US20050009730A1 - Treatment of cns disorders using cns target modulators - Google Patents

Treatment of cns disorders using cns target modulators Download PDF

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US20050009730A1
US20050009730A1 US10/492,990 US49299004A US2005009730A1 US 20050009730 A1 US20050009730 A1 US 20050009730A1 US 49299004 A US49299004 A US 49299004A US 2005009730 A1 US2005009730 A1 US 2005009730A1
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compound
group
therapeutic compound
cns
sleep disorder
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Dale Edgar
David Hangauer
Harry Leighton
Emmanuel Mignot
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Hypnion Inc
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Hypnion Inc
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Priority to US10/492,990 priority Critical patent/US20050009730A1/en
Assigned to HYPNION, INC. reassignment HYPNION, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EDGAR, DALE, MIGNOT, EMANUEL, HANGAUER, DAVID, LEIGHTON, HARRY
Publication of US20050009730A1 publication Critical patent/US20050009730A1/en
Assigned to HYPNION, INC. reassignment HYPNION, INC. RE-RECORD TO CORRECT THE NAMES OF THIRD AND FOURTH ASSIGNOR, PREVIOUSLY RECORDED ON REEL 015702 FRAME 0217. Assignors: EDGAR, DALE, MIGNOT, EMMANUEL, HANGAUER, DAVID, LEIGHTON, HARRY JEFFERSON
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    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • Difficulties in falling asleep, remaining asleep, sleeping for adequate lengths of time, or abnormal sleep behavior are common symptoms for those suffering with a sleep disorder.
  • sleep disorders e.g., insomnia or sleep apnea
  • insomnia or sleep apnea are described in the online Merck Manual of Medicinal Information.
  • over-the-counter antihistamines e.g., diphenhydramine or dimenhydrinate
  • This method of treatment is also associated with a number of adverse side effects, e.g., persistence of the sedating medication after the prescribed time of treatment, or the so-called “hangover effect”. Many of these side effects result from nonspecific activity in both the periphery as well as the Central Nervous System (CNS) during this period of extended medication.
  • CNS Central Nervous System
  • the strategy of treatment is applicable to a broader array of CNS targets.
  • the invention is directed to compositions used for treating Central Nervous System (CNS) disorders.
  • CNS Central Nervous System
  • the invention provides convenient methods of treatment of a CNS disorder.
  • the invention provides methods of treating sleep disorders using compositions that remain active for a discrete period of time to reduce side effects. More specifically, the invention is directed to the compositions and use of derivatized, e.g., ester or carboxylic acid derivatized, antihistamine antagonists for the treatment of sleep disorders.
  • the invention is a method of treating a sleep disorder.
  • the method comprises administering an effective amount of an antihistamine compound, such that the sleep disorder is treated, wherein the antihistamine compound has a favorable biological property (FBP).
  • FBP biological property
  • An additional aspect of the invention is a method of treating a Central Nervous System (CNS) disorder.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the therapeutic compound penetrates into the CNS and modulates the CNS target to treat the CNS disorder.
  • the therapeutic compound can have the formula: [ CA] ⁇ ( SP ) n ⁇ [DA] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, e.g., ester or carboxylic acid, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a method of treating a Central Nervous System (CNS) disorder.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the therapeutic compound penetrates into the CNS and modulates the CNS target to treat the CNS disorder.
  • the therapeutic compound can have the formula: [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • the invention is directed to a method of treating a sleep disorder.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder is treated.
  • the therapeutic compound can have the formula: [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • the invention is directed to a method of treating a sleep disorder target.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder is treated.
  • the therapeutic compound can have the formula: [ AD] ⁇ ( SP ) n ⁇ [EG] wherein AD is a moiety that agonizes an adenosine receptor or a collection of adenosine receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is directed to a method of treating a sleep disorder target.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder is treated.
  • the therapeutic compound can have the formula: [ AH] ⁇ ( SP ) n ⁇ [DA] wherein AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • the invention is directed to a method of treating a sleep disorder.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder is treated.
  • the therapeutic compound can have the formula: [ AH] ⁇ ( SP ) n ⁇ [EG] wherein AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a method of modulating a sleep disorder target.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder target is modulated, wherein the therapeutic compound comprises the formula: [ CA] ⁇ ( SP ) n ⁇ [DA] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, e.g., ester or carboxylic acid, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a method of modulating a sleep disorder target.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder target is modulated, wherein the therapeutic compound comprises the formula: [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a method of modulating a sleep disorder target.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder target is modulated, wherein the therapeutic compound comprises the formula: [ AD] ⁇ ( SP ) n ⁇ [EG] wherein AD is a moiety that agonizes an adenosine receptor or a collection of adenosine receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a method of modulating a sleep disorder target.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder target is modulated, wherein the therapeutic compound comprises the formula: [ AH] ⁇ ( SP ) n ⁇ [DA] wherein AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, e.g., ester or carboxylic acid, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a method of modulating a sleep disorder target.
  • the method comprises administering an effective amount of a therapeutic compound to a subject, such that the sleep disorder target is modulated, wherein the therapeutic compound comprises the formula: [ AH] ⁇ ( SP ) n ⁇ [EG] wherein AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • CA Central Nervous System
  • SP Central Nervous System
  • DA Drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, e.g., ester or carboxylic acid
  • SP is a spacer molecule
  • n is 0 or 1.
  • CNS disorder target modulator comprising the formula: [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a sleep disorder target modulator comprising the formula: [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • a sleep disorder target modulator comprises the formula: [ AH] ⁇ ( SP ) n ⁇ [DA] wherein AH is a moiety that antagonizes a histamine receptor, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, e.g., ester or carboxylic acid, SP is a spacer molecule, and n is 0 or 1.
  • a sleep disorder target modulator comprises the formula: [ AH] ⁇ ( SP ) n ⁇ [EG] wherein AH is a moiety that antagonizes a histamine receptor, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutic compound as prepared according to the methodology of this invention, and a pharmaceutically acceptable carrier.
  • FIGS. 1 A-C are graphs depicting the effect of a compound of the invention on parameters pertinent to sleep disorders.
  • FIGS. 2 A-G are graphs depicting the binding of reference compounds to the receptors as indicated.
  • the invention is directed to compositions used for treating Central Nervous System (CNS) disorders.
  • CNS Central Nervous System
  • the invention provides convenient methods of treatment of a CNS disorder.
  • the invention provides methods of treating sleep disorders using compositions that remain active for a discrete period of time to reduce side effects. More specifically, the invention is directed to the compositions and use of derivatized, e.g., ester or carboxylic acid derivatized, antihistamine antagonists for the treatment of sleep disorders.
  • One embodiment of the invention is a method of treating a Central Nervous System (CNS) disorder.
