Use of orexin 2 receptor agonists for postoperative recovery

Abstract

A method of post-operative recovery in a subject in need thereof is disclosed, the method comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)), or a salt thereof.

Description

[Technical field]

[0001] Certain embodiments of the present invention relate to the use of orexin type 2 receptor agonists for post-operative recovery (amelioration of delayed consciousness after maintenance of anesthesia, and amelioration of opioid-induced sedation and respiratory depression). [Background technology]

[0002] Currently, there is no drug that shortens the time required for recovery from anesthesia. To suppress pain during the postoperative period, an appropriate amount of analgesics, especially opioids, is usually used. However, the side effects associated with opioids, such as sedation and respiratory depression, may limit the use of opioids after surgery (Non-Patent Document 1). Opioid antagonists such as naloxone are widely used when opioid-induced severe sedation and respiratory depression are observed. However, opioid antagonists reduce not only these side effects but also the analgesic effect of opioids. Therefore, there is a need for a drug that accelerates the recovery time from anesthesia and suppresses opioid-induced side effects while maintaining the analgesic effect of opioids.

[0003] The orexin system plays an important role in controlling sleep / wake states (Non-Patent Document 2). There are two postsynaptic G protein-coupled receptors for orexin peptides: orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) (Non-Patent Document 3). Of these two receptors, OX2R is thought to play a crucial role in sleep / wake regulation, since abnormal sleep cycles are observed in OX2R KO mice but not in OX1R KO mice (Non-Patent Document 2). As an orexin 2 receptor agonist, methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (compound (I)) has been disclosed (Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special WO2017 / 135306 A1 [Non-patent literature]

[0005] [Non-Patent Document 1] Sleep Med Rev 11(2007)35-46

[0006] [Non-Patent Document 2] Pharmacol Rev 61(2009)162-176

[0007] [Non-Patent Document 3] Cell92(1998)573-585 Summary of the Invention [Problem to be solved by the invention]

[0008] Disclosed herein is a method for post-operative recovery (improving delayed emergence after maintenance of anesthesia and improving opioid-induced sedation and respiratory depression) in a subject in need thereof, the method comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)), or a salt thereof. [Means for solving the problem]

[0009] The present inventors have found that compound (I) in the present specification is useful for postoperative recovery (improving delayed consciousness after maintenance of anesthesia, and improving opioid-induced sedation and respiratory depression). As a result of further research, the present invention has been completed.

[0010] Therefore, the present invention includes the following embodiments.

[0011] [1] A method of post-operative recovery in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)), or a salt thereof.

[0012] [2] A method for enhancing recovery from anesthesia or shortening recovery time in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)) or a salt thereof.

[0013] [3] A method for preventing or treating postoperative respiratory disorder / respiratory depression or opioid-induced respiratory disorder / respiratory depression in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)) or a salt thereof.

[0014] [4] A method for reducing opioid side effects in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)), or a salt thereof.

[0015] [5] A method for preventing or treating post-operative sedation or opioid-induced sedation in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)), or a salt thereof.

[0016] [6] The method according to any one of [1] to [5], wherein the administration is parenteral administration.

[0017] [7] The method according to [6], wherein the parenteral administration is intravenous administration (also called IV), subcutaneous administration (also called SC), transdermal administration or transmucosal administration.

[0018] In other embodiments, the present invention relates to the following:

[0019] [8] A method for promoting emergence from anesthesia in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)), or a salt thereof.

[0020] [9] A method for preventing delayed emergence from anesthesia in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)) or a salt thereof.

[0021]

[10] Improving pain management in a subject suffering from pain by addressing the reduction in opioid side effects. A method for improving pain management in a subject suffering from pain by addressing the reduction in opioid side effects in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)), or a salt thereof.

[0022]

[11] A method for improving pain management in a subject during post-operative recovery by addressing the reduction in opioid side effects in a subject in need thereof, comprising administering to the subject an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)) or a salt thereof.

[0023] The present invention further relates to the following embodiments:

[0024] [1a] Use of compound (I) or a salt thereof for postoperative recovery.

[0025] [2b] Use of compound (I) or a salt thereof for promoting recovery or shortening recovery time from anesthesia.

[0026] [3c] Use of compound (I) or a salt thereof for preventing or treating postoperative respiratory depression / depression or opioid-induced respiratory depression / respiratory depression.

[0027] [4d] Use of compound (I) or a salt thereof for reducing the side effects of opioids.

[0028] [5e] Use of compound (I) or a salt thereof for the prevention or treatment of postoperative sedation or opioid-induced sedation.

