HK1160837A - Water-soluble acetaminophen analogs - Google Patents

Description

Water soluble acetaminophen analogs

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application 61/054,774 entitled "water-soluble acetaminophen analogs" filed on 20.5.2008, the contents of which are incorporated herein by reference in their entirety as if fully set forth below.

Background

Acetaminophen (USAN) or paracetamol (INN) (chemical name N- (4-hydroxyphenyl) acetamide) is a commonly used antipyretic analgesic for the control of fever, mild and severe pain (including post-operative pain) and various ailments and maladies of various etiologies. Acetaminophen is well tolerated and is free of the adverse side effects of many other analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) or Cyclooxygenase (COX) inhibitors (e.g., gastric mucosal irritation, adverse effects on platelet and renal function, complications of fetal arterial vessel closure, and lewy syndrome).

Acetaminophen has also been shown to be effective in protecting tissues from ischemic injury (i.e., injury due to ischemia and reperfusion following ischemia). Recently, it was discovered that acetaminophen can reduce cardiomyocyte apoptosis in guinea pigs when the guinea pigs were subjected to low-flow whole-myocardium ischemia for 30 minutes followed by reperfusion for 60 minutes (see Am J Physiol Heart Circuit Physiol 293: H3348-H3355, 2007). In another study, it was found that acetaminophen inhibits lipid peroxidation and superoxide anion production, thereby maintaining structural integrity in the hippocampus of quinolinic acid-challenged rats in a cerebral ischemia model (see Metabolic Brain Disease 21 (2-3): 180-190, 2006). As with its analgesic use, an important element of the treatment of ischemic diseases with acetaminophen is the therapeutic intervention and the rate at which therapeutic blood peak concentrations occur.

Opiates have found widespread clinical use (e.g., for the management of post-operative pain) due to their excellent analgesic properties and rapid onset of action. However, the use of certain opiates is often accompanied by significant adverse side effects (e.g., respiratory depression, biliary spasm, constipation, sedation, addiction and potential for abuse, as well as postoperative nausea and vomiting, etc.), which make them less than satisfactory. When NSAIDs are used, coagulation is affected (and other side effects as described above) which is highly undesirable after surgery, as effective wound healing and coagulation is required. Due to the adverse properties of certain NSAIDs, COX inhibitors, and opiates, particularly in certain clinical applications, there is a continuing need to develop effective paracetamol formulations.

Parenteral (e.g. intravenous) formulations of acetaminophen are particularly useful in clinical applications. Parenteral dosage forms of acetaminophen, such as intravenous bolus injection or subcutaneous injection, have many therapeutic advantages over oral formulations. For example, parenteral acetaminophen formulations have a relatively rapid onset of action and are easy to administer in situations such as postoperative recovery and trauma. In addition, the half-life of acetaminophen is relatively short (about 2 hours, see Goodman and Gillman's the pharmaceutical Basis of Therapeutics 10^thed, McGraw-Hill 2001, p704), the dose of paracetamol administered parenterally may be lower than that administered orally, since most of the paracetamol administered orally is cleared from the body before the peak blood concentration is reached.

While acetaminophen formulations suitable for parenteral administration are desirable, the development of effective therapeutic acetaminophen over oral formulations is still limited. One major obstacle in the development of parenteral dosage forms is the low water solubility of acetaminophen (about 1.3g/100 mL). In order to solve the problem of solubility of acetaminophen itself, U.S. Pat. No. 4,322,410 discloses a novel water-soluble phosphate ester derivative of acetaminophen (4-acetamidophenyl dihydrogen phosphate), which is reported to have a water solubility of 50g/100mL of water. However, the acetaminophen derivatives are reported to be less susceptible to chemical and/or enzymatic hydrolysis (and therefore are not suitable for clinical use) because they require alkaline phosphatase and require about 15 hours in vitro to produce the desired acetaminophen drug from the derivative (see chemical and Pharmaceutical Bulletin 29 (2): 577-580, 1981). Other phosphate-containing prodrugs are disclosed, for example, in U.S. patent 4,322,410; 5,985,856, respectively; 6,204,257; 6,451,776, respectively; 6,872,838, respectively; and 7,244,718; and U.S. patent application No. 11/999,660(US2008/0318905) filed on 5.12.2007.

An ester prodrug of acetaminophen was developed in europe,(4-Acetaminophenyl 2- (diethylamino) acetate), which was later found to have a local resistance lower than that of acetaminophen (90% to 52%, British Journal of Anaesthesia 94 (5): 642-648, 2005; 49% to 0%, Anasthesia and Analgesia 101; 90-96, 2005). Another acetaminophen product marketed in Europe isIt is a large volume (100-mL) intravenous formulation of acetaminophen for infusion administration over a relatively long period of time (about 15 minutes). None of these products is an optimal clinical solution due to problems with their tolerability and dosing requirements.

Thus, there remains a clear unmet need for improved acetaminophen-type drugs, such as acetaminophen prodrugs, that are suitable for parenteral administration in small volumes.

All publications, patents, patent applications, and other documents mentioned herein are incorporated by reference in their entirety.

Summary of The Invention

In one aspect, the invention provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof or a solvate thereof. In certain embodiments, the compound is in the form of the disodium salt or a solvate thereof.

In certain embodiments, the invention encompasses formulations comprising a compound of formula (I) and a carrier. In certain embodiments, the formulation comprises an effective amount of a compound of formula (I) and a carrier. In certain of these embodiments, the carrier is a pharmaceutically acceptable carrier, e.g., a carrier suitable for parenteral administration.

In certain embodiments, the invention encompasses formulations comprising a compound of formula (I) and opiates, non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines and/or barbiturates. In certain embodiments, the invention encompasses formulations comprising a compound of formula (I): codeine, morphine, hydrocodone, hydromorphone, levorphanol, aspirin, ketorolac, ibuprofen, naproxen, caffeine, tramadol, dexpropoxyphene, methohexital sodium, diazepam, lorazepam, midazolam, propoxyphene, ketoprofen, flurbiprofen, etodolac, diclofenac, misoprostol, meloxicam, piroxicam, doxylamine, pamabrom, carisoprodol, and/or butalbitude.

In certain embodiments, the invention encompasses the compounds of formula (I) in substantially pure form.

In another aspect, the present invention provides a method of treating a disease or condition responsive to acetaminophen (e.g., pain, fever, inflammation, ischemic injury (e.g., cardiac muscle and/or brain), neuronal injury, etc.) comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments of the method, the compound is administered parenterally. In certain embodiments, the compound is administered intravenously. In certain embodiments, the compound is administered intramuscularly. In certain embodiments, the compound is administered subcutaneously.

In another aspect, the invention provides a method of treating a disease or condition responsive to acetaminophen (e.g., pain, fever, inflammation, ischemic injury (e.g., cardiac muscle and/or brain), neuronal injury, etc.) comprising administering to a subject a formulation of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of delaying the onset of acetaminophen in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the compound is capable of providing a delayed onset of acetaminophen as compared to acetaminophen.

In another aspect, the present invention provides a method of prolonging acetaminophen activity in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the compound is capable of providing prolonged acetaminophen activity as compared to acetaminophen.

In certain embodiments, the compound of formula (I) is administered at a dose of about 300mg to about 2.6 g. In other embodiments, the compound is administered in a dose of about 1.3g to about 1.9 g. In certain of these embodiments, the volume of the dose is about 1-25 mL. In certain of these embodiments, the volume of the dose is about 10-20 mL. In certain embodiments, the volume of the dose is about 1-10 mL. In certain embodiments, the volume of the dose is about 5-10 mL. In certain of these embodiments, the dose is administered more than once daily. In other embodiments, the dose is administered once every other day or less.

In another aspect, methods of administering a low volume/high concentration formulation are provided, wherein the formulation comprises a compound of formula (I) and the compound exhibits increased solubility (e.g., aqueous solubility) compared to the solubility of acetaminophen. The present invention provides low volume/high concentration formulations, for example formulations comprising a compound of formula (I) and a pharmaceutically acceptable carrier. By "low volume/high concentration" formulation is meant a formulation comprising a carrier and a prodrug, wherein a given volume of carrier comprises a higher molar concentration of prodrug than is achievable using acetaminophen. In the case of the compounds of formula (I), low volume/high concentration of the prodrug refers to a formulation comprising a carrier and a prodrug, wherein the formulation comprises a higher molar concentration of the prodrug in a given volume of carrier than is achievable using acetaminophen. The present invention also provides methods of providing low volume/high concentration acetaminophen, comprising administering to a subject a low volume/high concentration formulation of a prodrug described in detail herein (e.g., a prodrug of formula (I) or a salt or solvate thereof). In one aspect, the prodrugs administered in this manner are such as to cause rapid release of acetaminophen (e.g., by enzymatic cleavage or hydrolysis) upon administration to a subject. The present invention also provides methods of providing a single dose of acetaminophen above the currently available doses by administering the prodrugs detailed herein.