  • the method of treating comprises the treatment of a Central Nervous System (CNS) disorder, comprising administering to a subject an effective amount of a therapeutic compound, such that the therapeutic compound penetrates into the CNS and modulates the CNS target, thereby treating the CNS disorder.
  • CNS Central Nervous System
  • Central Nervous System (CNS) disorder includes disorders or states of the central nervous system and that are treatable by the compounds described herein. Examples include, but are not limited to depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behavior disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington' disease and Gilles de la Tourett's syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenom
  • narcotics or withdrawal from narcotics sleep disorders, sleep apnea; narcolepsy, insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders, which include nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy and seizure disorders, attention-deficit hyperactivity disorder (ADHD)/cognition, Alzheimer's, drug abuse, stroke, multiple sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS).
  • nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex
  • pallido-ponto-nigral degeneration pallido-ponto-nigral degeneration
  • epilepsy and seizure disorders attention-deficit hyperactivity disorder (ADHD)/cognition
  • ADHD attention-deficit hyperactivity disorder
  • MS multiple sclerosis
  • ALS Amyotrophic Lateral Sclerosis
  • treating include administering a therapeutically effective amount of a compound sufficient to reduce or eliminate at least one symptom of the state, disease or disorder, e.g., a sleep disorder.
  • administering includes delivery to a subject by any means that does not affect the ability of the therapeutic compound to perform its intended function.
  • the therapeutic compound may be administered by any means that sufficiently treats the disorder target. Administration includes, but is not limited to parenteral, enteral, and topical administration. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition, which includes compositions that comprise the compounds of the present invention and a pharmaceutically acceptable carrier. In a specific embodiment, the therapeutic compound is administered orally.
  • Administration also includes the use of an additional modulating factor (AMF) in “combination therapy.”
  • AMF additional modulating factor
  • additional modulating factor includes additional factors, such as additional therapeutics or subject abnormalities, e.g., a chemical imbalance. It should be understood that the additional modulating factor may be directed to the same or a different disorder target as that being modulated by the compounds of the present invention.
  • combination therapy includes the co-administration of the modulating compound of the present invention in the presence of an additional modulating factor, e.g., an additional therapeutic agent.
  • Administration of the modulating compound may be first, followed by the other therapeutic agent; or administration of the other therapeutic agent may be first, followed by the modulating, e.g., inhibiting, compound.
  • the other therapeutic agent may be any agent which is known in the art to treat, prevent, or reduce the symptoms of the targeted disorder, e.g., a sleep disorder.
  • the compounds of the present invention can also be administered in combination with other known therapies for the target disorder.
  • the other therapeutic agent may be any agent of benefit to the patient when administered in combination with the administration of a modulating, e.g., inhibiting, compound.
  • the other therapeutic agent may also be a modulating compound.
  • a therapeutic compound of the invention may be administered in conjunction with a variety of commercially-available drugs, including, but not limited to, antimicrobial agents, such as pentamidine, lomefloxacin, metronidazole, fungistatic agents, germicidal agents, hormones, antipyretic agents, antidiabetic agents, bronchodilators, such as aminophylline, antidiarrheal agents, such as diphenoxylate hydrochloride with atropine sulfate, antiarrhythmic agents, such as disopyramide phosphate and bidisomide, coronary dilation agents, glycosides, spasmolytics, antihypertensive agents, such as verapamil and verapamil hydrochloride and their enantiomers, and betaxolol, antidepressants, antianxiety agents, other psychotherapeutic agents, such as zolpidem, cycloserine and milacemide, corticosteroids, analgesics,
  • a compound of the invention also may be administered in conjunction with any one or combination of the commercially-available, over-the-counter or prescription medications, including, but not limited to Avobenzene/padimate-O, ACCUPRIL® tablets (quinapril hydrochloride), Accutane capsules (isotretinoin), Achromycin V capsules (the monohydrochloride of (4S-(4.alpha., 4a.alpha.,5a.alpha.,6.beta., 12a.alpha.))-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octBPydro-3,6, 10,12,12a-pentBPydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide), Actifed cough syrup (codeine phosphate, triprolidine hydrochloride and pseudoephedrine hydrochloride), Aldactazide tablets (spir
  • a compound of the invention may also be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
  • pharmaceutically acceptable carrier include a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound(s) of the present invention within or to the subject such that it can perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound(s) of the present invention within or to the subject such that it can perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostea
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacitying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, for example, subcutaneous administration, such that it enters the patient's system and thus, is possibly subject to metabolism and other like processes.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracistemally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • the regimen of administration can affect what constitutes an effective amount.
  • the disorder target modulators e.g., CNS disorder target modulators
  • several divided dosages, as well as staggered dosages can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection.
  • the dosages of the disorder target modulators, e.g., CNS disorder target modulators, compound(s) can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • subject includes anirnals (e.g., mammals, e.g., cats, dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears, primates (e.g., chimpanzees, gorillas, and humans) which are capable of suffering from a CNS associated disorder, e.g., a sleep disorder.
  • anirnals e.g., mammals, e.g., cats, dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels
  • primates e.g., chimpanzees, gorillas, and humans
  • terapéuticaally effective amount of the compound is that amount necessary or sufficient to treat or prevent a state associated with a disorder, e.g., CNS disorder.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound. For example, the choice of the therapeutic compound can affect what constitutes an “effective amount”.
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • the language “penetrates into the CNS” includes the favorable biological property of a compound of the current invention to pass though, or penetrate, the blood brain barrier (EBB) and enter into the CNS.
  • EBB blood brain barrier
  • therapeutic compound includes compounds of the invention capable of performing their intended function, e.g., treating CNS disorders and/or modulating CNS targets.
  • the therapeutic compounds of the invention are described in detail herein.
  • the therapeutic compound can have the formula: [ CA] ⁇ ( SP ) n ⁇ [DA] wherein CA includes moieties that modulate an active CNS target receptor or a collection of active CNS target receptors.
  • drug activity modulating moiety is a moiety that provides the ability to modulate the activity of the therapeutic compound.
  • examples include functional moieties, e.g., ester, carboxylic acid or alcohol groups, selected and positioned within the therapeutic drug to provide the ability to modulate the activity of the drug, e.g., modulate, e.g., increase, the half-life of the drug, the ability of the drug to cross the blood brain barrier, or the ability of the drug to bind selectively to the desired receptor.
  • the drug activity modulating moiety is an ester group, EG.
  • the activity of the drug, e.g., half-life, of the therapeutic drug is modulated by controlling the rate of hydrolysis of the ester group by selection and positioning of steric bulk near the ester carbonyl of the ester group.
  • the steric bulk is provided by the selection of a bulky ester group.
  • the steric bulk is provided by substitution selected and positioned on the CA moiety, e.g., an AH moiety, near the carbonyl of the ester group.
  • the drug activity modulating moiety is a carboxylic acid.