[0029] The present invention further relates to the following embodiments:

[0030] [1aa] A pharmaceutical composition for postoperative recovery comprising compound (I) or a salt thereof.

[0031] [2bb] A pharmaceutical composition for promoting recovery from anesthesia or shortening recovery time, comprising compound (I) or a salt thereof.

[0032] [3cc] A pharmaceutical composition for preventing or treating postoperative respiratory disorder / respiratory depression or opioid-induced respiratory disorder / respiratory depression, comprising compound (I) or a salt thereof.

[0033] [4dd] A pharmaceutical composition for reducing the side effects of opioids, comprising compound (I) or a salt thereof.

[0034] [5ee] A pharmaceutical composition for preventing or treating postoperative sedation or opioid-induced sedation, comprising compound (I) or a salt thereof. Effect of the Invention

[0035] Compound (I) in the present specification has orexin type 2 receptor agonist activity and is useful for postoperative recovery (improvement of delayed consciousness after maintenance of anesthesia, and improvement of opioid-induced sedation and respiratory depression). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Disclosed herein are methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound (I)) or a salt thereof, compositions and kits comprising Compound (I) or a salt thereof, and methods of using Compound (I) or a salt thereof.

[0037] The definitions of each term used in this specification are set out in detail below.

[0038] As used herein, examples of "post-operative recovery" include "accelerating recovery from anesthesia," "reducing recovery time from anesthesia," "prevention or treatment of post-operative respiratory disorder / respiratory depression," "prevention or treatment of opioid-induced respiratory disorder / respiratory depression," "prevention or treatment of post-operative sedation," and "prevention or treatment of opioid-induced sedation." In some embodiments, "post-operative recovery" refers to "post-operative recovery" or "post-operative recovery."

[0039] In some embodiments, "post-operative" means "after an operation," "after an operation," or "after surgery." In some embodiments, "post-operative" means "after surgery."

[0040] In some embodiments, "anesthesia" is induced by an anesthetic. Examples of anesthetics include inhalational anesthetics and intravenous anesthetics. Examples of inhalational anesthetics include isoflurane, enflurane, methoxyflurane, sevoflurane, desflurane, halothane, and any combination thereof. Examples of intravenous anesthetics include propofol, thiopental, thiamylal, midazolam, flumazenil, ketamine, dexmedetomidine (hydrochloride), droperidol, etomidate, and any combination thereof. The anesthetic is used in an amount effective to induce anesthesia. These amounts are appropriately determined depending on the purpose and type of the anesthetic, the route of administration of the anesthetic, the subject of administration, and the like.

[0041] As used herein, examples of "postoperative respiratory disorder / depression" include hypoxemia, hypoxia, and hypercapnia. In some embodiments, hypoxemia is defined as a peripheral oxygen saturation (SpO2) of up to 90%.

[0042] As used herein, examples of "opioid side effects" include respiratory depression / respiratory depression and sedation. Examples of respiratory depression / respiratory depression include hypoxemia, hypoxia, and hypercapnia. In some embodiments, the respiratory depression / respiratory depression is post-operative respiratory depression / respiratory depression. In some embodiments, the sedation is post-operative sedation.

[0043] In the present specification, examples of "opioids" include fentanyl, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, buprenorphine, pethidine, pentazocine, doxapram, and any combination thereof. The opioids are used in effective amounts for pain management or pain control during surgery (or surgery). These amounts are appropriately determined depending on the purpose and type of opioid, the route of administration of the opioid, the subject of administration, etc.

[0044] As used herein, examples of "opioid side effects" include respiratory depression / respiratory depression and sedation. Examples of respiratory depression / respiratory depression include hypoxia and hypercapnia. In some embodiments, the respiratory depression / respiratory depression is post-operative respiratory depression / respiratory depression. In some embodiments, the sedation is post-operative sedation.

[0045] In some embodiments, compound (I) is an optically active compound. In some embodiments, compound (I) is methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound A) in any of the methods, uses, and pharmaceutical compositions disclosed herein. Compound (I), including its salts and optically active compounds, can be prepared as disclosed in WO2017 / 135306. In any of the uses and pharmaceutical compositions disclosed herein, compound (I) is used in an effective amount.

[0046] In some embodiments, the effective amount is about 3 mg to about 500 mg. In some embodiments, the effective amount is about 5 mg to about 300 mg. In some embodiments, the effective amount is about 5 mg to about 100 mg. In some embodiments, the effective amount is about 5 mg to about 50 mg.

