WO2011025728A1

WO2011025728A1 - Methods for sedation

Info

Publication number: WO2011025728A1
Application number: PCT/US2010/046302
Authority: WO
Inventors: Gary Bream; Stephen E. Butts; Moise A. Khayrallah
Original assignee: Shionogi Pharma, Inc.
Priority date: 2009-08-25
Filing date: 2010-08-23
Publication date: 2011-03-03

Abstract

The present invention relates to the use of compounds of the invention for producing and/or maintaining sedation in a subject in need thereof.

Description

Methods for Sedation

Field of the Invention

[0001] The present invention relates to the use of compounds of the invention for producing and/or maintaining sedation in a subject in need thereof.

Background of the Invention

[0002] Sedation is useful for patients undergoing medical or surgical procedures that are painful, uncomfortable, or frightening. Numerous sedative agents are known, including adrenergic receptor agonists, particularly alpha adrenergic receptor agonists. However, many of the adrenergic receptor agonists also have the side effect of inducing hypotension, which is undesirable in most sedation situations.

[0003] The present invention provides improved methods for producing and/or maintaining sedation in a subject without causing hypotension.

Summary of the Invention

[0004] The present invention is related to compounds that produce sedation. Thus, the present invention provides methods for producing and/or maintaining sedation in a subject in need thereof, comprising delivering to the subject a sedation-producing and/or -maintaining amount of a compound of Formula I:

wherein R is an unsubstituted alkyl or alkenyl having from 1 to 3 carbon atoms,

cyclopropane, or Br; and

R' is H or F; or a pharmaceutically acceptable salt or prodrug thereof.

[0005] In one embodiment, the compound of Formula I is

[0006] In some embodiments of the invention, the compound can be used to produce and/or maintain sedation without substantially lowering blood pressure. In other embodiments of the invention, the subject is undergoing a procedure for which sedation is desired, e.g., a diagnostic, therapeutic, or surgical procedure. In further embodiments, the compound of the invention is delivered concurrently with an additional agent, e.g., another sedative agent, an anesthetic agent, an analgesic agent, a paralytic agent, or a muscle relaxant.

[0007] The present invention further relates to a kit for producing and/or maintaining sedation in a subject in need thereof, comprising the compounds of the invention.

[0008] The present invention is explained in greater detail in the drawings herein and the specification set forth below.

Brief Description of the Drawings

[0009] Fig. 1 shows the lack of a hypotensive effect when a compound of the invention is administered to humans.

[0010] Fig. 2 shows the production of sedation in mice upon intravenous administration of a compound of the invention.

Detailed Description of the Invention

[0011] The present invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment can be deleted from that embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention,

[0013] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety.

Definitions.

[0014] As used herein, "a," "an," or "the" can mean one or more than one. For example, "a" cell can mean a single cell or a multiplicity of cells.

[0015] Also as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0016] Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ± 20%, + 10%, ± 5%, ± 1%, ± 0,5%, or even ± 0.1% of the specified amount.

[0017] The term "consists essentially of (and grammatical variants), as applied to the compositions of this invention, means the composition can contain additional components as long as the additional components do not materially alter the composition. The term "materially altered," as applied to a composition, refers to an increase or decrease in the biological effectiveness (e.g., ability to produce sedation) of the composition of at least about 20% or more as compared to the effectiveness of a composition consisting of the recited components. [0018] The term "sedation" is understood in the art and is generally defined as the act or process of depressing the function of the central nervous system, relieving anxiety and inducing a state of calmness in the conscious animal by administration of a drug.

[0019] The term "sedation-producing or -maintaining amount," as used herein, refers to that amount of a composition of the invention that produces or maintains a sedation effect in a subject in need thereof. For example, a sedation-producing or -maintaining amount can refer to the amount of a composition, compound, or agent that increases sedation in a subject by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. The level of sedation in a subject can be measured by methods known in the art, including subjective scoring systems such as the modified observers assessment of alertness/sedation (MOAA/S) or sedation-agitation scale (SAS), objective monitors such as the Bispectral Index (BIS) monitor, and assays described in U.S. Patent No. 5,908,869 or R. James and J. Glen, J. Med Chem. 23:1350 (1980).

[0020] The term "producing sedation" refers to the induction of at least partial sedation in a subject that is not currently sedated. The term "maintaining sedation" refers to ongoing sedation of a subject that has already been at least partially sedated.

