JP2014208673A - Treatment of drug-induced nausea with opioid antagonists - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide effective antinausea and antiemetic formulations which have few side effects and permit use of therapeutic agents to effectively treat a condition or illness.SOLUTION: Methods in accordance with the invention include treating gastrointestinal adverse side effects associated with treatment by anti-retroviral agent characterized by administering opioid antagonists of sufficient amount to treat drug induced gastrointestinal side effects together with the anti-retroviral agent to patients suffering from gastrointestinal adverse side effects associated with treatment with the anti-retroviral agent. The method of claim 1, wherein the side effects are nausea, emesis, or both of them.

Description

(Cross-reference with related applications)
This application claims the rights of US Provisional Application No. 60 / 992,555, filed Dec. 5, 2007; the contents of that application are hereby incorporated by reference in their entirety.
(preface)
Human immunodeficiency virus (HIV) infection is a fatal disease that can progress to acquired immunodeficiency syndrome (AIDS) and affects millions of people worldwide (Sande and Volberding, 1999; Selgelid, 2005). If the patient is not treated in a timely manner, the disease can become morbid and lead to death due to immune dysfunction and opportunistic infections. In order to reduce viral load and improve life expectancy, treatment guidelines often require patients to follow complex medications for extended periods of time (Proctor et al., 1999; Bartlett, 2004). A major obstacle to such compliance is compliance-induced side effects. Side effects not only impair quality of life, but also have a negative impact on compliance (Carr, 2002). Nausea and vomiting are examples of drug-induced side effects that can affect compliance (Gartland, 2001; Lichterfeld et al., 2002; Barlett, 2004). Such side effects can often limit the usefulness of the drug and even make it unacceptable.

  There are a number of anti-nausea and anti-emetic compositions, but these compositions often create their own undesirable patient side effects. The result is often that the patient is in a situation to choose between the symptoms she or he seeks to relieve and the side effects of treatment. It is desirable to have an effective anti-nausea and anti-emetic formulation that has few side effects and allows the use of therapeutic agents to effectively treat symptoms or illnesses.

(Summary of Invention)
The principle, ie the method of using the present invention, alleviates gastrointestinal side effects associated with the administration of certain drugs, especially antiretroviral drugs, in the treatment of viral infections, especially retroviral infections, eg HIV. Including doing. For example, protease inhibitors are among the various antiretroviral drug groups used to treat HIV. Protease inhibitors induce adverse gastrointestinal side effects such as nausea and vomiting (Elperin and Sax, 1996). In particular, according to the present invention, nausea, vomiting and anti-retroviral agents, such as protease inhibitors, such as effects associated with the treatment of retroviral infections such as HIV. Other adverse gastrointestinal effects are alleviated, eg, reduced, suppressed, attenuated, by administration of peripheral inhibitory opioid antagonists, for example, opioid antagonists such as methylnaltrexone, or Provide a way to reduce.

In one embodiment, the present invention provides a method of treating gastrointestinal disorders by co-administering an antiretroviral agent, particularly a protease inhibitor and an opioid antagonist. In a specific embodiment, nausea and vomiting induced by treatment of HIV with ritonavir is alleviated by administering an opioid antagonist such as the peripheral opioid antagonist methylnaltrexone.
The opioid antagonists used in the method according to the invention are generally heterocyclic amine compounds belonging to several compound groups. For example, one suitable group is tertiary derivatives of morphinan, especially tertiary derivatives of noroxymorphone. In one embodiment, the tertiary derivative of noroxymorphone is, for example, naloxone or naltrexone.

  In certain embodiments, the opioid antagonist is a peripheral opioid antagonist. Suitable peripheral opioid antagonists are generally heterocyclic amine compounds belonging to several groups of compounds. For example, one suitable group is quaternary derivatives of morphinan, especially quaternary derivatives of noroxymorphone. In one embodiment, the quaternary derivative of noroxymorphone is, for example, N-methylnaltrexone (or simply methylnaltrexone), N-methylnaloxone, N-methylnalolphine, N-diallylnormorphine, N-allyllevororphan or N-methylnalmefene. Another group is N-substituted piperidines. In one embodiment, the N-piperidine is piperidine-N-alkylcarbonylate such as, for example, albimopan. Yet another group of compounds that may be valuable in the methods of the present invention are quaternary derivatives of benzomorphan.

  In certain embodiments of the invention, the opioid antagonist may be a μ-opioid antagonist. In other embodiments, the opioid antagonist may be a kappa-opioid antagonist. The present invention also includes combinations of μ-antagonists, κ-antagonists, and μ- and κ-antagonists, such as a combination of methylnaltrexone and albimopan or a combination of naltrexone and methylnaltrexone. It extends to the administration of two or more opioid antagonists.

  The present invention may be better understood and appreciated by reference to the detailed description of specific embodiments presented herein in connection with the accompanying drawings.

The chemical structure of naltrexone and methylnaltrexone and the conversion reaction of naltrexone to methylnaltrexone are shown. 2 is a graph showing dose related effects of treatment with ritonavir on kaolin intake in rats. 2 is a graph showing the dose-related effects of prior treatment with naloxone on ritonavir-induced kaolin intake in rats. (NLX = naloxone; RIT = ritonavir). FIG. 6 is a graph of the area under the curve (AUC) for kaolin intake from time 0 to 120 hours, comparing naltrexone treatment versus control (no treatment). 2 is a graph of dose related effects of prior treatment with methylnaltrexone on ritonavir-induced kaolin intake in rats. (MNTX = methylnaloxone; RIT = ritonavir). FIG. 6 is a graph of the area under the curve (AUC) for kaolin intake from time 0 to 120 hours comparing methylnaltrexone treatment versus control (no treatment). 1 shows HPLC chromatograms of methylnaltrexone and naltrexone in a plasma sample, where (A) is a chromatogram of a standard plasma extract of methylnaltrexone and naltrexone. (MNTX = methylnaltrexone; NTX = naltrexone). 2 shows HPLC chromatograms of methylnaltrexone and naltrexone in a plasma sample, and (B) in the figure is a chromatogram showing a high concentration of methylnaltrexone detected after administration. (MNTX = methylnaltrexone; NTX = naltrexone). 1 shows HPLC chromatograms of methylnaltrexone and naltrexone in a plasma sample, and (C) in the figure is a chromatogram showing methylnaltrexone levels 120 minutes after administration. (MNTX = methylnaltrexone; NTX = naltrexone).

(Detailed explanation)
The present invention provides compositions and methods using a combination of antiretroviral agents, particularly protease inhibitors such as ritonavir and opioid antagonists. The method according to the present invention comprises treating adverse gastrointestinal side effects associated with the treatment of HIV, for example with protease inhibitors. As described in the examples below, the combination of ritonavir with an opioid antagonist such as methylnaltrexone (MNTX) unexpectedly treated the gastrointestinal side effects of ritonavir.

  Before describing at least one embodiment of the present invention, it is to be understood that the present invention is not limited in its application to the details set forth in the following description as illustrated in the examples. . Such description and examples are not intended to limit the scope of the invention as set forth in the appended claims. The invention is capable of other embodiments or of being practiced or carried out in various ways. The detailed description below illustrates the invention with reference to embodiments using ritonavir as a drug, but other protease inhibitors or combinations thereof where nausea and other gastrointestinal effects are deleterious side effects are also present. It should be understood that it may be suitable for use in accordance with the principles of the present invention.