[0047] Compound (I) (hereinafter, sometimes simply referred to as the compound of the present invention) can be used as it is, or can be mixed with a pharmacologically acceptable carrier or the like in the form of a pharmaceutical composition (also called a drug) and administered to mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys).

[0048] As the pharmacologically acceptable carrier, various organic or inorganic carrier substances that have been conventionally used as pharmaceutical materials can be used. These are blended as excipients, lubricants, binders, and disintegrants in solid preparations, and as solvents, solubilizers, suspending agents, isotonicity agents, buffers, sedatives, etc. in liquid preparations. In addition, additives for preparations such as preservatives, antioxidants, colorants, and sweeteners can be added as necessary.

[0049] Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminum metasilicate.

[0050] Preferred examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.

[0051] Preferred examples of binders include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

[0052] Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.

[0053] Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

[0054] Preferred examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

[0055] Preferred examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates; and polyoxyethylene hydrogenated castor oil.

[0056] Preferred examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.

[0057] Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.

[0058] Preferred examples of sedatives include benzyl alcohol.

[0059] Preferred examples of the preservative include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

[0060] Preferred examples of antioxidants include sulfites and ascorbates.

[0061] Preferred examples of the coloring agent include water-based edible coal-tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-based edible coal-tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide), and the like.

[0062] Preferred examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame and stevia.

[0063] Examples of the dosage form of the pharmaceutical composition include parenteral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, and buccal tablets), capsules (including soft capsules and microcapsules), tablet pills, granules, powders, troches, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal adhesive films, etc.), and parenteral preparations such as injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), external preparations (transdermal preparations, ointments, lotions, patches, etc.), suppositories (rectal suppositories, vaginal suppositories, etc.), pellets, nasal drops, pulmonary preparations (inhalants), and eye drops. The compounds and pharmaceutical agents of the present invention can each be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, subcutaneously, intraorgan, intranasally, intradermally, by instillation, intracerebrally, intravaginally, intraperitoneally, intratumorally, proximal to a tumor, and to a lesion).

[0064] These formulations may be immediate release formulations, sustained release formulations, or controlled release formulations (eg, sustained release microcapsules).

[0065] This pharmaceutical composition can be produced according to a method conventionally used in the field of pharmaceutical preparations, such as the method described in the Japanese Pharmacopoeia.

[0066] The content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.

[0067] When preparing oral preparations, coatings may be applied as necessary for the purposes of taste masking, enteric properties, and durability.

[0068] Examples of coating bases used for coating include sugar coating bases, water-soluble film coating bases, enteric film coating bases and sustained release film coating bases.

[0069] As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination.

[0070] Specific examples of water-soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], and polyvinylpyrrolidone; and polysaccharides such as pullulan.

[0071] Specific examples of enteric film coating bases include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (trade name)], and methacrylic acid copolymer S [Eudragit S (trade name)]; and natural products such as shellac.

[0072] Specific examples of sustained-release film coating bases include cellulose polymers such as ethyl cellulose, and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS (trade name)) and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE (trade name)).

[0073] The above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. In addition, a light-shielding agent such as titanium oxide or red ferric oxide may be used during coating.

[0074] The compounds of the present invention have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and therefore can be used as preventive, therapeutic, and diagnostic agents for various diseases in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats).

[0075] In addition, the compounds of the present invention are expected to have excellent central nervous system penetration properties.

[0076] Examples of subjects used in the methods or uses of the present invention include mammals such as humans, cows, horses, dogs, cats, monkeys, mice and rats, preferably humans. In some embodiments, the subject is at high risk of Obstructive Sleep Apnea (OSA) or has OSA after surgery requiring general anesthesia.

[0077] The dosage of the compound of the present invention varies depending on the subject, route of administration, target disease, symptoms, etc., but for example, when the compound of the present invention is orally or parenterally administered to an adult patient, the dosage is, for example, about 0.01 to 100 mg / kg body weight per dose, preferably 0.1 to 50 mg / kg body weight per dose, more preferably 0.5 to 20 mg / kg body weight per dose. This amount is preferably administered in 1 to 3 doses per day. In some embodiments, the compound of the present invention is administered after administration of an opioid as an analgesic after surgery (or surgical operation).

[0078] In some embodiments, the methods of the invention comprise the steps of administering:

[0079] Prior to the operation (or surgery), the subject is administered an effective amount of an anesthetic to induce anesthesia, and then after the operation (or surgery), the subject is administered an effective amount of Compound (I) or a salt thereof.

