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WO1999000346A1 - Synthese de compositions de dihydrohonokiol - Google Patents

Synthese de compositions de dihydrohonokiol Download PDF

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Publication number
WO1999000346A1
WO1999000346A1 PCT/US1998/013265 US9813265W WO9900346A1 WO 1999000346 A1 WO1999000346 A1 WO 1999000346A1 US 9813265 W US9813265 W US 9813265W WO 9900346 A1 WO9900346 A1 WO 9900346A1
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WO
WIPO (PCT)
Prior art keywords
cooh
compound
och
anxiety
composition
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Application number
PCT/US1998/013265
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English (en)
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WO1999000346A8 (fr
Inventor
William B. Stavinoha
Neera Satsangi
Rajiv K. Satsangi
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Board Of Regents, The University Of Texas System
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Publication date
Application filed by Board Of Regents, The University Of Texas System filed Critical Board Of Regents, The University Of Texas System
Priority to AU81689/98A priority Critical patent/AU8168998A/en
Priority to CA002297723A priority patent/CA2297723A1/fr
Priority to EP98931609A priority patent/EP0991614A1/fr
Priority to JP50574599A priority patent/JP2002507211A/ja
Publication of WO1999000346A1 publication Critical patent/WO1999000346A1/fr
Publication of WO1999000346A8 publication Critical patent/WO1999000346A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to the synthesis of dihydrohonokiol, its derivatives, analogs and homologs, and to methods of use for the dihydrohonokiol compounds. Also included are compositions particularly useful for treatment of anxiety disorders.
  • Benzodiapenes can act to counteract anxiety by depressing the electrical afterdischarge in the limbic system, and may possibly inhibit neurotransmission mediated by gamma- aminobutyrate (GABA).
  • GABA gamma- aminobutyrate
  • Saiboku-To A Chinese herbal medicine, Saiboku-To, has long been used to treat a variety of conditions, including anxiety.
  • a disadvantage of Saiboku-To is that it requires approximately seven days or more of daily administration before an anxiolytic effect is observed.
  • Saiboku-Tu is believed to exert its effects through the GABA/benzodiazepine receptors.
  • Saiboku-To is composed of ten herbs. One of these herbs, Magnolia officinalis, has been identified as the major source of anxiolytic activity. The anxiolytic effect has been associated with one component of Magnolia officinalis, honokiol. In studies using mice, a minimum of seven days of oral administration of
  • Saiboku-To was required in order to produce the anxiolytic effect. Seven daily doses of an amount of honokiol equivalent to the honokiol content in Saiboku-To was shown to have an anxiolytic effect equivalent to that of Saiboku-To. The seven day delay in the onset of anxiolytic activity of honokiol was thought to be due to either changes in receptors or a slow build-up of metabolites of honokiol within the body.
  • the invention also includes a method of treating anxiety disorders with dihydrohonokiol, its derivatives, analogs and homologs.
  • This method comprises administration of an anxiolytic amount of a suitable composition containing dihydrohonokiol, its derivatives, analogs and homologs, to a subject in need thereof. Administration is preferably by oral dosage.
  • the treatment may be maintained as long as necessary and may be used in conjunction with other forms of treatment.
  • the invention relates to synthetic methods for producing dihydrohonokiol and its various derivatives.
  • the compounds may be synthesized from honokiol derived from plant sources.
  • the inventors have accomplished total synthesis from the asymmetric coupling of 4-allylphenylalkyl ether with 4-alkoxy haloaryls, followed by dealkylation of the dialkoxyl biaryl formed.
  • compositions comprising the novel dihydrohonokiol, its derivatives, analogs and homologs.
  • the composition comprises at least dihydrohonokiol.
  • the composition may further comprise a second dihydrohonokiol, its derivatives, analogs or homologs, or one or more other pharmacologically-active compounds, and particularly one or more anxiety-altering comounds.
  • the methods of the invention may thus entail the administration of one, two, three, or more, of the new dihydrohonokiol, its derivatives, analogs and homologs.
  • the maximum number of species that may be administered is limited only by practical considerations, such as the particular effects of each compound.
  • compositions employing the novel compounds will contain a biologically effective amount of the compounds.
  • a biologically effective amount of a compound or composition refers to an amount effective to alter, modulate or reduce anxiety or related conditions.