  • the presence of the carboxylic acid results in increased concentration of the therapeutic compound within the CNS for a discrete period of time as a result of the existence of an ionic bond that includes the carboxylate ion of the corresponding carboxylic acid, e.g., zwitterion species formation with a nitrogen atom within the compound or salt bridge formation.
  • penetration through the blood brain barrier into the CNS results from the lipophilicity of substituents or conformational lipophilicity, i.e., lipophilicity as a result of a particular conformation, such as internal salt formation between a carboxylate anion and a protonated amine.
  • the presence of the carboxylic acid improves the ability of the compound to bind selectively to the desired receptor.
  • esters group includes an organic ester functionality that is selected and positioned within the compound providing the ability to modulate the activity or modify the properties of the corresponding therapeutic compound.
  • the organic ester group may be terminal, e.g., a substituent, or internal.
  • the carboxylate of the ester may be oriented from left to right or from right to left, e.g., a reverse ester.
  • esters of the current invention include, but are not limited to hydrocarbons and perfluorocarbons. In a preferred embodiment, the hydrocarbons posses 1 to 20 carbons.
  • the hydrocarbons can be linear, branched, cyclic, aromatic, and a combination of aliphatic and aromatic, which are optionally substituted with O, N, S, and/or halogens and may additionally include a center of chirality.
  • the ester can be an n-propyl, an isopropyl, a t-butyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, and a benzyl group.
  • pool ester is intended to include an ester that has sufficient steric properties such that the rate of hydrolysis of the therapeutic compound is modulated, e.g., reduced, such that the activity of the therapeutic compound is modified, e.g., the length of activity is increased (i.e., the half-life of the therapeutic compound is increased). Examples of bulky ester groups are depicted in Table 1. TABLE 1 Bulky Groups for H1 Antagonist Esters Type A: Type B:
  • the ester is not methyl, ethyl, or n-propyl.
  • the bulky ester is not an n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl ester.
  • the ester is not a C-1 to C-4 ester.
  • the ester is not a C-1 to C-4 ester and/or a C-3 to C-4 bulky ester.
  • hydrocarbon as used herein, includes substituted or unsubstituted alkyl, alkenyl, alkynyl, and aromatic or aryl moieties.
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain), and more preferably 4 or fewer.
  • preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 1 -C 6 includes alkyl groups containing 1 to 6 carbon atoms.
  • alkyl includes both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamiino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, s
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An “alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids.
  • aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, de
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • the term C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both “unsubstituted alkynyls” and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulffhydryl, alkylthio, arylthio, thiocarboxylate,
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure. “Lower alkenyl” and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • acyl includes compounds and moieties that contain the acyl radical (CH 3 CO—) or a carbonyl group.
  • substituted acyl includes acyl “groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino,
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulflhydryl, alkylthio, arylthio, thiocarboxy
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • alkyl amino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group that is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom that is also bound to an alkyl group.
  • amide or “aminocarboxy” includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups that include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy alkenylaminocarboxy
  • a “kynylaminocarboxy” arylaminocarboxy
  • carbonyl or “carboxy” includes compounds and moieties that contains a carbon connected with a double bond to an oxygen atom.
  • moieties that contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties that contain a carbon connected with a double bond to a sulfur atom.
  • ether includes compounds or moieties that contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • thioether includes compounds and moieties that contain a sulfur atom bonded to two different carbon or hetero atoms.
  • Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alvicoalkynyls.
  • alkioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom that is bonded to an alkyl group.
  • alkthioalkenyls and alvicoalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom that is covalently bonded to an alkynyl group.
  • hydroxy or “hydroxyl” includes groups with an H or O.
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated e.g., perfluorinated, generally refers to a moiety, e.g., perfluorocarbons, wherein all hydrogens are replaced by halogen atoms, e.g., fluorine.
  • polycyclyl or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • the ester group does not substantially effect the biological activity of the therapeutic compound. Alternatively, in certain other embodiments the ester group significantly effects the biological activity of the therapeutic compound. In one embodiment of the invention, the ester group improves the biological activity of the therapeutic compound.
  • the formulation of the therapeutic compound is formulated to sufficiently treat the target disorder.
  • formulations of the therapeutic compound can be used to provide controlled in vivo adsorption of the therapeutic compound over a discrete period of time.
  • the compound containing the drug activity modulating group e.g., an ester, carboxylic acid, or alcohol group
  • the compound containing the drug activity modulating group e.g., an ester, carboxylic acid, or alcohol group
  • the compound containing the drug activity modulating group is more active as a therapeutic agent for treating disorders than the corresponding compound without this group.
  • the ester is more active as a therapeutic agent for treating disorders than the corresponding acid of the ester.
  • the corresponding acid of the ester is not a therapeutically active agent for treating disorders.
  • the corresponding acid of an ester is more active as a therapeutic agent for treating disorders than the corresponding ester of the acid.
  • the carboxylic acid drug activity modulating group provides an internal salt with an amine and facilitates crossing the blood brain barrier.
  • ester groups as described above, could be extended to thioesters.
  • Labile amides may also be used in replacement of the ester group, wherein the in vivo hydrolysis would be performed by peptidases in the CNS.
  • biological activity includes activity associated with the intended biological function of the compounds of the present invention, e.g., treating a CNS disorder.
  • the language “modulate a target” or “modulation of a target” includes the act of agonizing or antagonizing a receptor or group of receptors of a target disorder.
  • a compound that agonizes or antagonizes a receptor or group of receptors is referred to herein as a target modulator, e.g., CNS disorder target modulator.
  • target modulator includes compounds or compositions, e.g., pharmaceutical compositions, which are used to modulate a target, e.g, a CNS disorder target, e.g., a sleep disorder target
  • modification include controlling or adjusting physical or chemical parameters, e.g., the half-life, of the therapeutic compound in vivo by changing one or more factors, e.g., the lipophilicity, electronic properties and/or steric size of the drug activity modulating moiety, e.g., ester group.
  • spacer molecule or “SP” includes molecules or moieties that are positioned within the compound to allow the compound to perform its intended function.
  • the spacer molecule may be present. Alternatively, in certain other embodiments, the spacer molecule may not be present.
  • the spacer molecule may be (CH 2 ) m , where m is an integer number selected from 1 to 20.
  • the spacer molecule e.g., the (CH 2 ) m linker to an ester or a carboxylic acid group, can be substituted with one or more substituents.
  • the spacer molecule is mono-substituted. In another embodiment of the invention, the spacer molecule is disubstituted.
  • the linkers of the invention may be geminally-dialkylated, e.g., gem-dimethylated, singly substituted with a substituent other than a noncyclic alkyl group, e.g., a heteroatom, or a cyclic substituent wherein one or more of the carbons of the spacer molecule is contained in the ring, e.g., heterocycle (e.g., tetrahydropyran or tetrahydrofuran), or cyclic alkyl, e.g., cyclopropyl.