[0080] In some embodiments, the methods of the invention comprise the steps of administering:

[0081] Prior to the operation (or surgery), an effective amount of an anesthetic to induce anesthesia is administered to the subject, and after the operation (or surgery), an effective amount of Compound (I) or a salt thereof is administered to the subject, and then an effective amount of an opioid is administered to the subject.

[0082] In some embodiments, the methods of the invention comprise the steps of administering:

[0083] Prior to surgery (or a surgical procedure), an effective amount of an anesthetic to induce anesthesia is administered to the subject, and after surgery (or a surgical procedure), an effective amount of Compound (I) or a salt thereof is administered to the subject, an effective amount of an opioid is administered to the subject, and then an effective amount of Compound (I) or a salt thereof is administered.

[0084] The compound of the present invention can be used in combination with other drugs (hereinafter, abbreviated as concomitant drugs).

[0085] By combining the compound of the present invention with a concomitant drug, for example, the following excellent effects can be obtained.

[0086] (1) The dosage can be reduced compared to when the compound of the present invention or a concomitant drug is administered alone.

[0087] (2) Drugs to be used in combination with the compounds of the present invention can be selected depending on the condition of the patient (mild, severe, etc.).

[0088] (3) By selecting a concomitant drug having an action and mechanism different from that of the compound of the present invention, the treatment period can be set longer.

[0089] (4) By selecting a concomitant drug having an action and mechanism different from that of the compound of the present invention, a sustained therapeutic effect can be designed.

[0090] (5) A synergistic effect can be obtained by using the compound of the present invention in combination with a concomitant drug.

[0091] In this specification, the compound of the present invention and a concomitant drug used in combination are referred to as the "concomitant drug of the present invention."

[0092] When the combination drug of the present invention is used, the administration time of the compound of the present invention and the combination drug is not limited, and the compound of the present invention or a pharmaceutical composition thereof, or the combination drug or a pharmaceutical composition thereof may be administered to the subject at the same time or at different times. The dosage of the combination drug may be determined according to the dosage used clinically, and can be appropriately selected depending on the subject, administration route, disease, combination, etc.

[0093] The administration form of the combination agent and combination drug of the present invention is not particularly limited, as long as the compound of the present invention and the combination drug are combined at the time of administration. Examples of such administration forms include the following.

[0094] (1) Administration of a single preparation obtained by simultaneous processing of the compound of the present invention and the concomitant drug; (2) Simultaneous administration of two types of preparations of the compound of the present invention and the concomitant drug that have been separately manufactured by the same administration route; (3) staggered administration of two types of preparations of the compound of the present invention and the concomitant drug that have been separately manufactured by the same administration route; (4) Simultaneous administration of two types of preparations of the compound of the present invention and the concomitant drug that have been separately manufactured by different administration routes; (5) staggered administration of two types of preparations of the compound of the present invention and the concomitant drug that have been separately manufactured by different administration routes (e.g., administration of the compound of the present invention and the concomitant drug in the same order, or in the reverse order), etc.

[0095] The dosage of the concomitant drug can be appropriately determined based on the dosage used in clinical situations. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptoms, combination, etc.

[0096] For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, and is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight, based on the total formulation.

[0097] For example, the content of the concomitant drug of the present invention in the concomitant preparation of the present invention varies depending on the form of the preparation, and is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight based on the total preparation.

[0098] The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the formulation, and is usually about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight, based on the formulation.

[0099] Even when the compound of the present invention and the concomitant drug are formulated separately, the same contents can be employed.

