WO2018183264A1 - Nouvel acide alpha-hydroxy carboxylique et dérivés et autres promédicaments d'opioïdes à base de gras et leurs utilisations - Google Patents

Nouvel acide alpha-hydroxy carboxylique et dérivés et autres promédicaments d'opioïdes à base de gras et leurs utilisations Download PDF

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WO2018183264A1
WO2018183264A1 PCT/US2018/024476 US2018024476W WO2018183264A1 WO 2018183264 A1 WO2018183264 A1 WO 2018183264A1 US 2018024476 W US2018024476 W US 2018024476W WO 2018183264 A1 WO2018183264 A1 WO 2018183264A1
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acid
opioid
isomers
alpha
prodrug
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PCT/US2018/024476
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John K. Thottathil
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Thottathil John K
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Priority to EP18774382.8A priority Critical patent/EP3600319A4/fr
Publication of WO2018183264A1 publication Critical patent/WO2018183264A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Definitions

  • the present invention relates to pharmaceutical compounds, compositions, and methods of using chemical moieties that are generally recognized as safe (GRAS), which are attached to the opioid (e.g. hydrocodone, hydromorphone, morphine, codeine,
  • GRAS chemical moieties that are generally recognized as safe
  • dihydrocodeine, buprenorphine, oxycodone, oxymorphone molecules.
  • These chemical moieties are monomers, homo- and hetero- oligomers, of alpha-hydroxy carboxylic acids and their chemical derivatives.
  • These inventions provide a variety of beneficial effects, particularly a substantial decrease in the potential of opioids to cause overdose or to be abused.
  • Some embodiments of the invention provide therapeutic activity similar to that of unmodified opioid at typical dosage ranges; but when delivered at higher doses, the potential for overdose is reduced due to decreased bioavailability of the opioid, especially when taken by non-approved routes, as compared to the opioid that is administered by the approved oral route and delivered in a non-conjugated form.
  • these prodrugs may be designed to provide fast or slow release of opioid depending on its standard use for chronic or acute pain.
  • Opioid overdose is a significant and growing problem associated with drug abuse, but overdoses also occur accidentally (e.g., when a child obtains and ingests an opioid drug, say Oxycontin® or Opana® or vicodin®), or intentionally (e.g., when related to suicide attempts).
  • Accidental overdose can also commonly occur when unusually potent batches of illicit opioids are ingested by drug addicts or other abusers.
  • Opioid abuse is an increasing problem, and opioids have become one of the most widely abused drugs.
  • the opioid drug is also known as "a poor man's heroin" because of its comparatively lower street price.
  • crushing and snorting intranasally the delayed release form of oxycodone results in rapid drug release and absorption, which results in high peak blood concentrations that produce a quick "high” but can also precipitate a fatal overdose (Aquina et al (2009) Post graduate Medicine 121 : 163-167).
  • Oxycontin® the delayed release form of oxycodone
  • necrosis of intranasal structures similar to the damage associated with cocaine use, is also a consequence of prolonged Oxycontin® abuse by snorting crushed tablets.
  • Opana-ER® oxymorphone
  • a further shortcoming of many opioids is their generally low oral bioavailability. Poor oral bioavailability results in variable blood levels, and consequently variable patient response - a highly undesirable feature in the treatment of pain where rapid and reliable relief is critical.
  • opioids have been combined with opioid antagonists.
  • Such formulations are designed to counteract an oral opioid if the formulation is disrupted (e.g., crushed) prior to oral administration, or if the drug is taken administered parenterally (e.g., injected intravenously).
  • extended-release methylphenidate Concerta®
  • Embeda® where the opioid drug morphine is co-formulated with the antagonist naltrexone in sequestered fashion.
  • compositions have been coated with emetic agents in quantities that - if administered in moderation as intended - no emesis occurs; however, if excessive amounts are ingested, emesis is induced to prevent overdose.
  • emesis is induced to prevent overdose.
  • methods as well as conventional controlled-release formulations, are often ineffective and can be circumvented.