  Moreover, any document such as any patent or patent document cited herein is not an admission that it constitutes prior art. In particular, unless otherwise specified, references to any document herein constitute acceptance that any of these documents constitutes part of common general knowledge in the United States or elsewhere. It should be understood that it is not. All discussions of the literature explain what the authors of those documents claim, and the applicant has the right to question the accuracy and appropriateness of any document cited herein. Reserve.

  Throughout this disclosure, various aspects of this invention can be presented in a range fashion. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, as will be appreciated by those skilled in the art, for all purposes, and in particular in terms of presenting the specification, all ranges disclosed herein are intended to represent all possible subranges, Combinations as well as all integer and fractional values within the range are also included. As one example, the range of 20% to 40% can be broken down into ranges of 20% to 32.5% and 32.5% to 40%, 20% to 27.5% and 27.5% to 40%, and so on. In addition, any of the ranges described fully explain and allow for the range to be broken down into at least one half, one third, one fourth, one fifth, one tenth, etc. It can be easily recognized as. As a non-limiting example, the ranges described herein can easily be broken down into the lower third, the middle third, the upper third, and the like. Also, as those skilled in the art understand, “up to”, “at least”, “greater than”, “less than” “ All terms such as “more than” refer to ranges that include the listed numbers and, as described above, can be substantially resolved into sub-ranges. Similarly, all ratios disclosed herein include all sub- ratios that fall within that broad ratio. These are merely examples of what is specifically intended. Furthermore, the terms “range” between the first indication number and the second indication number and the term “range” from the first indication number to the “second indication number” are interchangeable in this specification. Use it.

  In addition, the use of “comprising”, “including”, “having” and variations thereof herein is intended to include the details described below and their equivalents and additional details. Other steps, components and elements that are meant to be included and do not affect the end result, for example, may be added. These terms also extend to the terms “consisting of” and “consisting essentially of”. Use of “consisting essentially of” means that the composition or method may include additional components and / or steps, but the additional components and / or steps claim basic and novel features of the composition or method. This means that this is only when there is substantially no change.

Unless defined otherwise, all scientific and technical terms are used herein according to common usage and have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. . However, as used herein, the following definitions may be useful in helping the skilled artisan understand the present invention:
“Subject” refers to mammals, eg, humans, mice, dogs, cats, rats.
“Alkyl” is a monovalent aliphatic hydrocarbon group that is saturated and may be linear, branched or cyclic, having from 1 to about 10 carbon atoms in the chain, as well as all of the chains Refers to combinations and subcombinations. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
“Lower alkyl” refers to an alkyl group having 1 to about 6 carbon atoms.

“Alkenyl” means a monovalent aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having from 2 to about 10 carbon atoms in the chain, as well as all combinations of such chains and Refers to sub-combination. Typical alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl and heptenyl.
“Alkynyl” refers to monovalent aliphatic hydrocarbon groups containing at least one carbon-carbon triple bond and having from 2 to about 10 carbon atoms in the chain, as well as combinations and subcombinations of those chains. Called. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl and heptynyl.

“Alkylene” refers to a divalent aliphatic hydrocarbon group containing from 1 to 6 carbon atoms, such as —CH 2-(methylene), and all combinations and subcombinations of these chains. The alkylene group can be linear, branched or cyclic. If desired, one or more oxygen atoms, sulfur atoms or optionally substituted nitrogen atoms can be introduced along the alkylene group, the nitrogen substituent having an alkyl group as described above.
“Alkenylene” refers to a divalent alkylene group that contains at least one carbon-carbon double bond and can be linear, branched or cyclic. Exemplary alkenylene groups include, but are not limited to, ethenylene (—CH═CH—) and propenylene (—CH═CHCH 2 —).

“Cycloalkyl” refers to a saturated monocyclic or bicyclic hydrocarbon ring having from about 3 to about 10 carbons, and all combinations and subcombinations of those rings. A cycloalkyl group can be optionally substituted by one or more cycloalkyl group substituents. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
“Acyl” means an alkyl-CO group in which alkyl is as previously described. Typical acyl groups include, but are not limited to, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

“Aryl” refers to an aromatic carbocyclic group containing from about 6 to about 10 carbons, and all combinations and subcombinations of those rings. The aryl group can be optionally substituted by one or two or more aryl group substituents. Typical aryl groups include, but are not limited to phenyl and naphthyl.
“Aryl substituted alkyl” refers to an optionally substituted aryl group, preferably a linear alkyl group substituted at the terminal carbon by an optionally substituted phenyl ring, preferably a lower alkyl group. Exemplary aryl substituted alkyl groups include, for example, phenylmethyl, phenylethyl, and 3 (4-methylphenyl) propyl.

“Heterocycle” refers to a carbocyclic group of a monocyclic or polycyclic ring system containing from about 4 to about 10 members, and all combinations and subcombinations of these rings, wherein one or more members of the ring Elements other than carbon, such as nitrogen, oxygen or sulfur. Heterocyclic groups can be aromatic or non-aromatic. Typical heterocyclic groups include, for example, pyrrole and piperidine groups.
“Halo” refers to fluoro, chloro, bromo or iodo.

  “Peripheral” with respect to opioid antagonists refers to opioid antagonists that act primarily on physiological systems and components outside the central nervous system. In other words, these opioid antagonists exhibit reduced central nervous system (CNS) activity or substantially no central nervous system activity. For example, these opioid antagonists do not readily cross the blood-brain barrier in effective amounts that inhibit the central effects of opioids, i.e., these opioid antagonists are effective at the opioid analgesic effect when administered peripherally. These opioid antagonists do not reduce the analgesic effect of opioids. Peripheral opioid antagonist compounds for use in the methods of the present invention suitably exhibit pharmacological activity lower than about 5-15% in the CNS; about 0% CNS activity (ie, inactivity) is most suitable. The non-central effect properties of peripheral opioid antagonists are often related to the charge, polarity and / or size of the molecule or species. For example, peripherally acting quaternary amine opioid antagonists as described herein are positively charged, while centrally acting tertiary amine opioid antagonists are neutral molecules. Peripheral opioid antagonists useful in the present invention are typically μ- and κ-opioid antagonists.

The term “pharmaceutically acceptable” or “pharmacologically acceptable” refers to a molecular entity that does not cause an adverse, allergic or other troublesome reaction when administered to a subject such as a human. Or means to refer to the composition. The opioid antagonists according to the invention may be formulated as the free base, in neutral or salt form. “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts are non-toxic ordinary salts and quaternary ammonium salts of the compounds according to the invention having properties that are acceptable in therapeutic applications. Such salts can be prepared, for example, from inorganic or organic bases or acids. For example, acid addition salts include acetate, ascorbate, benzoate, bisulfate, chloride, citrate, lactate, maleate, oxalate, sulfonate, tartrate, etc. obtain. Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metals such as calcium and magnesium salts, and organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. The ammonium salt of In addition, basic nitrogen-containing groups are quaternized by agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide, and long chain halides and dialkyl sulfate or diamyl sulfate. Can be Unless expressly indicated otherwise by context, as used herein “compounds of the invention”, “a compound of the invention” or “invention” Terms such as “compounds according to” are intended to encompass chemically-generated pharmaceutically acceptable salts of the relevant compounds. More information on suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy , 21st ed., Lippincott Williams and Wilkens, Philadelphia, PA; which is incorporated herein by reference. Let

The term “treating” or “treatment” as used herein refers to any pathology or condition such as prevention, treatment, alleviation of symptoms; reduction, reduction or reduction of symptoms; and suppression or prevention of progression of symptoms. Includes management means.
As used herein, the term “side effects” is meant to refer to effects other than the purpose or desired effect of the drug when administered to a subject. Side effects can be beneficial or undesirable, i.e. harmful. In the case of the present invention, undesirable effects often occur after administration of an antiretroviral agent such as ritonavir. Such side effects include gastrointestinal side effects such as nausea, vomiting, diarrhea and abdominal pain.
As used herein, the term “efficacy” refers to the ability or efficacy of an antiretroviral agent to treat a retroviral infection, eg, HIV, in a subject suffering from such an infection. Means that. Efficacy can also be expressed as the dose of drug required to produce a specific effect of a given intensity.

In the following description of the method of the invention, the processing steps are carried out at room temperature and atmospheric pressure unless otherwise specified.
According to the present invention, an antiretroviral agent that is particularly important for treating retroviral infections, primarily HIV, is a protease inhibitor. Proteases (also known as peptidases) are enzymes that cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors.

  The retroviral genome encodes a protease involved in proteolytic processing of one or more polyprotein precursors, such as the pol and gag gene products. (See Wellink, Arch. Virol. 98 1 (1988)). Retroviral proteases most commonly process the gag precursor into the core protein, and also process the pol precursor into reverse transcriptase and retroviral protease. Accurate processing of these precursor polyproteins by retroviral protease is necessary for the assembly of new infectious virions. It has been demonstrated that in vitro mutagenesis that produces protease deficient viruses results in the production of immature core forms that lack infectivity. (See Crawford, J. Virol. 53 899 (1985); Katoh, et al., Virology 145 280 (1985)). Thus, retroviral protease inhibition provides an attractive target in antiviral therapy. (See Mitsuya, Nature 325 775 (1987)).

  Several protease inhibitors are used as effective antiretroviral agents; however, these agents produce several adverse effects, especially gastrointestinal side effects. Because drug protocol compliance is a prerequisite for effective antiviral therapy in HIV and AIDS patients, drug-induced side effects can interfere with compliance. To date, the mechanism by which protease inhibitors cause gastrointestinal effects such as nausea and / or vomiting has not been studied. Although the use of anti-nausea drugs is somewhat effective in reducing nausea and vomiting, these harmful gastrointestinal effects remain problematic in protease inhibitor treatment protocols.

Protease inhibitors are classified as peptidic and non-peptidic. Peptide protease inhibitors include amprenavir, atazanavir, phosamprenavir (metabolized to active amprenavir), indinavir, lopinavir, nelfinavir, ritonavir and scheinavir. Non-peptide protease inhibitors include darunavir and tipranavir. Of particular interest is ritonavir, which is a potent protease inhibitor alone, and also used at low doses to enhance the activity of other protease inhibitors, such as that of ritonavir and lopinavir. Used together. Ritonavir is a tripeptide, as shown by formula (A) below:

  Ritonavir was originally designed as an inhibitor of HIV protease, but was also found to enhance the effectiveness of other protease inhibitors. In particular, ritonavir inhibits cytochrome P450-3A4 (CYP3A4), a liver enzyme involved in the metabolism of protease inhibitors. Inhibition of HIV protease by ritonavir and / or other protease inhibitors enhanced by ritonavir results in an increase in non-infectious viral particles, resulting in a reduction in HIV symptoms. However, the side effects of ritonavir are nausea and vomiting.

As described in the examples below, the inventors evaluated the effect of opioid receptor antagonists on protease inhibitor-induced nausea and vomiting, such as ritonavir-induced. Both naloxone (a centrally acting opioid antagonist) and methylnaltrexone (a peripherally acting opioid antagonist) were found to reduce ritonavir-induced nausea and vomiting.
Thus, the opioid antagonists according to the present invention include both central and peripheral acting opioid antagonists. Particularly valuable antagonists are suitably intended to be peripheral inhibitory opioid antagonists. Particularly suitable may be μ-opioid antagonists, especially peripheral μ-opioid antagonists.

  Opioid antagonists constitute a group of compounds that can structurally change while retaining their antagonist properties. These compounds include tertiary and quaternary morphinans, especially noroxymorphone derivatives; N-substituted piperidines, especially piperidine-N-alkylcarboxylates; and tertiary and quaternary benzoates. There are morphans and normorphinan derivatives, especially 6-carboxy-normorphinan derivatives. Tertiary compound antagonists are fairly lipid soluble and easily cross the blood brain barrier.

  Examples of opioid antagonists that cross the blood brain barrier and are central (and peripheral) active include, for example, naloxone, naltrexone (each commercially available from Baxter Pharmaceutical Products), and nalmefene (e.g., Available from Dupont Pharma). On the other hand, peripheral inhibitory antagonists are typically charged, polar and / or have a high molecular weight, and such properties prevent these antagonists from crossing the blood brain barrier. For example, methylnaltrexone is a quaternary derivative of naltrexone, a tertiary opioid antagonist (FIG. 1). By adding a methyl group to naltrexone, a compound with higher polarity and lower liposolubility is formed. Thus, methylnaltrexone does not cross the blood brain barrier and has the potential to block unwanted gastrointestinal side effects typically mediated by peripherally located receptors.

(式中、Rは、アルキル、アルケニル、アルキニル、アリール、シクロアルキル置換アルキルまたはアリール置換アルキルであり；X-は、アニオン、とりわけ、クロリド、ブロミド、イオジドまたはメチルサルフェートアニオンである)。
式(I)のノルオキシモルホン誘導体は、例えば、米国特許第4,176,186号の手順に従って調製し得る；該特許は、参考として本明細書に合体させる。また、米国特許第4,719,215号、第4,861,781号、第5,102,887号、第5,972,954号および第6,274,591号；米国特許出願第2002/0028825号および第2003/0022909号；並びPCT公開公報WO 99/22737号およびWO 98/25613号も参照されたい；これらは、全て参考として本明細書に合体させる。 Peripheral opioid antagonists suitable for use in the present invention may be quaternary morphinan derivatives, especially compounds that are quaternary noroxymorphones of the following formula (I):

Wherein R is alkyl, alkenyl, alkynyl, aryl, cycloalkyl-substituted alkyl or aryl-substituted alkyl; X- is an anion, especially chloride, bromide, iodide or methylsulfate anion.
Noroxymorphone derivatives of formula (I) may be prepared, for example, according to the procedure of US Pat. No. 4,176,186; which is incorporated herein by reference. Also, U.S. Pat. Nos. 4,719,215, 4,861,781, 5,102,887, 5,972,954 and 6,274,591; U.S. Patent Applications Nos. 2002/0028825 and 2003/0022909; and PCT Publications WO 99/22737 and WO See also 98/25613; all of which are incorporated herein by reference.

(式中、X-は、上述したとおりである)。 A particularly valuable compound of formula (I) is N-methylnaltrexone (or simply methylnaltrexone) where R is cyclopropylmethyl, as shown in formula (II) below:

(Wherein X- is as described above).

  As mentioned above, methylnaltrexone is a quaternary derivative of the opioid antagonist naltrexone. Methylnaltrexone exists as a salt (eg, N-methylnaltrexone bromide) and thus the term “methylnaltrexone” or “MNTX” as used herein also includes such salts. Thus, “methylnaltrexone” or “MNTX” specifically includes, but is not limited to, methylnaltrexone bromide, chloride, iodide, carbonate and sulfate. Various names used for bromide salts of MNTX in the literature include, for example, methylnaltrexone bromide, N-methylnaltrexone bromide, naltrexone methbromide, naltrexone methylbromide, SC-37359, MRZ-2663-BR, and N- There is cyclopropylmethylnoroxy-morphine-methobromide.

  Methylnaltrexone is commercially available from, for example, Mallinckrodt Pharmaceuticals, Inc., St. Louis, MO. Methylnaltrexone is provided as a white crystalline powder that is freely soluble in water, typically as a bromide salt. The compound as provided is 99.4% pure by reverse phase HPLC and contains less than 0.011% non-quaternized naltrexone by the same method. Methylnaltrexone can be prepared, for example, as a sterile solution at a concentration of about 5 mg / mL.

(式中、R¹は、水素またはアルキルであり；R²は、水素、アルキルまたはアルケニルであり；R³は、水素、アルキル、アルケニル、アリール、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキルであり；R⁴は、水素、アルキルまたはアルケニルであり；Aは、OR⁵またはNR⁶R⁷であり；R⁵は、水素、アルキル、アルケニル、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキルであり；R⁶は、水素またはアルキルであり；R⁷は、水素、アルキル、アルケニル、アリール、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキル、またはアルキレン置換Bであるか、或いは、R⁶とR⁷が結合している窒素原子と一緒に、R⁶とR⁷は、ピロールまたはピペリジンから選ばれる複素環を形成しており；Bは、下記：

(式中、R⁸は、水素またはアルキルであり；R⁹は、水素、アルキル、アルケニル、アリール、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキルあるか、或いは、R⁸とR⁹が結合している窒素原子と一緒に、R⁸とR⁹は、ピロールまたはピペリジンから選ばれる複素環を形成しており；Wは、OR¹⁰、NR¹¹R¹²またはOEであり；R¹⁰は、水素、アルキル、アルケニル、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルケニルまたはアリール置換アルキルであり；R¹¹は、水素またはアルキルであり；R¹²は、水素、アルキル、アルケニル、アリール、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキル、またはアルキレン置換C(=O)Yであるか、或いは、R¹¹とR¹²が結合している窒素原子と一緒に、R⁶とR⁷は、ピロールまたはピペリジンから選ばれる複素環を形成しており；Eは、下記：

、アルキレン置換(C=O)Dまたは-R¹³OC(=O)R¹⁴であり；R¹³は、アルキル置換アルキレンであり；R¹⁴は、アルキルであり；Dは、OR¹⁵またはNR¹⁶R¹⁷であり；R¹⁵は、水素、アルキル、アルケニル、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキルであり；R¹⁶は、水素、アルキル、アルケニル、アリール、アリール置換アルキル、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキルまたはシクロアルケニル置換アルキルであり；R¹⁷は、水素またはアルキルであり；或いは、R¹⁶とR¹⁷が結合している窒素原子と一緒に、R¹⁶とR¹⁷は、ピロールまたはピペリジンから選ばれる複素環を形成しており；
Yは、OR¹⁸またはNR¹⁹R²⁰であり；R¹⁸は、水素、アルキル、アルケニル、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキルであり；R¹⁹は、水素またはアルキルであり；R²⁰は、水素、アルキル、アルケニル、アリール、シクロアルキル、シクロアルケニル、シクロアルキル置換アルキル、シクロアルケニル置換アルキルまたはアリール置換アルキルであるか、或いは、R¹⁹とR²⁰が結合している窒素原子と一緒に、R¹⁹とR²⁰は、ピロールまたはピペリジンから選ばれる複素環を形成しており；R21は、水素またはアルキルである)
であり；そして、nは、0〜4である)。 Other suitable peripheral opioid antagonists may include N-substituted piperidines, especially piperidine-N-alkylcarboxylates as shown by the following formula (III):

Wherein R ¹ is hydrogen or alkyl; R ² is hydrogen, alkyl or alkenyl; R ³ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cyclo R ⁴ is hydrogen, alkyl or alkenyl; A is OR ⁵ or NR ⁶ R ⁷ ; R ⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl R ⁶ is hydrogen or alkyl; R ⁷ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl; Cycloalkenyl-substituted alkyl or aryl-substituted aryl Kill or alkylene substituted B,, or, together with the nitrogen atom to which R ⁶ and R ⁷ are attached, R ⁶ and R ⁷ forms a heterocyclic ring selected from pyrrole or piperidine; B The following:

Wherein R ⁸ is hydrogen or alkyl; R ⁹ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl, or together with the nitrogen atom to which R ⁸ and R ⁹ are attached, R ⁸ and R ⁹ forms a heterocyclic ring selected from pyrrole or piperidine; W is, in oR ^10, NR ¹¹ R ¹² or OE R ¹⁰ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkenyl or aryl-substituted alkyl; R ¹¹ is hydrogen or alkyl; R ¹² is hydrogen, Alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl Le substituted alkyl or aryl-substituted alkyl or alkylene substituted C (= O) or a Y,, or, together with the nitrogen atom to which R ¹¹ and R ¹² are attached, R ⁶ and R ^7, pyrrole or piperidine Forms a selected heterocycle; E is:

, Alkylene substituted (C═O) D or —R ¹³ OC (═O) R ¹⁴ ; R ¹³ is alkyl substituted alkylene; R ¹⁴ is alkyl; D is OR ¹⁵ or NR ¹⁶ R be ^17; R ¹⁵ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl; R ¹⁶ is hydrogen, alkyl, alkenyl, aryl, aryl-substituted Alkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl; R ¹⁷ is hydrogen or alkyl; or, together with the nitrogen atom to which R ¹⁶ and R ¹⁷ are attached, R ¹⁶ And R ¹⁷ form a heterocyclic ring selected from pyrrole or piperidine;
Y is OR ¹⁸ or NR ¹⁹ R ²⁰ ; R ¹⁸ is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aryl-substituted alkyl; R ¹⁹ is hydrogen Or R ²⁰ is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aryl-substituted alkyl, or R ¹⁹ and R ²⁰ are bonded. R ¹⁹ and R ²⁰ together with the nitrogen atom in question form a heterocycle selected from pyrrole or piperidine; R21 is hydrogen or alkyl)
And n is 0-4).

A particular piperidine-N-alkylcarboxylate that may have value is an N-alkylamino-3,4,4-substituted piperidine such as albimopan shown below as formula (IV):

  Suitable N-substituted piperidines can be prepared as disclosed in US Pat. Nos. 5,270,328, 6,451,806, 6,469,030; all of these US patents are incorporated herein by reference. Albimopan is available from Adolor, Exton, Pennsylvania. Such compounds have moderate high molecular weight, zwitterionic form, and polarity that blocks blood brain barrier penetration.

(式中、R¹は、水素、アシルまたはアセトキシであり；R¹は、アルキルまたはアルケニルであり；Rは、アルキル、アルケニルまたはアルキニルであり；X-は、アニオン、とりわけ、クロリド、ブロミド、イオジドまたはメチルサルフェートアニオンである)。 Still other suitable peripheral opioid antagonist compounds may include quaternary benzomorphan compounds. The quaternary benzomorphan compounds that can be used in the method of the invention have the following formula (V):

Wherein R ¹ is hydrogen, acyl or acetoxy; R ¹ is alkyl or alkenyl; R is alkyl, alkenyl or alkynyl; X- is an anion, especially chloride, bromide, iodide Or a methyl sulfate anion).