[0100] Examples of concomitant medications include the following: narcolepsy medications (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drugs (amphetamine, benzphetamine, bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, phendimetrazine, phenmetrazine, phentermine, Qunexa®, phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), anti-dementia agents (e.g., memantine), inhibitors of the production, secretion, accumulation, aggregation and / or deposition of beta-amyloid protein, beta-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydrocannabinol, tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-N,N-diethylamino]ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N -dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, their optically active forms, their salts and their hydrates,OM99-2 (WO01 / 00663), gamma secretase inhibitors, beta amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (national publication of International Patent Application No. 11-514333), PPI-558 (national publication of International Patent Application No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289), beta-amyloid vaccines, beta-amyloid decomposing enzymes, brain function enhancers (e.g., aniracetam, nicergoline), Parkinson's disease treatment drugs [(e.g., dopamine receptor agonists (e.g., L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline, remamide, rilozoline, anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone), drugs for treating amyotrophic lateral sclerosis (e.g., riluzole, neurotrophic factors), drugs for treating abnormal behaviors associated with the progression of dementia and wandering (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), neurodifferentiation and regeneration promoters (e.g., leteprinim, xaliproden; SR-57746-A), SB -216763, Y-128, VX-853, prosapeptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2, 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active substances, salts, or hydrates), non-steroidal anti-inflammatory agents (e.g., meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin), steroid agents (e.g., dexamethasone, hexestrol, cortisone acetate),Disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), drugs for treating incontinence and frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine), phosphodiesterase inhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or derivatives thereof (e.g., progesterone, estradiol, estradiol benzoate), osteoporosis treatment agents (e.g., Alfacalcidol, calcitriol, ercatriol, calcitonin, salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, drugs for treating insomnia (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, orexin receptor antagonists), drugs for treating schizophrenia (e.g., typical antipsychotics such as haloperidol; clozapine, olanzapine) , atypical antipsychotics such as risperidone, aripiprazole; drugs acting on metabotropic glutamate receptors or ionotropic glutamate receptors; phosphodiesterase inhibitors), benzodiazepines (chlordiazepoxide, diazepam, clorazepate potassium, lorazepam, clonazepam, alprazolam, etc.), L-type calcium antagonists (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.) ), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT, 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonist, 5-HT2A Inverse agonists, 5-HT3 antagonists (such as cyamemazine), cardiac nonselective beta inhibitors (propranolol hydrochloride, oxprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saledant, etc.), medicines acting on metabolic glutamate receptors, CCK antagonists, beta3 adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium antagonists, carbonic anhydrase II inhibitors, N MDA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), bipolar disorder medications (lithium carbonate, sodium valproate, lamotrigine, rilozole, etc.) ol, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), drugs for treating alcoholism, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia syndrome, drugs for treating headaches, drugs for treating smoking cessation, drugs for treating myasthenia gravis, drugs for treating cerebral infarction, drugs for treating mania, drugs for treating hypersomnia, drugs for treating pain, drugs for treating intractable disorders, drugs for treating autonomic nervous system imbalances, drugs for treating male and female dysfunction, drugs for treating migraines, drugs for treating pathological gamblers, drugs for treating restlessness Drugs for chronic hepatitis, drug addiction, drug for alcohol-related syndrome, drug for irritable bowel syndrome, drugs for dyslipidemia such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.)), fibrates (clofibrate, etc.), squalene synthase inhibitors), agents for suppressing abnormal behavior and abnormal odor due to dementia (sedatives, anti-anxiety drugs, etc.), drugs for diabetes, drugs for diabetic complications, drugs for hypertension, drugs for hypotension, diuretics, chemotherapy drugs, immunotherapy drugs, antithrombotic drugs, anticancer drugs, etc.

[0101] The above-mentioned concomitant drugs may be used in combination of two or more kinds in an appropriate ratio.

[0102] The compounds of the present invention may be used in combination with biological preparations (e.g., antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), in combination with gene therapy methods, or in combination with psychiatric treatments without the use of drugs.

[0103] Examples of non-pharmacological psychiatric treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy, including cognitive behavioral therapy.

[0104] The effects of Compound (I) as typified by "postoperative recovery," "promoting recovery from anesthesia," "shortening recovery time from anesthesia," "prevention or treatment of postoperative respiratory disorder / respiratory depression," "prevention or treatment of opioid-induced respiratory disorder / respiratory depression," "reduction of opioid side effects," "prevention or treatment of postoperative sedation," and "prevention or treatment of opioid-induced sedation" are evaluated or assessed by the methods shown in the experimental examples of this specification.

[0105] In some embodiments, respiratory disorder / depression is assessed by whole body plethysmography (WBP), which assesses respiratory parameters such as respiratory rate (RR), tidal volume (TV), and minute ventilation (MV). In some embodiments, respiratory disorder / depression is assessed by arterial oxygen saturation (SaO2), peripheral (or transcutaneous) oxygen saturation (SpO2), end-tidal carbon dioxide tension (PETCO2), or any combination thereof.

[0106] In some embodiments, sedation is assessed by the Richmond Agitation-Sedation Scale (RASS), the Ramsay sedation scale (RSS), the Modified Observer's Assessment of Alertness, Sedation Scale (MOAAS), or any combination thereof.

[0107] As shown in the following experimental examples, compound (I) does not affect or counteract the analgesic effect of opioids. Therefore, compound (I) is extremely useful in the methods of "preventing or treating opioid-induced respiratory depression / respiratory disorder", "reducing opioid side effects", and / or "preventing or treating opioid-induced sedation".