  • oxymorphone is also an ingredient of Opana® Injection (injectable), Opana® ER (extended-release tablet), Opana® IR (immediate- release tablet), Numorphan® (suppository and injectable solution), and O-Morphon® (both tablet and injectable). It is a semi synthetic narcotic analgesic derived from thebaine. Typical adult doses of opioid range from 5-40 mg as the oral hydrochloride salt, whereas the injectable adult dose is approximately 1 mg as the hydrochloride salt, with a dosing interval ranging from 4-12 hours.
  • oxycodone is also an ingredient of well-known drugs such as Percodan®, Percocet®, Roxicet®, and Tylox®.
  • oxycodone is also available in oral formulations combined with aspirin, phenacetin, and caffeine.
  • a typical adult dose of oxycodone is 2.5-5 mg administered orally as the hydrochloride or terephthalate salt every 6 hours. While typically used for the relief of moderate to moderately severe pain, opioid can also produce drug dependence of the morphine type.
  • hydrocodone there are several FDA approved products in the market, but most of them are combination products, mainly co-formulated with acetaminophen.
  • hydrocodone is also an ingredient of well-known drugs such as Hyphen®, Co-gesic®, Hycodan®, Codamine®, Hysingla®, Lortab®, Lorcet-HD®, Norcet®, Vicoprin®, Zohydro ER®, Zydone® etc. to mention a few.
  • a prodrug moiety and its linkage to a particular opioid would be cleaved at an appropriate rate and site, which would then release the active opioid compound into the blood and provide the intended analgesic benefit.
  • opioids There remains a critical need for the treatment of severe pain with opioids using products that retain all their pharmacological advantages but sharply reduce their principal limitations, including adverse gastrointestinal effects (e.g., constipation), variable bioavailability after oral dosing, opioid overdose, and misuse, illegal/illicit use and product tampering.
  • GRAS generally recognized as safe
  • These chemical moieties are monomers, homo- and hetero- oligomers of alpha-hydroxy carboxylic acids, and their chemical derivatives.
  • the compounds may provide a substantial decrease in the potential of opioid to cause overdose or to be abused.
  • the opioid prodrug conjugates provide therapeutic activity which is similar to that of unmodified parent drug when delivered at typical dosage ranges. However, when delivered at higher doses the potential for overdose is reduced as compared to conventional non-conjugated opioid due to decreased bioavailability of the opioid, especially when taken by non-approved oral routes.
  • the prodrugs may be designed to provide fast or slow release of the opioid depending on its standard use for chronic or acute pain.
  • the drugs/molecules that are covered in this invention include all the opioid drugs including but not limited to; Oxycodone, Hydrocodone, Oxymorphone, Hydromorphone, Morphine, Codeine, Dihydrocodeine, and Buprenorphine.
  • a first aspect of the invention relates to changing the pharmacokinetic
  • GRAS GRAS-based moieties to produce prodrugs of opioids.
  • Covalent attachment of a chemical moiety - specifically, 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.
  • 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.
  • 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.
  • 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).
  • 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”.
  • 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 th position oxygen atom of hydrocodone as its ketone enolate ester.
  • Formula B is the hydromorphone prodrug in which the prodrug moiety X is
  • Formula C is the morphine prodrug in which the prodrug moiety X is chemically/covalently attached to morphine at the 6 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 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 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. [019] Alpha-hydroxy carboxylic acids and other GRAS-based monomers used to make the monomer-based and oligomer-based opioid prodrugs are depicted below.
  • 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.
  • 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.
  • 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).
  • 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).
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 2.
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 4.
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 4.
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 4.
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 4.
  • the prodrug component X may be represented as,
  • 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,
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 4.
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 4.
  • the prodrug component X may be represented as,
  • 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,
  • n is an integer selected from 0 to 4.
  • the prodrug component X may be represented as,
  • 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,
  • R4 is the side chain of a natural or non-natural amino acid, including side chains of
  • n is an integer selected from 0 to 4, and,
  • n is an integer selected from 0 to 2
  • n is an integer selected from 0 to 2
  • p is an integer selected from 0 to 1 .
  • the prodrug component X may be represented as,
  • CZ CH2, or CHOFM ;
  • 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,
  • 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,
  • n is an integer selected from 0 to 4, and,
  • n is an integer selected from 0 to 2
  • n is an integer selected from 0 to 2
  • p is an integer selected from 0 to 1 , and,
  • v is an integer selected from 0 to 5.