Specific quaternary derivatives of benzomorphan compounds that can be used in the process of the present invention include the following compounds of formula (V): 2'-hydroxy-5,9-dimethyl-2,2- Diallyl-6,7-benzomorphanium-bromide, 2'-hydroxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide, 2'-hydroxy- 5,9-dimethyl-2-n-propyl-2-propargyl-6,7-benzomorphanium-bromide, and 2'-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6 , 7-Benzomorphium-bromide.
Other quaternary benzomorphan compounds that can be used in the methods of the invention are described, for example, in US Pat. No. 3,723,440; the entire contents of the US patent are incorporated herein by reference.

Other peripheral opioid antagonists include 6-carboxy-normorphinan derivatives, especially N-methyl, as described in US application Ser. No. 11 / 888,955 entitled “6-Carboxy-Normorphinan Derivatives, Synthesis and Uses Thereof”. There may be -C-normorphinan derivatives; the above-mentioned US application is incorporated herein by reference in its entirety.
As mentioned above, the compounds of the present invention may suitably exist and be formulated as pharmaceutically acceptable salts.

  The compounds used in the methods of the invention can exist in prodrug form. As used herein, “prodrugs” release active parent drugs according to Formulas (I)-(V) or other formulas when such prodrugs are administered to a mammalian subject, or these Any drug that converts to an active parent drug or a compound that is metabolized in vivo to an active drug or other compound used in vivo in the methods of the invention is intended to be included. Since prodrugs are known to enhance many desirable properties (e.g., solubility, bioavailability, manufacturability, etc.) of pharmaceuticals, the compounds used in some methods of the present invention are necessary. Depending, it can be transmitted in prodrug form. Accordingly, the present invention contemplates a prodrug delivery method. A prodrug of a compound used in the present invention is prepared by modifying a functional group present in the compound by a general operation or by a method in which a modified product is cleaved in vivo to become a parent compound. obtain.

  Accordingly, prodrugs include, for example, compounds disclosed herein in which a hydroxy, amino, or carboxy group is attached to any group, and any of the above groups can administer the prodrug to a mammalian subject. When cleaved to form free hydroxyl, free amino or carboxylic acid, respectively. Other examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functions; and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl There are alkyl, carbocycle, aryl and alkylaryl esters, such as phenyl, benzyl and phenethyl esters.

As explained, the compounds used in the methods of the invention can be prepared in a number of ways well known to those skilled in the art. The formulations disclosed in connection with the present invention are intended to be practiced on any scale, such as milligram, gram, multigram, kilogram, multikilogram or commercial pharmaceutical scale.
The compounds used in the methods of the invention can contain one or more asymmetrically substituted carbon atoms and can be isolated in optically active or racemic forms. Accordingly, all chiral, diastereomeric, racemic, epimeric, and all geometric isomer forms of a structure are contemplated unless a specific stereochemistry or isomer form is specifically indicated. It is well known in the art how to prepare and separate such optically active forms. For example, a mixture of stereoisomers includes, but is not limited to, resolution of racemic forms; standard, reverse phase and chiral chromatography; by standard methods such as selective salt formation, recrystallization, or chiral starting materials. Or by careful synthesis of the target chiral center.

In some embodiments of the invention, the opioid antagonist may be a μ-opioid antagonist. In other embodiments, the opioid antagonist may be a kappa-opioid antagonist. The present invention also relates to combinations of μ-opioid antagonists, combinations of κ-opioid antagonists and combinations of μ-opioid antagonists and κ-opioid antagonists, such as a combination of methylnaltrexone and albimopan. Administration of two or more opioid antagonists is also included.
In the illustrated embodiment, the inventors have found that methylnaltrexone and naltrexone significantly reduce protease inhibitor-induced nausea and vomiting. Methylnaltrexone and other peripheral inhibitory opioid antagonists generally do not affect sedation from opioid therapy, particularly when treated with protease inhibitors-induced nausea and vomiting Has clinical value.

  Nausea and vomiting symptoms were assessed using a rat dysphagia (pika) model, as described in later examples. Rats were exposed to a variety of non-nutrient-based vomiting-stimulated diets such as clay, a phenomenon called pika behavior. Thus, eating behavior in rats is similar to nausea and vomiting in humans and other species (Mitchell et al., 1976; Takeda et al., 1993). Eating behavior in rats is mediated by serotonin and dopamine-related mechanisms and receptors, as in humans and other species (Takeda et al., 1993; Takeda et al., 1995). The rat dysphagia model is widely used and has been validated in several studies testing antiemetics (Takeda et al., 1995; Aung et al., 2004). The dose-dependent food response induced by ritonavir has already been demonstrated (Aung et al., 2005). As demonstrated below, the inventors have demonstrated that treatment with methylnaltrexone and naltrexone significantly reduces ritonavir-induced dysphagia using the phagocytic model described above.

  In the treatment of rodents with methylnaltrexone, it has been suggested that methylnaltrexone can be partially metabolized by demethylation as measured by the breath 14CO2 test (Kotake et al., 1989). However, systemic methylnaltrexone administration does not antagonize morphine-induced analgesia in rats subjected to a radiant-heat tail-flick assay, and methylnaltrexone for morphine-induced reduction of gastrointestinal motility Was antagonizing in a dose-related manner (Gmerek et al., 1986). Plasma naltrexone levels after methylnaltrexone administration were measured using HPLC. No detectable naltrexone level was found at the highest methylnaltrexone dose, suggesting that methylnaltrexone was not demethylated at the dose tested.

The methods of the present invention generally use any medically acceptable mode of administration, eg, any mode that produces an effective amount of the active compound without causing clinically unacceptable adverse effects. Can be implemented. Such modes of administration include oral, rectal, topical (such as by powder, ointment, droplet, transdermal patch, or iontophoresis device), transdermal, sublingual, intramuscular, infusion, intravenous, lung Intramuscular, intracavitary, aerosol can be in the ear (eg, by ear drops), nasal, inhalation, intraocular or subcutaneous.
Furthermore, the opioid antagonist may be administered as an enteric-coated tablet or capsule. In certain embodiments, the opioid antagonist is administered by a slow infusion method, by a sustained or controlled release method, or as a lyophilized powder.

When administered, the compounds of the invention are administered in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions or formulations. Such formulations generally can contain salts, buffering agents, preservatives, and other therapeutic ingredients as optional ingredients.
When used in medicine, the salts should be pharmaceutically acceptable, but salts that are not pharmaceutically acceptable can be used for convenience to prepare the pharmaceutically acceptable salts and are within the scope of the present invention. It is not excluded from. Such pharmacologically acceptable and pharmaceutically acceptable salts include, but are not limited to, salts prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, Maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, succinic acid, naphthalene-2-sulfonic acid, pamonic acid, 3-hydroxy-2-naphthalenecarboxylic acid and benzenesulfonic acid .

Suitable buffering agents include, but are not limited to, acetic acid and its salts (1-2% (mass / volume)), citric acid and its salts (1-3% (mass / volume)), boric acid and There are its salts (0.5-2.5% (mass / volume)), and phosphoric acid and its salts (0.8-2% (mass / volume)).
Suitable preservatives include, but are not limited to, benzalkonium chloride (0.003-0.03% (mass / volume)), chlorobutanol (0.3-0.9% (mass / volume)), parabens (0.01-0.25). % (Mass / volume)), and thimerosal (0.004-0.02% (mass / volume)).