[0108] Similar to compound (I), other orexin receptor agonists can be used in the subject postoperative recovery method. As the orexin receptor agonist, the compounds disclosed in the following documents can be used (WO2017 / 135306, WO2018 / 164191, WO2018 / 164192, WO2019 / 027003, WO2019 / 027058, WO2020 / 004536, WO2020 / 004537, WO2020 / 122092, WO2020 / 122093, WO2020 / 158958, WO2020 / 167701, WO2020 / 167706, WO2021 / 026047).

[0109] Among the orexin receptor agonists, orexin 2 receptor selective agonists are preferred. Orexin 2 receptor selective agonists are compounds that have orexin 2 receptor agonist activity that is more than 200 times greater than orexin 1 receptor agonist activity. More preferably, orexin 2 receptor selective agonists are compounds that have orexin 2 receptor agonist activity that is more than 500 times greater than orexin 1 receptor agonist activity. More preferably, orexin 2 receptor selective agonists are compounds that have orexin 2 receptor agonist activity that is more than 1000 times greater than orexin 1 receptor agonist activity.

[0110] In some embodiments, Compound (I) or a salt thereof is useful for providing respiratory control and preventing hypoxemia in adults at high risk for obstructive sleep apnea (OSA) or in adults with post-operative OSA requiring general anesthesia (inhalation or intravenous).

[0111] In some embodiments, Compound (I) or a salt thereof reduces the proportion of postoperative patients with hypoxemia, defined as SpO2 ≦90%, by 20% versus placebo (greater than 70% probability) within 90 minutes of initiating Compound (I) or a salt thereof. As used herein, the dosage of Compound (I) ranges from 5.6 mg to 22.4 mg in some embodiments. In some embodiments, this dosage is for intravenous infusion. EXAMPLES

[0112] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compounds and therapeutic methods of the present invention, and are not intended to limit the scope of what the inventors regard as their invention.

[0113] Compound (I) (methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate) was prepared according to the method described in WO2017 / 135306 A1 and used in the following experimental examples.

[0114] Recovery time from anesthesia (isoflurane and propofol) Experimental Example 1: Effect of Compound (I) on recovery time from isoflurane-induced anesthesia as assessed by righting reflex in rats. Eight-week-old male Sprague-Dawley rats were purchased from Charles River, Japan. To induce and maintain isoflurane anesthesia, rats were placed in a pre-filled anesthesia induction chamber (insoflurane 4%). Anesthesia induction was defined as the inability to move left or right in the prone position (loss of righting reflex: LORR) after the rat was placed in the dorsal position in the cage. After confirming LORR, rats were exposed to 3% isoflurane using a face mask and maintained for 30 minutes. 15 minutes after LORR, Compound (I) was administered subcutaneously (SC) to rats at a volume of 5 mL / kg body weight (BW). As a vehicle-treated control, rats were administered Captisol® (CyDex Pharmaceuticals, KS, USA) 10.5% (w / v) / 1.5 mM Na2HPO4 in distilled water. Thirty minutes after confirming LORR, isoflurane inhalation was terminated, and the time until recovery from LORR was recorded as the anesthesia time. Body temperature during and after anesthesia was maintained at 37.0-37.5 °C using a heating pad. The results are shown in Table 1.

[0115] [Table 1]

[0116] Experimental Example 2: Effect of Compound (I) on recovery time from propofol-induced anesthesia as assessed by righting reflex in rats. Eight-week-old male Sprague-Dawley rats were purchased from Charles River, Japan. A bolus dose of propofol (10 mg / kg) was administered intravenously to the rats to induce and maintain propofol anesthesia. After confirming LORR, the rats were gently placed in a supine position on a heating pad to maintain body temperature at 37.0-37.5°C. Propofol was then administered continuously at 60 mg / kg / hr for 30 min. 15 min after LORR, Compound (I) was administered SC to the rats at 5 mL / kg body weight. As a vehicle-treated control, rats were administered 10.5% (w / v) Captisol® / 1.5 mM Na2HPO4 in distilled water. Thirty min after confirming LORR, the propofol infusion was terminated and the time to recovery from LORR was recorded as the anesthesia time. The results are shown in Table 2.

[0117] [Table 2]

[0118] As can be seen from Tables 1 and 2, Compound (I) shortened the recovery time from isoflurane- and propofol-induced anesthesia as assessed by righting reflex in rats.