  • a satisfactory result may be obtained employing the compounds in an amount within the range of from about 0.001 mg/kg to about 50 mg/kg, preferably from about 0.005 mg/kg to about 35 mg/kg and more preferably from about 0.01 mg/kg to about 20 mg/kg alone or in combination with one or more additional anti-anxiety compounds in an amount within the range from about 0.001 mg/kg to about 50 mg/kg, preferably from about 0.005 mg/kg to about 35 mg/kg and more preferably from about 0.01 mg/kg to about 20 mg/kg both being employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
  • compositions that provide dihydrohonokiol in accordance with the present invention will be compositions that preferably comprise dihydrohonokiol, either 3-n.- propyl-5'-(2-propenyl)-l,l'-biphenyl-2',4-diol (I) or 5'-n.-propyl-3-(2-propenyl)-l,l'- biphenyl-2',4-diol (II).
  • compositions may comprise any ratio of the two isomers such as 10-90% of I or II and 90-10% of II or I. Of course other derivatives of I or II may be preferable, depending on their particular physical properties and physiological effects.
  • compositions of the invention may include a dihydrohonokiol, its derivatives, analogs and homologs, modified to render it biologically protected.
  • Biologically protected compounds have certain advantages over unprotected compounds when administered to human subjects and, may exhibit increased pharmacological activity. It will also be understood that, if desired, the disclosed dihydrohonokiol, its derivatives, analogs and homologs, could be administered in combination with additional agents, such as, e.g., proteins or polypeptides or various pharmaceutically active agents.
  • the composition comprises a dihydrohonokiol, its derivatives, analogs and homologs
  • additional agents do not cause a significant adverse effect upon contact with the target cells or host tissues.
  • the dihydrohonokiol, its derivatives, analogs and homologs may thus be delivered along with various other agents as required in the particular instance.
  • the pharmaceutical compound(s) alone or in combination with one or more anxiety-modulating compounds may be administered to mammalian species, such as monkeys, dogs, cats, rats and humans, and as such may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable.
  • the above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), antioxidants (ascorbic acid of sodium bisulfite) or the like.
  • Oral dosage forms are preferred, although parenteral forms such as intramuscular, intraperitoneal, or intravenous are quite satisfactory as well.
  • the dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
  • compositions disclosed herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds may be incorporated with excipients and used in the form of solutions, suspensions, elixirs, troches, tablets, pills, capsules, sustained release formulations, powders, syrpus, wafers and the like, and contain about 0.1% to about 95% of active ingredient, preferably about 1% to about 70%.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder as gum tragacanth, acacia, cornstarch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavor
  • any material may be present as coatings or to otherwise modify the physical form of the dosage unit.
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup of elixir may contain the active compounds sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compounds may be incorporated into sustained-release preparation and formulations.
  • Tablets of various sizes can be prepared, e.g., of about 30 to 900 mg in total weight, containing one or more of the active substances in the ranges described above, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. These tablets can, of course, be scored to provide for fractional doses. Gelatin capsules can be similarly formulated. Liquid formulations can also be prepared by dissolving or suspending one or the combination of active substances in a conventional liquid vehicle acceptable for pharmaceutical administration so as to provide the desired dosage in one to four teaspoonfuls. Such dosage forms can be administered to the patient on a regimen of one to four doses per day.
  • the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times. Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances.
  • the respective substances can be individually formulated in separate unit dosage forms in a manner similar to that described above.
  • compositions are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective.
  • quantity to be administered depends on the subject to be treated, including, e.g., age, physical condition and degree of symptoms presented. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are of the order of several hundred micrograms active ingredient per dose. Suitable regimes for initial administration and booster doses are also variable, but are typified by an initial administration followed by subsequent administrations.
  • the methods may thus entail the administration of one, two, three, or more, of the new dihydrohonokiol, its derivatives, analogs and homologs.
  • the maximum number of species that may be applied is limited only by practical considerations, such as the particular effects of each compound.
  • Clinical doses will of course be determined by the nutritional status, age, weight and health of the patient.
  • the quantity and volume of the composition administered will depend on the subject and the route of administration.
  • the precise amounts of active compound required will depend on the judgment of the practitioner and may be peculiar to each individual.
  • the determination of a suitable dosage range for use in humans will be straightforward.