In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a condition responsive to acetaminophen. In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the treatment of a condition responsive to acetaminophen. In some variations, the condition is pain, fever, inflammation, ischemic injury, or neuronal injury.

In another aspect, the invention provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or solvate thereof and instructions for use. In certain embodiments, the description relates to the use of a compound of formula (I) to treat or prevent a disease or disorder responsive to acetaminophen (e.g., pain, fever, inflammation, ischemic injury (e.g., cardiac muscle and/or brain), or neuronal injury.

In another aspect, the invention provides a kit comprising a formulation of a compound of formula (I) and instructions for use. In certain embodiments, the description relates to the use of a compound of formula (I) to treat or prevent a disease or disorder responsive to acetaminophen (e.g., pain, fever, inflammation, ischemic injury (e.g., cardiac muscle and/or brain), or neuronal injury).

Brief description of the drawings

FIG. 1 shows paracetamol formed from the prodrug at 15 μ g/mL in human plasma.

FIG. 2 shows acetaminophen formed from 0.3 μ g/mL prodrug in human plasma.

Figure 3 shows the pharmacokinetic profile of paracetamol in rats: time-dependent plasma concentrations of the compound of formula (I) compared to the parent drug acetaminophen.

Detailed Description

The present invention provides acetaminophen prodrugs which have one or more improved properties (e.g., increased water solubility and/or time of onset) compared to existing therapies, thereby making them possible for low volume/high concentration parenteral administration, such as intravenous injection. These compounds may be particularly useful for the rapid treatment of diseases or conditions that respond to acetaminophen, such as pain, fever, inflammation, ischemic injury (e.g., cardiac muscle and/or brain), or neuronal injury.

Accordingly, in one aspect, the present invention provides a paracetamol prodrug, 4-acetamidophenoxy) methyl phosphate ester or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention provides methods of treating a disease or condition responsive to acetaminophen (e.g., pain, fever, inflammation, ischemic injury (e.g., cardiac muscle and/or brain), or neuronal injury, etc.) using acetaminophen prodrugs described herein.

The invention also provides kits, formulations, and unit dosage forms of the prodrugs.

Abbreviations and Definitions

Nomenclature for certain compounds described herein can be used with ChemDraw Ultra Version 10.0 (obtained from ChemDraw Ultra Version 10.0)) And (4) determining.

The term "prodrug" refers to a compound that, upon administration to a subject, provides an active compound in the body of the user through chemical and/or biological processes in the body (e.g., through hydrolysis and/or enzymatic conversion). Prodrugs may be active themselves or may be relatively inactive and then converted to more active compounds. The present invention includes prodrugs of acetaminophen described herein.

As used herein, "delayed onset" or "delayed onset" refers to an increase in onset time provided by an acetaminophen prodrug as compared to an equimolar amount of acetaminophen administered by the same route of administration over the same period of time. For example, a delay in the release of acetaminophen from the prodrug (4-acetaminophenoxy) methyl dihydrogen phosphate can result in delayed systemic exposure to acetaminophen as compared to administration of an equimolar amount of acetaminophen.

As used herein, "extended activity" or "extended activity" refers to the sustained action provided by a acetaminophen prodrug due to the time required to release or generate acetaminophen from the prodrug. For example, administration of the acetaminophen prodrug (4-acetaminophenoxy) methyl dihydrogen phosphate can provide sustained release of acetaminophen as compared to administration of an equimolar amount of acetaminophen by the same route of administration over the same period of time. By "sustained release" is meant a release rate of acetaminophen that is capable of maintaining the concentration of acetaminophen (or a metabolite thereof) at or within a therapeutic range (e.g., above the minimum effective analgesic concentration but below toxic levels) in an individual over an extended duration of time. Wherein an extended duration is a time that is longer than the time at which an equimolar amount of the corresponding acetaminophen, administered by the same route of administration, causes a blood concentration of acetaminophen (or a metabolite thereof) that is within the therapeutic range.

"protecting group" means a chemical group having the following characteristics: 1) is stable to the target reaction needing protection; 2) can be removed from the protected substrate to produce the desired functional group; and 3) removable by a reagent compatible with one or more other functional groups present or formed in the target reaction. The selection of suitable protecting groups for use in the methods described herein is well known to those of ordinary skill in the art. Examples of suitable protecting groups can be found in Greene et al (2006) P_ROTECTIVE G_{ROUPS IN} O_RGANIC S_YNTHESIS4 th edition (John Wiley)&Sons, inc., New York), the contents of which are incorporated herein by reference. As used herein, "hydroxy protecting group" refers to a group capable of protecting a free hydroxy group to form a "protected hydroxy group" which can be removed after the reaction for which protection is sought without disturbing the rest of the compound. Exemplary hydroxyl protecting groups include, but are not limited to, ethers (e.g., allyl, triphenylmethyl (trityl or Tr), benzyl, p-methoxybenzyl (PMB), p-oxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), 3-methoxyethoxymethyl (MEM), Tetrahydropyranyl (THP), ethoxyethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoate (Bz), allyl carbonate, 2, 2, 2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate), silyl ethers (e.g., Trimethylsilyl (TMS), Triethylsilyl (TES), Triisopropylsilyl (TIPS), Triphenylsilyl (TPS) Tert-butyldimethylsilyl (TBDMS),Tert-butyldiphenylsilyl (TBDPS), and the like.

As used herein, "treatment" is a method of achieving beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms of a disease or disorder responsive to acetaminophen, reducing the extent of a disease or disorder, stabilizing a disease or disorder (e.g., arresting or delaying the worsening of a disease or disorder), delaying or slowing the progression of a disease or disorder, ameliorating a disease or disorder, reducing the dose of one or more other drugs required to treat a disease or disorder, and increasing the quality of life of an individual having or suspected of having a disease or disorder responsive to acetaminophen. The disease or condition can be a disease or condition that is or is believed to be responsive to acetaminophen (e.g., a disease or condition with fever and/or pain). The disease or disorder may be accompanied by inflammation. The disease or condition may be ischemic injury. The disease or disorder may be neuronal damage. In one instance, the condition is post-operative pain and/or fever. In certain embodiments, a acetaminophen prodrug and/or a formulation comprising an acetaminophen prodrug can reduce the severity of one or more symptoms associated with a disease or disorder responsive to acetaminophen by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as compared to the corresponding symptoms in the same individual prior to treatment or as compared to the corresponding symptoms in other individuals not receiving the acetaminophen prodrug and/or formulation. As used herein, "responsive to acetaminophen" refers to a disease or disorder and/or symptoms of a disease or disorder that can be treated with acetaminophen.

As used herein, "delay" refers to delaying, hindering, slowing, delaying, stabilizing, and/or delaying the development of one or more symptoms of a disease or disorder responsive to acetaminophen and/or a disease or disorder responsive to acetaminophen. The delay may be of varying lengths of time depending on the medical history and/or the individual being treated. It will be apparent to those skilled in the art that a sufficient or significant delay includes actually preventing the occurrence of the disease or disorder in an individual who does not have the disease or disorder. A method of "delaying" the onset of a disease or condition responsive to acetaminophen is a method that reduces the likelihood of the onset of the disease or condition and/or reduces the extent of the disease or condition in a given time frame as compared to the absence of the method. The comparison is typically based on clinical studies and employs a statistically significant number of individuals.

As used herein, an "at-risk" individual refers to an individual at risk of developing a disease or condition responsive to acetaminophen, such as pain, fever, inflammation, ischemic injury (e.g., cardiac muscle and/or brain) or neuronal injury. An individual "at risk" may or may not have a detectable disease or condition and may or may not exhibit symptoms associated with the detectable disease or condition prior to treatment with the treatment methods described herein. By "at risk" is meant that the individual has one or more so-called risk factors that are quantifiable parameters associated with the occurrence of the disease or condition. Individuals with one or more risk factors are more likely to develop a disease or condition than individuals without such risk factors.