  For ease of administration, the opioid antagonist pharmaceutical composition may also contain one or more pharmaceutically acceptable excipients such as lubricants, diluents, binders, carriers and disintegrants. . Other auxiliaries include, for example, stabilizers, wetting agents, emulsifiers, salts to influence osmotic pressure; coloring, flavor and / or fragrance active compounds.

  A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, or any type of formulation aid. For example, suitable pharmaceutically acceptable carriers, diluents, solvents or vehicles include, but are not limited to: water: salt (buffer) solutions; alcohols; gum arabic; mineral and vegetable oils; benzyl alcohol; Gelatin; carbohydrates such as lactose, amylose or starch; magnesium stearate; talc; silicic acid; viscous paraffin; vegetable oil; fatty acid monoglyceride and diglyceride; pentaerythritol fatty acid ester; hydroxylmethyl cellulose; The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial agents, for example antibacterial or antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like.

When a pharmaceutically acceptable solid carrier is used, the dosage form of the compound suitable for use in the method of the invention can be a tablet, capsule, powder, suppository, or lozenge. When using a liquid carrier, soft gelatin capsules, transdermal patches, aerosol sprays, topical creams, syrups or liquid suspensions, emulsions or solutions may be in dosage form.
Particularly suitable for parenteral administration are sterile solutions for injection, preferably non-aqueous or aqueous solutions, as well as implants such as dispersions, suspensions or emulsions, or suppositories. Ampules are often convenient unit dosages. Injectable depot dosage forms may also be appropriate, produced by forming a microcapsule matrix of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides). Can do. Depending on the drug to polymer ratio and the nature of the particular polymer employed, the rate of drug release can be adjusted.
Particularly suitable for enteral administration are syrups or elixirs using sweetened vehicles, such as tablets, dragees, solutions, drops, suppositories, or capsules such as soft gelatin capsules. Can be used.

  As explained, other delivery systems can include sustained release, delayed release or sustained release delivery systems. Such systems can avoid repeated administration of the compounds of the invention, increasing convenience to patients and physicians and maintaining sustained plasma levels of the compounds. Many types of controlled release delivery systems are available and are known to those skilled in the art. Sustained or controlled release compositions can be formulated as compositions in which the liposomes or active ingredient are protected by microencapsulation, multilayer coating, etc., by a stepwise degradable coating. As such, the opioid antagonist according to the present invention can be administered as an enteric coated tablet or capsule. In certain embodiments, the opioid antagonist is administered by a slow infusion method or by a sustained or controlled release method or as a lyophilized powder.

  For example, the compounds of the present invention can be mixed with a pharmaceutically acceptable sustained release matrix such as a biodegradable polymer to prepare a therapeutic composition. Sustained release matrices, as used in the present invention, are matrices made from materials (usually polymers) that can be degraded by enzymatic or acid-base hydrolysis or by dissolution. When inserted into the body, the matrix acts according to enzymes and body fluids. The sustained release matrix is desirably a biocompatible material such as liposomes; polylactide (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymer of lactic acid and glycolic acid), polyanhydride , Poly (ortho) esters, polysaccharides, polyamino acids, hyaluronic acid, collagen, chondroitin sulfate, polynucleotides, polymer systems such as polyvinylpropylene, polyvinylpyrrolidone and silicone; carboxylic acids, fatty acids, phospholipids, amino acids, and Non-polymeric systems such as lipids (eg sterols); hydrogel release systems; silastic systems; peptide systems; Specific examples include, but are not limited to, (a) polysaccharides found in U.S. Pat.Nos. 4,452,775, 4,675,189, and 5,736,152 (incorporated herein in their entirety by reference) within the matrix. And (b) as described in U.S. Pat. Nos. 3,854,480, 5,133,974, and 5,407,686 (incorporated herein in their entirety by reference) There are diffusion systems in which the active ingredient penetrates from the polymer at a controlled rate. In addition, pump-based hard-wired delivery systems can be used, some of which are adapted for implantation. Suitable enteric coatings are described in PCT Publication WO 98/25613 and US Pat. No. 6,274,591, both incorporated herein by reference. Sustained or controlled release compositions may also be formulated as compositions in which the active ingredient is protected by microencapsulation, multilayer coating, etc., by a stepwise degradable coating.

  With particular reference to methylnaltrexone, an aqueous formulation may include a chelating agent, a buffer, an antioxidant, and an optional isotonic agent, preferably at a pH adjusted to 3.0-3.5. A formulation that is stable to autoclaving and long-term storage has been published as 2004/0266806 and is described in US patent application Ser. No. 10/821811 entitled “Pharmaceutical Formulation”; , Incorporated herein by reference. A formulation of methylnaltrexone with increased shelf life is also described in International Patent Publication WO 2008/19115 entitled “Formulations for Parenteral Delivery of Compounds and Uses Thereof”. To unite). Freeze-dried formulations of methylnaltrexone are described in US patent application Ser. No. 11 / 899,724, and formulations containing particles containing methylnaltrexone are described in US Pat. No. 6,419,959; Each is incorporated herein by reference. Formulations suitable for transdermal delivery of methylnaltrexone are described in International Patent Publication No. 2007/41544 (which is also incorporated herein by reference).

  In one embodiment, a compound of the invention maintains a minimum plasma level of an opioid antagonist, preferably a drug level according to a normal formulation, which provides the subject with a continuous dosage formulation of the compound to the subject. Administer in a regimen that eliminates spikes and troughs. Suitably, continuous administration may be achieved by administering the compound to a subject by any of the delivery methods disclosed herein, in principle daily or in principle controlled release. In one embodiment, continuous administration can be accomplished using continuous infusion to the subject or by a mechanism that facilitates release of the compound over time, such as by a transdermal patch or by a sustained release formulation. Suitably, the compounds of the present invention provide a subject plasma compound effective to inhibit or reduce nausea, vomiting and other adverse gastrointestinal effects induced by treatment with a protease inhibitor such as ritonavir. Release continuously in an amount sufficient to maintain concentration.

  The compounds according to the invention are administered in anti-nausea and anti-emetic effective amounts, either alone or in combination with other therapeutic agents. It should be understood, however, that the total dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular therapeutically effective dose level for any particular patient is the disorder to be treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the patient's age, weight, overall health, Gender and diet; administration time; route of administration; elimination rate of the particular compound used; duration of treatment; drugs used in conjunction with or in conjunction with the particular compound used; and similar factors well known in the medical arts It depends on various factors such as For example, one method is to start with a dose of the compound that is lower than that required to achieve the desired intellectual effect, and gradually increase the dose until the desired effect is obtained.

  If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Thus, a single dose composition may contain such an amount or about the amount that constitutes a daily dose. Those skilled in the art will be able to easily optimize effective dosages and combination dosage regimens (as described herein) as determined by good medical practice and individual patient clinical symptoms. .

  In general, oral dosages of the opioid antagonists, especially peripheral antagonists, range from about 0.01 to about 80 mg / kg body weight per day. It is expected that desired results will be obtained with oral doses in the range of 1-20 mg / kg body weight. In general, parenteral administration, such as intravenous and subcutaneous administration, ranges from about 0.001 to 5 mg / kg body weight. It is expected that desired results will be obtained with dosages in the range of 0.05-0.5 mg / kg body weight. Dosage may be adjusted appropriately to achieve the desired local or systemic amount of drug, depending on the mode of administration. For example, the oral dose of opioid antagonist in an enteric coating formulation is expected to be 10-30% of the non-coated oral dose. If the patient's response is insufficient with such a dose, a somewhat higher dose (or, effectively, a dose higher than 30% by a different, more localized transmission pathway) It can be used within the tolerance of patient tolerance. Multiple doses per day are intended to achieve the appropriate systemic level of compound. Appropriate system levels can be determined, for example, by measuring the patient's plasma drug levels using general HPLC methods known to those skilled in the art.