[0021] The term "without substantially decreasing blood pressure" refers to a decrease in mean systolic blood pressure during and/or after delivery of a compound of the invention that is less than about 20%, e.g., less than about 15%, 10%, or 5%. In other words, an insubstantial decrease in blood pressure is a decrease of less than about 30 mm Hg, e.g., less than about 25, 20, 15, 10, or 5 mm Hg.

[0022] "Pharmaceutically acceptable," as used herein, means a material that is not biologically or otherwise undesirable, i. e. , the material can be administered to an individual along with the compositions of this invention, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science; 21^st ed. 2005). Exemplary pharmaceutically acceptable carriers for the compositions of this invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free physiological saline solution. [0023] The term "a subject in need thereof," as used herein, refers to any subject or patient who currently is in need of sedation or for which sedation is desired.

[0024] "Concurrently" means sufficiently close in time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other). In some embodiments, the administration of two or more compounds "concurrently" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two compounds can be administered in the same or different formulations or sequentially. Concurrent administration can be carried out by mixing the compounds prior to administration, or by administering the compounds in two different formulations, for example, at the same point in time but at different anatomic sites or using different routes of administration.

[0025] The term "alkyl" denotes a straight or branched hydrocarbon chain containing 1-24 carbon atoms, e.g., 1-12 carbon atoms. Examples of alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0026] The term "alkenyl" refers to an alkyl having one or more double bonds. Examples include ethenyl and propenyl.

[0027] The present invention provides methods for producing and/or maintaining sedation in a subject in need thereof, comprising delivering to the subject a sedation- producing or -maintaining amount of a compound of Formula I:

wherein R is an unsubstituted alkyl or alkenyl having from 1 to 3 carbon atoms,

cyclopropane, or Br; and

R' is H or F;

or a pharmaceutically acceptable salt or prodrug thereof. [0028] In one embodiment of the invention, R is ethyl, In another embodiment, R' is H. In a further embodiment, the compound of Formula I is

[0029] The surprising benefit of the present invention is the ability of the compounds of the invention to produce and/or maintain sedation without substantially lowering blood pressure. In one embodiment, the compounds of the invention are delivered to a subject to produce and/or maintain sedation and the mean systolic blood pressure of the subject decreases by less than about 30 mm Hg, e.g., less than about 25, 20, 15, 10, or 5 mm Hg during and/or after delivery of the compound to the subject.

[0030] Without being bound by any particular theory, it is thought that the ability of the compounds of the invention to provide sedation without any hypotensive effect may be due at least in part to the presence of a major metabolite in humans that has reduced efficacy at alpha-2 adrenergic receptors. The major metabolite is a compound that is N-alkylated (e.g., methylated) at the Nl position as exemplified by the following compound.

It is also possible that the ability of the compounds of the invention to provide sedation without any hypotensive effect may be due at least in part to secondary binding of the compounds of the invention to other receptors.

[0031] The compounds of the invention can be synthesized by methods known to a skilled artisan. The salts of the compounds can be produced by treating the compound with a suitable mineral or organic acid (HX) in a suitable solvent or by other means well known to those of skill in the art. Details of reaction schemes for synthesizing compounds of Formula I as well as representative examples of the preparation of specific compounds have been described in U.S. Patent Nos. 5,478,858, 5,541,210, 5,691,370, 6,066,740, 6,486,190, and 7,304,084, all incorporated herein by reference in their entirety.

[0032] For any compounds of Formula I having one or more asymmetric carbon atoms, the present invention includes within its scope the stereochemically pure isomeric forms of the compounds as well as their racemates. Stereochemically pure isomeric forms may be obtained by the application of art known principles. Diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereoselective reactions.

[0033] Similarly, compounds of the invention containing a double bond can exist in the form of geometric isomers, which can be readily separated and recovered by conventional procedures. Such isomeric forms are included in the scope of this invention.

[0034] During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0035] Other embodiments of the invention include the use, for the preparation of a medicament for the production and/or maintenance of sedation, of one of the compounds described above or a pharmaceutically acceptable salt or prodrug thereof.