  • the prodrug components X may be represented as,
  • 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,
  • 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,
  • n is an integer selected from 0 to 4, and,
  • n is an integer selected from 0 to 2
  • the prodrug component X may be represented as,
  • CZ CH2, or CHOFM ;
  • 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,
  • 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,
  • n is an integer selected from 0 to 4, and,
  • n is an integer selected from 0 to 2
  • n is an integer selected from 0 to 2
  • v is an integer selected from 0 to 5.
  • the prodrug component X may be represented as,
  • CZ CH2, or CHOFM ;
  • 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,
  • 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 alkyi esters (O-alkyI, alkyi group is 1 - 4 carbon linear and branched, saturated and non-saturated alkyi groups), and,
  • 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,
  • n is an integer selected from 0 to 4, and,
  • n is an integer selected from 0 to 2
  • n is an integer selected from 0 to 2
  • q is an integer selected from 2 to 6.
  • the prodrug component X may be represented as
  • 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,
  • 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 alkyi esters (O-alkyI, alkyi group is 1 - 4 carbon linear and branched, saturated and non-non-saturated alkyi groups), and
  • 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,
  • n is an integer selected from 0 to 4, and,
  • n is an integer selected from 0 to 2
  • n is an integer selected from 0 to 2
  • q is an integer selected from 2 to 6.
  • the prodrug components X may be represented as,
  • 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 alkyi esters (O-alkyI, alkyi group is 1 - 4 carbon linear and branched, saturated and non-non-saturated alkyi groups), and,
  • n is an integer selected from 0 to 4, and,
  • n is an integer selected from 0 to 2
  • q is an integer selected from 2 to 6
  • v is an integer selected from 0 to 6.
  • the prodrug component X may be represented as,
  • FA is C8 to C20 saturated and unsaturated fatty acids including sorbic acid, stearic acid, oleic acid, palmitic acid, linoleic acid.
  • fatty acids may be linear or branched chain acids, or a combination thereof;
  • the ketone 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.
  • 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.
  • the hydroxyl group (-OH group) is reacted with an activated prodrug side chain to form the corresponding prodrug of buprenorphine.
  • this prodrug will revert back to the original buprenorphine molecule with the hydroxyl group (-OH group) present intact.
  • 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.
  • a dicarboxylic acid e.g., succinic acid, maleic acid, fumaric acid
  • the amino group that is attached to the opioid referred to in this invention is from an amino acid
  • 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.
  • a dicarboxylic acid e.g., succinic acid, maleic acid, fumaric acid
  • 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.
  • 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).
  • the covalently modified opioid when 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.
  • oral dosage form e.g., a tablet, capsule, caplet, liquid dispersion, etc.
  • 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.
  • 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.
  • 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).
  • 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.
  • Another embodiment of the invention is a composition or method for preventing an extreme spike in plasma C max for opioid while still providing therapeutically effective bioavailability curve for opioid that has been covalently bonded to the prodrug moiety.
  • 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.
  • compositions are 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.).
  • 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.
  • 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, cit
  • 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, unde
  • 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).
  • 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.
  • opioid prodrugs of the present invention are shown in Formulae 1 -90.
  • 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.
  • "OP" represent the opioid and the prodrug component - X, the ligand is chemically/covalently attached to the opioid "OP”.
  • the opioids represented here include non-limiting examples of
  • hydrocodone hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, and buprenorphine.
  • the point of covalent attachment of the ligands to the opioids hydrocodone and hydromorphone is the 6 th position ketone enolate oxygen.
  • morphine, codeine, and dihydrocodeine it is the 6 th position hydroxyl group oxygen
  • buprenorphine it is the 17 th position hydroxyl group oxygen.
  • Non-limiting examples of opioid prodrugs include the following compounds (formulae 1 -90):
  • the procedure involves treating opioid first with a base followed by reaction with the carboxyl-activated prodrug moieties.
  • phenolic opioids e.g., hydroxymorphone, morphine, buprenorphine
  • the phenolic -OH group of the starting material opioid is protected with Boc.
  • the turbid reaction mixture is poured into saturated (satd) NH 4 CI solution (150 mL), stirred for 5 mins and extracted with EtOAc (250 mL). The organic part is washed with aqueous (aq) NH 4 CI, aq. NaHC0 3 , brine, dried over Na 2 S0 4 and evaporated to dryness to give the product (1 .5 g, purity 96.5%).