  • the substitution of the spacer molecule is independent of the substitution elsewhere in the molecule.
  • target includes a receptor or group of receptors that have been identified as useful point of action for a therapeutic compound, e.g., CNS target, e.g., sleep disorder target, e.g., histamine receptor.
  • CNS target e.g., sleep disorder target, e.g., histamine receptor.
  • receptor includes specific sites of binding or action within a subject, associated or responsible for the activity of the target disorder, e.g., a histamine or adenosine receptor.
  • group of receptors includes two or more receptors that may comprise the same receptor type or may comprise two or more receptor types.
  • the therapeutic compound of the invention may comprise the formula: [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a compound that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • the CNS disorder is a sleep disorder.
  • the therapeutic compound of the invention may comprise one of the formulae: [ AD] ⁇ ( SP ) n ⁇ [EG] [ AH] ⁇ ( SP ) n ⁇ [DA ], or [ AH] ⁇ ( SP ) n ⁇ [EG] wherein AH is a compound that antagonizes a histamine receptor or a collection of histamine receptors, AD is a compound that agonizes an adenosine receptor or a collection of adenosine receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • compounds that agonize a receptor, e.g., agonizes an adenosine receptor, are intended to include compounds that induce the activity of the receptor and agents that up-regulate (i.e., induce) the synthesis or production of the receptor.
  • a receptor e.g., a histamine receptor
  • compounds that antagonize are intended to include compounds that inhibit the activity of the receptor and agents that down-regulate (i.e., inhibit) the synthesis or production of the receptor.
  • adenosine receptor agonist is intended to include art recognized allosteric and nonallosteric adenosine receptor agonists, including, but not limited to cyclohexyladenosine, pentostatin, conformycin, and purine and adenyl derivatives that useful as adenosine precursors for the enhancement of adenosine synthesis.
  • Adenosine has been reported to have cardioprotective and neuroprotective properties. It is reportedly released from cells in response to alterations in the supply of or demand for oxygen, is said to be a potent vasodilator, and is believed to be involved in the metabolic regulation of blood flow.
  • adenosine has a short half-life ( ⁇ 1 sec) in human blood, and therefore high doses of adenosine would need to be administered continuously to achieve effective levels.
  • high doses of adenosine have been reported to be toxic, and thus limit its therapeutic potential. It is also believed that by increasing adenosine concentration locally, i.e., at the target site within the target tissue, the beneficial effects of adenosine can be provided and the toxic systemic effects minimized.
  • the therapeutic compounds of formula [AD] ⁇ (SP) n ⁇ [EG], described above may be used in the methods of the current invention to increase the local adenosine concentration.
  • antihistamine antagonist is used interchangeably and are intended to include any compound that antagonizes a histamine or group of histamine receptors.
  • the compound of the invention will bind to a histamine receptor with an affinity of less than about 100 ⁇ M, e.g., less than about 10 ⁇ M.
  • antihistamines of the present invention contain at least two aryl rings that are separated by about 2-5 atoms from a basic nitrogen atom in specific embodiments, the two aryl rings are connected to the same atom.
  • the language “histamine antagonist” is intended to include art-recognized antihistamines, including both first and second generation antihistamines.
  • the antihistamines of the invention include, but are not limited to, antihistamines such as ethylenediamines, ethanolamines, alkylamines, phenothiazines, piperazines, piperdines, ketotifen, ebastine, terfenadine, acrivastine, triprolidine, doxepin, amitriptyline, triipramine, protriptyline, nortriptyline, desipramine, pheniramine, diphenhydramine, mequitazine, cyproheptadine, clemastine, diphenylpyraline, promethazine, homochlorocyclizine, alimemazine, mepyramine, methapyraline, peroxatine, trazodone, nefazodone, hydroxyzine, meclizine loratidine, azelastine, levocabastine, cetirizine, fexofenadine, mi
  • Classes of antihistamines of the instant invention also include pheniramine-like compounds, doxepin-like compounds, diphenhydramine-like compounds, triprolidine-like compounds, pheniramine analogs, and acrivastine analogs (see for example, Tables 2 and 3). It should be understood that the classes of antihistamines can be substituted or unsubstituted. In addition, the substituent(s) is selected and positioned within the molecule such that the compound is able to perform its intended function. Specific examples and locations of the substituents are discussed below.
  • pheniramine-like compounds is intended to include antihistamines that include two aryl groups linked to the same atom, not linked through a tricyclic ring system.
  • pheniramine-like compounds are distinguished from diphenhydramine-like compounds by the lack of an oxygen atom linking the carbon atom, which is attached to the aryl groups, to a piperidine ring.
  • the pheniramine-like compounds are represented by Formula (I) and Formula (II): wherein a 0 through 5, b 0 through 5, and R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.
  • diphenhydramine-like compounds is intended to include antihistamines that include two aryl groups linked to the same atom, not linked through a tricyclic ring system, and are distinguished by the presence of an oxygen atom linking the carbon atom, which is attached to the aryl groups, to a piperidine ring.
  • doxepin-like compounds is intended to include analogs of doxepine or antihistamines that include two aryl groups linked to the same atom that are linked through a tricyclic ring system, e.g. a seven membered ring (i.e., similar to that of doxepine).
  • doxepin-like compounds may posses a piperidine ring or the ring can be replaced by a linear structure, e.g., an alkylene group (i.e., similar to that of doxepine).
  • the doxepin-like compounds are represented by Formula (VI): wherein the dashed line represents a single or double bond; R 1 and R 2 are substituents that are selected such that the compound can perform its intended function, e.g., substituents that are described for antihistamines; X 1 is O, S, H, or CH 2 and n 1 to 6. In one embodiment, n is 1 to 4. In a specific embodiment, n is 1, 2, or 3.
  • triprolidine-like compounds is intended to include antihistamines that include two aryl groups linked to the same atom, not linked through a tricyclic ring system, and are distinguished by the presence of a pyrrolidine ring.
  • the (CH 2 ) m linker to the ester or carboxylic acid group can be substituted with one or more substituents.
  • acrivastine analogs is intended to include the particular embodiment of Formula (IV), wherein the side chain that contains the CO 2 R is an acrylate, e.g., acrylic acid (as depicted in Scheme 1).
  • pheniramine analogs is intended to include antihistamines that include two aryl groups linked to the same atom, not linked through a tricyclic ring system.
  • pheniramine analogs are distinguished by the presence of a dimethylamine moiety.
  • the (CH 2 ) m linker to the ester or carboxylic acid group can be substituted with one or more substituents.
  • an antihistamine of the instant invention may be substituted by one or more substituents, which are selected and positioned within the molecule such that the compound is able to perform its intended function.
  • the substituent(s) can be located on any available position, such as, the aryl rings, the spacer molecule, the drug activity modulating moiety, any branching moieties, or on other substituents.