[0036] The compounds of this invention include all pharmaceutically acceptable salt forms thereof. Examples of such salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include, without limitation, acetate, adipate, alginate, aspartate, benzoate, butyrate, citrate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, hydroxynapthoate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. Pharmaceutically acceptable salt forms include forms having multiple salts, such as di-salts and tri-salts. In one embodiment, the compounds of the invention are di-salts, e.g., dimaleate salts.

[0037] Salts derived from appropriate bases include, without limitation, alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N-(alkyl)₄ ⁺ salts.

[0038] Compounds of the invention include those having quaternization of any basic nitrogen-containing group therein.

[0039] Further, the compounds of the invention include prodrugs of the compounds of the invention that are converted to the active compound in vivo. For example, the compound can be modified to enhance cellular permeability (e.g., by esterification of polar groups) and then converted by cellular enzymes to produce the active agent. Methods of masking charged or reactive moieties as a pro-drug are known by those skilled in the art (see, e.g., P. Korgsgaard-Larsen and H. Bundgaard, A Textbook of Drug Design and Development, Reading U.K., Harwood Academic Publishers, 1991).

[0040] The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood, see, e.g., T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference herein. See also U.S. Patent No. 6,680,299. Exemplary prodrugs include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of the compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an amide of an amine group or carboxylic acid group, if such groups are present in the compound; a urethane of an amine group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described, for example, in U.S. Patent No. 6,680,324 and U.S. Patent No. 6,680,322. In some embodiments, the prodrug can be a compound that is alkylated (e.g., methylated) at the Nl position of Formula I.

[0041] The term "pharmaceutically acceptable prodrug" (and like terms) as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and/or other animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

[0042] In one embodiment of the invention, the compounds of the invention are delivered to a subject in need of sedation. In one embodiment, the subject is currently undergoing or about to undergo a procedure for which sedation is needed or desired, e.g., to provide sedation for subjects undergoing painful, uncomfortable or otherwise frightening (anxiety inspiring) medical or surgical procedures. Examples of procedures and situations for which sedation is needed or desired include, without limitation, preoperative sedation, conscious sedation during short diagnostic, operative or endoscopic procedures (e.g., gastrointestinal endoscopy, colonoscopy, bronchoscopy), interventional radiology and cardiology procedures, anxiolysis and amnestic use for perioperative events, intensive care unit sedation, and induction and/or maintenance of sedation for intubated, mechanically ventilated patients.

[0043] The compounds of the invention can be delivered by any means suitable for producing and/or maintaining sedation. Suitable routes of administration include, without limitation, parenteral (by intravenous, intramuscular, topical, or subcutaneous routes), oral, rectal, buccal (e.g., sub-lingual), vaginal, topical (i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration. In one embodiment, the compounds are delivered intravenously. In general, the compounds can be administered as is, or after dilution in a suitable diluent, as an initial bolus dose to produce sedation, followed by a continuous infusion of compound at a rate that is sufficient to achieve and maintain the level of sedation desired. Alternatively, a continuous infusion of a compound of the invention can be used to maintain sedation following induction or induction and maintenance with another sedative agent, (e.g., propofol, a barbiturate (such as pentobarbital sodium or methohexital sodium), or a benzodiazepine (such as diazepam)). Or, in yet another alternative protocol, a bolus dose of the present compound to induce sedation can be followed by infusion of a different sedative agent. The effective dosage will depend on many factors including the gender, age, weight, and general physical condition of the subject, the degree of sedation required, the particular compound or composition being administered, the duration of the treatment, the nature of any concurrent treatment, the carrier used, and like factors within the knowledge and expertise of those skilled in the art. As appropriate, a treatment effective amount in any individual case can be determined by one of skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation (see, e.g., Remington, The Science and Practice of Pharmacy (21^st ed. 2005)). For example, a suitable bolus dose of the compounds of the invention for a human subject will typically be in the range of from about 0.0001 to about 50 mg/kg or more, e.g., about 0.01 to about 20 mg/kg, e.g., about 0.1 to about 10 mg/kg, e.g., about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/kg. The rate of infusion will typically be in the range from about 1 to about 5000 μg/kg/min or more, e.g., about 10 to about 2000 μg/kg/min, e.g., about 1, 5, 10, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 μg/kg/min. The present invention encompasses every sub-range within the cited ranges and amounts.