As used herein, "pharmaceutically acceptable" refers to a substance that has no biological or other adverse effect, e.g., a substance that can be incorporated into a pharmaceutical composition at the time of manufacture or administration, and which can be administered to an individual without causing any significant adverse biological effect or interacting in a deleterious manner with any of the other ingredients of the composition. The term "pharmaceutically acceptable carrier" as used herein refers to, for example, solvents, stabilizers, pH-adjusting agents, tonicity-adjusting agents, excipients, binders, diluents, and the like known to those skilled in the art to be suitable for administration to a subject (e.g., a human). The invention also relates to combinations of two or more vectors. For a particular dosage form to be used for the intended route of administration (e.g., oral, parenteral), the pharmaceutically acceptable carrier, as well as the other ingredients described herein, should be compatible. Such applicability will be readily appreciated by those skilled in the art, particularly in view of the teachings provided herein. The pharmaceutically acceptable carrier or excipient should preferably meet the standards required for toxicological and manufacturing testing and/or be included in the guidelines for the active ingredient set forth by the U.S. food and drug administration.

The term "effective amount" as used herein refers to an amount capable of eliciting a desired pharmacological and/or physiological effect in an individual who has or is suspected of having (e.g., as judged by symptoms and/or perception/sensation of the individual) a disease or disorder or who exhibits one or more symptoms of the disease or disorder. An effective amount can completely or partially arrest the occurrence or recurrence of a disease or condition or symptoms thereof and/or can, in terms of treatment, partially or completely cure the disease or condition and/or adverse effects (e.g., pain) caused by the disease or condition. For diseases or conditions described herein (e.g., pain), an effective amount can include an amount sufficient to alleviate and/or relieve to some extent one or more symptoms associated with a disease or condition responsive to acetaminophen (e.g., pain, fever, inflammation, ischemic injury (e.g., heart muscle and/or brain), or neuronal injury). In certain embodiments, when administered prophylactically to a subject, an effective amount is sufficient to prevent the condition. An effective amount includes eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more symptoms associated with the underlying disorder, such that the individual reports an improvement in sensation or disorder (e.g., a reduction or shortening of the intensity and/or duration of pain), although the individual may still have the underlying disease or disorder. An effective amount also includes stopping or slowing the progression of the disease or condition, whether or not an improvement in the disease or condition is sensed.

The "effective amount" may vary with the composition administered, the condition being treated/prevented (e.g., the type of pain), the severity of the condition being treated or prevented, the age, physical constitution, weight and relative health of the individual, the route and form of administration, the judgment of the attending physician or veterinarian, if applicable, and other factors that can be considered by those skilled in the art in light of the teachings provided herein. The effective amount may be estimated, for example, using one or more clinical, physiological, biochemical, histological, electrophysiological and/or behavioral assessment data.

As understood in the art, an "effective amount" may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic goal. An effective amount may need to be considered one or more additional drugs administered, and if combined with one or more additional drugs, the acetaminophen prodrug may be considered to be administered in an effective amount that may achieve one or more desired or beneficial effects.

An "in need" subject as described with respect to the treatment and/or prevention methods described herein and the use of acetaminophen prodrugs can be a subject who has been diagnosed as having, previously received a related treatment, and/or is suspected of having a disease or disorder being treated. For prophylaxis, an individual in need thereof can also be an individual at risk of having a disease or disorder (e.g., family history of disease, lifestyle factors leading to risk of disease, etc.).

In some embodiments, the individual is identified as having one or more of the diseases or disorders described herein and/or symptoms thereof. The determination of a disease or condition and/or symptoms thereof by a skilled physician is routine in the art (e.g., detecting allergies, colds, coughs, flu, pain, etc.) and may also be inferred by the individual or others, e.g., from pain, fever, etc.

In certain embodiments, an individual is identified as susceptible to one or more of the diseases or disorders described herein. Susceptibility of an individual may be determined based on any one or more of a variety of risk factors and/or diagnostic methods known to the skilled artisan, including but not limited to genetic mapping, family history, medical history (e.g., occurrence of related conditions), lifestyle, or habits.

In certain embodiments, the subject is a mammal, including but not limited to a bovine, equine, feline, rabbit, canine, rodent, or primate. In certain embodiments, the mammal is a primate. In certain embodiments, the primate is a human. In certain embodiments, the subject is a human, including adults, children, infants, and premature infants. In certain embodiments, the subject is a non-mammal. In certain embodiments, the primate is a non-human primate such as gorilla and other apes and monkey species. In certain embodiments, the mammal is a domestic animal, such as cattle, horses, sheep, goats, and pigs; pets such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. In certain embodiments, the subject is a non-mammal, including but not limited to, birds and the like. The term "individual" does not refer to a particular age or gender.

As used herein, "combination therapy" refers to the combination of a first therapy comprising a acetaminophen prodrug with a second therapy (e.g., surgery and/or another drug) for treating, stabilizing, preventing and/or delaying a disease or condition. Administration "in combination with" another compound includes administration in the same composition, or sequentially, simultaneously or consecutively in different compositions, by the same or different routes. In one embodiment, the combination therapy may include a acetaminophen prodrug and acetaminophen. In certain embodiments, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, pharmaceutically inactive compounds, and/or inert substances.

The term "additional agent" as used herein refers to an active agent other than the acetaminophen prodrug (e.g., another drug and/or acetaminophen itself) that is administered to produce a therapeutic effect. Additional drugs may be directed to (1) therapeutic effects associated with diseases or conditions (e.g., pain) that are intended to be treated or prevented with the acetaminophen prodrugs; (2) treating or preventing symptoms of the underlying disorder; (3) reducing/lessening the occurrence or severity of side effects of administration of acetaminophen prodrugs; and/or (4) a therapeutic effect associated with a disease or condition that is non-responsive or relatively less responsive to acetaminophen (e.g., insomnia, anxiety, depression, inflammation, nausea, and/or vomiting).

Herein, reference to a value or parameter of "about" includes and describes embodiments that are directed to that value or parameter per se. For example, a description of "about X" includes a description of "X".

As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It is to be understood that the various aspects and embodiments of the invention described herein include forms that "consist of" and/or "consist essentially of" the aspects and embodiments.

Unless defined or clearly indicated by context, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Acetaminophen prodrugs

The present invention includes acetaminophen prodrugs, which are useful for treating diseases or disorders responsive to acetaminophen. In certain embodiments, the acetaminophen prodrugs contain a phosphate group attached to the hydroxyl group of acetaminophen through a linking group. In certain embodiments, the linking group is an alkylene linking group (e.g., methylene). In certain embodiments of the invention, the acetaminophen prodrugs have the formula:

in certain embodiments, the acetaminophen prodrugs have the formula:

in certain embodiments, the acetaminophen prodrug is in a substantially pure form. Unless otherwise indicated, "substantially pure" means that the prodrug formulation contains no more than 15% impurities, where the impurities refer to compounds other than the acetaminophen prodrug and the acetaminophen itself, but do not include other forms of acetaminophen and/or the prodrug (e.g., different salts or non-salt forms of the prodrug). In one embodiment, a substantially pure prodrug formulation is provided, wherein the formulation contains no more than 25% impurities, or no more than 20% impurities, or no more than 10% impurities, or no more than 5% impurities, or no more than 3% impurities, or no more than 1% impurities, or no more than 0.5% impurities.

The present invention also includes all solvate, hydrate, and/or salt (e.g., pharmaceutically acceptable salt) forms of the acetaminophen prodrugs described herein and methods of use thereof. In certain embodiments, acetaminophen prodrugs of the present invention may exist in unsolvated as well as solvated forms (i.e., solvates). Acetaminophen prodrugs also include hydrated forms (i.e., hydrates).