  • compositions that provide dihydrohonokiol in accordance with the present invention will be compositions that preferably comprise dihydrohonokiol, either 3-n.- propyl-5'-(2-propenyl)-l,l'-biphenyl-2',4-diol (I) or 5'-n.-propyl-3-(2-propenyl)-l,l'- biphenyl-2',4-diol (II).
  • compositions may comprise any ratio of the two isomers such as 10-90% of I or II and 90-10% of II or I. Of course other derivatives of I or II may be preferable, depending on their particular physical properties and physiological effects.
  • Biologically protected compounds have certain advantages over unprotected compounds when administered to human subjects and, may exhibit increased pharmacological activity.
  • the disclosed dihydrohonokiol, its derivatives, analogs and homologs could be administered in combination with additional agents, such as, e.g., proteins or polypeptides or various pharmaceutically active agents. So long as the composition comprises a dihydrohonokiol, its derivatives, analogs and homologs, there is virtually no limit to other components which may also be included, given that the additional agents do not cause a significant adverse effect upon contact with the target cells or host tissues.
  • the dihydrohonokiol, its derivatives, analogs and homologs may thus be delivered along with various other agents as required in the particular instance.
  • compositions proposed to be suitable for use in treating anxiolytic disorders may be prepared most readily directly from dihydrohonokiol, its derivatives, analogs and homologs, disclosed herein.
  • the compositions may be prepared as injectables. Either liquid solutions or suspensions, or solid forms suitable for solution or suspension in liquid prior to injection, may also be prepared.
  • the preparation may also be emulsified.
  • the active ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof.
  • the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants which enhance the effectiveness.
  • compositions may be conventionally administered by parenteral injection, for example, either subcutaneously or intramuscularly.
  • Additional formulations which are suitable for other modes of administration include suppositories and, preferably, oral formulations.
  • suppositories traditional binders and carriers may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10%, preferably about 1 to about 2%.
  • the active compounds may also be administered parenterally or intraperitoneally.
  • Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain about 0.1% to about 95% of active ingredient, preferably about 1% to about 70%.
  • the compositions are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective.
  • the quantity to be administered depends on the subject to be treated, including, e.g., age, physical condition and degree of symptoms presented. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are of the order of several hundred micrograms active ingredient per dose. Suitable regimes for initial administration and booster doses are also variable, but are typified by an initial administrationfollowed by subsequent administrations.
  • the manner of application may be varied widely. Any of the conventional methods for administration are applicable. These are believed to include oral application on a solid physiologically acceptable base or in a physiologically acceptable dispersion, parenterally, by injection or the like.
  • the dosage will depend on the route of administration and will vary according to the size, age and sex of the host.
  • liposomes and/or nanocapsules for the introduction of one or more of the disclosed pharmaceutical composition into a host cell.
  • Such formulations may be preferred for the introduction of pharmaceutically-acceptable formulations of the honokiol derivatives and/or analogs disclosed herein.
  • the formation and use of liposomes is generally known to those of skill in the art
  • liposomes were developed with improved serum stability and circulation half-times (Gabizon and Papahadjopoulos, 1988; Allen and Choun, 1987).
  • the disclosed composition may be entrapped in a liposome.
  • Liposomes are vesicular structures characterized by a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium.
  • the term "liposome” is intended to mean a composition arising spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh and Bachhawat, 1991).
  • Nanocapsules can generally entrap compounds in a stable and reproducible way (Henry-Michelland et al, 1987). To avoid side effects due to intracellular polymeric overloading, such ultrafine particles (sized around 0.1 ⁇ m) should be designed using polymers able to be degraded in vivo. Biodegradable polyalkyl-cyano-acrylate nanoparticles that meet these requirements are contemplated for use in the present invention, and such particles may be are easily made, as described (Couvreur et al, 1977; 1988). Methods of preparing polyalkyl-cyano-acrylate nanoparticles containing biologically active substances and their use are described in U.S. Patent 4,329,332, U.S. Patent 4,489,055, and U.S. Patent 4,913,908.
  • compositions containing nanocapsules for the oral delivery of active agents are described in U.S. Patent 5,500,224 and U.S. Patent 5,620,708.
  • U.S. Patent 5,500,224 describes a pharmaceutical composition in the form of a colloidal suspension of nanocapsules comprising an oily phase consisting essentially of an oil containing dissolved therein a surfactant and suspended therein a plurality of nanocapsules having a diameter of less than 500 nanometers.