  • Exemplary substituents include substituted or unsubstituted alkyl, alkenyl, alkynyl, and aromatic or aryl moieties as defined herein.
  • the antihistamines of the invention may be substituted by substituents including, but not limited to, hydrogen; halogen, e.g.
  • the aryl rings may be substituted with one or more substituents, each of which may be different or the same, and include, for example, hydrogen, halogens, alkyl, fluoroalkyl, e.g., trifluoromethyl, hydroxy, alkoxy, and other substituents, such as, —(O) u —(CH 2 ) t —C(O)OR 4 , —(O) u —(CH 2 ) t —OC(O)R 4 , —(O) u —(CH 2 ) t —C(O)—NR 5 R 6 or —(O) u —(CH 2 ) t —NHC(O)O—R 4 wherein: t is an integer, such as an integer from zero to about three, and the methylene group —(CH 2 ) t — can be substituted or unsubstituted; and R 4 , R 5 or R 6 are independently hydrogen, an integer, such as an
  • Suitable substituents on an aliphatic group, aromatic group (carbocyclic and heteroaryl), non-aromatic heterocyclic ring or benzyl group include, for example, an electron withdrawing group, a halogen, azido, cyano, fluoroalkyl, e.g., trifluoromethyl, carboxylic acid, hydroxy, —CONR 8 R 9 , —NR 8 R 9 , —OS(O) 2 NR 8 R 9 , —S(O) 2 NR 8 R 9 , sulfonic acid, sulfonamide, guanidino, —(O) u —(CH 2 ) t —C(O)OR 4 , —(O) u —(CH 2 ) t —OC (O) R 4 , —(O) u —(CH 2 ) t —C(O)—NR 5 R 6 , —(O) u —(CH 2 )
  • a substituted non-aromatic heterocyclic ring, benzyl group or aromatic group can also have an aliphatic or substituted aliphatic group, as a substituent.
  • a substituted aliphatic group can also have an oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group as a substituent.
  • a substituted non-aromatic heterocyclic ring can also have ⁇ O, ⁇ S, ⁇ NH or ⁇ N(aliphatic, aromatic or substituted aromatic group) as a substituent.
  • a substituted aliphatic, substituted aromatic, substituted non-aromatic heterocyclic ring or substituted benzyl group can have more than one substituent.
  • Acyl groups include substituted and unsubstituted aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl and aromatic sulfonyl.
  • Suitable electron withdrawing groups include, for example, alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters, —CH ⁇ NH, —CN, —NO 2 and halogens.
  • the therapeutic compound has a favorable biological property.
  • the invention is a method of treating a sleep disorder. The method comprises administering an effective amount of an antihistamine compound, such that the sleep disorder is treated, wherein the antihistamine compound has a favorable biological property (FBP).
  • FBP favorable biological property
  • favorable biological property includes one or more biological properties that allow the compound to perform its intended function in an enhanced manner.
  • favorable biological properties include but are not limited to induction of a discrete sleep or hypnotic state, activity of the therapeutic compound for a discrete period of time, penetration through the blood brain barrier into the CNS, e.g., resulting from lipophilicity of substituents or conformational lipophilicity (i.e., lipophilicity as a result of a particular conformation, such as internal salt formation between a carboxylate anion and a protonated amine), modulation of the half-life of the therapeutic compound, in vivo hydrolysis of an ester by esterases that allows sequestration of the therapeutic compound in the CNS, an alteration of charge, an alteration of pharmacology-kinetics, an alteration of log P by a value of 1 or more, increased receptor selectivity, reduced peripheral half-life, the ability to increase dosage, increased peripheral elimination, decreased anti-muscarinic activity
  • the language “FPB” is intended to include a single property or a combination of two or more properties.
  • the therapeutic compound induces a discrete sleep or hypnotic state by penetration into the CNS.
  • the FBP includes increased concentration within the CNS for a discrete period of time as a result of a slower rate of conversion to the corresponding carboxylic acid by in vivo esterase activity within the CNS as compared with the periphery.
  • the FBP includes increased concentration within the CNS for a discrete period of time as a result of the existence of an ionic bond that includes the carboxylate ion of the corresponding carboxylic acid, e.g., zwitterion species formation with a nitrogen atom within the compound or salt bridge formation.
  • the FBP is a reduced ability of the subject to form a tolerance to the therapeutic compound.
  • tolerance includes the natural tendency of a subject to become less affected by continued administration of a particular therapeutic compound due to repeated exposure to the compound. It should be noted that tolerance is typically increased coincident with the increased time that a compound is present in its active state within the subject. Reduced tolerance would coincide with increased therapeutic effectiveness.
  • discrete sleep or hypnotic state include a state of consciousness that is induced by the presence of active therapeutic compound of the invention, for a defined period of time. This is in contrast to the lingering hangover effect resulting from the existing treatments, e.g., antihistamines, used for their sedative effect that maintain active drug concentrations for extended periods of time in the periphery.
  • discrete period of time includes a defined period of time in which the therapeutic compound is active, and depends upon the physical and reactive properties of the ester group.
  • the half-life of the therapeutic compound is 1 to 8 hours. In a preferred embodiment, the half-life of the therapeutic compound is 6 hours.
  • the language “sequestration” includes having enhanced concentration in the CNS and more rapid elimination from the periphery.
  • the product of hydrolysis can exit the brain by various carboxylate excretion mechanisms, possibly at a slower rate than from the periphery producing a CNS sequestration of the carboxylate for a defined, or discrete, period of time.
  • elimination of the hydrolyzed carboxylate-containing metabolite occurs predominately by excretion though the kidneys, due to enhanced polarity of the metabolite, either as the free carboxylate or after Phase II further metabolism.
  • elimination occurs predominately by metabolism in the liver, e.g. hydrolysis of the ester followed by glucuronidation, and excretion into the bile.
  • the brain assists in the elimination.
  • Another embodiment of the current invention is a method of modulating a sleep disorder target comprising administering to a subject an effective amount of a therapeutic compound, such that the therapeutic compound penetrates into the CNS and modulates the sleep disorder target, wherein the therapeutic compound is as described above and comprises any one of the following formulae: [ CA] ⁇ ( SP ) n ⁇ [DA], [ CA] ⁇ ( SP ) n ⁇ [EG], [ AD] ⁇ ( SP ) n ⁇ [EG], [ AH] ⁇ ( SP ) n ⁇ [DA], or [ AH] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, AD is a moiety that agonizes an adenosine receptor or a collection of adenosine receptors, AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, DA is a drug activity modulating moiety
  • the invention is a CNS disorder target modulator comprising the formula: [ CA] ⁇ ( SP ) n ⁇ [DA], or [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • Another embodiment of the invention is a sleep disorder target modulator comprising the formula: [ CA] ⁇ ( SP ) n ⁇ [EG] wherein CA is a moiety that modulates an active CNS target receptor or a collection of active CNS target receptors, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • a sleep disorder target modulator comprises the formula: [ AH] ⁇ ( SP ) n ⁇ [DA ] or [ AH] ⁇ ( SP ) n ⁇ [EG] wherein AH is a moiety that antagonizes a histamine receptor or a collection of histamine receptors, DA is a drug activity modulating moiety that provides the ability to modulate the activity of the therapeutic compound, EG is an ester group that modifies the half-life of the therapeutic compound, SP is a spacer molecule, and n is 0 or 1.