The present invention includes all salts of the compounds described herein and methods of using the salts of the compounds. The invention also includes all non-salt forms of any salt of the compounds described herein, as well as other salts of any salt named herein. In certain embodiments, the salt of the compound is a pharmaceutically acceptable salt. "pharmaceutically acceptable salts" are those salts that retain the biological activity of the free compound and that can be administered to an individual (e.g., a human) as a pharmaceutical or pharmaceutical product. In certain embodiments, the acetaminophen prodrugs are mono-or disubstituted with an alkali metal or alkaline earth metal. In certain embodiments, the acetaminophen prodrug is a monobasic phosphate salt (e.g., monosodium phosphate). In certain embodiments, the acetaminophen prodrug is a dibasic phosphate salt (e.g., disodium phosphate salt). The desired salts of the basic functional groups of the compounds can be prepared by methods known to those skilled in the art by treating the compounds with acids. The desired salts of the acidic functional groups of the compounds can be prepared by treating the compounds with bases by methods known to those skilled in the art. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth metal salts, such as sodium, potassium, magnesium, bismuth and calcium salts; an ammonium salt; and an aluminum salt. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N' -dibenzylethylenediamine, trimethylamine, and triethylamine salts.

In certain embodiments, acetaminophen prodrugs exhibit enhanced solubility over acetaminophen. For example, acetaminophen has a solubility in water at room temperature of about 13mg/mL, while sodium (4-acetaminophenoxy) methyl phosphate and sodium (4-acetaminophenoxy) methyl phosphate have solubilities in water at room temperature of about 145mg/mL and 160mg/mL, respectively. In certain embodiments, the acetaminophen prodrugs show reduced or no biological activity, or reduced or no receptor affinity, as compared to acetaminophen.

The acetaminophen prodrugs described herein are relatively stable under certain conditions (e.g., during storage and/or when prepared in saline), but can be converted to their parent drugs under other conditions (e.g., after introduction into an in vitro or in vivo system, e.g., after administration into an individual). In certain embodiments, a prodrug (e.g., a prodrug of formula I or II at a plasma concentration of about 0.3ng/mL or about 15ng/mL, or a plasma concentration of between about 0.3ng/mL and about 15 ng/mL) is capable of being converted to acetaminophen by greater than 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 60%, or 75% after about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes, or 45 minutes, or 1 hour at 37 ℃. In certain embodiments, a prodrug (e.g., a prodrug of formula I or II that is about 0.3ng/mL or about 15ng/mL in human plasma, or between about 0.3ng/mL to about 15ng/mL in human plasma) is capable of greater than about 30%, or about 45%, conversion to acetaminophen after about 1 hour at 37 ℃. In certain of these embodiments, the acetaminophen prodrug is not convertible to acetaminophen in water, propylene glycol, and/or saline at room temperature. For example, in certain of these embodiments, the prodrug is not converted to the parent drug more than about 5%, or 10%, or 20%, or 25%, or 30% or 40%, or 60%, or 70% in water or propylene glycol at room temperature within 30 minutes or 60 minutes. In one embodiment, a acetaminophen prodrug of formula I or II at a concentration of about 15ng/mL (or 0.3ng/mL, or between 0.3ng/mL and 15 ng/mL) in human plasma is capable of more than 30% conversion to the parent drug in 45 minutes at 37 ℃ while the conversion in 45 minutes is no more than 30% in water at room temperature at the same concentration. In certain embodiments, the conversion of a prodrug (e.g., a acetaminophen prodrug of formula I or II) to the parent drug in human plasma is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to contact with water at room temperature for the same time.

Synthesis method

The compounds of the present invention may be prepared using a variety of methods well known to those skilled in the art. The following discussion is intended to illustrate one of the processes that may be used to prepare the compounds of the present invention and is not intended to limit the scope of the reactions or reaction sequences and/or conditions that may be used to prepare the compounds of the present invention.

The target compounds of the present invention can be synthesized starting from readily available acetaminophen as shown in scheme I below.

Scheme i. preparation of acetaminophen prodrugs.

As shown in scheme I, acetaminophen is treated with sodium hydride and then with chloromethyl methyl sulfide to give the corresponding sulfide, which can be converted to a protected phosphate by adding a di-protected phosphate ester, such as dibenzyl phosphate or di-t-butyl phosphate, in the presence of a halogenating agent, such as N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS). Deprotection under reducing conditions and then conversion to the desired salt, e.g., sodium salt, produces sodium (4-acetamidophenoxy) methyl phosphate. Any suitable protecting group and corresponding deprotection conditions may be used.

The invention also includes methods of making the prodrugs described herein. In one aspect, there is provided a process for preparing a compound of formula (I):

comprises that

(a) Reacting a compound of formula SI-A:

or a pharmaceutically acceptable salt thereof or a solvate thereof, with a halomethyl sulfide in a suitable solvent;

(b) reacting the compound formed in step (a) or a pharmaceutically acceptable salt thereof or a solvate thereof with a di-protected phosphate ester in a suitable solvent; and

(c) deprotecting the di-protected phosphate of the compound formed in step (b).

In certain embodiments of step (a) of the process for preparing a compound of formula I, said halomethyl sulfide is chloromethyl methyl sulfide. In certain embodiments of step (a), a suitable solvent is HMPA. In certain embodiments of step (a), the reaction further comprises NaH. In certain embodiments of step (b) of the process for preparing a compound of formula I, the di-protected phosphate is di-tert-butyl phosphate or dibenzyl phosphate. In some embodiments of step (b)In one embodiment, the suitable solvent is THF. In certain embodiments of step (b), the reaction further comprises NIS or NBS. In certain embodiments of step (c) of the process for the preparation of a compound of formula I, the deprotection comprises reducing conditions. In certain embodiments of step (c), the deprotection comprises use of Pd (OH)₂/H₂. In certain embodiments of step (c), the deprotection comprises acidic conditions. In certain embodiments of step (c), the deprotection comprises treatment with acetic acid. In certain embodiments of step (c), a suitable solvent is a protic solvent (e.g., methanol).

Preparation

Acetaminophen prodrugs described herein can be formulated with additives such as excipients (e.g., one or more excipients), antioxidants (e.g., one or more antioxidants), stabilizers (e.g., one or more stabilizers), preservatives (e.g., one or more preservatives), pH adjusting and buffering agents (e.g., one or more pH adjusting and/or buffering agents), tonicity adjusting agents (e.g., one or more tonicity adjusting agents), thickening agents (e.g., one or more thickening agents), suspending agents (e.g., one or more suspending agents), binders (e.g., one or more binders), viscosity increasing agents (e.g., one or more viscosity increasing agents), and the like, pharmaceutical formulations (including pharmaceutical compositions) are prepared, either alone or in combination with one or more additional agents, provided that the additional agent(s) is/are pharmaceutically acceptable for the particular disease or condition being treated. In certain embodiments, the formulation may further comprise a combination of two or more other ingredients described herein (e.g., 2, 3, 4, 5, 6, 7, 8, or more other ingredients). In certain embodiments, additives include processing aids and modulators and enhancers of drug delivery, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, glucose, hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more of these. Other suitable pharmaceutically acceptable excipients are described in R_EMINGTON’S P_{HARMACEUTICAL} S_CIENCESMarck pub. Co., New Jersey 18 th edition (1996) and R_EMINGTON：T_HE S_{CIENCE AND} P_{RACTICE OF} P_HARMACY，Lippincott Williams&Wilkins, philiadelphia, 20 th edition (2003) and 21 th edition (2005).

The formulations may be varied or tailored depending on the condition being treated, the amount of compound administered, the individual's condition, and other variables as would be readily understood by one of skill in the art in light of the teachings herein.

In certain embodiments, the formulation (e.g., a formulation suitable for parenteral administration) is an aqueous formulation having a pH of from about 3.5 to about 9.5, or from about 4.5 to about 8.5, or from about 5.0 to about 9.0, or from about 5.5 to about 8.5, or from about 6.0 to about 8.0, or from about 6.5 to about 8.0, or from about 7.0 to about 8.0, or about 7.4.

Formulations comprising a prodrug of formula I or II and saline are provided. In one aspect, the formulation has a physiological pH (about 7.4). The formulations are suitable for storage for extended periods of time (e.g., during storage) and for subsequent use the prodrug remains intact and is converted to acetaminophen upon administration to a subject (e.g., an adult, child or infant). In certain embodiments, the prodrug is stored in the form of a dry powder and is formulated by dissolving the dry powder in saline prior to administration. In one aspect, prodrug formulations are provided, e.g., formulations comprising about 50mg/mL, 75mg/mL, 100mg/mL, 125mg/mL, 150mg/mL, 175mg/mL, or 200mg/mL molar equivalents of acetaminophen, where the molar equivalents are the amount of prodrug that can produce the indicated amount of acetaminophen after complete conversion. For any amount (e.g., dose) of the prodrug described herein, the molar prodrug equivalent of acetaminophen in that amount is also included. Single dose bolus formulations, e.g., up to about 5mL, 10mL, or 15mL (e.g., molar prodrug equivalent of about 1450mg to about 1600mg of acetaminophen) are also provided.