[0119] Suppression of opioid (fentanyl)-induced side effects without affecting pain Experimental Example 3: Effect of Compound (I) on fetanyl (0.1 mg / kg)-induced sedation as assessed by righting reflex in rats. Eight-week-old male Sprague-Dawley rats were purchased from Charles River, Japan. In this study, LORR was used as an index of sedation. To induce sedation, 0.1 mg / kg fentanyl was administered SC to rats at 2 mL / kg body weight. Ten minutes after fentanyl administration, all rats were observed for LORR, and then Compound (I) was administered SC at 5 mL / kg body weight. Vehicle-treated controls were administered 10.5% (w / v) Captisol® / 1.5 mM Na2HPO4 in distilled water. The recovery time from LORR was recorded as the duration of sedation.

[0120] The results are shown in Table 3. Compound (I) reduced the duration of fentanyl-induced sedation as assessed by righting reflex in rats.

[0121] [Table 3]

[0122] Experimental Example 4: Effect of Compound (I) on fentanyl (0.1 mg / kg)-induced respiratory depression assessed by whole-body plethysmography (WBP) in rats. Eight-week-old male Sprague-Dawley rats were purchased from Charles River, Japan. Respiratory function was assessed by WBP, which was continuously supplied with fresh room air and equipped with inflow and outflow ports to remove exhaled carbon dioxide. Under these experimental conditions, rats were placed in the WBP chamber immediately after administration of fentanyl (0.1 mg / kg, SC). Respiratory parameters, such as respiratory rate (RR), tidal volume (TV), and minute ventilation (MV), were detected from a pressure transducer and recorded with data acquisition software (FinePoint software, Data Sciences International, Inc.). All respiratory parameters were analyzed as individual integrated values ​​of 1-minute measurements from 0 to 30 minutes after fentanyl administration, integrated over a 30-minute period. Compound (I) was administered SC to rats 15 minutes before fentanyl administration.

[0123] The results are shown in Table 4. As a result, fentanyl (0.1 mg / kg as vehicle group) decreased RR and MV compared to the basal group. Under these experimental conditions, compound (I) increased RR, TV and MV compared to the vehicle group, suggesting that compound (I) suppressed fentanyl-induced respiratory depression in rats.

[0124] [Table 4]

[0125] Experimental Example 5: The effect of Compound (I) on fentanyl-induced analgesia assessed by using the formalin test in rats. Eight-week-old male Sprague-Dawley rats were purchased from Charles River, Japan. 2.5% by volume formalin solution was SC injected into the left hind leg 30 min after administration of compound (I), and fentanyl (0.045 mg / kg) was administered 15 min after administration of compound (I). For the measurement of pain threshold, the number of pain behaviors (flinching) was counted at 13 time points: 1, 6, 11, 16, 21, 26, 31, 36, 41, 46, 51, 56, and 61 min after formalin injection. Phase I (pain caused by direct stimulation of the peripheral nervous system from formalin) was 1 to 11 min after formalin injection, and Phase II (pain related to increased sensitivity of spinal dorsal horn neurons induced by stimulation in Phase I) was 16 to 61 min after formalin injection, and the number of flinchings in each phase was summed.

[0126] The results are shown in Table 5. Fentanyl (0.045 mg / kg) exhibited analgesic effects in the formalin pine model, as assessed by a reduction in the total number of flinches in rats. Under these experimental conditions, Compound (I) did not interfere with the analgesic effects of fentanyl in rats.

[0127] [Table 5]

[0128] Experimental Example 6: Effect of Compound (I) on fentanyl-induced analgesia assessed by using a postoperative skin incision pain model in rats. Eight-week-old male Sprague-Dawley rats were purchased from Charles River, Japan. Under isoflurane anesthesia, a 1 cm longitudinal incision was made through the skin of the plantar aspect of the right foot, starting 0.5 cm from the edge of the heel and extending toward the toes. The exposed plantar muscle was lifted with tweezers and incised longitudinally. After the plantar muscle was returned to its original position, the skin incision was mattress sutured in two places with sterile needle thread (nylon, 5-0). After suturing, an ointment containing an antibiotic was applied to the surgical site. The surgical foot was disinfected with iodine and alcohol, and sterile gloves and sterile surgical instruments were used. Measurement of the pain threshold (g) of the right hind footpad was performed using a dynamic plantar anesthesia meter set to apply pressure from 0 g to 50 g in 10 seconds. The pain threshold was the average of three measurements. Fentanyl was administered SC immediately after skin incision, and compound (I) was administered SC 15 min before skin incision.

[0129] The results are shown in Table 6. Fentanyl (0.03 mg / kg) showed analgesic effects in a postoperative skin incision model, as measured by pain threshold (g) in rats. Under these experimental conditions, Compound (I) did not interfere with the analgesic effects of fentanyl in rats.

[0130] [Table 6]

[0131] The results suggest that compound (I), an OX2R selective agonist, may accelerate recovery time from anesthesia and suppress opioid-induced side effects without affecting pain.

