrug moiety X is attached covalently to the opioid molecules,

(89) ##STR00034## ##STR00035##
or a pharmaceutically acceptable salt thereof.

Embodiment 2

(90) Opioid prodrugs of embodiment 1 wherein the opioids are Hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, or buprenorphine.

Embodiment 3

(91) Opioid prodrugs of embodiment 1 or 2 wherein the prodrug moiety X is chemically/covalently attached to hydrocodone and hydromorphone at their 6.sup.th position oxygen atoms as its ketone enolate esters respectively.

Embodiment 4

(92) Opioid prodrugs of embodiment 1 or 2 wherein the prodrug moiety X is chemically/covalently attached to morphine, codeine and dihydrocodeine at their 6.sup.th position oxygen atoms as their alcohol esters respectively.

Embodiment 5

(93) Opioid prodrugs of embodiment 1 or 2 wherein the prodrug moiety X is chemically/covalently attached to buprenorphine at its 17.sup.th position oxygen atoms as its alcohol ester.

Embodiment 6

(94) The opioid prodrugs of embodiments 1 or 2, wherein X is a prodrug moiety ligand selected from alpha-hydroxy carboxylic acid and derivatives as monomers, alpha-hydroxy carboxylic acid homo-oligomers, alpha-hydroxy carboxylic acid hetero oligomers with another alpha-hydroxy carboxylic acid, alpha-hydroxy carboxylic acid hetero oligomers with amino acids, alpha-hydroxy carboxylic acid hetero oligomers with dicarboxylic acids, alpha-hydroxy carboxylic acid hetero oligomers with fatty acids, fatty acids, and other GRAS-based reagents.

Embodiment 7

(95) The opioid prodrugs of embodiment 6 wherein homo- and hetero-mers include both linear and branched mers. The homo- and hetero-mers may also be cross linked with other GRAS reagents such as alpha-hydroxy carboxylic acids and amino acids.

Embodiment 8

(96) The opioid prodrugs of embodiment 6 wherein the alpha-hydroxy carboxylic acid is selected from lactic acid, tartaric acid, malic acid, citric acid, mandelic acid, pantoic acid, pantothenic acid, 2-hydroxy glutaric acid, 3-hydroxy glutaric acid, and other poly-hydroxy carboxylic acids derived from sugars and carbohydrates. The naturally occurring (L)-isomers, the non-natural (D)-isomers, varying mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, and meso-isomers are all included in the term alpha-hydroxy carboxylic acid.

Embodiment 9

(97) The opioid prodrugs of embodiment 6 wherein the amino acids represented here include both natural (all 22 of the proteinogenic amino acids), and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, varying mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers. The amino acids represented here also include alpha amino acids, beta amino acids, gamma amino acids, and epsilon amino acids (amino group remote relative to the carboxyl group).

Embodiment 10

(98) The opioid prodrugs of embodiment 6 wherein the fatty acids represented here include long chain carboxylic acids, ranging in lengths between eight carbons (C8) to twenty carbons (C20), and said fatty acids may be linear or branched chains, and include both saturated and non-non-saturated chains, and in the case of unsaturated fatty acids include both cis- and trans-isomers (Z and E isomers), wherein examples of such fatty acids include, but are not limited to, sorbic acid, stearic acid, oleic acid, palmitic acid, and linoleic acid.

Embodiment 11

(99) The opioid prodrugs of embodiment 6 wherein the dicarboxylic acids represented here to make hetero oligomers with alpha-hydroxy carboxylic acid include, but are not limited to, fumaric acid, maleic acid, and succinic acid.

Embodiment 12

(100) The opioid prodrugs of embodiment 1 or 2, wherein ligand X is further represented as X is equal to ligands 1-16 (shown below);

(101) ##STR00036## ##STR00037##
Wherein,
in ligands 1-16,
CZ=CH2, or CHOR1,
R1=H, an acyl linkage of a fatty acid, an acyl linkage of an alpha-hydroxy acid, an acyl linkage of an amino acid, or an acyl linkage of a dicarboxylic acid including, but not limited to, fumaric acid, maleic acid and succinic acid,
R=Me, Ph, CH2COR2, CHOR1COR2, or COR2 (when n is not zero),
R2=OH, or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, and the amino acids represented here depicts both natural and non-non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, or O-alkyl (alkyl esters, where the alkyl group is 1-4 carbon linear and branched, saturated and non-saturated alkyl groups),
R3=Me, Ph, CH2COR2, CHOR1COR2, or COR2 (when n is not zero),
R4 is the side chain of a natural or non-natural amino acid, including side chains of (L)-isomers, (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers (R4 in ligands 10 and 12),
R5=H, or COR2,
CW=(CH2)q, or CHCH (both E and Z isomers),
R6=OH or is an ester formed by the hydroxyl group of another alpha-hydroxy acid or is an amide formed by the amine group of an amino acid, or alkyl esters, and the amino acids represented here depicts both natural and non-natural amino acids, the naturally occurring (L)-isomers, the non-natural (D)-isomers, mixtures of (L) and (D) isomers, racemates and mixtures of diastereomers, or R6 is an ester with an alkyl group (O-alkyl, alkyl group is 1-4 carbon linear and branched, saturated and non-saturated alkyl groups),
and m is an integer selected from 0 to 4, and n is an integer selected from 0 to 2, and q is an integer selected from 2 to 6, and v is an integer selected from 0 to 6

Embodiment 13

(102) The opioid prodrugs of embodiment 1 or 2, wherein X is a prodrug moiety and is represented by ligand 17;

(103) ##STR00038##
Wherein,
FA is C8 to C20 saturated fatty acids, C8 to C20 unsaturated fatty acids, including but not limited to, sorbic acid, stearic acid, oleic acid, palmitic acid, linoleic acid. These fatty acids could be both linear and branched chain fatty acids,
and in the case of unsaturated fatty acids both cis- and trans-isomers (Z and E isomers) are included.

Embodiment 14

(104) Opioid prodrug compounds represented by any one of formulae 1-90.

Embodiment 15

(105) A composition comprising the compound of any of embodiments 1-13.

Embodiment 16

(106) The compound of embodiment 14 wherein the compound, or a pharmaceutically acceptable salt thereof, maintains a steady-state release curve in blood that provides therapeutically effective opioid bioavailability.

Embodiment 17

(107) The composition of embodiment 15, wherein when said composition is administered orally and the bioavailability of opioid is maintained.

Embodiment 18

(108) A method of treating pain comprising orally administering the composition of embodiment 15 to a patient.

Embodiment 19

(109) The composition of embodiment 14, wherein the said composition comprises a pharmaceutically acceptable salt form of the opioid prodrug compound.

Embodiment 20

(110) A pharmaceutical composition comprising one or more of the opioid prodrugs of embodiment 14 and one or more pharmaceutically acceptable excipients.