  • U.S. Patent 5,620,708 describes compositions and methods for the oral administration of drugs and other active agents.
  • the compositions comprise an active agent carrier particle attached to a binding moiety which binds specifically to a target molecule present on the surface of a mammalian enterocyte.
  • the binding moiety binds to the target molecule with a binding affinity or avidity sufficient to initiate endocytosis or phagocytosis of the particulate active agent carrier so that the carrier will be absorbed by the enterocyte.
  • the active agent will then be released from the carrier to the host's systemic circulation. In this way, degradation of the disclosed pharmaceutical compounds in the intestines can be avoided while absorption of compound form the intestinal tract is increased.
  • U.S. Patent 5,641,515 and U.S. Patent 5,698,515 describe the use of nanocapsules for the oral administration of a polypeptide, specifically, insulin and are incorporated herein by reference.
  • U.S. Patent 5,698,515 described insulin containing nanocapsules intended for oral administration of insulin which comprises a hydrophilic polymer modified with an inhibitor of proteolytic enzyme, insulin and water, wherein the inhibitor of proteolytic enzymes is ovomucoid isolated from duck or turkey egg whites.
  • US. Patent 5,556,617 describes the use of nanoparticles as pharmaceutical treatment of the upper epidermal layers by topical application on the skin.
  • octreotide loaded nanocapsules significantly improved the reduction of prolactin secretion and slightly increased plasma octreotide levels (Damge et al, 1997).
  • nanocapsules make them particularly susceptible to lysozyme (LZM), a positively-charged enzyme that is highly concentrated in mucosas.
  • LZM lysozyme
  • This interaction causes destabilization of the nanocapsule by LZM; however, it was observed that the destabilizing effects caused by the adsorption of LZM onto the nanocapsules can be prevented by previous adsorption of the cationic poly(amino acid) poly-L-lysine (Calvo et al, 1997).
  • PECL poly-epsilon-caprolactone
  • the idea is based on a graft copolymer model embodying a link site for attachment to the carrier, a floating pad for maintaining the particles afloat in the blood stream, an affinity ligand for site-specific delivery and a structural tune for balancing the overall structure of the homing device.
  • U. S. Patent 5,451,410 describes the use of modified amino acid for the encapsulation of active agents.
  • Modified amino acids and methods for the preparation and used as oral delivery systems for pharmaceutical agents are described.
  • the modified amino acids are preparable by reacting single amino acids or mixtures of two or more kinds of amino acids with an amino modifying agent such as benzene sulfonyl chloride, benzoyl chloride, and hippuryl chloride.
  • the modified amino acids form encapsulating microspheres in the presence of the active agent under sphere-forming conditions.
  • the modified amino acids may be used as a carrier by simply mixing the amino acids with the active agent.
  • the modified amino acids are particularly useful in delivering peptides, e.g., insulin or calmodulin, or other agents which are sensitive to the denaturing conditions of the gastrointestinal tract.
  • the components of the kit may be provided as liquid solution(s), or as dried powder(s).
  • the liquid solution is an aqueous solution, with a sterile aqueous solution being particularly preferred.
  • the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means.
  • the liquid solution is an aqueous solution, with a sterile aqueous solution being particularly preferred.
  • the dihydrohonokiol, its derivatives, analogs and homologs, may also be formulated into a syringeable composition.
  • the container means may itself be a syringe, or other such like apparatus, from which the formulation may be administered into the body, preferably by injection or even mixed with the other components of the kit prior to injection.
  • the dihydrohonokiol, its derivatives, analogs and homologs, to be administered may be a single compound, or a composition comprising two or more of dihydrohonokiol, its derivatives, analogs and homologs, in a single or multiple dose for administration.
  • one or more dihydrohonokiol, its derivatives, analogs and homologs may be administered consecutively or concurrently with other agents as deemed appropriate by the clinician. Dosage of each of the compositions will vary from subject to subject depending upon severity of conditions, size, body weight, etc. The calculation and adjustment of dosages of pharmaceutical compositions is well-known to those of skill in the art.
  • components of the kit may be provided as dried powder(s).
  • the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means.