  • pheniramine-like therapeutic compound used for treating CNS disorders e.g., sleep disorders
  • a 0 through 5
  • b 0 through 5
  • R is H or any group which imparts properties to the therapeutic compound to promote penetration into the CNS and to modify the half-life of the compound.
  • R is a bulky ester.
  • the compound of the invention is doxepin, pheniramine, diphenhydramine, triprolidine, or acrivastine.
  • An additional embodiment of the invention is the composition of several analogs of doxepin and acrivastine.
  • the structures of several compounds, as well as their activity, are shown in Scheme 1. These compounds have demonstrated anti-H1 activity related to other antihistamine compounds of the invention.
  • the doxepin-like therapeutic compound is represented by the following formula: wherein
  • the R 1 substituents will alter the in vivo half-life of the drug.
  • the R 2 substituents enhance the H1 receptor binding affinity.
  • the spacer molecule e.g., the (CH 2 ) m linker to the carboxylic acid group, can be substituted with one or more substituents.
  • the spacer molecule is mono-substituted. In another embodiment of the invention, the spacer molecule is disubstituted.
  • the linkers of the invention may be geminally-dialkylated, e.g., gem-dimethylated, singly substituted with a substituent other than a noncyclic alkyl group, e.g., a heteroatom, or a cyclic substituent wherein one or more of the carbons of the spacer molecule is contained in the ring, e.g., heterocycle (e.g., tetrahydrofuran or tetrahydropyran), or cyclic alkyl, e.g., cyclopropyl.
  • the substitution of the spacer molecule is independent of the substitution at the R 1 and R 2 positions.
  • the compound of the invention is not a doxepin-like compound of Formula (V), wherein the alkylene spacer molecule is unsubstituted, and R 1 and R 2 are selected from the group consisting of H, halogen CF 3 , OH, C 1-6 alkyl, C 1-6 alkoxy.
  • R 1 and R 2 are not both H when the alkylene spacer molecule is unsubstituted.
  • n is not 2 or 3 when the spacer molecule is unsubstituted.
  • Another embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutic compound as prepared according to the methodology of this invention, and a pharmaceutically acceptable carrier.
  • the therapeutic compounds of the invention for treating CNS disorders are selected from Table 2.
  • the therapeutic compounds of the invention for treating CNS disorders are selected from Table 3.
  • the invention is intended to include any novel compounds, including compounds prepared as intermediates, described herein.
  • the scope of the present invention is also intended to include the existence of stereocenters within the compounds of the invention, including compounds in both their racemic and stereoisomer enriched forms.
  • the compounds described above are intended to include analogs containing art-recognized substituents that do not significantly effect the analog's ability to perform its intended function.
  • any novel synthesis of the compounds of the invention described herein is also intended to be included within the scope of the present invention.
  • Assays can be used to design and/or select compounds useful within the present invention.
  • the SCORE method, described in Example 9, would be an example of such an assay.
  • Multiple assay components such as total sleep time, cumulative nonREM sleep profile, maximum nonREM sleep bout length, average nonREM sleep bout length, nonREM sleep time, nonREM onset of action profile, sleep latency, REM sleep time, REM sleep bout length, cumulative REM sleep profile, maximum wake bout length, average wake bout length, locomotor activity, locomotor activity intensity, body temperature, and drinking are used to define compounds that would be useful in the present invention.
  • Antidepressant therapeutic compounds would use the components of total sleep time, cumulative nonREM sleep profile, maximum nonREM sleep bout length, REM sleep time, REM sleep bout length, locomotor activity, locomotor activity intensity, and body temperature for determination of preferred therapeutic compounds.
  • reaction mixture was cooled to room temperature and the mixture was then filtered.
  • the reaction vessel and filter cake were subsequently washed with toluene (50 mL) and the filtered solid was then partitioned between water (125 mL) and ethyl acetate (100 mL). Stirring was required to dissolve the potassium carbonate within the solid and the layers were subsequently separated.
  • the organic layer was dried with Na 2 SO 4 , filtered, and concentrated to yield 2.9 g of starting amine.
  • the toluene layer obtained from washing the reaction vessel and the filter cake was dried with Na 2 SO 4 , filtered, concentrated, and the residue purified by flash chromatography (5/1 heptane/EtOAc) to yield 11.47 g (51%) of 19.
  • the HCl salt of carboxylic acid Ha was prepared in a manner equivalent to that used to prepare 16a-HCl (see experimental for the 16 series).
  • Carboxylic acid 13a was prepared in a manner equivalent to that followed to prepare 16a (see experimental for the 16 series).
  • a mixture of 16b (700 mg), isobutyl alcohol (10 mL), anhydrous THF (5 mL), and sodium hydride (15 mg of a 60% oil dispersion) was prepared in a sealed vial and was shaken at 75° C. for 3 h, and subsequently poured over a H2O/EtOAc two-phase mixture. The aqueous layer was removed and extracted once with EtOAc. The combined organics were dried with Na 2 SO 4 , filtered, and evaporated to dryness. Chromatography over silica gel using 5:1 heptane/EtOAc gave 665 mg of 16e as a colorless oil. The structure of the product was confirmed by 1 H NMR. (Acetate ester 16f was similarly prepared.)
  • 4-(diphenylmethoxy)-1-(ethoxyearbonyl)piperidine (a). 4-(Diphenylmethoxy)-1-(methyl)piperidine (prepared by neutralization of the commercial HCl salt; 4 g, 14.2 mmol, 1 equiv.) in anhydrous toluene (20 mL) was stirred at room temperature under nitrogen. Ethyl chloroformate (4.66 g, 43 mmol, 4.1 mL, 3 equiv.) was added dropwise over 5 minutes, whereupon significant effervescence was noted. The mixture was heated over the course of 1 h to reflux with an oil bath (bath temperature 104° C.).
  • 4-(diphenylmethoxy)piperidine (5) 4-(Diphenylmethoxy)-1-(ethoxycarbonyl)piperidine (4a) (11.45 g, 33.7 mmol) was dissolved in ethanol (72 mL). A cold solution of sodium hydroxide (8.2 g, 205 mmol) in water (12 mL) was added slowly and a small amount of heat was detected. The mixture was heated at reflux for 17 h and then cooled to room temperature. The mixture was subsequently diluted with water (100 mL) and ethyl acetate (100 mL) and stirred for 0.5 h to dissolve the resultant solid.