Medicine box

The invention also provides kits comprising substances useful for treating or preventing a condition responsive to acetaminophen (e.g., pain). The kit may contain a acetaminophen prodrug of the present invention and instructions for use. The kit may comprise a container with a label. Suitable containers include, for example, vials, and test tubes. The container may be made of various materials, such as glass or plastic. The container may contain a paracetamol prodrug or a formulation of a paracetamol prodrug (e.g. a formulation which also contains one or more additional drugs). The label on the container may indicate that the acetaminophen prodrug or formulation is to be used to treat or inhibit an acetaminophen-responsive condition (e.g., pain), and may also give instructions for in vitro or in vivo use, such as those described herein.

The invention also provides kits containing one or more acetaminophen prodrugs of the invention. In certain embodiments, a kit of the invention comprises a container as described above. In other embodiments, kits of the invention comprise a container as described above and a second container comprising a buffer. It may also contain other materials as desired from a commercial or user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any of the methods described herein.

In another aspect, the kit can be used in any of the methods described herein, including, for example, treating a subject having one or more conditions responsive to acetaminophen (e.g., pain and/or fever), or inhibiting one or more of the conditions.

In certain embodiments, a kit can comprise one dose of at least one formulation disclosed herein. In one aspect, the dosage form corresponds to a dosage in excess of 4 g/day of molar equivalents of acetaminophen. The kit may further comprise means for administering the formulation.

The kit may comprise additional agents for use in combination with the formulations described herein. In certain embodiments, the additional agent may be one or more analgesics. These agents may be provided in individual form or mixed with the compounds of the present invention, provided that such mixing does not reduce the efficacy of the agent or formulation described herein and is compatible with the route of administration. Similarly, the kit may comprise additional agents for use in combination therapy or additional agents known to the skilled person to be effective in the treatment or prevention of the conditions described herein.

The kit may optionally contain appropriate instructions for preparing and/or administering a formulation comprising a paracetamol prodrug of the invention. Information detailing possible side effects of the formulation may also be included, as well as any other relevant information. The instructions may be in any suitable form including, but not limited to, printed material, video tape, computer readable disk, optical disk, or instructions for internet information.

Another aspect of the invention provides a kit for treating a subject suffering from or susceptible to a disease or condition described herein (e.g., pain and/or fever), comprising a first container containing one dose of a composition disclosed herein and instructions for use. The container may be any container known in the art and suitable for storing and delivering intravenous formulations. In certain embodiments, the kit further comprises a second container containing a pharmaceutically acceptable carrier, diluent, excipient, etc., for preparing the formulation for administration to a subject.

The kit can further comprise a sufficient dose of a compound described herein (including formulations thereof) to provide effective treatment to a subject over an extended period of time, e.g., 1-3 days, 1-5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or longer.

The kit may further comprise a composition as described herein packaged in unit dosage form or for multiple use. The kit may also include multiple units of the unit dosage form.

Method of treatment

The acetaminophen prodrugs of the present invention may be used to treat diseases or conditions responsive to acetaminophen (e.g., pain and/or fever). In one embodiment, the present invention provides a method of treating a disease or disorder responsive to acetaminophen, comprising administering to a subject an effective amount of an acetaminophen prodrug (e.g., (4-acetamidophenoxy) methyl phosphate or sodium (4-acetamidophenoxy) methyl phosphate). In certain embodiments, the subject is at risk of developing a disease or disorder responsive to acetaminophen. In certain embodiments, there is provided a method of treating pain, fever, inflammation, ischemic injury (e.g., myocardium and/or brain), or neuronal injury in a subject comprising administering to the subject an effective amount of a acetaminophen prodrug (e.g., (4-acetamidophenoxy) methyl phosphate or sodium (4-acetamidophenoxy) methyl phosphate). In one embodiment, the individual is a post-operative patient and has or is believed to have or develop post-operative pain. In one embodiment, the prodrug is administered prophylactically for post-operative pain. In one embodiment, the individual is not eligible for oral administration of acetaminophen.

The invention includes methods of treating pain of any etiology, including acute and chronic pain, as well as any pain that can be analgesic with acetaminophen. Examples of pain include postoperative pain, postoperative pain (including dental pain), migraine, headache and trigeminal neuralgia, pain associated with burns, wounds or kidney stones, pain associated with trauma (including traumatic head injury), neuropathic pain (e.g., peripheral neuropathy and postherpetic neuralgia), pain associated with musculoskeletal disorders, injuries, sprains, contusions, fractures, e.g., myalgia, rheumatoid arthritis, osteoarthritis, cystitis, pancreatitis, inflammatory bowel disease, ankylosing spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism and periarticular disease, and pain associated with cancer (including "breakthrough pain" and/or pain associated with advanced cancer). Examples of pain with an inflammatory component (in addition to certain pain described above) include rheumatic pain, pain associated with mucositis, and dysmenorrhea. In certain embodiments, the formulations and methods of the invention are useful for treating or preventing post-operative pain and/or cancer pain. In certain embodiments, the methods and compositions of the invention are useful for treating or preventing pain such as: pain associated with surgery, trauma, osteoarthritis, rheumatoid arthritis, back pain, fibromyalgia, postherpetic neuralgia, pain associated with diabetic neuropathy, HIV-related neuropathy, and complex regional pain syndrome.

In certain embodiments, the methods and compositions of the present invention (e.g., (4-acetamidophenoxy) methyl phosphate or sodium (4-acetamidophenoxy) methyl phosphate) are useful for treating or preventing pain and/or fever (e.g., in adults, children, and/or infants). In certain embodiments, the methods and compositions of the invention (e.g., (4-acetamidophenoxy) methyl phosphate or sodium (4-acetamidophenoxy) methyl phosphate) are useful for treating pain, e.g., acute pain (e.g., post-operative, e.g., acute pain following orthopedic surgery in adults, children, and/or infants). In certain embodiments, the methods and compositions of the present invention (e.g., (4-acetamidophenoxy) methyl phosphate or (4-acetamidophenoxy) sodium methyl phosphate) are useful for treating or preventing fever, e.g., endotoxin-induced fever (e.g., endotoxin-induced fever in adults, children, and/or infants). In certain embodiments, the methods and compositions of the present invention (e.g., (4-acetamidophenoxy) methyl phosphate or sodium (4-acetamidophenoxy) methyl phosphate) are useful for treating or preventing fever in children and/or infants. In certain embodiments, the fever is selected from low fever, moderate fever, high fever, and ultra-high fever. In certain embodiments, the fever is selected from the group consisting of periodic fever, sustained fever, intermittent fever, and heat of relaxation.

In certain embodiments, the invention encompasses methods of delaying the onset of acetaminophen in a subject in need of acetaminophen treatment, comprising administering to the subject an effective amount of an acetaminophen prodrug (e.g., (4-acetaminophenoxy) methyl phosphate or sodium (4-acetaminophenoxy) methyl phosphate), wherein the prodrug provides a slower onset of acetaminophen as compared to acetaminophen. In one embodiment, administration of an acetaminophen prodrug (e.g., (4-acetaminophenoxy) methyl phosphate or sodium (4-acetaminophenoxy) methyl phosphate) delays the onset of the parent drug by more than about 5 minutes, or 10 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 2 hours, or 3 hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 18 hours, or 24 hours as compared to administration of acetaminophen. In certain embodiments, the invention encompasses little or no delay in the onset of the parent drug.

In certain embodiments, the invention includes a method of prolonging acetaminophen activity in a subject in need of acetaminophen treatment, the method comprising administering to the subject an effective amount of an acetaminophen prodrug (e.g., (4-acetaminophenoxy) methyl phosphate or sodium (4-acetaminophenoxy) methyl phosphate), wherein the prodrug provides longer acetaminophen activity than acetaminophen. In one embodiment, administration of an acetaminophen prodrug (e.g., (4-acetaminophenoxy) methyl phosphate or sodium (4-acetaminophenoxy) methyl phosphate) extends activity by more than about 5 minutes, or 10 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 2, hours, or 3 hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 18 hours, or 24 hours as compared to administration of acetaminophen. In certain embodiments, the invention comprises little or no prolonged activity compared to administration of acetaminophen.