  • the container means will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which the dihydrohonokiol, its derivatives, analogs and homologs, may be placed, preferably, suitably allocated. Where two or more of dihydrohonokiol, its derivatives, analogs and homologs, are provided, the kit will also generally contain a second vial or other container into which this additional comound may be formulated. The kits may also comprise a second/third container means for containing a sterile, pharmaceutically acceptable buffer or other diluent.
  • kits of the present invention will also typically include a means for containing the vials in close confinement for commercial sale, such as, e.g., injection or blow- molded plastic containers into which the desired vials are retained.
  • a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow- molded plastic containers into which the desired vials are retained.
  • the vials may be prepared in such a way as to permit direct introduction of the composition into an intravenous drug delivery system.
  • kits of the invention may also comprise, or be packaged with, an instrument for assisting with the injection administration or placement of the ultimate dihydrohonokiol, its derivatives, analogs and homologs, composition within the body of an animal.
  • an instrument may be a syringe, pipette, forceps, measured spoon, eye dropper or any such medically approved delivery vehicle.
  • anxiety is intended to refer to a condition of apprehension, uncertainty, dread, or fear unattached to a clearly defined stimulus accompanied by numerous physiological and psychological symptoms such as tachycardia, dyspnia, tension, restlessness, inattentiveness, and loss of appetite, skeletal motor function, initiative, cognitive logic, short- and long-term memory, and the like.
  • Practice of the method of the present invention can combat, i.e., reduce or alleviate, some, most, or all of these physiological symptoms.
  • a suitable subject to be treated by the present method is an animal, such as a human or other mammal (e.g., house pets such as dogs and cats, or other commercially valuable or domestic animals), which experience anxiety-related symptoms due to some external or internal stimulus that are desirably combatted.
  • the subject is human.
  • the term “treating” includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.
  • antianxiety dose represents an amount of compound necessary to prevent or treat a human susceptible to or suffering from anxiety following administration to such human.
  • the active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.005 to about 500 mg/kg of body weight. In the treatment of adult humans, the range of about 0.05 to about 100 mg/kg, in single or divided doses, is preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • the present compounds are preferably administered orally to humans susceptible to or suffering from anxiety, the compounds may also be administered by a variety of other routes such as the transdermal, parenterally, subcutaneous, intranasal, intramuscular and intravenous routes.
  • Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known in the art.
  • anxiety disorders which may preferredly be treated using an effective amount of a named compound or pharmaceutically acceptable salt thereof include, but are not limited to: Panic Attack; Agoraphobia; Acute Stress Disorder; Specific Phobia; Panic Disorder; Psychoactive Substance Anxiety Disorder; Organic Anxiety Disorder; Obsessive-Compulsive Anxiety Disorder; Posttraumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.
  • the named anxiety disorders have been characterized in the DSM-IV-R. Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed. (1994).
  • the DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides clear descriptions of diagnostic categories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
  • the anxiolytic compounds of the present invention can be administered without significant side effects.
  • the benzodiazepines have side effects including sedation, ataxia, amnesia, dependence, tolerance, and behavioral disturbances. These side effects have not been observed with therapeutic doses of dihydrohonokiol.
  • Homologs and analogs of 3-n-propyl-5'-(2-propenyl)-l,l'-biphenyl-2',4-diol (I) may be generated by converting 4-allylphenyl alkyl ethers to 2-alkoxy-5-allylphenyl metel halides by a directed ortho metalation reaction, which in turn will be reacted with various 4-alkoxyhaloaryls in-situ.
  • UT 2 -92 Pure major component isolated by HPLC purification from hemisynthetic dihydrohonokiols(UT 2 ). Chemically this is 3-n.propyl-5'-(2-propenyl)- l,l'-biphenyl-2',4-diol (I).
  • UT 2 -08 Pure minor component isolated by HPLC purification from hemi synthetic dihydrohonokiols(UT 2 ).
  • the benzodiazepine compound diazepam was used as a positive control for anxiolytic activity in this series of tests because of wide use and its acceptance as representative of the benzodiazepine series of compounds.
  • the time of peak anxiolytic action of diazepam is 0.17 hr (10 min.).
  • the anxiolytic tests in the subsequent series were done on diazepam 10 min. after oral dosing to obtain the peak response.
  • the duration of diazepam following the effective dose of 1 mg/kg orally is shown to be 1 hr. for its anxiolytic activity and 0.17 hr for its effect on motor activity and its detrimental affect on traction (ataxia production).