  In the illustrated embodiment of the invention, the opioid antagonist is administered in combination with an antiretroviral agent, eg, ritonavir or a combination of antiretroviral agents. The term “combination administration” is meant to refer to combination treatment by any route of administration in which two or more agents are administered to a patient or subject. Also, the combined administration of multiple drugs may be referred to as combination therapy or combination therapy. These agents can be present in the same dosage formulation or in separate formulations. In combination therapy with two or more active agents, if these active agents are present in separate dosage formulations, these active agents may be administered simultaneously, or these active agents may be administered separately with a time lag. May be. These agents can be administered simultaneously or sequentially (for example, one agent can be administered as long as both agents are administered in a form sufficient to allow both agents to achieve effective concentrations in the body). These drugs may follow immediately after administration of other drugs, or these drugs may be administered separately, for example, one drug is administered at a time, followed by another drug at a later time, eg, one week Or may be administered in). These agents may also be administered by different routes, for example, one agent is administered intravenously while the second agent is administered intramuscularly, intravenously or orally. In other words, administration of an opioid antagonist compound according to the present invention, e.g., ritonavir or a combination of ritonavir and one or more other protease inhibitors, suitably comprises an opioid antagonist and a protease inhibitor, e.g. A combination pharmaceutical formulation comprising ritonavir or a combination of protease inhibitors, such as ritonavir and other protease inhibitors, wherein the formulation is a daily or intermittent administration of a peripheral opioid antagonist, and a protease Inhibitors, such as ritonavir, are considered to be adapted for daily or intermittent administration. Thus, the opioid antagonist may be administered before, simultaneously with, or after administration of a protease inhibitor, such as ritonavir. In the illustrated embodiment, particularly suitable is administration of an opioid antagonist prior to administration of ritonavir.

Agents that can be co-administered can also be formulated, for example, as a single formulation or as a mixture as in a single tablet. These formulations can be parenteral or oral, such as, for example, those described in US Pat. Nos. 6,277,384; 6,261,599, 5,958,452; and PCT Publication WO 98/25613; Each of the US patents and the like is incorporated herein by reference.

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
(Example)

Example 1 Animal Model Rats for Nausea Responds to vomiting stimuli due to changes in eating habits that manifest as increased intake of non-nutrients such as kaolin (a type of clay), known as dysphagia ( Mitchell et al., 1976; Takeda et al., 1993; Takeda et al., 1995). The inventor has quantified kaolin intake in laboratory animals as a measure of nausea and observed that drug-induced food intake can be reduced by selected drugs (Aung et al., 2003; Aung et al., 2005).
The experimental protocol described herein was approved by the Institutional Animal Care and Use Committee or IACUC at the University of Chicago.

Example 2 In vivo test Adult male rats weighing 150-300 g (Harlan Sprague Dawley, Indianapolis, IN) were used. All animals were enclosed in standard isolation cages (45 cm x 35 cm x 25 cm) in environmentally controlled conditions with a 12 hour light / 12 hour dark cycle. Each rat had free access to water, standard rat diet (Harlan-Teklad, Madison, Wis.) And kaolin (see below) in separate containers available continuously throughout the study. .
There was an acclimatization period of 3 days before the start of observation (day 0).

Preparation of kaolin Kaolin pellets were produced based on previously disclosed methods (Mitchell et al., 1976; Takeda et al., 1995). In short, 99 g of pharmacological grade kaolin (ie hydrated aluminum silicate; Fisher, Fairlawn, NJ) is mixed with 1 g of Acacia (Fisher), ie in a 99: 1 ratio, with distilled water. A thick paste was prepared. The kaolin paste was rolled on a stainless steel tray and cut into sections of the same shape and size as regular rat feed pellets. The pellet was placed on a steel tray and allowed to dry completely at room temperature for 72 hours.

Measurement of food intake behavior (kaolin intake) Ritonavir is a protease inhibitor used by rats, and rats were divided into 4 groups. There were 6-7 rats in each of the four groups: vehicle + vehicle, vehicle + ritonavir, naloxone + ritonavir, and methylnaltrexone + ritonavir. Rats received ritonavir, 20 mg / kg (Abbott Laboratories, Inc., North Chicago, Ill.) By oral gavage tube for two consecutive mornings (0 and 24:00) (Denissen et al., 1997 Yamaji et al., 1999; Shibata et al., 2002). Pretreatment of vehicle, naloxone 0.1 mg / kg or 0.3 mg / kg (Sigma, St. Louis, MO), or methylnaltrexone 0.3 mg / kg, 1.0 mg / kg or 3.0 mg / kg (Mallinckrodt Chemicals, St. Louis, MO) Was administered intraperitoneally 30 minutes prior to 20 mg / kg ritonavir (Aung et al., 2003). Each rat was directly observed for signs of pain such as emotional anxiety, dyspnea or diarrhea after study drug administration at 15 minutes, 2 hours and daily thereafter.

  During the trial, kaolin and feed pellets were weighed to the nearest 0.1 g and the remaining kaolin and feed from the previous day were collected and then replaced in the container at the same time every morning. Kaolin and feed intake were measured every 24 hours for 5 days. Kaolin and feed pellets were weighed to the nearest 0.1 g and placed in a container in the cage every morning. Residual kaolin and feed from the previous day were collected, dried for 72 hours and weighed. Daily kaolin and feed intake was measured for 5 days after the first ritonavir treatment.

Blood Sample Collection In one study, a blood sample was collected to determine plasma naltrexone levels, ie, an indication of possible demethylation of methylnaltrexone (Kotake et al., 1989). Rats were restrained and the tail vein was exposed. The tail was immersed in warm water to help dilate the blood vessels. A small rubber band was placed around the base of the tail. Blood samples were collected using microhematocrit tubes inserted into small needle hubs placed intravenously. Blood samples were taken at 0 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes or 120 minutes after the first dose of methylnaltrexone.

Measurement of naltrexone and methylnaltrexone concentrations Plasma naltrexone and methylnaltrexone levels were measured by high performance liquid chromatography (HPLC) adapted from previously reported methods (Osinski et al., 2002). Naltrexone and methylnaltrexone were separated from plasma by solid phase extraction (SPE). Plasma samples (100-200 μl) diluted in water were passed through a SPE column (Varian CBA column, 100 mg; Harbor City, Calif.) Conditioned with n-propanol and water. The analyte was eluted from the column with a mixture of n-propanol prepared in a 2: 1 ratio and trifluoroacetic acid (25 mM) in aqueous solution. The eluate was evaporated to dryness in a stream of nitrogen at 55 ° C. The residue was reconstituted in the mobile phase, filtered through a nylon HPCL syringe filter and subjected to analysis. In HPLC analysis, electrochemical detectors have high sensitivity in automated analytical chromatography of electroactive compounds. HPLC system (Shimadzu Corporation; Kyoto, Japan) and electrochemical detector (ESA Coulochem, model 5100A; Chelmsford, Mass.) Equipped with LC-10AD pump, SCL-10A system controller, and sample cooler It consisted of a SIL-10A autoinjector. The electrochemical detector was run at the following settings: Detector 1, +360 mV; Detection 2, +600 mV; guard cell, +650 mV. Data was collected using EZChrom 2-2 HPLC software. In the mobile phase, sodium phosphate 30 mM, sodium acetate 20 mM, methanol 6%, tetrahydrofuran 1% and pH 4.2 were used. The system was calibrated daily in the range of 5-100 ng / mL. The practical detection limit in plasma samples was about 2 ng / mL (100 pg / infusion).