  • 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.
  • the turbid reaction mixture is poured into satd NH 4 CI solution (150 mL) , stirred for 5 mins and extracted with EtOAc (250 mL). The organic part is washed with aqueous (aq) NH 4 CI, aq. NaHC0 3 , brine, dried over Na 2 S0 4 , and evaporated to dryness to yield the product (1 .4 g, purity 95%).
  • the crude product may require further purification by standard column chromatography.
  • the product may be further characterized by NMR, MS and elemental analysis.
  • Boc group protection is used to protect the hydroxyl group(s) of the alpha-hydroxy carboxylic acids.
  • the Boc group is removed by the following general procedure.
  • 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 HCI salt. HPLC purity -95%.
  • the product may be further characterized by NMR, MS and elemental analysis.
  • a third general procedure may also be used to remove the Boc group from the coupled enol-ester prodrug product.
  • 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 3hrs.
  • 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.
  • N-hydroxy succinimide ester activated carboxylic acid of the alpha-hydroxy carboxylic acid is used for oxycodone coupling.
  • 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.
  • the -OSu ester also can be precipitated and crystallized.
  • Embodiment 1 Opiod prodrugs of the following formulae where the prodrug moiety X is attached covalently to the opioid molecules,
  • Embodiment 2 Opioid prodrugs of embodiment 1 wherein the opioids are
  • Hydrocodone Hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, or buprenorphine.
  • Embodiment 3 Opioid prodrugs of embodiment 1 or 2 wherein the prodrug moiety X is chemically/covalently attached to hydrocodone and hydromorphone at their 6 th position oxygen atoms as its ketone enolate esters respectively.
  • Embodiment 4 Opioid prodrugs of embodiment 1 or 2 wherein the prodrug moiety X is chemically/covalently attached to morphine, codeine and dihydrocodeine at their 6 th position oxygen atoms as their alcohol esters respectively.
  • Embodiment 5 Opioid prodrugs of embodiment 1 or 2 wherein the prodrug moiety X is chemically/covalently attached to buprenorphine at its 17 th position oxygen atoms as its alcohol ester.
  • Embodiment 6 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.
  • 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
  • Embodiment 7 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 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 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 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 1 1 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 The opioid prodrugs of embodiment 1 or 2, wherein ligand X is further represented as X is equal to ligands 1 - 16 (shown below);
  • 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, CHOR1 COR2, 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
  • 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, CHOR1 COR2, 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
  • 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),
  • n is an integer selected from 0 to 2
  • q is an integer selected from 2 to 6
  • v is an integer selected from 0 to 6
  • Embodiment 13 The opioid prodrugs of embodiment 1 or 2, wherein X is a prodrug moiety and is represented by ligand 17; 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,
  • Embodiment 14 Opioid prodrug compounds represented by any one of formulae 1 - 90.
  • Embodiment 15 A composition comprising the compound of any of embodiments 1 - 13.
  • Embodiment 16 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 The composition of embodiment 15, wherein when said composition is administered orally and the bioavailability of opioid is maintained.
  • Embodiment 18 A method of treating pain comprising orally administering the composition of embodiment 15 to a patient.
  • Embodiment 19 The composition of embodiment 14, wherein the said composition comprises a pharmaceutically acceptable salt form of the opioid prodrug compound.
  • Embodiment 20 A pharmaceutical composition comprising one or more of the opioid prodrugs of embodiment 14 and one or more pharmaceutically acceptable excipients.

Abstract

La présente invention concerne des composés et des compositions pharmaceutiques comprenant un ligand fixé à des opioïdes d'une manière qui réduit sensiblement ou empêche le potentiel d'abus, d'addiction, d'utilisation illicite et illégale, et d'overdose d'opioïdes. Lorsqu'elle est administrée sous une dose correcte, la composition pharmaceutique fournit une activité thérapeutique semblable à celui de l'agent actif parent.
PCT/US2018/024476 2017-03-29 2018-03-27 Nouvel acide alpha-hydroxy carboxylique et dérivés et autres promédicaments d'opioïdes à base de gras et leurs utilisations WO2018183264A1 (fr)

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