  • the data for the plus-maze are mean times ⁇ SEM spent in the open arm during the observation period of 5 min.
  • the data for the activity test are mean counts ⁇ SEM during the test period of 5 min. Traction was evaluated by the ability of the mouse to hold on to a bar for 60 sec. The group size was 10 mice. * p ⁇ 0.016 vs vehicle control
  • Flumazenil blocks the motor activity effect of diazepam and significantly decreases the diazepam alteration of traction.
  • UT-2 was given 3 h before testing and diazepam and bicuculline were given 10 min before testing.
  • the data for the plus-maze are mean times ⁇ SEM spent in the open arms during the observation period of 5 min.
  • the data for the motor activity are mean counts ⁇ SEM during the test period of 5 min. Traction was evaluated by the ability of the mouse to hold on to a bar for 60 sec. The group size was 10 mice. * p ⁇ 0.5 vs control vehicle.
  • the GABAergic antagonist bicuculline abolished the anxiolytic activity of both UT-2 and diazepam identifying a common effect on the GABAergic system. Bicuculline did not block the effect of diazepam on motor activity or traction.
  • Caffeine is an axiogenic agent in high doses and increases motor activity. Given at a high dose with UT-2 caffeine abolished the anxiolytic activity of UT-2. A series of doses would be needed to establish a dose effect curve. Diazepam combined with caffeine resulted in increased anxiolytic activity and motor activity but did not change the ataxia production. TABLE 11 Effect of UT-2, Diazepam and UT-2 plus Diazepam on the Duration of Hexobarbital
  • mice received a sedative dose of hexobarbital.
  • the duration of the loss of righting reflex was recorded.
  • Doses of UT-2 up to 2 mg/kg which is 10 times the effective anxiolytic doses caused no increase in sleep time.
  • Diazepam at the effective anxiolytic dose of 1 mg/kg increased sleep time significantly.
  • time spent at the site of six days prior administration of the drug was observed.
  • the time spent at the site of administration following diazepam was significantly increased over saline administration.
  • the time spent at the site following UT-2 administration was no different from that of saline administration.
  • UT-2 was given 0.2 mg/kg po 3 h before the test. Diazepam 1.0 mg/kg po and CCK 50 ug/kg ip were given 10 min before the test.
  • the data for the plus-maze test are mean ⁇ SEM time spent in the open arms during the 5 min observation period.
  • the data for the motor activity are mean counts ⁇ SEM during the 5 min test period. Traction was evaluated by the ability of the mouse to hold on to a bar for 60 sec. The group size was 10 mice. * ? ⁇ 0.008 vs UT-2 alone.
  • CCK is cholecystokinin Ac-fragment 26-29 amide non-sulfated.
  • CCK Cholecystokinin
  • the data for the plus-maze are mean times ⁇ SEM spent in the open arms during the 5 min observation period.
  • the data for the motor activity are mean coutns ⁇ SEM during the 5 min test interval.
  • the group size was 10 mice. *p ⁇ 0.05 vs CCK # p ⁇ 0.05 vs control vehicle.
  • CCK is cholecystokinin Ac-fragment 26-29 amide non- sulfated.
  • UT-2 consists of two isomers in the ratio of 92:08. These isomers were separated and their anxiolytic activity compared using a modified elevated plus maze.
  • the major modification change from the maze used in the previous studies was the use of a camcorder placed above and to the side of the maze so that no human observer was visible to the mouse running the maze. This change resulted in an increase in the time that the mouse remained on the transparent arm.
  • the control time increased from 13 seconds to 41 seconds and the treated times also increased.
  • the small amount of the UT-2-08 isomer separated limited our group size to 5 instead of 10 mice.
  • the oral doses were diazepam 1 mg/kg and UT-2-92 isomer and UT-2-08 isomer each at 0.2 mg/kg. Both isomers were active but the UT-2-92 isomer was more active than the UT-2-08 isomer.
  • UT-2-92 was further tested as shown in Tables 17 and 18. Following these studies, the UT-2-92 isomer was chosen as the compound to focus on for development as an anxiollytic drug. Therefore research was initiated on a method for complete synthesis. The 100% pure synthetic UT-2-92 isomer was assigned the name UT-2-92S.
  • the anxiolytic activity of UT-2-92 at an oral dose of 0.2 mg/kg was compared to diazepam at an oral dose of 1 mg/kg using the new elevated plus maze system with camcorder. Both compounds showed significant anxiolytic effect.