Statistical analysis data were expressed as mean ± standard error (SE). The area under the concentration curve (AUC) was calculated. Data were analyzed using two-way analysis of variance (ANOVA) with groups and time as two factors. Statistical significance was considered to be P <0.05.
The results of the above test will be described below.

Effect of naloxone on ritonavir-induced nausea and vomiting In saline-treated rats, less than 1.0 g of kaolin was ingested daily for 5 consecutive days. After administration of 10 or 20 mg / kg oral ritonavir, kaolin intake increased significantly in a dose-related manner from 24 to 48 hours (FIG. 2; P <0.01). At 30 mg / kg, kaolin intake has not increased further, suggesting a possible toxic effect at higher doses, supported by a decrease in feed intake. The ritonavir dose used in this study was 20 mg / kg.
FIG. 3 shows that the ritonavir-induced increase in kaolin intake is mitigated by pretreatment with naloxone of 0.1 or 0.3 mg / kg (P <0.01). The area under the curve (AUC) for kaolin intake from time 0 to 120 hours was as follows: vehicle + vehicle, 87 ± 8.1 g · hr; 0.3 mg / kg naloxone + vehicle, 86 ± 9.2 g · hr Vehicle + ritonavir, 351 ± 18.2 g · hr; 0.1 mg / kg naloxone + ritonavir, 264 ± 16.7 g · hr; and 0.3 mg / kg naloxone + ritonavir, 205 ± 11.3 g · hr (FIG. 4). Naloxone significantly reduced kaolin intake induced by ritonavir (P <0.01 compared to vehicle). Naloxone (0.3 mg / kg) alone did not significantly affect kaolin intake.

Effect of methylnaltrexone on ritonavir-induced nausea and vomiting The effect of pretreatment with methylnaltrexone on kaolin intake after ritonavir is shown in FIG. Kaolin intake induced by ritonavir is mitigated in a dose-dependent manner by methylnaltrexone (P <0.01). The AUC for kaolin intake from time 0 to 120 hours was as follows: vehicle + vehicle, 92 ± 8.6 g · hr; vehicle + ritonavir, 360 ± 15.7 g · hr; methylnaltrexone (0.3 mg / kg) + Ritonavir, 302 ± 13.2 g · hr; methylnaltrexone (1.0 mg / kg) + ritonavir, 242 ± 14.9 g · hr; and methylnaltrexone (3.0 mg / kg) + ritonavir, 168 ± 11.5 g · hr (Figure 6) ).
Kaolin intake was not significantly affected by methylnaltrexone alone (3.0 mg / kg). In all test groups, feed intake was not significantly affected.

HPLC analysis of naltrexone No detectable naltrexone was found in relation to methylnaltrexone (3.0 mg / kg). In contrast, methylnaltrexone levels were detected after its administration. The chromatogram is shown in FIG. However, at all measurement time points, naltrexone levels were not detected as shown in (B) and (C).
In summary, the present invention addresses drug-induced gastrointestinal side effects such as nausea and vomiting induced by antiretroviral agents such as protease inhibitors, and opioid antagonists, particularly peripheral inhibitory opioid antagonists such as methylnaltrexone. To provide a method of treatment using

The present invention has now been described with reference to various specific embodiments and methods. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
All publications, patents and patent applications are hereby expressly incorporated by reference as if each individual publication, patent or patent application was shown in detail and individually as a reference. Combine. In case of conflict between patents, publications and literature combined with this disclosure, the present disclosure should control.

References

Claims (24)

  Administer sufficient amounts of opioid antagonists to treat drug-induced gastrointestinal side effects in combination with the antiretroviral agent to patients suffering from adverse gastrointestinal side effects associated with treatment with antiretroviral agents A method for treating adverse gastrointestinal side effects associated with treatment with an antiretroviral agent.   The method of claim 1, wherein the side effect is nausea or vomiting or both.   2. The method of claim 1, wherein the opioid antagonist is administered prior to administering the antiretroviral agent.   The method of claim 1, wherein the antiretroviral agent is a protease inhibitor.   The method of claim 4, wherein the protease inhibitor is ritonavir.   The method of claim 1, wherein the opioid antagonist is naloxone.   The method of claim 1, wherein the opioid antagonist is a peripheral opioid antagonist.   8. The method of claim 7, wherein the peripheral opioid antagonist is methylnaltrexone.   8. The method of claim 7, wherein the peripheral opioid antagonist is a piperidine-N-alkylcarboxylate compound.   8. The method of claim 7, wherein the peripheral opioid antagonist is a quaternary morphinan compound.   The quaternary morphinan compound is selected from the group consisting of N-methylnaltrexone, N-methylnaloxone, N-methylnalorphine, N-diallylnormorphine, N-allyllevororphan, and N-methylnalmefene 11. The method of claim 10, comprising a quaternary salt of   The method of claim 1, wherein the opioid antagonist is a μ-opioid antagonist, a κ-opioid antagonist, or a combination thereof.   A method for treating adverse gastrointestinal side effects associated with the administration of antiretroviral agents to HIV-infected human subjects, said antiretrovirus being ritonavir or a combination of ritonavir and other protease inhibitors The method of treatment, comprising administering together an effective amount of a protease inhibitor and an effective amount of an opioid antagonist to treat the adverse side effects.   14. The method of claim 13, wherein the adverse side effect is nausea, vomiting, diarrhea, abdominal pain, or a combination thereof.   14. The method of claim 13, wherein the opioid antagonist is a quaternary morphinan compound.   The quaternary morphinan compound is selected from the group consisting of N-methylnaltrexone, N-methylnaloxone, N-methylnalorphine, N-diallylnormorphine, N-allyllevororphan, and N-methylnalmefene 16. The method of claim 15, comprising a quaternary salt of   The process according to claim 16, wherein the quaternary salt of the quaternary morphinan compound is N-methylnaltrexone.   Method of treating nausea and vomiting after administration to an HIV-infected patient in need of an effective amount of ritonavir or a combination of ritonavir and another protease inhibitor, characterized by administering an effective amount of an opioid antagonist .   19. The method of claim 18, wherein the opioid antagonist is administered prior to administering the combination with the ritonavir or other protease inhibitor.   19. The method of claim 18, wherein administration of the opioid antagonist is oral, sublingual, intramuscular, subcutaneous, intravenous, and transdermal.   21. The method of claim 20, wherein administration is oral.   The method of claim 18, wherein the opioid antagonist is methylnaltrexone.   The effective amount of methylnaltrexone is about 0.001 mg / kg body weight to about 80 mg / kg body weight per day, about 0.05 mg / kg body weight to about 50 mg / kg body weight per day, or about 1 mg / kg body weight to about 20 mg / kg body weight per day. 23. The method of claim 22, wherein   A method of treating a retroviral infection in a human subject in need of such treatment, comprising an antiretroviral amount of ritonavir or a combination of ritonavir with another protease inhibitor and ritonavir or a combination-induced property in said subject The method of treatment, comprising administering an opioid antagonist in an amount effective to attenuate the frequency and / or severity of gastrointestinal side effects.

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