  • (+/ ⁇ )-Brompheniramine 17 (obtained, by neutralization of the maleate salt; 38 g, 120 mmol) was dissolved in dry THF under nitrogen and the solution was cooled in a dry ice/acetone bath. n-butyllithium (1.6 M, hexanes, 90 mL, 144 mmol) was added dropwise to the reaction mixture to give a red solution. After 2 h of stirring, carbon dioxide was bubbled into the solution as the bath slowly warmed to room temperature. The resulting mixture was stirred overnight and the reaction was quenched with water (500 mL).
  • the aqueous layer was extracted with ethyl acetate (2 ⁇ 500 mL). The organic layer was discarded and the aqueous layer was concentrated to a yellow paste.
  • the paste was digested in sodium hydroxide (1 N, 150 mL) and chloroform (200 mL) and the layers were separated.
  • the aqueous layer was extracted with chloroform (200 mL) and ethyl acetate (2 ⁇ 150 mL).
  • the chloroform layers were concentrated to yield unreacted 17 (17 g, 44%).
  • the ethyl acetate layers were concentrated to 1.4 g of a complex mixture which was discarded.
  • the aqueous layer was concentrated to a thick oil, filtered to remove insoluble solid, and dissolved in ethanol (100 mL) and water (40 mL). The pH was adjusted to 2 by the careful addition of concentrated HCl (about 17 mL). The resulting solution was concentrated, dissolved in 1:1 methanol:ethanol, filtered to remove insoluble NaCl and concentrated to a brown oil (13 g). The oil was purified by column chromatography (8.5/1/0.5 CH 2 Cl 2 /MeOH/triethylamine) to yield 18a as a white solid (3 g, 8%). The structure was confirmed by 1 H NMR, LC/MS, and elemental analysis.
  • Acid 18a (927 mg, 3.26 mmol) was stirred in oxalyl chloride (5 mL) at room temperature for 2 minutes and dry toluene (4 mL) was added to facilitate stirring. After 1 h, the mixture was concentrated. Ethanol (10 mL) and triethylamine (1.35 mL) were added and the dark yellow mixture was stirred overnight. The mixture was then concentrated and partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL).
  • 6-Bromo-2-pyridyl 4-tolyl ketone (3) A solution of 1 (50.02 g, 0.211 mol) was added to a stirred and cooled ( ⁇ 78° C.) solution of 1.6 M n-BuLi/hexanes (132 mL) over a period of 1 h and 20 min. After an additional 15 min at ⁇ 78° C., a solution of p-tolunitrile (25.64 g, 0.219 mol) in anhydrous THF (100 mL) was added rapidly (4 min) and the reaction mixture was stirred for another 4.75 h. During this time the temperature was controlled to rise slowly from ⁇ 78° C. to ⁇ 20° C.
  • Cyclopentyl acrylate Acryloyl chloride (75 mL) was added to a stirred solution of cyclopentanol (88 g, 1 mol) and triethylamine (175 mL) in dry THF (500 mL) at a rate slow enough to prevent overheating of the reaction. The reaction mixture was allowed to stand overnight, filtered through a pad of Celite, evaporated to an oil, and distilled to give cyclopentyl acrylate as a colorless liquid (bp 74-79/ ⁇ 60 mm Hg). The structure of the product was confirmed by 1 H NMR.
  • Ethyl (E)-3-[6-(4-toluoyl)-2-pyridyl]acrylate (5c).
  • a mixture of ketone 3 (16.90 g, 61.2 mmol), triphenylphosphine (1.64 g, 6.25 mmol), tributylamine (15 mL), and ethyl acrylate (16 mL) was stirred and heated (hot bath at 125-135° C.) for 7 h. Two additional aliquots of ethyl acrylate (7 mL each) were added at 4h and 6h. After the reaction was cooled to room temperature, the reaction mixture was poured over water (300 mL) and EtOAc (300 mL).
  • Triprolidine E,E-7c A solution of 25 mL of 1.6 M n-BuLi/hexanes was added to a stirred and cooled (0° C.) suspension of (2-pyrrolidinoethyl)triphenylphosphonium bromide (17.24 g, 39.18 mmol) in dry THF (250 mL) over a period of ⁇ 4 min. The ylide-forming reaction mixture was stirred an additional 10 min at 0° C., followed by the addition of one aliquot of a solution of 5c (4.52 g, 15.3 mmol) in dry THF (75 mL). After stirring at 0° C.
  • Triprolidine E,E-7f Sodium hydride (25 mg of a 60% oil dispersion) was added to a solution of E,E-7c (1.116 g, 2.96 mmol) in cyclopentanol (10 mL) and dry THF (8 mL). After stoppering the reaction flask, the reaction mixture was stirred at room temperature for 1.5 h and quenched by the addition of saturated brine (30 mL). The mixture was extracted twice with EtOAc and the combined organics were dried with Na 2 SO 4 , filtered, and evaporated to dryness. Chromatography over silica gel using MeOH/EtOAc (starting at 2% MeOH) gave 1.04 g of the desired product as a viscous oil. The structure of the product was confirmed by 1 H NMR. (Triprolidine esters E,E-7d was similarly prepared.)
  • Triprolidine acid E,E-7a was prepared in a manner similar to that used to prepare acids 11a, 13a, 15a, and 16a described above.
  • Phenol (2.79 g, 29.63 mmol, 1.1 eq.) was dissolved in 2-butanone (75.0 mL) and potassium carbonate (11.17 g, 80.82 mmol., 3.0 eq.) was added, followed by compound 4 (7.1 g, 26.94 mmol., 1.0 eq.) dissolved in 2-butanone (75.0 mL).
  • a catalytic amount of potassium iodide (0.05 g) was added and the mixture was refluxed overnight. The cooled reaction mixture was filtered and the solids were washed with 2-butanone.
  • the ketone 7, was subjected to McMurray reaction. Accordingly, titanium chloride (4.05 mL, 36.85 mmol.) was slowly added to a mixture of zinc dust (5.31 g, 81.2 mmol., 5.4 eq.) in anhydrous THE (60 mL) at 0° C. The mixture was then refluxed for 2.5 hours. N-carbethoxy-4-piperidone, (5.5 mL, 36.3 mmol., 2.4 eq.) and ketone 7 (3.69 g, 15.12 mmol., 1.0 eq.) were dissolved in anhydrous THF (40.0 mL) and added to the titanium (0) mixture, and the reaction mixture was refluxed for 6 h.
  • Teflon-coated stainless steel wires were positioned under the nuchal trapezoid muscles for EMG recording. All leads were soldered to a miniature connector prior to surgery, and gas sterilized in ethylene oxide. The implant assembly was affixed to the skull with dental acrylic. A minimum of three weeks was allowed for surgical recovery.