[0044] In one aspect of the invention, the compound of the invention is delivered to a subject concurrently with an additional agent. The additional agent can be delivered in the same composition as the compound or in a separate composition. The compound of the invention may be administered simultaneously with the other agent or may precede or follow the other agent treatment by intervals ranging from minutes to hours. The additional agent can be delivered to the subject on a different schedule or by a different route as compared to the compound. The additional agent can be any agent that provides a benefit to the subject, e.g., to provide sedation and/or anesthesia or as treatment and/or prevention for a disease, disorder, or condition. Additional agents include, without limitation, other sedation agents, anesthetic agents, analgesic agents (e.g., opioids and/or systemic local anesthetics), paralytic agents, and muscle relaxants.

Sedatives include, without limitation, benzodiazepine derivatives such as diazepam, triazolam, lormetazeban, clotiazepam, flurazepam, nitrazepam and flunitrazepam, propofol, or a barbiturate, such as pentobarbital sodium or methohexital sodium. Anesthetic agents may be either inhalational or intravenous anesthetic agents. Agents commonly used in the co-induction of anesthesia include midazolam, fentanyl, sufentanil, alfentanil and propofol. Inhalational anesthetic agents include, but are not limited to, nitrous oxide (N₂O), halothane, enflurane, isoflurane, desflurane and sevoflurane. Intravenous anesthetic agents and balanced anesthetic agents include, but are not limited to, barbiturates (barbital, phenobarbital, pentobarbital, secobarbital, hexobarbital), ultrashort-acting barbiturates (thiopental sodium, thiamylal sodium, methohexital sodium), benzodiazepines (diazepam, midazolam), opioid analgesics (morphine, fentanyl, hydromorphone, oxymorphone, codeine, hydrocodone, thebacon, thebaine, heroin, pethidine, levomethadone, dextromoramide, pentazocine, sufentanil, remifentanil, droperidol (an antipsychotic drug; non-opioid), nalbuphinem ND or alfentanil).

Other agents include ketamine, propofol and etomidate and local drugs (benzocaine, ***e, chlorprocaine, lidocaine, bupivocaine, procaine, piperocaine, tetracaine, lignocaine, prilocaine, proxymetacaine, ropivacaine, and dibucaine).

Less potent analgesics include, without limitation, anthranilic acid derivatives (flufenamic acid, mefenamic acid), acrylic acid derivatives (diclofenac, tolmetin, zomepirac), arylpropionic acid derivatives (ibuprofen, naproxen, phenoprofen, ketoprofen) and indoleacetic or indenacetic acid derivatives (indomethacin, sulindac).

Muscle relaxants can be central muscle relaxants, for example baclofen, carisoprodol, chlordiazepoxide, chlormezanone, chloroxazone, dantrolene, diazepam, phenyramidol, meprobamate, phenprobamate and orphenadrine.

Paralytic agents include, without limitation, atracurium besylate and pancuronium bromide.

[0045] The present invention finds use in research as well as veterinary and medical applications. Suitable subjects are generally mammalian subjects. The term "mammal" as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), etc. Human subjects include neonates, infants, juveniles, adults and geriatric subjects.

[0046] The compounds of the invention described above can be formulated for administration as a pharmaceutical composition comprising a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (21^st ed. 2005). In the manufacture of a pharmaceutical formulation according to the invention, the compound is typically admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient. The carrier can be a solid or a liquid, or both, and can be formulated with the compound as a unit-dose formulation, for example, a tablet, which can contain from 0.01% or 0.5% to 95% or 99% by weight of the compound. One or more compounds can be incorporated in the formulations of the invention, which can be prepared by any of the well known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients.

[0047] The formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical (i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.

[0048] Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions can include suspending agents and thickening agents. The formulations can be presented in unit\dose (e.g., in a syringe or other injection device) or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use. In one embodiment, formulations of the invention may be diluted with Water for Injection or introduced into other fluids suitable for either intravenous bolus injection or for intravenous infusion, including Ringers Solution, Hartmanns Solution, Dextrose Solutions, Saline Solution, Buffered Saline Solution, or Sterile Water. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. For example, in one aspect of the present invention, there is provided an injectable, stable, sterile or non-sterile composition comprising one or more compounds, in a unit dosage form in a sealed container. The compound is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject. The unit dosage form typically comprises from about 1 μg to about 10 grams of the compound. [0049] When the compound is substantially water-insoluble, the compounds of the invention are typically formulated in aqueous media using water-immiscible solvents, solubilizers, emulsifiers, surfactants or other solubilizing agents. Some emulsifiers are variously termed surfactants in the literature.