In certain embodiments, the present invention includes methods of providing acetaminophen to a subject, the methods comprising administering an acetaminophen prodrug (e.g., a prodrug of formula I or II), wherein the acetaminophen prodrug is convertible to acetaminophen. Also provided are methods of providing acetaminophen to a subject by administering an acetaminophen prodrug (e.g., a prodrug of formula I or II), wherein the prodrug is convertible in vivo to acetaminophen. In one aspect, a prodrug (e.g., a prodrug of formula I or II) can be converted to acetaminophen about 1, 5, 10, 15, or 30 minutes after administration. Transformation can be determined by techniques known in the art, including the methods described in detail in the experimental section herein. In certain embodiments, the invention encompasses methods of providing acetaminophen to a subject (e.g., a subject in need of acetaminophen treatment), the method comprising administering to the subject an effective amount of an acetaminophen prodrug (e.g., a prodrug of formula I or II), wherein greater than about 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 60%, or 75% or 85%, or 90%, or 95% of the prodrug is converted to acetaminophen in less than about 1 minute, 3 minutes, 5 minutes, 10 minutes, 20 minutes, or 30 minutes, or 45 minutes, or 1 hour after administration. In certain embodiments, the methods comprise administering to the subject an effective amount of a acetaminophen prodrug (e.g., a prodrug of formula I or II), wherein greater than about 10% or about 20% of the prodrug is converted to acetaminophen in less than about 1 minute or about 3 minutes after administration.

In certain embodiments, the invention encompasses methods of providing acetaminophen to a subject (e.g., a subject in need of acetaminophen treatment), the method comprising administering (e.g., intravenously) an effective amount of an acetaminophen prodrug (e.g., a prodrug of formula I or II) to the subject, wherein the acetaminophen concentration produced (e.g., about 10 minutes, or 20 minutes, or 30 minutes, or 45 minutes, or 1 hour, or 2 hours, or 3 hours after administration) is about 50%, or 40%, or 30%, or 25%, or 20%, or 15%, or 10%, or 5% lower than acetaminophen alone when administered under the same conditions. For example, in certain embodiments, a method of providing acetaminophen to a subject in need of acetaminophen treatment is provided, the method comprising intravenously administering to the subject an effective amount of an acetaminophen prodrug (e.g., a prodrug of formula I or II), wherein the concentration of acetaminophen or a metabolite thereof produced (e.g., at about 30 minutes or 1 hour after administration) is about 15% or about 5% less than the concentration of acetaminophen or a metabolite thereof produced when acetaminophen is administered alone under the same conditions.

Combination therapy

The acetaminophen prodrugs described herein can be formulated and/or administered with one or more additional agents described herein and known in the art, including one or more additional agents used to further reduce the occurrence and/or severity of symptoms and/or their clinical manifestations, an additional agent used to treat or prevent the underlying condition, or in combination with (e.g., prior to, concurrently with, or subsequent to) other therapies. The acetaminophen prodrugs described herein can be administered prior to, simultaneously with, or after the administration of one or more additional drugs. The acetaminophen prodrugs described herein can also be administered in combination (e.g., prior to, simultaneously with, or subsequent to) an agent used to alleviate symptoms associated with the condition or treatment regimen.

In certain embodiments of the formulations and methods of the present invention, the acetaminophen prodrug is used in combination with one or more additional drugs. Representative additional drugs include opioids (natural, semi-synthetic or synthetic), non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, barbiturates and other compounds, such as caffeine. Examples of compounds that may be used in combination with the prodrugs of the present invention include, but are not limited to, codeine, morphine, hydrocodone, hydromorphone, levorphanol, aspirin, ketorolac, ibuprofen, naproxen, caffeine, tramadol, dexpropoxyphene, methohexital sodium, diazepam, lorazepam, midazolam, propoxyphene, ketoprofen, flurbiprofen, etodolac, diclofenac, misoprostol, meloxicam, piroxicam, doxylamine, pamabrom, carisoprodol, and butapril.

One potential advantage of the combination formulation is that the formulation can elicit an analgesic effect that exceeds the maximum effect of acetaminophen without approaching the toxic or near toxic dose levels of acetaminophen. In addition to analgesia, combined preparations of acetaminophen prodrugs and benzodiazepines such as diazepam, lorazepam, midazolam or any other benzodiazepine may also be used to treat pre-and post-operative anxiety. The combination is particularly useful in dental surgery (e.g. mole removal).

The additional agents described above for use in combination with the acetaminophen prodrugs of the present invention may be used in therapeutic amounts, for example, inP_HYSICIANS’D_ESK R_EFERENCE(PDR) the dosages shown in 53 rd edition (1999), or the therapeutic amounts described, are known to those of ordinary skill in the art.

Additional drugs (e.g., analgesics) administered with one or more acetaminophen prodrugs of the invention may be administered at the recommended maximum clinical dose or at lower doses. The dosage level of the additional agent in the formulations of the invention may vary depending on the route of administration, the severity of the disease and the characteristics and response of the patient to achieve the desired therapeutic response. The combined preparation may be administered as separate preparations or as a single dosage form containing both drugs. When administered as a combined preparation, the acetaminophen prodrugs can be formulated as separate preparations for administration at the same or different times, or the acetaminophen prodrugs can be administered as a single preparation.

It will be appreciated by those skilled in the art that different additional drugs and/or other forms of treatment may be employed for a particular condition.

In certain embodiments, the acetaminophen prodrugs of the present invention may be formulated and/or administered with acetaminophen itself. The combination therapy may provide an initial therapeutic dose of the parent drug followed by a delayed and/or prolonged activity of the parent drug provided by the prodrug. For example, (4-acetamidophenoxy) methyl dihydrogen phosphate in combination with acetaminophen can provide pain therapy first with acetaminophen and then prolonged pain therapy with acetaminophen prodrugs. The preparation can reduce administration frequency. Alternatively, an initial dose of prodrug I or II can be administered after administration of acetaminophen to treat pain and/or fever (e.g., after discharge from a hospital or leaving an operating table) (e.g., in a low volume, high concentration administration to treat post-operative pain and/or fever).

The formulations and methods described herein can be used alone or in combination (e.g., prior to, concurrently with, or subsequent to) other therapeutic modalities (e.g., adjunctive therapy and/or other therapeutic modalities employing additional agents described herein with respect to pharmaceutical formulations of the claimed compounds or known to those of skill in the art for the treatment or prevention of the conditions being treated/prevented, or combinations of the foregoing). For example, in combination with one or more additional drugs described herein and known to those skilled in the art and/or therapeutic modalities currently available (including, for example, surgery or radiation therapy). The term "additional therapeutic modality" as used herein refers to the absence of a drug to treat/prevent the conditions described herein (e.g., surgery, radiation therapy, etc.). When a combination of drugs and/or additional therapeutic modalities is employed, they may be administered independently prior to, concurrently with, or subsequent to the administration of one or more acetaminophen prodrugs (or formulations thereof) described herein.

The optimal combination of one or more additional therapeutic modalities and/or additional drugs with administration of the formulations described herein can be determined by the attending physician or veterinarian according to the individual's circumstances and taking into account various factors affecting the particular individual, including those described herein.

Dosage and method of administration

The acetaminophen prodrugs and formulations described herein are generally administered in an amount effective to achieve the desired result, e.g., to treat or prevent the particular condition being treated or prevented (e.g., pain and/or fever). The amount of acetaminophen prodrug or formulation administered for administration of an effective amount depends on various factors including, for example, the particular condition being treated, the frequency of administration, the particular formulation being administered, the severity of the condition being treated, as well as the age, weight and general health of the individual, the side effects experienced by the individual being treated, and the like. Determination of an effective dose is within the ability of those skilled in the art, particularly in light of the teachings provided herein. The dosage can also be assessed using in vivo animal models.

The amount of acetaminophen prodrug that can be combined with the carrier material to produce a single dosage form can vary depending upon the host and the particular mode of administration of the acetaminophen prodrug and one or more of the various factors described above. The selected drug unit dose can be determined and administered to provide a determined final drug concentration in the blood, tissue, organ, or other target region of the body. For a given situation, an effective amount can be determined by routine experimentation and is within the skill and judgment of the ordinary practitioner.