  • Each rat was permanently housed in its own individual recording cage located within separate, ventilated compartments of custom-designed stainless steel cabinets.
  • Each Nalgene microisolator cage was enhanced with a filter-top riser and low-torque swivel-commutator. Food and water were available ad libitum.
  • a 24-hr light-dark cycle (12 hours light, 12 hours dark) was maintained throughout the study using 4-watt fluorescent bulbs 5 cm from the cage. Animals were undisturbed for at least 48 hours before and after treatments.
  • the classification algorithm used individually-taught EEG-arousal-state templates, plus EMG criteria to differentiate REM sleep from theta-dominated wakefulness, plus behavior-dependent contextual rules (e.g., if the animal was drinking, it is awake).
  • Drinking and locomotor activity (LMA) were recorded as discrete events every 10 seconds, while body temperature was recorded each minute. Locomotor activity was detected by a telemetry receiver (Minimitter, Sunriver, Oreg.) beneath the cage. Telemetry measures (LMA and body temperature) were not part of the scoring algorithm; thus, sleep-scoring and telemetry data were independent measures.
  • the effect on maximum sleep bout length (a measure of sleep continuity) during the initial 5 hours post-treatment sleep bout versus dose is shown in FIG. 1 ( c ).
  • 11f increased sleep continuity at both 10 and 30 mg/kg doses relative to vehicle control.
  • the treatment effects of Zolpidem are also shown for comparison.
  • FIG. 1 ( a ) A comparison of the total sleep time resulting from 11f (30 mg/kg), the sedative hypnotic positive control standard (Zolpidem, 10 mg/kg), and the vehicle control as a function of time from the administration of the dose is depicted as a time series plot in FIG. 1 ( a ).
  • the time series plot shows the sleep patterns before and after treatment, wherein the arrow indicates the primary soporific effect of 11f.
  • 6f and 15f did not produce REM sleep inhibition or rebound insomnia under the conditions studied.
  • 11f, 6f and 15f are representative novel antihistaminergic soporific chemical compounds of the invention.
  • 11f increased sleep, e.g., sleep time and sleep continuity (sleep bout lengths), in laboratory rats in a dose-dependent fashion.
  • Single doses of 6f and 15f also increased sleep in laboratory rats.
  • binding assays were performed on the Series 11 compounds described above by displacement of known standards from the H1, M1, M2, and M3 receptors, wherein H1 is a histamine receptor, and M1, M2, and M3 are muscarinic receptors.
  • the binding studies against the histamine receptor, H1 indicate binding affinity, and therefore the results of the binding assays are an indication of the activity of the compound.
  • binding studies against the muscarinic receptors indicate the extent to which the compounds bind the muscarinic receptors, responsible for anti-cholinergic activity of the compound. Binding to muscarinic receptors results in several undesired side effects of many known antihistamines, e.g., dry-mouth. A decrease in the binding of the compounds to the M1-M3 receptors, relative the binding of the compound to the H1 receptor, is an indication of the greater specificity of the compound for the histamine receptor over the muscarinic receptor. Moreover, a drug with increased specificity for the histamine receptor would possess less anti-cholinergic side effects.
  • This increased affinity may be an indication of increased water solubility or that the altered ring conformation may have any affect on the steric properties at the carbonyl of the ester, e.g., a beneficial change in the ring conformation due to the presence of the oxygen.
  • the presence of the oxygen may lend itself to alteration of the physical properties of the molecule in other ways, e.g., the electronic properties help to control ester cleavage, or the presence of the oxygen adds to receptor affinity through increased binding interactions with the receptor.
  • Table 4 also indicates that the binding data for the enantiomeric compounds, 11h and 11g, do not result in a substantial difference in binding affinity towards the H1 receptor, but do show a substantial difference in binding affinity towards the muscarinic receptors. This indicates that the muscarinic receptors may have a stereochemical preference, and therefore the selectivity of the receptor may be used to assist in the selection of a therapeutic compound that would provide reduced side effects.
  • binding assays were performed on additional compounds described above by displacement of known standards from the H1, M1, M2, and M3 receptors, wherein H1 is a histamine receptor, and M1, M2, and M3 are muscarinic receptors.
  • the binding studies against the histamine receptor, H1 indicate binding affinity, and therefore the results of the binding assays are an indication of the activity of the compound.
  • binding studies against the muscarinic receptors indicate the extent to which the compounds bind the muscarinic receptors, responsible for anti-cholinergic activity of the compound. Binding to muscarinic receptors results in several undesired side effects of many known antihistamines, e.g., dry-mouth. A decrease in the binding of the compounds to the M1-M3 receptors, relative the binding of the compound to the H1 receptor, is an indication of the greater specificity of the compound for the histamine receptor over the muscarinic receptor. Moreover, a drug with increased specificity for the histamine receptor would possess less anti-cholinergic side effects.
  • the binding assays for H1 was the same as described in Example 10 and the M1, M2, and M3 binding assays are the same as those described in Example 10 for human recombinant expressed cells.
  • the data indicates that the compounds have greater affinity for the H1 receptors as compared with the M1, M2, and M3 receptors, which as described above, indicates that these drugs should result in the reduction of anti-cholinergic side effects.
  • the selectivity for H1 is increased relative other receptors (i.e., resulting highly soporific compounds with fewer unwanted side effects from binding at adrenergic, muscarinic, serotonergic, and other receptors).

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US20070123571A1 (en) * 2003-05-30 2007-05-31 Raj Palaniswamy S Use of a compound in the treatment of sleep disorders
US20080287531A1 (en) * 2004-07-16 2008-11-20 Kyowa Hakko Co., Ltd. Preventive and/or Therapeutic Agent for Sleeping Disorder
CN104447516A (zh) * 2014-12-15 2015-03-25 重庆华邦制药有限公司 一种阿伐斯丁的制备方法
US10420756B2 (en) 2015-03-26 2019-09-24 Sen-Jam Pharmaceutical Llc. Methods and compositions to inhibit symptoms associated with veisalgia
US11464766B2 (en) 2015-03-26 2022-10-11 SEN-JAM Pharmaceutical LLC Methods and compositions to inhibit symptoms associated with veisalgia
CN108558860A (zh) * 2018-06-04 2018-09-21 成都伊诺达博医药科技有限公司 一种合成芜地溴铵的新方法

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WO2003032912A8 (fr) 2004-08-19
US7317026B2 (en) 2008-01-08
EP1443929A4 (fr) 2008-02-06
WO2003032912A2 (fr) 2003-04-24
EP1443929A2 (fr) 2004-08-11
JP2005529840A (ja) 2005-10-06
AU2002347906A2 (en) 2003-04-28
CA2463579A1 (fr) 2003-04-24
US20040142972A1 (en) 2004-07-22
WO2003032912A9 (fr) 2005-01-06

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