  • the rats were divided into four groups depending on their level of ultrasonic vocalization. Each of these groups was divided into an ultrasonic vocalization matched control and drug test group consisting of three rats each. * p ⁇ 0.0001 vs vehicle.
  • the conditioned ultrasonic distress vocalization test for anxiolytic activity in rats was used to compare UT-2-92 to geperone, an anxiolytic of the azapirone class of compounds.
  • the azapirone class of anxiolytics differ structurally and pharmacologically from the benzodiazepines. Their exact mechanism is unknown. The primary action appears to be binding to serotonin receptors in the brain. Only Buspirone is marketed and it is not prescribed often the benzodiazepines being preferred. In this test single pure isomer UT-2-92 reduced vocalization effectively indicating it is effective in aversive conditioning test for anxiolytic activity.
  • EXAMPLE 5 Methods for Assessing Antianxiety Activity of the Disclosed compounds
  • the antianxiety activity of the compounds employed in the method of the present invention is established by demonstrating that the compounds increase punished responding. This procedure has been used to establish antianxiety activity in clinically established compounds.
  • the responding of rats or pigeons is maintained by a multiple schedule of food presentation.
  • responding produces food pellet presentation only.
  • responding produces both food pellet presentation and is also punished by presentation of a brief electric shock.
  • Each component of the multiple schedule is approximately 4 minutes in duration, and the shock duration is approximately 0.3 seconds.
  • the shock intensity is adjusted for each individual animal so that the rate of punished responding is approximately 15 to 30% of the rate in the unpunished component of the multiple schedule.
  • Sessions are conducted each weekday and are approximately 60 min in duration.
  • Vehicle or a dose of compound are administered 30 min to 6 hr before the start of the test session by the subcutaneous or oral route.
  • Compound effects for each dose for each animal are calculated as a percent of the vehicle control data for that animal. The data are expressed as the mean +- the standard error of the mean.
  • the pole prod response-inhibition induced by a compound of this invention may be analyzed and compared with that of a standard antianxiety compound such as diazepam as a measure of antiaggressive potential, and to obtain an indication of the duration of action of the compound.
  • a standard antianxiety compound such as diazepam as a measure of antiaggressive potential

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Abstract

L'invention concerne la synthèse et l'utilisation du composé anxiolytique dihydrohonokiol, ses dérivés, ses analogues et ses homologues. L'invention concerne également un procédé anxiolytique destiné à un mammifère.
PCT/US1998/013265 1997-06-26 1998-06-26 Synthese de compositions de dihydrohonokiol WO1999000346A1 (fr)

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AU81689/98A AU8168998A (en) 1997-06-26 1998-06-26 Synthesis of dihydrohonokiol compositions
CA002297723A CA2297723A1 (fr) 1997-06-26 1998-06-26 Synthese de compositions de dihydrohonokiol
EP98931609A EP0991614A1 (fr) 1997-06-26 1998-06-26 Synthese de compositions de dihydrohonokiol
JP50574599A JP2002507211A (ja) 1997-06-26 1998-06-26 ジヒドロホノキオール組成物の合成

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US60/050,845 1997-06-26

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040532A3 (fr) * 1998-12-31 2000-11-16 Univ Texas Synthese de compositions a base de dihydrohonokiol
CN101279901B (zh) * 2007-12-25 2011-08-17 四川大学 和厚朴酚系列衍生物及其制备方法和用途
WO2012013691A1 (fr) 2010-07-28 2012-02-02 Prous Institute For Biomedical Research, S.A. Dérivés biphényl diols substitués multicibles