In certain embodiments, the dose of acetaminophen prodrug required to achieve the same blood concentration level as acetaminophen is low due to the increased solubility of the prodrug. In certain embodiments, the dosage of prodrug required to achieve the same blood concentration level as acetaminophen is 1.2, 2, 5, 7.5, 10, 15, 20, 50, or 100 times lower than acetaminophen.

Examples of dosages of acetaminophen prodrugs that may be employed (alone or in combination) are effective amounts within the following dosage ranges: from about 0.1 μ g/kg to about 300mg/kg, or from about 1.0 μ g/kg to about 40mg/kg body weight, or from about 1.0 μ g/kg to about 20mg/kg body weight, or from about 1.0 μ g/kg to about 10mg/kg body weight, or from about 10.0 μ g/kg to about 10mg/kg body weight, or from about 100 μ g/kg to about 10mg/kg body weight, or from about 1.0mg/kg to about 10mg/kg body weight, or from about 10mg/kg to about 100mg/kg body weight, or from about 50mg/kg to about 150mg/kg body weight, or from about 100mg/kg to about 200mg/kg body weight, or from about 150mg/kg to about 250mg/kg body weight, or from about 200mg/kg to about 300mg/kg body weight, or from about 250mg/kg to about 300mg/kg body weight. Other doses that may be employed are about 0.01mg/kg body weight, about 0.1mg/kg body weight, about 1mg/kg body weight, about 10mg/kg body weight, about 20mg/kg body weight, about 30mg/kg body weight, about 40mg/kg body weight, about 50mg/kg body weight, about 75mg/kg body weight, about 100mg/kg body weight, about 125mg/kg body weight, about 150mg/kg body weight, about 175mg/kg body weight, about 200mg/kg body weight, about 225mg/kg body weight, about 250mg/kg body weight, about 275mg/kg body weight, or about 300mg/kg body weight. The compounds of the present invention may be administered alone or in combination in a single daily dose, or the total daily dose may be administered in divided doses of two, three, four, five or six times daily.

The frequency and duration of administration of the acetaminophen prodrug depends on the condition being treated, the condition of the individual, and the like. The formulation may be administered to a subject one or more times, e.g., 2, 3, 4, 5, 10, 15, 20 or more times. The formulation can be administered to a subject, e.g., greater than, equal to, or less than once per day, twice per day, three times per day, or more than three times per day; or 1-6 times per day, 2-6 times per day or 4-6 times per day. The formulation may also be administered to the individual, for example, less frequently than once a day, such as once every two days, once every three days, once a week, or less frequently. The formulation may be administered for days, weeks or months.

The acetaminophen prodrugs of the present invention can be administered enterally (e.g., orally or rectally), parenterally (e.g., by injection (e.g., intravenously or intramuscularly), by inhalation (e.g., in the form of a mist or spray), or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, excipients, and excipients as desired Intravenous, intramuscular, intrasternal injection or infusion techniques. The acetaminophen prodrugs can be combined with pharmaceutically acceptable carriers, excipients, and excipients suitable for the desired route of administration. The route of administration may vary depending on the condition being treated. Other methods of administration are known in the art.

In certain embodiments of the methods, the route of administration is oral. In certain embodiments, the formulation is suitable for oral administration. The acetaminophen prodrugs described herein can be administered in solid form, liquid form, aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectable preparations, creams, solutions, suppositories, enemas, colonic lavage, emulsions, dispersions, food premixes, and other suitable forms.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In the solid dosage form, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. The dosage form may also contain other substances in addition to inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills may also have an enteric coating.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. The formulations may also contain adjuvants such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

In certain embodiments, the acetaminophen prodrugs are administered parenterally (e.g., intravenously or intramuscularly). Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in propylene glycol. Sterile injectable preparations may also be sterile powders for reconstitution with an acceptable carrier before administration. Acceptable carriers and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. In this regard, any brand of fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

In certain embodiments, a high dose of acetaminophen prodrug is provided in a low volume (e.g., in a low volume saline). Non-limiting examples of effective amounts (e.g., for parenteral administration, such as intravenous or intramuscular administration) include acetaminophen prodrugs in the following dosage ranges: from about 20 mg/day to about 8 g/day, or from about 60 mg/day to about 6g, or from about 200 mg/day to about 4g, or from about 300mg to about 2.6 g/day, or from about 500mg to about 2 g/day. In certain embodiments, an effective amount for parenteral (e.g., intravenous or intramuscular) administration is about 200mg to about 5g, or about 500mg to about 4g, or about 750mg to about 3g, or about 1g to about 2.5g, or about 1.3g to about 1.9g in a dosage volume of about 1mL to about 30mL, or about 1mL to about 25mL, or about 5mL to about 20mL, or about 5mL to about 15mL, or about 10mL to about 15mL, or about 5mL to about 10 mL. In certain of these embodiments, the acetaminophen prodrug is administered in a solution having a concentration of from about 10mg/mL to about 1000mg/mL, or from about 25mg/mL to about 750mg/mL, or from about 50mg/mL to about 500mg/mL, or from about 75mg/mL to about 400mg/mL, or from about 100mg/mL to about 300mg/mL, or from about 150mg/mL to about 250 mg/mL.

The invention also includes formulations of acetaminophen prodrugs for rectal administration in the form of suppositories. The formulations may be prepared by mixing the active agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. Suitable materials include cocoa butter, beeswax and polyethylene glycols.

The acetaminophen prodrugs of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are typically formed from phospholipids or other lipid materials. Liposomes are formed from single or multiple layers of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and/or metabolizable lipid capable of forming liposomes can be used. The liposome-form preparations of the present invention may contain, in addition to the acetaminophen prodrug, stabilizers, preservatives, excipients, and the like. In certain embodiments, the lipid is a natural and/or synthetic phospholipid and/or phosphatidylcholine (lecithin). Methods of forming liposomes are known in the art. See, e.g., Prescott, Ed., Methods in Cell Biology, volume XIV, Academic Press, New York, N.W., p.33 et seq (1976).

Examples

The present invention may be understood more readily by reference to the following examples, which are provided for purposes of illustration and are not intended to be limiting of the present invention.

Example 1: synthesis of (4-acetamidophenoxy) methyl dihydrogen phosphate

N- (4- (methylthiomethoxy) phenyl) acetamide

To a stirred suspension of grey sodium hydride (1.9 g; 75.49mmol) in hexamethylphosphoramide (HMPA; 25mL) cooled to 0 deg.C was slowly added a solution of acetaminophen (10 g; 66.22mmol in 35mL HMPA) over about 15 minutes. After stirring for about 15 minutes, the grey suspension turned into a light brown, transparent solution. The reaction mixture was stirred for an additional 20 minutes at 0 ℃. Chloromethyl methyl sulfide (7.67 g; 79.47mmol) was then added slowly to the reaction mixture over about 10 minutes. The color of the reaction mixture did not change. The reaction mixture was slowly warmed to room temperature and stirring was continued for 3 hours. In TLC silica gel 60F using a methanol/dichloromethane solvent system (3: 97)₂₅₄Detection of R at λ 254nm on Merck, starting materials and products_fThe values are 0.4 and 0.6, respectively. The reaction mixture was quenched with saturated ammonium chloride solution (80mL), extracted with ethyl acetate (2 × 75mL), and the light brown organic layer separated, dried over sodium sulfate and concentrated in vacuo. The crude light brown compound was purified by washing with hexane (3 × 50mL), acetonitrile (15mL), diethyl ether (100mL) to afford N- (4- (methylthiomethoxy) phenyl) acetamide product as a white solid (3.5g, 25% yield).

(4-Acetylaminophenoxy) methyl dibenzyl phosphate

To a stirred solution of N- (4- (methylthiomethoxy) phenyl) acetamide (1.5 g; 7.1mmol) in THF (with 5g of activatedMolecular sieves stirred together for 15 minutes) was added to the colorless solution brown N-iodosuccinimide (2.6 g; 10.7mmol), then dibenzyl phosphate (3.1 g; 11.14mmol) in DCM. The resulting brown reaction mixture was stirred at room temperature for 2 hours. In TLC silica gel 60F using a methanol/dichloromethane solvent system (3: 97)₂₅₄R of starting material, dibenzyl phosphate and product, detected at λ 254nm on Merck_fThe values are 0.6, 0.2 and 0.5, respectively. The reaction mixture was filtered through Whatman filter paper, the brown filtrate was washed with water (20mL), extracted with dichloromethane (50mL), the organic layer was separated, washed with 20% sodium thiosulfate (2x50mL) and 10% sodium bicarbonate (30mL), dried over sodium sulfate and evaporated to give a brown viscous liquid product (1.9g, 60% yield) which was purified by column chromatography (silica gel) using 5% methanol in dichloromethane as eluent.