[0050] Individual formulations may include one or more additional components such as stabilizers, tonicity modifiers, bases or acids to adjust pH, and solubilizers. The formulations can also optionally contain a preservative, such as ethylenediaminetetraacetic acid (EDTA) or sodium metabisulfate, to prevent the growth of microorganisms.

[0051] The pharmaceutical compositions of the invention can be made isotonic with blood by the incorporation of a suitable tonicity modifier. Glycerol is most frequently used as a tonicity modifier. Alternative tonicity modifying agents include xylitol, mannitol, sorbitol, dextrose, and salts such as sodium chloride, potassium chloride, etc. The pharmaceutical compositions are typically formulated to be at physiologically neutral pH, typically in the range 6.0 8.5. The pH can be adjusted by the addition of base, for example NaOH or NaHCO₃, or in some cases acid, such as HCl.

[0052] Formulations suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations can be prepared by any suitable method of pharmacy which includes the step of bringing into association the compound and a suitable carrier (which can contain one or more accessory ingredients as noted above). In general, the formulations of the invention are prepared by uniformly and intimately admixing the compound with a liquid or finely divided solid earner, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules containing the compound, optionally with one or more accessory ingredients, Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.

[0053] Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the compound in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia. [0054] Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by admixing the compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0055] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

[0056] Formulations suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharm. Res. 3:318 (1986)) and typically take the form of an optionally buffered aqueous solution of the compound. Suitable formulations comprise citrate or bis\tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2 M active ingredient.

[0057] Other pharmaceutical compositions can be prepared from the compounds disclosed herein, such as aqueous base emulsions. In such an instance, the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound. Particularly useful emulsifying agents include phosphatidyl cholines and lecithin.

[0058] In addition to the compound, the pharmaceutical compositions can contain other additives, such as pH-adjusting additives. In particular, useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Further, the compositions can contain microbial preservatives. Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use. Other additives that are well known in the art include, e.g., detackifiers, anti-foaming agents, antioxidants (e.g., ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g., α-tocopherol (vitamin E)), preservatives, chelating agents (e.g., EDTA), viscomodulators, tonicifiers (e.g., a sugar such as sucrose, lactose, or mannitol), flavorants, colorants odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. [0059] The additive can also comprise a thickening agent. Suitable thickening agents can be those known and employed in the art, including, e.g., pharmaceutically acceptable polymeric materials and inorganic thickening agents. Exemplary thickening agents for use in the present pharmaceutical compositions include polyacrylate and polyacrylate co-polymer resins, for example poly-acrylic acid and poly-acrylic acid/methacrylic acid resins; celluloses and cellulose derivatives including: alkyl celluloses, e.g., methyl-, ethyl- and propyl- celluloses; hydroxyalkyl-celluloses, e.g., hydroxypropyl-celluloses and hydroxypropylalkyl- celluloses such as hydroxypropyl -methyl-celluloses; acylated celluloses, e.g., cellulose- acetates, cellulose-acetatephthallates, cellulose-acetatesuccinates and hydroxypropylmethyl- cellulose phthallates; and salts thereof such as sodium-carboxymethyl-celluloses; polyvinylpyrrolidones, including for example poly-N-vinylpyrrolidones and vinylpyrrolidone co-polymers such as vinylpyrrolidone-vinylacetate co-polymers; polyvinyl resins, e.g., including polyvinylacetates and alcohols, as well as other polymeric materials including gum traganth, gum arabicum, alginates, e.g., alginic acid, and salts thereof, e.g., sodium alginates; and inorganic thickening agents such as atapulgite, bentonite and silicates including hydrophilic silicon dioxide products, e.g., alkylated (for example methylated) silica gels, in particular colloidal silicon dioxide products. Such thickening agents as described above can be included, e.g., to provide a sustained release effect. However, where oral administration is intended, the use of thickening agents as aforesaid will generally not be required and is generally less preferred. Use of thickening agents is, on the other hand, indicated, e.g., where topical application is foreseen.