US8859540B2 (en) 2002-10-10 2014-10-14 Boehringer Ingelheim Vetmedica Gmbh Use of dihydroimidazolones for the treatment of dogs
WO2014170902A1 (fr) * 2013-04-17 2014-10-23 Ariel - University Research And Development Company, Ltd. Ligands du récepteur cb2 pour le traitement de troubles psychiatriques
WO2016201188A1 (fr) * 2015-06-11 2016-12-15 The Medical College Of Wisconsin, Inc. Composés mito-honokiol et leurs procédés de synthèse et d'utilisation
WO2017070568A1 (fr) * 2015-10-23 2017-04-27 Colgate-Palmolive Company Synthèse améliorée d'honokiol
US9820988B2 (en) 2014-03-24 2017-11-21 Boehringer Ingelheim Vetmedica Gmbh Treatment of epileptic disorders in feline animals
US20220142945A1 (en) * 2019-08-06 2022-05-12 Justin Kirkland Formulations including dihydrohonokiol
US11897910B2 (en) 2015-06-11 2024-02-13 The Medical College Of Wisconsin, Inc. Mito-honokiol compounds and methods of synthesis and use thereof

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* Cited by examiner, † Cited by third party
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WO2006107451A2 (fr) * 2005-02-23 2006-10-12 Univ Emory Derives d'honokiol pour traiter les maladies proliferantes
CN112125805B (zh) 2020-09-11 2022-10-18 北京红惠新医药科技有限公司 水溶性厚朴酚衍生物及和厚朴酚衍生物和其中间体的制备方法、和相关的单羟基保护中间体

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040532A3 (fr) * 1998-12-31 2000-11-16 Univ Texas Synthese de compositions a base de dihydrohonokiol
US8859540B2 (en) 2002-10-10 2014-10-14 Boehringer Ingelheim Vetmedica Gmbh Use of dihydroimidazolones for the treatment of dogs
US8962617B2 (en) 2002-10-10 2015-02-24 Boehringer Ingelheim Vetmedica Gmbh Use of dihydroimidazolones for the treatment of dogs
US9469611B2 (en) 2002-10-10 2016-10-18 Boehringer Ingelheim Vetmedica Gmbh Use of dihydroimidazolones for the treatment of dogs
CN101279901B (zh) * 2007-12-25 2011-08-17 四川大学 和厚朴酚系列衍生物及其制备方法和用途
WO2012013691A1 (fr) 2010-07-28 2012-02-02 Prous Institute For Biomedical Research, S.A. Dérivés biphényl diols substitués multicibles
EP2423181A1 (fr) 2010-07-28 2012-02-29 Prous Institute For Biomedical Research S.A. Dérivés de biphényldiol substitués à cible multiple
US10016373B2 (en) 2013-04-17 2018-07-10 Sharon Anavi-Goffer CB2 receptor ligands for the treatment of psychiatric disorders
WO2014170902A1 (fr) * 2013-04-17 2014-10-23 Ariel - University Research And Development Company, Ltd. Ligands du récepteur cb2 pour le traitement de troubles psychiatriques
US9486419B2 (en) 2013-04-17 2016-11-08 Ariel-University Research And Development Company CB2 receptor ligands for the treatment of psychiatric disorders
US10420774B2 (en) 2014-03-24 2019-09-24 Boehringer Ingelheim Vetmedica Gmbh Treatment of epileptic disorders in feline animals
US9820988B2 (en) 2014-03-24 2017-11-21 Boehringer Ingelheim Vetmedica Gmbh Treatment of epileptic disorders in feline animals
CN108883082A (zh) * 2015-06-11 2018-11-23 威斯康星州医药大学股份有限公司 丝-和厚朴酚化合物及其合成和使用方法
WO2016201188A1 (fr) * 2015-06-11 2016-12-15 The Medical College Of Wisconsin, Inc. Composés mito-honokiol et leurs procédés de synthèse et d'utilisation
US10836782B2 (en) 2015-06-11 2020-11-17 The Medical College Of Wisconsin, Inc. Mito-honokiol compounds and methods of synthesis and use thereof
CN108883082B (zh) * 2015-06-11 2021-10-26 威斯康星州医药大学股份有限公司 丝-和厚朴酚化合物及其合成和使用方法
US11897910B2 (en) 2015-06-11 2024-02-13 The Medical College Of Wisconsin, Inc. Mito-honokiol compounds and methods of synthesis and use thereof
WO2017070568A1 (fr) * 2015-10-23 2017-04-27 Colgate-Palmolive Company Synthèse améliorée d'honokiol
US10053406B2 (en) 2015-10-23 2018-08-21 Colgate-Palmolive Company Synthesis of honokiol
US20220142945A1 (en) * 2019-08-06 2022-05-12 Justin Kirkland Formulations including dihydrohonokiol

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CA2297723A1 (fr) 1999-01-07
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AU8168998A (en) 1999-01-19
WO1999000346A8 (fr) 2000-02-17

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