(4-Acetylaminophenoxy) methyl dihydrogen phosphate

To a stirred brown solution of (4-acetamidophenoxy) methyldibenzylphosphate (0.4g, 0.9mmol) in methanol (15mL) was added Pd (OH)₂(0.2g) in methanol (10 mL). The reaction mixture was charged to a glass vessel and hydrogenated in a Parr hydrogenator at room temperature and 60 psi. TLC silica gel 60F using a methanol/dichloromethane solvent system (10: 90)₂₅₄Detection of R at λ 254nm on Merck, starting materials and products_fThe values are 0.0 and 0.5, respectively. The catalyst was filtered through celite and washed with methanol (3 × 5 mL). The filtrate was concentrated in vacuo to give a brown gum which was washed by pentane (2 × 50mL) and diethyl ether (30mL)Purification gives 50mg (30% yield) of the product as an off-white solid (melting range: 109 ℃ C.).¹H NMR(400MHz，DMSO-d₆)：δ9.82(s，1H)，7.48(d，2H，J＝8.8Hz)，6.98(d，2H，J＝8.8Hz)，5.43(d，2H，J＝10.0Hz)，2.50(s，3H)。

Example 2: synthesis of (4-acetamidophenoxy) sodium methyl phosphate

To a stirred milky suspension of (4-acetamidophenoxy) methyl dihydrogen phosphate (20 mg; 0.076mmol) in ethyl acetate (5mL) was added a solution of sodium 2-ethylhexanoate (25 mg; 0.15mmol) in ethyl acetate (2 mL). The reaction suspension was stirred for 3 hours. After 1 h, the milky suspension turned to a white solid, which was filtered and washed with ethyl acetate (3X 15mL) and ether (3X 20mL) to give 10mg (50% yield) of the product as a white solid (melting range: 206-.¹H NMR(400MHz，DMSO)：δ9.8(s，1H)，7.41(d，2H，J＝10.8Hz)，6.96(d，2H，J＝11.6Hz)，5.26(d，2H，J＝10.4Hz)，1.97(s，3H)。

Example 3: solubility of acetaminophen analogs

The solubilities of (4-acetamidophenoxy) methyl dihydrogen phosphate and its disodium salt are listed in Table 1.

Table 1: solubility of acetaminophen prodrugs

Example 4: in vitro conversion of acetaminophen prodrugs to acetaminophen

Known amounts of acetaminophen prodrug are incubated with human plasma samples at physiological temperatures. Small aliquots were taken at predetermined time points (0, 5, 10, 15, 20, 25, 30, 40, 60 and 120 minutes) and analyzed for acetaminophen content. Experiments were performed with two different concentrations of prodrug in collected human plasma at 37 ℃ to determine the kinetics of the metabolic reaction and whether saturation of the enzyme system involved in the conversion of the prodrug to the acetaminophen drug occurred. Acetaminophen was found to be present in the first sample collected at nominally 0 minutes and increased in concentration over time over 60 minutes as shown in figures 1 and 2.

Example 5: conversion of acetaminophen prodrugs to acetaminophen in vivo

The conversion of acetaminophen prodrugs to acetaminophen via metabolism in the body was studied in rats. Similar to the experimental design described above for the in vitro studies, acetaminophen prodrugs were administered intravenously to test animals and blood was drawn at predetermined time points. The blood is analyzed for acetaminophen content or acetaminophen alone and the half-life of the prodrug is determined.

The pharmacokinetics of acetaminophen and the compound of formula I were evaluated after Intravenous (IV) administration to determine the plasma acetaminophen concentration formed. Acetaminophen and compound I were administered on an equimolar basis to provide the same level of contact with acetaminophen (25mg/kg) and to obtain the characteristic of the compound of formula I converting to acetaminophen in vivo. The experimental animals were male and female Sprague Dawley (7 to 8 weeks old)IGS) rats (Charles River Laboratories), weighing 220 to 270 grams. Blood was withdrawn from the rats at 7 time points in succession: 5, 15, 30 minutes and 1, 4, 8 and 24 hours after administration. The whole blood sample (300. mu.L) taken from the tail vein was collected in a microtank containing lithium heparin, plasma was obtained by centrifugation and was taken at-70 ℃And (5) freezing and preserving until analysis. The results of the plasma analysis of acetaminophen content are shown in fig. 3 and table 2.

Table 2: summary of calculated pharmacokinetic parameters of acetaminophen following intravenous administration of Compound I to rats

It is: 25mg/kg paracetamol molar equivalent: all values being equal

Claims (29)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof or a solvate thereof.

2. The compound of claim 1, wherein the compound is a disodium salt of formula (II):

3. a formulation comprising a compound of claim 1 or 2 and a carrier.

4. A formulation comprising an effective amount of a compound of claim 1 or 2 and a pharmaceutically acceptable carrier.

5. The formulation of claim 3 or 4, wherein the carrier is saline.

6. A formulation comprising a compound of claim 1 or 2 and a compound selected from the group consisting of opioids, non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines and barbiturates.

7. A formulation comprising a compound of claim 1 or 2 and a compound selected from the group consisting of: codeine, morphine, hydrocodone, hydromorphone, levorphanol, aspirin, ketorolac, ibuprofen, naproxen, caffeine, tramadol, dexpropoxyphene, methohexital sodium, diazepam, lorazepam, midazolam, propoxyphene, ketoprofen, flurbiprofen, etodolac, diclofenac, misoprostol, meloxicam, piroxicam, doxylamine, pamabrom, carisoprodol, and butalbitude.

8. A compound according to claim 1 or 2 in substantially pure form.

9. A method of treating a disease or condition responsive to acetaminophen, comprising administering to a subject an effective amount of a compound of claim 1 or 2.

10. A method of treating a disease or disorder responsive to acetaminophen, comprising administering to a subject the formulation of any one of claims 3-7.

11. The method of claim 9 or 10, wherein the disease or condition is selected from the group consisting of pain, fever, inflammation, ischemic injury, and neuronal injury.

12. The method of any one of claims 9 or 11, wherein the compound is administered parenterally.

13. The method of claim 12, wherein the compound is administered intravenously.

14. The method of claim 12, wherein the compound is administered intramuscularly.

15. The method of claim 12, wherein the compound is administered subcutaneously.

16. The method of any one of claims 9 or 11-15, wherein the dose of the compound is from about 300mg to about 2.6 g.

17. The method of claim 16, wherein the dose of the compound is from about 1.3g to about 1.9 g.

18. The method of claim 16 or 17, wherein the volume of the dose is from about 1mL to about 25 mL.

19. The method of claim 18, wherein the volume of the dose is from about 10mL to about 20 mL.

20. The method of claim 18, wherein the volume of the dose is from about 1mL to about 10 mL.

21. The method of claim 18, wherein the volume of the dose is from about 5mL to about 10 mL.

22. The method of any one of claims 16-21, wherein the dose is administered more than once daily.

23. The method of any one of claims 16-21, wherein the dose is administered once every other day or less.

24. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use as a medicament.

25. Use of one or more compounds of claim 1 or 2 or a pharmaceutically acceptable salt thereof or a solvate thereof in the manufacture of a medicament for the treatment of pain, fever, inflammation, ischemic injury or neuronal injury.

26. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate of either, for the treatment of pain, fever, inflammation, ischemic injury, or neuronal injury.

27. A kit for treating or preventing pain, fever, inflammation, ischemic injury, or neuronal injury comprising a compound of claim 1 or 2; and instructions for use in treating or preventing pain, fever, inflammation, ischemic injury, or neuronal injury.

28. A kit for treating or preventing pain, fever, inflammation, ischemic injury, or neuronal injury comprising the formulation of any one of claims 3-7; and instructions for use in treating or preventing pain, fever, inflammation, ischemic injury, or neuronal injury.

29. A low volume/high concentration formulation comprising a compound of claim 1 or 2 and a pharmaceutically acceptable carrier.