[0060] A further aspect of the invention relates to kits for producing and/or maintaining sedation in a subject in need thereof. The kits can comprise the compounds of the invention. The kits can comprise further components useful for carry out the methods of the invention, including without limitation, containers, diluents, pharmaceutically acceptable carriers, buffers, etc. In other embodiments, the kits can further comprise additional agents, e.g., another sedative agent, an anesthetic agent, an analgesic agent, a paralytic agent, and/or a muscle relaxant.

[0061] The present invention is more particularly described in the following examples that are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art. EXAMPLE 1

Absence of hypotensive effect with delivery of compound I

[0062] Compound I was administered orally in 20% cherry syrup to human subjects at doses in the range of 0.001 mg/kg to 0.128 mg/kg. The majority of subjects (80%) experienced somnolence at the highest dose. However, none of the subjects experienced a substantial drop in mean systolic blood pressure (Fig. 1).

EXAMPLE 2

Compound I produces sedation in mice

[0063] Compound I was administered intravenously in saline to mice over a range of doses. Compound I produced dose-dependent inhibition of locomotor activity following intravenous dosing which was similar in maximum inhibitory response to other alpha-2 agonists such as clonidine (Fig. 2). The compound designated as PGV30459 in Fig. 2 is

[0064] The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein. All publications, patent applications, patents, patent publications, and any other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and/or paragraph in which the reference is presented.

Claims

What is Claimed is:

1. A method for producing and/or maintaining sedation in a subject in need thereof, comprising delivering to the subject a sedation-producing or -maintaining amount of a compound of Formula I:

wherein R is an unsubstituted alkyl or alkenyl having from 1 to 3 carbon atoms, cyclopropane, or Br; and

R' is H or F;

or a pharmaceutically acceptable salt or prodrug thereof.

2. The method of claim 1, wherein R is ethyl.

3. The method of claim 1 or 2, wherein R' is H.

4. The method of any one of claims 1-3, which is:

5. The method of any one of claims 1-4, wherein said compound induces sedation without substantially decreasing blood pressure.

6. The method of claim 5, wherein the decrease in blood pressure is a decrease in mean systolic blood pressure of less than 20 mm Hg.

7. The method of claim 6, wherein the decrease in blood pressure is a decrease in mean systolic blood pressure of less than 10 mm Hg.

8. The method of any one of claims 1-7, wherein said compound is delivered to the subject intravenously, orally, intramuscularly, subcutaneously, or transdermally.

9. The method of claim 8, wherein said compound is delivered to the subject intravenously.

10. The method of any one of claims 1-9, wherein said compound is delivered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

11. The method of any one of claims 1-10, wherein said compound is delivered as a bolus dose of about 0.0001 mg/kg to about 50 mg/kg.

12. The method of any one of claims 1-10, wherein said compound is delivered as an infusion at a rate of about 5 to about 5000 μg/kg/min.

13. The method of any one of claims 1-12, wherein the subj ect is undergoing or is about to undergo a procedure for which sedation is desired.

14. The method of claim 13, wherein the procedure is a diagnostic, therapeutic, or surgical procedure.

15. The method of any one of claims 1-14, wherein the compound is delivered concurrently with an additional agent.

16. The method of claim 15, wherein the additional agent is selected from the group consisting of another sedative agent, an anesthetic agent, an analgesic agent, a paralytic agent, a muscle relaxant, and a combination thereof.

17. Use of a compound of Formula I:

R' is H or F;

or a pharmaceutically acceptable salt or prodrug thereof;

for producing and/or maintaining sedation in a subject in need thereof.

18. Use of a compound of Formula I:

wherein R is an unsubstituted alkyl or alkenyl having from 1 to 3 carbon atoms, cyclopropane, or Br; and R' is H or F;

or a pharmaceutically acceptable salt or prodrug thereof;

in the preparation of a medicament for producing and/or maintaining sedation in a subject in need thereof.

19. A kit for producing and/or maintaining sedation in a subject in need thereof, comprising a compound of Formula I:

R' is H or F;

or a pharmaceutically acceptable salt or prodrug thereof.

20. The kit of claim 19, wherein the compound is

21. The kit of claim 19 or 20, further comprising an additional agent.

22. The kit of claim 21, herein the additional agent is selected from the group consisting of another sedative agent, an anesthetic agent, an analgesic agent, a paralytic agent, a muscle relaxant, and a combination thereof.