[0132] Formulation Example 1 (Capsule Production) 1) Compound (I) 30mg

[0133] 2) Crystalline cellulose 10mg

[0134] 3) Lactose 19mg

[0135] 4) Magnesium stearate 1mg

[0136] Total 60mg

[0137] 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0138] Formulation Example 2 (Tablet Production) 1) Compound (I) 30g

[0139] 2) Lactose 50g

[0140] 3) 15g cornstarch

[0141] 4) Calcium carboxymethylcellulose 44g

[0142] 5) Magnesium stearate 1g

[0143] Total 1000 tablets 140g

[0144] The total amount of 1), 2), 3) and 30g of 4) are mixed with water, vacuum dried, and sieved. The sieved powder is mixed with 14g of 4) and 1g of 5), and the mixture is punched out by a tablet press. In this way, 1000 tablets containing 30mg of compound (I) per tablet are obtained.

[0145] Formulation Example 3 (Production of freeze-dried preparation for injection) Compound (I) (50 mg) is dissolved in Japanese Pharmacopoeia distilled water for injection (50 ml), and Japanese Pharmacopoeia distilled water for injection is added to 100 ml. The solution is filtered under sterile conditions, and 1 ml of the solution is filled into an injection vial under sterile conditions, lyophilized, and sealed. [Industrial Applicability]

[0146] Compound (I) of the present invention has orexin type 2 agonist activity and is useful for postoperative recovery (improvement of delayed consciousness after maintenance of anesthesia, and improvement of sedation and respiratory depression caused by opioids).

Claims

1. 2. Use of an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, or a salt thereof, in the manufacture of a medicament for preventing or treating postoperative respiratory disorder / depression or opioid or anesthetic induced respiratory disorder / depression in a subject in need thereof.

2. 2. Use of an effective amount of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, or a salt thereof, in the manufacture of a medicament for preventing or treating post-operative sedation or opioid- or anesthetic-induced sedation in a subject in need thereof.

3. 3. The use according to claim 1 or claim 2, wherein the medicament is for parenteral administration.

4. The use according to claim 3, wherein the parenteral administration is intravenous, subcutaneous, transdermal or transmucosal administration.

5. The use described in claim 3, wherein the parenteral administration is intravenous (IV) administration.

6. The use described in claim 1 or claim 2, wherein the opioid is selected from fentanyl, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, buprenorphine, pethidine, pentazocine, doxapram and combinations thereof.

7. The use described in claim 1 or claim 2, wherein the anesthetic is selected from inhalational anesthetics and intravenous anesthetics.

8. The use described in claim 1 or claim 2, wherein the anesthetic agent is selected from isoflurane, enflurane, methoxyflurane, sevoflurane, desflurane, halothane, propofol, thiopental, thiamylal, midazolam, flumazenil, ketamine, dexmedetomidine (hydrochloride), droperidol, etomidate and combinations thereof.

9. The use of claim 1 or claim 2, wherein the opioid or anesthetic is administered to the subject prior to administration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof.

10. The use described in claim 1 or claim 2, wherein the methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof is administered in an amount of about 5 mg to about 50 mg.

11. A parenteral dosage form comprising about 5 mg to about 50 mg of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof, and water.

12. The parenteral dosage form of claim 11 comprising from about 5 mg to about 22 mg of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof.

13. The parenteral dosage form of claim 11 comprising from about 5.6 mg to about 22.4 mg of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof.

14. The parenteral dosage form of claim 11, wherein the dosage form is formulated for intravenous infusion.

15. The parenteral dosage form of claim 11, wherein the dosage form is formulated for administration by intravenous infusion over 90 minutes.

16. A composition comprising an opioid or anesthetic; and 12. The parenteral dosage form of claim 11 : Combinations including:

17. The combination of claim 16, wherein the opioid is selected from fentanyl, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, buprenorphine, pethidine, pentazocine, doxapram, and combinations thereof.

18. The combination described in claim 16, wherein the anesthetic agent is selected from an inhaled anesthetic agent and an intravenous anesthetic agent.

19. The combination of claim 16, wherein the anesthetic agent is selected from isoflurane, enflurane, methoxyflurane, sevoflurane, desflurane, halothane, propofol, thiopental, thiamylal, midazolam, flumazenil, ketamine, dexmedetomidine (hydrochloride), droperidol, etomidate, and combinations thereof.

20. The combination of claim 16, wherein the parenteral dosage form comprises from about 5.6 mg to about 22.4 mg of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof.