SYNTHESIS OF DIHYDROHONOKIOL COMPOSITIONS

Abstract: The synthesis and use of the anxiolytic compound dihydrohonokiol, its derivatives, analogs and homologs are disclosed. A method for reducing anxiety in a mammal is also disclosed.

Description: SYNTHESIS OF DIHYDROHONOKIOL COMPOSITIONS BACKGROUND OF THE INVENTION The present application claims priority on co-pending U.S. Provisional Patent Application Serial No. 60/050,845 filed June 26, 1997. The entire text of the above- referenced disclosure is specifically incorporated by reference herein without disclaimer. 1. Field of the Invention 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. 2. Description of Related Art Anxiety and anxiety-related disorders are extremely common. Anxiety-related conditions can be relatively mild or can be sufficiently severe as to be quite disabling. Also noteworthy is that anxiety, while infrequently a "disease" in itself, is an almost inevitable and often exacerbating consequence of many other medical and surgical conditions. Estimates of the number of patients suffering from various anxiety disorders range between 12 and 35 million persons in seven major industrialized nations. The most common treatment for anxiety is to administer one of a class of anxiolytic agents. The most common of these are benzodiapenes such as diazepam and alprazolam. 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). Gilman et al., The Pharmaceutical Basis of Therapeutics 434 (Gilman et al., eds., 7th ed., McMillan Publishing Co., New York 1985). These compounds have proven to be effective at reducing anxiety, but they also have significant side effects (including sedation, ataxia, amnesia, dependence, tolerance, and behavioral disturbances) and act as skeletal muscle relaxers. These side effects can render these compounds unsuitable for many patients, particularly those whose anxiety is coupled to another form of illness. British Patent No. 2 225 325 to Gozzini et al. discloses an opioid peptide with high affinity for delta opioid receptors. Administration of the peptide is said to control pain and the symptoms of depression and anxiety. No mention is made therein of reduced sedative effects. In view of the foregoing, it is an object of the present invention to provide new treatment methods for combatting the effects of anxiety, along with compositions for carrying out the same. 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 metabolic pathway of honokiol has not been established. Magnolol is a positional isomer of honokiol and has been identified as a precursor of the fecal and urinary metabolite tetrahydromagnolol. Tetrahydromagnolol was shown in some mouse experiments to slowly increase to a maximum after 120 hours. A very small amount of another metabolite, dihydromagnolol, was also reported to increase with time. SUMMARY OF THE INVENTION The present invention addresses some of the problems associated with Saiboku- To therapy in general, and honokiol in particular, for treatment of anxiety. The invention provides anxiolytically-active compounds which are active in hours, presumably without the need to be metabolized and allowed to build up within the body. The present invention provides new anxiolytic compounds that do not have the adverse side effects of the benzodiazepines. In particular embodiments, the invention relates to the use of dihydrohonokiol, its derivatives, analogs and homologs, as anxiolytic agents. The inventors have demonstrated that dihydrohonokiol, for example, exerts an anxiolytic effect more rapidly than honokiol and exhibits greater potency and fewer side effects than diazepam, a benzodiazepine anxiolytic. 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. In yet another aspect, the invention relates to synthetic methods for producing dihydrohonokiol and its various derivatives. The compounds may be synthesized from honokiol derived from plant sources. Alternatively, 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. Pharmaceutical Compositions Another aspect of the present invention includes novel compositions comprising the novel dihydrohonokiol, its derivatives, analogs and homologs. In a preferred embodiment the composition comprises at least dihydrohonokiol. It will, of course, be understood that 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. As used herein a "biologically effective amount" of a compound or composition refers to an amount effective to alter, modulate or reduce anxiety or related conditions. For oral administratoin, 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. The 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). Alternatively, 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. The 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. 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. In carrying out the method of the present invention, 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. The pharmaceutical 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. For oral therapeutic administration, 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%. Normally employed excipients may include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit. The amount of active compounds in such therapeutically useful compositions is such that a suitable dosage will be obtained. 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. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, 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. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, 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. According to another modification, in order to more finely regulate the dosage schedule, 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. In formulating the compositions, the active substances, in the amounts described above, are compounded according to accepted pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in the particular type of unit dosage form. 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. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants which enhance the effectiveness. For parenteral administration, e.g., subcutaneously or intramuscularly, the dihydrohonokiol compound(s) will be employed in an amount within the range of from about 0.005 mg kg to about 10 mg/kg and preferably from about 0.01 mg kg to about 1 mg kg, alone or with the additional anti-anxiety compounds in an amount within the range of from about 0.005 mg/kg to about 20 mg kg and preferably from about 0.01 mg/kg to about 2 mg/kg. Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. The formulation should be sufficiently fluid that easy syringeability exists. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Such preparations should be stable under the conditions of manufacture and storage, and ordinarily contain in addition to the basic solvent or suspending liquid, preservatives in the nature of bacteriostatic and fungistatic agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and the like. In many cases, it is preferable to include osmotically active agents, for example, sugars or sodium chloride in isotonic concentrations. Injectable formulations according to the invention generally contain from 0.1 to 5% w/v of active compound and are administered at a rate of 0.1 ml/min/kg. The dihydrohonokiol compound(s) described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination. The formulations as described above may be administered for a prolonged period, that is, for as long as the potential for onset of anxiety remains or the symptoms of anxiety continue. Sustained release forms of such formulations which may provide such amounts biweekly, weekly, monthly and the like may also be employed. A dosing period of at least one to two weeks are required to achieve minimal benefit. Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound as an optionally buffered aqueous solution of, for example, 0.1 to 0.2M concentration with respect to the said active compound. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6), 318, (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient. 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 administration followed 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. 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. However, in light of the data presented herein, the determination of a suitable dosage range for use in humans will be straightforward. The 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). Alternatively, 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. The 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. 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. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants which enhance the effectiveness. The 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. For 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. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. 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. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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. As used herein, "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 NANOCAPSULES In certain embodiments, the inventors contemplate the use of 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 (see for example, Couvreur et al, 1977 which describes the use of liposomes and nanocapsules in the targeted antibiotic therapy of intracellular bacterial infections and diseases). More recently, liposomes were developed with improved serum stability and circulation half-times (Gabizon and Papahadjopoulos, 1988; Allen and Choun, 1987). In one instance, 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 μm) 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. Pharmaceutical 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. Poly(alkyl cyanoacrylate) nanocapsules have been used as biodegradable polymeric drug carriers for subcutaneous and peroral delivery of octreotide, a long-acting somatostatin analogue. The nanocapsules, prepared by interfacial emulsion polymerization of isobutyl cyanoacrylate, were 216 run in diameter and incorporated 60% of octreotide. Nanocapsules were administered subcutaneously and the octreotide-loaded nanocapsules (20 mg/kg) suppressed the insulinaemia peak induced by intravenous glucose overload and depressed insulin secretion over 48 h. When administered perorally to oestrogen-treated rats, octreotide loaded nanocapsules (200 and 100 mg/kg) significantly improved the reduction of prolactin secretion and slightly increased plasma octreotide levels (Damge et al, 1997). The negative surface charge of nanocapsules makes them particularly susceptible to lysozyme (LZM), a positively-charged enzyme that is highly concentrated in mucosas. 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). Calvo et al, 1996 describe the use of poly-epsilon-caprolactone (PECL) microparticles for the ocular bioavailability of drugs. Their study showed that PECL nanoparticles and nanocapsules as well as submicron emulsions are shown to be novel corneal drug carriers, and represent a useful approach for increasing the ocular bioavailability of drugs. An excellent review of nanoparticles and nanocapsular carriers is provided by Arshady 1996. Arshady notes that one of the major obstacles to the targeted delivery of colloidal carriers, or nanocapsules, is the body's own defense mechanism in capturing foreign particles by the reticuloendothelial system (RES). This means that following intravenous administration, practically all nanometer size particles are captured by the RES (mainly the liver). The review describes recent initiatives on the design of macromolecular homing devices which seem to disguise nanoparticles from the RES and, hence, are of potential interest to the targeted delivery of nanocapsular carriers. 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. Yu and Chang, 1996 describe the use of nanocapsules containing hemoglobin as potential blood substitutes. They use different polymers including polylactic acid and polyisobutyl-cyanoacrylate and modify the surface of the nanocapsules with polyethylene glycol (PEG) or with PEG 2000 PE. The surface modified nanocapsules containing hemoglobin survive longer in the circulation. 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. Alternatively, 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. DIAGNOSTIC/THERAPEUTIC KITS Therapeutic kits comprising dihydrohonokiol, its derivatives, analogs and homologs, comprise another aspect of the present invention. Such kits will generally contain, in suitable container means, a therapeutically-effective amount of a pharmaceutically acceptable composition of dihydrohonokiol, its derivatives, analogs or homologs, and a pharmaceutically acceptable excipient. The diagnostic/therapeutic kits comprising the pharmaceutical compositions disclosed herein will generally contain, in suitable container means, a therapeutically-effective amount of dihydrohonokiol, its derivatives, analogs and homologs, in a pharmaceutically acceptable excipient. The kit may have a single container means that contains the dihydrohonokiol, its derivatives, analogs and homologs, and a suitable excipient or it may have distinct container means for each compound. The components of the kit may be provided as liquid solution(s), or as dried powder(s). When the components are provided in a liquid solution, the liquid solution is an aqueous solution, with a sterile aqueous solution being particularly preferred. When reagents or components are provided as a dry powder, 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. When the components of the kit are provided in one or more liquid solutions, 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. In which case, 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. Alternatively, 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. In an alternate embodiment, components of the kit may be provided as dried powder(s). When reagents or components are provided as a dry powder, 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. The 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. Alternatively, the vials may be prepared in such a way as to permit direct introduction of the composition into an intravenous drug delivery system. Irrespective of the number or type of containers, the 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. Such an instrument may be a syringe, pipette, forceps, measured spoon, eye dropper or any such medically approved delivery vehicle. ANXIETY As used herein, the term "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. Preferably, the subject is human. As used herein 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. The term "antianxiety dose", as used herein, 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. However, it will be understood that 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. While 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. Examples of 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, including dihydrohonokiol, its derivatives, analogs and homologs, in contrast to the benzodiazepines, 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. In tests in mice maximum anxiolytic activity of dihydrohonokiol was observed three hours after oral administration. This contrasts with up to at least seven days for anxiolytic activity to manifest in mice treated with honokiol. The novel dihydrohonokiols shown below have been synthesized. The structures are shown in I and II: 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. Similarly, various substituted-phenyl alkyl ethers will be converted to 2-alkoxy-substituted phenyl metel halides and be reacted in-situ with various 3-allyl-4-alkoxyhalophenyls to generate the homologs and analogs of 5'-n- propyl-3-(2-propenyl)-l,l'-biphenyl-2',4-diol (II). The last step in the synthesis of I and/or II is the removal of ether linkage and the deprotection of phenol groups. Derivatives of dihydrohonokiol that may be prepared with this synthesis include but are not limited to: where R is -CH 2 -CH=CH 2 , CH=CH-CH 3 , or -CH 2 -CH 2 CH 3 . X is 5'-CH=CH 2 ; 5'-CH 2 -CH 3; 5'-CH=CH 2 , 3'-OH; 5'-CH 2 -CH=CH 2 .5'-CH 2 -CH 2 -CH 3 . 5'-CH 2 -CH=CH 2 , 3'-OH; 5'-CH 2 -CH 2 -CH 3 , 3'-OH; 5'-CH 2 -CH=CH 2 ' 3'-OCH 3 .5'-CH 2 - ' CH 2 -CH 3 , 3'-OCH 3; 5'-CH=CH-CH 3 , 3'-OH; 5'-CH=CH-CH 3 , 3'-OCH 3 .5'-CH 3 .5'- CH(CH 3 ) 2; 5'-CH 2 CH(CH 3 ) 2 .5'-C(CH 3 ) 3 .5'-CH(CH 3 ) 2 C 2 H 5 .5'-(l-adamantyl); 5'- CH(CH 3 ) 2 ' , 6 -CH 3 .5'-CH(CH 3 ) 2ι 4 -CH 3; ' 5'-C(=O)-CH 3 .5'-C(-OH)-CH 3 .5'-CH 2 -C(=O)- CH 3 .5'-CH 2 .C(-OH)-CH 3 .5'-CH 2 -COOH; 5'-CH 2 CH 2 -COOH; 5'-CH 2 CH 2 CH 2 -COOH; 5'-CH 2 -COOH, 3-OH; 5'-OH; 5'-OCH 3; 3'-F; 4'-F; 5'-F; 3'-F, 5'-CH 3 ; 3'-F, 5'-CH 2 -CH 3 ; 3'-F, 5'-CH 2 -OH; 3'-F, 5'-CH 2 -CH 2 -OH; 3'-F, 5'-COOH; 3'-F, 5'-CH 2 -COOH; 3'-F, 5'- CH=CH-CH 3 ; 3'-F, 5'-CH 2 -CH 2 -CH 3 ; 3'-F, 5'-CH 2 -CH=CH 2 ; 3'-F, 5'-CH 2 -CHF-CH 3 ; 3'- F, 5'-CH 2 -CHF-CH 2 F; 4'-F, 5'-CH 3 ; 4'-F, 5'-CH 2 -OH; 3'-F, 5'-CH 2 -CH 3 ; 6'-F, 5'-CH 2 - CH 3 ; 6'-F, 5'-CH 2 -OH and 6'-F, 5'-COOH; and X' is 3 -CH 3 .3 -CH 2 -CH 3 .3 -CH 2 -CH=CH 2; 3 -CH 2 -CH 2 -CH 3; 3 -CH 2 -CH=CH 2 , 5-OH; 3 -CH 2 -CH 2 -CH 3 , 5-OH; 3 -CH 2 -CH=CH 2 , 5-OCH 3 .3 -CH 2 CH 2 CH 3 , 5-OCH 3 .3 -CH=CH- CH 3 .3 -CH 3> 6-CH(CH 3 ) 2 .3,5 di-CH 3 . 2,6 di-CH 3 .3 -CH(CH 3 ) 2; 3-CH(CH 3 ) 2 6-CH 3; 3 - CH 2 CH(CH 3 ) 2; 3-C(=O)-CH 3 .3-C(-OH)-CH 3; 3-CH 2 .C(=O)-CH 3; 3-CH 2 .C(-OH)-CH 3 .3- COOH, 6-OH; ' 2-COOH; 3-OCH 3; ; 3-CH 2 COOH; 3-CH 2 CH 2 COOH; 3-CH=CHCOOH; 3-CHO, 2-OH; 3-CH 2 OH, 2-OH; 3-CHO, 5-OCH 3 .3-CH 2 OH, 5-OCH 3 .3-CHO, 5-CH 3 ; 3-CH 2 OH, 5-CH 3 ; 3-F; 2F; 2-F, 3-CH 3 ; 6-F, 3-CH 3 ; 5-F, 3-CH=CH-CH 3 ; 5-F,3-CH 2 - CH 2 -CH 3 ; 5-F, 3-CH 2 -CH=CH 2 ; 5-F, 3-CH 2 -CHF-CH 3 and 5-F, 3-CH 2 -CHF-CH 2 F. EXAMPLE 1 ANXIOLYTIC EFFECT OF DIHYDROHONOKIOL Dihydrohonokiol was shown to have an anxiolytic effect when administered to mice. In one study male mice were given a single dose of honokiol, dihydrohonokiol, tetrahydrohonokiol, or diazepam (for comparison) orally in a solution of physiological saline containing Tween-80. Physiological saline containing Tween-80 was administered as a control. Several different doses of the drugs were administered and evaluated. In a second study the time-course of behavioral effects of dihydrohonokiol, diazepam, and vehicle (as control) was assessed. A third study assessed the effect of seven daily oral doses of either honokiol, dihydrohonokiol, or tetrahydrohonokiol twenty-four hours after the final dose was administered. Three tests were used to evaluate the effects of the drugs: the elevated plus-maze test (for anxiety), the activity test, and the traction test (to assess muscle strength). Results of the above experiments demonstrated that dihydrohonokiol had a potent anxiolytic effect after a single dose of 0.2 mg/kg, with maximum effect at 3 hours and duration of effect lasting up to 12 hours after administration. Seven daily oral doses of dihydrohonokiol did not enhance this anxiolytic effect significantly. A single dose of honokiol produced an anxiolytic effect only at a very high dose (20 mg/kg). A single dose of tetrahydrohonokiol did not produce any anxiolytic effect, even at 20 mg/kg. Seven daily oral doses of either honokiol or tetrahydrohonokiol produced an anxiolytic effect. Diazepam at 1 mg/kg produced an anxiolytic effect (lasting no more than 2 hours), but also increased ambulatory activity and disrupted the traction performance. All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. EXAMPLE 2 SYNTHESIS OF DIHYDROHONOKIOLS Nomenclature: UT 2 : mixture of two isomers of dihydrohonokiol [3-n.propyl-5'-(2-propenyl)- l,l'-biphenyl-2',4-diol (I) and 5'-n.propyl-3-(2-propenyl)-l,l'-biphenyl- 2',4-diol (II) in an approximate ratio of 92:8], obtained from the partial hydrogenation of honokiol. 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 ). Chemically this is 5'-n.propyl-3-(2-propenyl)- l,l'-biphenyl-2',4-diol (II) UT 2 -92 S : 3-n.propyl-5'-(2-propenyl)- 1 , 1 '-biphenyl-2',4-diol (I), obtained by the total synthesis as described in this text. UT 2 -08 S: 5'-n.proρyl-3-(2-propenyl)-l,l'-biphenyl-2',4-diol (II) and is obtained by the total synthesis as described in this text. Materials and Methods: 4-Allyl anisole, tert-Butyllithium (1.7 M solution in anhydrous pentane), anhydrous Tetrahydrofuran, anhydrous Dichloromethane, anhydrous Zinc chloride (1.0 M solution in anhydrous diethyl ether), Bis(triphenylphosphine) palladium(II)chloride, Diisobutylaluminum hydride (1.0 M solution in hexane), Hexane, tris-(Triphenylphosphine) rhodium(I) chloride, toluene, deuterated chloroform, tetramethylsilane and florisil were purchased from Aldrich Chemical Co. Milwaukee, Wisconsin. Honokiol was a product of Wako Pure Chemical Industries Ltd., Osaka, Japan. 2-Propyl 4-iodo anisole was a gift from Rann Research Laboratory, San Antonio, Texas. Ammonium chloride, sodium chloride, anhydrous diethyl ether and anhydrous sodium sulphate were purchased from Fisher Scientific, Fair Lawn, New Jersey. HPLC grade Ethyl acetate, Acetone, water and acetonitrile were obtained from Berdick and Jackson Inc., Muskegon, Michigan. Analytical and preparative TLC plates (20 x 20 cm glass plates coated with 250 micron and 1 mm thickness of silica gel (G) were purchased from Analtech Inc., Newark, Delaware. The analytical and preparative high pressure liquid chromatographies were performed on a Milton Roy HPLC equipment consisting of a CM 4000 solvent delivery system, the autoinjector A1000 and the spectro-monitor and the spectro-monitor 3100 variable wavelength detector from LCD Analytical, Riviera Beach, Florida. A reverse phase HPLC column (Econosil C18, lOμ, 250 x 10 mm, Catalog #C231) was purchased from Alltech Associates, Inc. Deerfield, Illinois. The solvent for elution consisted of a mixture of acetonitrile and water (6:4). The elution of the honokiol and its analogs was detected at a wavelength of 280 nm. The chart speed was 0.5 cm/min, solvent flow rate was 5 ml/min and the detection was performed at the sensitivity of AUFS 0.05 and 2.0 (for analytical and preparative use, respectively). The proton magnetic resonance spectra were recorded on a 300 MHz GE QE 300 NMR spectrometer. The samples were dissolved in deuterated chloroform and tetramethylsilane was used as the internal standard. Hemi-synthesis of 3-n.propyl-5'-(2-propenyl)-l,l'-biphenyI-2',4-diol (I, UT 2 92) and 5'-n.propyl-3-(2-propenyl)-l,l'-biphenyI-2',4-diol (II, UT 2 08) from Honokiol: Hydrogen gas was passed for two h with stirring in a solution of tris-(Triphenylphosphine) rhodium(I) chloride (10 mg) in toluene (4 ml) at room temperature. Then, honokiol (20 mg) dissolved in toluene (1 ml) was added slowly into the reaction flask with stirring and the hydrogen gas was passed for another 10 min after the complete addition of honokiol solution. The reaction mixture was stirred overnight at room temperature. The reaction mixture was passed through a column of florisil (5 gm), which was finally washed with 50 ml of dry diethyl ether. The solvents were evaporated to get crude residue which was resuspended in aforesaid HPLC eluant to be injected in the HPLC system for analysis. The HPLC analysis indicated the presence of three peaks as follows- (a) peak 1 : Retention time- 9 min, confirmed to be the starting material (honokiol), recyclable. (b) peak 2 (86.4% based on honokiol consumed): Retention time- 11 min, m/z 268; NMR(CDC1 3 ): δ: 0.994 (t,3H), 1.663 (dt,3H), 2.629 (t,2H), 3.347 (d,2H), 5.03-5.11 (m,2H), 5.90-6.04 (m,lH), 6.88-7.20 (m, 6H) with small shoulders (approximately 8% of total peak 2) at δ 2.55, 3.45 and 5.13. (c) peak 3 (13.6% based on honokiol consumed): Retention time- 14.2 min, m/z 270, confirmed to be tetrahydrohonokiol when compared with the standard. Thus, compounds eluted off under peak 2 were identified as the partial hydrogenation products of honokiol. A careful examination of the aforesaid peak 2 revealed the presence of a very shallow shoulder on the main peak and was thought to be representing the minor component as mentioned above. Using preparative HPLC purification, the minor component was isolated from the main peak and thus both the isomers (I and II) were obtained in very pure form as confirmed by the HPLC analysis. The retention time for isomer I was 11 min and that for the isomer II was 12 min. The major component was assigned the structure as 3-n.propyl-5'-(2-propenyl)-l,l'-biphenyl- 2',4-diol (I,UT 2 92 approximately 92%) while the minor component was assigned the structure as 5'-n.propyl-3-(2-propenyl)-l,l ' -biphenyl-2',4-diol (II, UT 2 08, approximately 8%). Both isomers were tested for their anxiolytic potency, but 3-n.propyl-5'- (2-propenyl)-l,l'-biphenyl-2',4-diol [isomer, I, UT 2 92]; NMR (CDC1 3 ): δ: 0.994 (t,3H), 1.663 (dt,3H), 2.629 (t,2H), 3.347 (d,2H), 5.03-5.11 (m,2H), 5.90-6.04 (m,lH), 6.88-7.20 (m, 6H)] was found to be far better than 5'-n.propyl-3-(2-propenyl)-l,l'-biphenyl- 2',4-diol (II,UT 2 08). Total Synthesis of 3-n.propyl-5'-(2-propenyl)-l,l'-biphenyl-2',4-diol (I) and 5 ' -n.propyl-3-(2-propenyl)-l,l'biphenyl-2',4-diol (II) 2'4-dimethoxy-3-n.propyl-5'-(2-propenyI)-l,l'-biphenyl: To a solution of 4-allylanisole (148 mg, 1.0 mmol) in 1 ml anhydrous tetrahydrofuran was added a solution of tert-butyllithiurn in pentane (1.5 mmol; as 0.88 ml of 1.7 M solution in anhydrous pentane) with stirring under the nitrogen atmosphere at -78°C. After two h, the mixture was warmed to -10°C and the solution was reacted with anhydrous zinc chloride (1 ml, 1.0 mmol; as 1.0 M solution in anhydrous diethyl ether). Then, the reaction mixture was stirred at room temperature for 1 h. The palladium catalyst was prepared separately. Thus, an anhydrous hexane solution of diisolbutyl aluminum hydride (0.066 ml, 0.066 mmol; 1.0 M solution in hexane) was added to a solution of bis-(triphenylphosphine)palladium (IΙ)chloride (22 mg; 0.033 mmol) in 1 ml anhydrous tetrahydrofuran with stirring under nitrogen atmosphere. This organic catalyst solution was then reacted with 2-propyl-4-iodoanisole (193 mg, 0.70 mmol) in 2 ml of anhydrous tetrahydrofuran and a solution of the aryl zinc chloride, prepared as above. The mixture was stirred for 2 h at room temperature and then quenched with 5 ml saturated ammonium chloride solution. The aqueous layer was extracted with three 10 ml portions of ethyl acetate. The combined extract was washed once with brine and dried over anhydrous sodium sulphate. After the removal of solvent in vacuo, the crude product was chromatographed on a 1 mm thickness 20 x 20 cm silica gel plate (silica gel G; eluent: Hexane,Ethyl acetate; 9:1) to get 2',4-dimethoxy- 3-n.propyl-5'-(2-propenyl)-l,l'-biphenyl (95 mg, 45.9%; based on the amount of 2-propyl-4-iodoanisole): m/z: 296; 1H NMR (CDC1 3 ): δ: 0.90 (t, 3H, 3-CH 2 .CH 2 .CH 3 ), 1.45 (qt,3H, 3-CH 2 .CH 2 .CH 3 ), 2.53 (t,2H, 3-C CH 2 .CH 3 ), 3.38 (d,2H, 5'-CH 2 .HC=CH 2 ), 3.71 (s, 3H, 4-OCFI 3 ), 3.77 (s, 3H, 2'-OCH 3 ), 4.99 (dd,2H, 5'-CH 2 .HC=CH 2 ), 5.85-5.98 (m, 1H, 5'-CH 2 .HC=CH 2 ), 6.79-7.28 (m, 6H, aromatic H). 3-n.propyl-5'-(2-propenyl)-l,l'-biphenyl-2',4-dioI (I, UT 2 92 S): To a solution of 2',4-dimethoxy-3-n.propyl-5'-(2-propenyl)-l,l'-biphenyl (10 mg: 0.03 mmol) in 1 ml of anhydrous dichloromethane was slowly added a dichloromethane solution of borontribromide (75 microliters, 1M solution in dichlormethane) at -78°C with magnetic stirring for one h. Then, the reaction mixture was stirred at room temperature overnight. Next day, the reaction was cooled and subjected to an aqueous quenching. The aqueous phase was .extracted three times with 2 ml portions of dichloromethane. The combined organic layer was washed once with brine (1 ml) and dried over anhydrous sodium sulfate. The solid was filtered off and the solvent was evaporated under nitrogen. The crude product was chromatographed on a 250 micro thickness 20 x 20 cm silica gel plate (silica gel G; eluent: Hexane, Ethylacetate, 80:20) to get 3-n.propyl-5'-(2-propenyl)-l,l'-biphenyl-2',4-diol (6.5 mg; 72%). In a HPLC analysis, the retention time of total synthetic 3-n.propyl-5'-(2-propenyl)-l,l'- biphenyl-2',4-diol was comparable to that of the hemi-synthetic sample made earlier; and in a mixed co-injection both co-eluted together. The structure was further confirmed by the proton magnetic resonance analysis on a HPLC pure sample. H NMR (CDC1 3 ): δ: 0.994 (t, 3H, 3-CH 2 .CH 2 .CH 3 ), 1.663 (qt,3H, 3-CH 2 .CH 2 .CH 3 ), 2.629 (t,2H, 3-CH 2 .CH 2 .CH3), 3.347 (d,2H, 5'-CH 2 .HC=CH 2 ), 5.03-5.11 (dd,2H, 5'CH 2 .HC=CH 2 ), 5.90-6.04 (m,lH, 5'-CH 2 .HC=CH 2 ), 6.88-7.20 (m, 6H, aromatic H). Using the same methodology, 5 ' -n.propyl-3-(2-propenyl)-l,l ' -biphenyl-2',4-diol (II, UT2-08 S) is also synthesized. Thus, 4-propylanisole is reacted with tert-butyllitbium and anhydrous zinc chloride followed by the coupling with 2-allyl 4-iodo-anisole, in the presence of the aforesaid palladium catalyst, to get 5'-n.propyl-3-(2-propenyl)-l,l'-biphenyl-2',4-diol(II, UT 2 08 S). Hemi-synthesis of 3-n.propyl-5'-(2-propenyl)-l,l'-biphenyl-2',4-diol (I,UT 2 92) and 5'-n.propyl-3-(2-propenyl)-l, -biphenyl-2',4-diol (II, UT 2 08) from Honokiol: Total synthesis of 3-n.propyl-5'-(2-propenyl)- 1 , 1 '-biphenyl-2',4-diol (I, UT 2 92 S) and 5'-n.propyl-3-(2-propenyl)-l,l'-biphenyl-2',4-diol (II, UT 2 08 S) EXAMPLE 3 SYNTHESIS OF ANALOGS AND HOMOLOGS OF DIHYDROHONOKIOL For the synthesis of analogs and homologs of dihydrohonokiol, 4-allylphenyl alkyl ethers are converted to 2-alkoxy, 5-allylphenyl metal halids by a directed orth metalation reaction, which in turn is reacted with various 4-alkoxyhaloaryls in-situ to generate the homogos and analogs of 3-n.propyl, 5'-(2-propenyl)-l,l'-biphenyl-2',4-diol. Similarly, various substituted-phenyl metal halides are reacted in-situ with various 5'- n.propyl,3-(2-propenyl)-l ,1 '-biphenyl-2',4-diol. For example, 4-allylphenyl methyl ether is treated with tert-butyllithium in THF at below freezing temperature. The reasction mixture is transferred toa n etherial solution of zinc chloride. This reaction mixture is trated with a mixture of palladium (o) catalyst (prepared by the reaction PdCl 2 (PPh 3 ) 2 and diisobutyl aluminum hydride) and 2-n.propyl- 4-iodophenyl methyl ether in tetrahydrofuran. The reactoin is quenched with saturated ammonium chloride solution. The organic extraction, followed by chromatographic purification yelds 3-n.propyl-5'-allyl-2',4-bis(methoxy-l,r-biphenyl from a one-pot reaction. The demethylation of this compound, facilitated by a hydrolysis with BB 3 , yielded 3-n.propyl-5'-allyl-l , 1 '-biphenyl-2',4-diol. EXAMPLE 4 TABLE 1 Dose Effect in the Mouse of UT-2 Assessed Using the Elevated Plus-Maze and Motor Activity 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 observation period of 5 min. The group size was 10. *p<0.002 Increasing doses of UT-2 cause an increasing anxiolytic effect- a dose/effect relationship. A 0.2 mg/kg oral dose of UT-2 shows significant anxiolytic effects at 3 hrs post administration, while a higher dose of 1 mg/kg is significantly anxiolytic at only 1 hr. Since we used the 0.2 mg/kg dose orally in this series the tests were performed 3 hrs after dosing of the UT-2 motor activity was unchanged by dose or time except for the 0.2 mg/kg dose at 3 hrs post administration. TABLE 2 Duration of Pharmacological Action Following 0.5 mg/kg UT-2 Given Orally The data for the plus-maze test are rnean times ± SEM spent in the open arm during the observation period of 5 min. The data for the activity test are the mean counts ± SEM during the test period of 5 min. The group size was 10 mice. * p<0.02 vs control vehicle. The duration of anxiolytic activity of UT-2 following an oral dose of 0.5 mg/kg extends for at least 12 hrs post administration, ending between 12 hrs and 24 hrs after oral administration. The anxiolytic activity was not measured between 12 and 24 hrs. This long duration of action indicates the possibility of a one single dose per day schedule. Single dosage greatly improves patient compliance. The motor activity was unchanged. TABLE 3 Duration of Pharmacological Action Following 1.0 mg/kg Diazepam Given Orally The data for the plus-maze test are mean times ± SEM spent in the open arm during the observation period of 5 min. The data for the activity test are the mean counts ± SEM during the test period of 5 min. The group size was 10 mice. * p<0.04 vs control. 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). TABLE 4 Effect of seven days treatment with 0.2mg kg po UT-2 and l.Omg/kg po diazepam 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 Tolerance following chronic use, that is diminished anxiolytic activity requiring increasing doses in long term use, is evaluated in this data. UT-2 and diazepam were given orally each day for 7 days and then the anxiolytic activity was tested. There was no decrease in the effectiveness of either agent. The dose of each compound produced the same anxiolytic activity after 7 days of dosing as occurred after one dose. UT-2 still did not change motor activity. Diazepam still retained its change of motor activity and diminution of traction. TABLE 5 Synergy in the anxiolytic activity of UT-2 and Diazepam UT-2 was given 3 hours before testing and diazepam was given 10 min before testing. The datafor the plus-maze are mean times ± SEM spent in the open arm 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<0.02 vs vehicle control * *p<0.0001 vs UT-2 or diazepam alone #p<0.02 vs UT-2 + diazepam. To establish whether UT-2 and diazepam interact, an effective dose of UT-2 and diazepam were given to separate mice to show the anxiolytic activity of each compound when given alone. The effective dose of each compound given using appropriate timing was then combined mice. The combination of UT-2 and diazepam resulted in a 3 fold increase in anxioyltic activity over either agent given separately. The compounds act synergistically as anxiolytics. The effect of diazepam on motor activity is abolished by combining with UT-2 but UT-2 has no effect on the ataxia produced by diazepam. TABLE 6 The Effect of the Benzodiazepine Receptor Antagonist Flumazenil on the Anxiolytic Effect of UT-2 and Diazepam The time in the open arm of the elevated plus maze was observed during a 5 min period. UT-2 (0.2 mg/kg po) was given 3 h before testing. Diazepam (1 mg/kg po) was given 10 min before testing. Flumazenil (0.3 mg/kg sc) was given 10 min before testing. *P<0.0001 vs the mice pretreated only with diazepam. Flumazenil is a benzodiazepine receptor blocking agent which when given blocks the anxiolytic effects of benzodiazepines. Flumazenil blocks the anxiolytic activity of diazepam but does not block the anxiolytic activity of UT-2. This indicates that UT-2 does not act at the same site as the benzodiazepine anxiolytics. TABLE 7 The Effects of the Benzodiazepine Receptor Antagonist Flumazenil on Motor Activity and Traction Measured Following Administration of Diazepam or UT-2 The data for the activity test are for an observation period of 5 min. The data for the traction test are the mean duration of clinging. UT-2 (0.2 mg/kg po) was given three hours before testing. Diazepam (1 mg/kg po) was given ten min before testing as was flumazenil (0.3 mg/kg sc). *p< 0.01 vs. Control **p< 0.007 vs diazepam alone #p<0.0001 vs control ##p<0.004 vs diazepam alone Motor activity and traction are not changed by UT-2 or flumazenil. Flumazenil blocks the motor activity effect of diazepam and significantly decreases the diazepam alteration of traction. These serious side effects of the benzodiazepine anxiolytics appear to reside in that receptor interaction. TABLE 8 Number of Mice in Groups of Ten Showing Symptoms When Treated with Flumazenil Following 12 Days Administration of Diazepam or UT-2 Saline and Tween 80, UT-2 and Diazepam were given orally once a day for twelve days. The challenge with 10 mg/kg I p Flumazenil followed 24 h after the last treatment. The number represents the number of mice of the ten treated mice showing symptoms during the 20 min observation period following Flumazenil treatment. Hr: hyper-reactivity indicated by vocalization caused by light pressure on the back Tr: tremor Cc: clonic convulsions Tc: tonic convulsions Tf: tail flick Rf: running fit evoked by auditory stimulus To evaluate dependence liability, UT-2 and diazepam were given 12 days. This was followed by administration of flumazenil the benzodiazepine antagonist. No UT-2 antagonist is known. Six signs of withdrawal following flumazenil were observed and recorded. Diazepam showed extensive withdrawal signs following all doses 0.5 mg/kg to 10 mg/kg. UT-2 showed no withdrawal response. The HR response of UT-2 given flumazenil was no different from flumazenil given alone. The 0.5 mg/kg dose of UT-2 followed by flumazenil produced no HR response at all. TABLE 9 The Effect of the G ABA Antagonist Bicuculline Administered with UT-2 and Diazepam 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. TABLE 10 Effect of Caffeine on the Pharmacological Activity of Diazepam and UT-2 UT-2 0.2 mg/kg was given po 3 hr before testing. Diazepam 1.0 mg/kg was given po 10 min before testing. Caffeine 30 mg/kg was given ip 15 min before testing. The time in sec in the open arms is reported as means ± SEM during a 5 min observation period. The motor activity is reported as mean ± SEM for the five min test period. Traction reports the ability of the mouse to hold to a bar for 60 sec mean ± SEM. Group size was 10 mice. *p<0.003 vs UT-2 **p<0.0001 vs diazepam ***p<0.0001 vs control #p<0.0001 vs UT-2 ##p<0.03 vs diazepam + p<0.05 vs vehicle control 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 Induced Sleep All mice received 100 mg/kg hexobarbital ip. UT-2 was given orally 3 h prior to hexobarbital to obtain the maximum anxiolytic effect of UT-2. Diazepam was given 10 min before hexobarbital to obtain the maximum effect. The time from loss of righting reflex in each mouse to the return of the righting reflex was recorded as the sleep duration. *p<0.0003 vs vehicle containing hexobarbital control. To evaluate the sedative effects of UT-2 and diazepam all mice received a sedative dose of hexobarbital. The duration of the loss of righting reflex (ability of the mouse to change from lying on the side to upright posture) 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. UT-2, when combined with diazepam, and hexobarbital, caused no increase in sleep time over that of diazepam plus hexobarbital. TABLE 12 Effect of Diazepam and UT-2 on Learning and Memory UT-2 was given 3 h before testing and Diazepam was given 10 min before testing. Group size was 10 mice * ?<0004 vs control vehicle and saline To test the cognitive effects of UT-2 and diazepam, training latency and retention latency were evaluated. On one of two tests diazepam showe significant retention latency at the effective anxiolytic doses of 1 mg/kg po. In one of two tests UT-2 showed only at 10 times the effective anxiolytic dose a training and retention latency. TABLE 13 The Effect of UT-2 and Diazepam on Conditioned Place Preference Group size was 10 mice *p<0.002 vs saline To evaluate the ability of the drugs to engender a desire to continue the drug, 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. TABLE 14 The Effect of Cck on the Pharmacological Activity of UT-2 and Diazepam 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. Cholecystokinin (CCK) is anxiogenic and its administration is used as a screen for discovery of new anxiolytic agents. CCK in this initial test shows it anxiogenic effect and effectively abolished the anxiolytic effect of UT-2. It had no effect on any of the three effects of diazepam. TABLE 15 The Effect of a Constant Dose of CCK on Three Doses of UT-2 before the test. 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. CCK at a constant dose of 50 micrograms/kg abolishes the anxiolytic activity of UT-2 at a dose of 0.2 mg/kg po. CCK is antagonized in a dose dependent manner by 0.5 mg/kg and 2 mg/kg doses of UT-2. TABLE 16 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. Experiment: Anxiolytic Activity on New Plus Maze System Control Group A: Diazepam Control Group B: UT-2(92%) Descriptive Statistics Split by: Group Fisher's PLSD for Maze Effect: Group Significance Level: 5% TABLE 17 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. TABLE 18 The Effect of UT-2-92, Gepirone and the Anxiogenic Compound WAY on Conditioned Ultrasonic Distress Vocalizations in Adult Male Rats 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 Punished Responding 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. According to this procedure, the responding of rats or pigeons is maintained by a multiple schedule of food presentation. In one component of the schedule, responding produces food pellet presentation only. In a second component, 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. Monkey Taming Model The antianxiety activity of a compound may also be established by demonstrating that the compounds are effective in the monkey taming model. Plotnikoff Res. Comm. Chem. Path. & Pharmacol., 5: 128-134 (1973) described the response of rhesus monkeys to pole prodding as a method of evaluating the antiaggressive activity of a test compound. In this method, the antiaggressive activity of a compound was considered to be indicative of its antianxiety activity. Hypoactivity and ataxia were considered to be indicative of a sedative component of the compound. In one study, 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. Male and female rhesus, cynomologous or squinel monkeys, selected for their aggressiveness toward a pole, are housed individually in a primate colony room. Compounds or appropriate vehicle are administered orally or subcutaneously and the animals are observed by a trained observer at varying times after drug administration. A minimum of three days (usually a week or more) elapses between treatments. Treatments are assigned in random fashion except that no monkey receives the same compound two times consecutively. Aggressiveness and motor impairment are graded by response to a pole being introduced into the cage. The individuals responsible for grading the responses are unaware of the dose levels received by the monkeys. Human Clinical Trials The antianxiety activity of the disclosed compounds may also be demonstrated by human clinical trials. A study may be designed as a double-blind, parallel, placebo- controlled multicenter trial. Patients are randomized into four groups, placebo and 25, 50, and 75 mg tid of test compound. The dosages may be administered orally with food. Patients are then observed during four visits to provide baseline measurements, and then visits 5 and beyond may be used as the treatment phase for the study. During the visits, patients and their caregivers may be questioned and observed for signs of agitation, mood swings, vocal outbursts, suspiciousness, and fearfulness. Each of these behaviors are indicative of the effect of the test compound on an anxiety disorder. REFERENCES The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. U. S. Patent 4,329,332, issued May 11, 1982. U. S. Patent 4,489,055, issued Dec. 18, 1984. U. S. Patent 5,451,410, issued Sept. 19, 1995. U. S. Patent 5,500,224, issued Mar. 19, 1996. U. S. Patent 5,556,617, issued Sept. 17, 1996. U. S. Patent 5,620,708, issued April 15, 1997. U. S. Patent 5,641,515, issued June 24, 1997. U. S. Patent 5,698,515, issued Dec. 16, 1997. Allen and Choun, "Large unilamellar liposomes with low uptake into the reticuloendothelial system," FEBS Lett., 223 :42-46, 1987. Arshady, "In vivo targeting of colloidal carriers by novel graft copolymers," J. Mol Recognit., 9(5-6):536-542, 1996. Calvo, Vila-Jato, Alonso, "Effect of lysozyme on the stability of polyester nanocapsules and nanoparticles: stabilization approaches," Biomaterials, 18(19):1305-1310, 1997. Calvo, Vila-Jato, Alonso, "Improved ocular bioavailability of indomethacin by novel ocular drug carriers," J. Pharm. Pharmacol, 48(11):1147-1152, 1996. Couvreur et al, "Nanocapsules, a new lysosomotropic carrier," FEBS Lett., 84:323-326, 1977. Damge, Vonderscher, Marback, Pinget, "Poly(alkyl cyanoacrylate) nanocapsules as a delivery system in the rate for octreotide, a long-acting somatostatin analogue," J. Pharm. Pharmacol, 49(10):949-954, 1997. Gabizon and Papahadjopoulos, "Liposomes formulations with prolonged circulation time in blood and enhanced uptake by tumors," Proc. Natl. Acad. Sci. USA, 85:6949- 6953, 1988. Gardner, Tully, Hedgecock, "The rapidly expanding range of neuronal benzodiazepine receptor ligands," Proc. Neurobiol, 40:1-61, 1993. Ghosh and Bachhawat, "Targeting of liposomes to hepatocytes," In: Liver diseases, targeted diagnosis and therapy using specific receptors and ligands, Wu G, Wu C ed., New York: Marcel Dekker, pp. 87-104, 1991. Hattori, Sakamoto, Endo, Kakiuchi, Kobashi, Mizuno, Nambe, "Metabolism of magnolol from Magnoliae cortex. I. Application of liquid chromatography-mass spectrometry to the analysis of metabolites of magnolol in rats," Chem. Pharm. Bull, 32:5010-5017, 1984a. Hattori, Sakamoto, Endo, Kakiuchi, Kobashi, Mizuno, Nambe, "Metabolism of magnolol from Magnoliae cortex. II. Absorption, metabolism and excretion of [ring- 14C]magnolol in rats," Chem. Pharm. Bull, 34:157-167, 1984b. Henry-Michelland et al, "Attachment of antibiotics to nanoparticles; Preparation, drug- release and antimicrobial activity in vitro, Int. J. Pharm., 35:121-127, 1987. Hosaya and Yamamura (Eds.), Recent Advances in the Pharmacology of Kampo (Japanese Herbal) Medicines, International Congress Series 854, Excerpta Medica, Tokyo, 1988. Kuribara and Maruyama, "The anxiolytic effect of oriental herbal medicines by an improved plus-maze test in mice: involvement of benzodiazepine receptors," Jpn. J. Neuropsycholpharmacol, 18:179-190 (Abstract in English), 1996. Kuribara, Morita, Ishige, Hayashi, Maruyama, "Investigation of the anxiolytic effect of the extracts derived from Saiboku-To, an oriental herbal medicine, by an improved plus-maze test in mice," Jpn. J. Neuropsychopharmacol, 18:179-190 (Abstract in English), 1996. Maruyama, Kuribara, Morita, Yuzurihara, Weintraub, "Identification of magnolol and honokiol in the anxiolytic extracts of Saiboku-To, an oriental herbal medicine," J. Nautural Products, in submission, 1997. Maruyama, Kuribara, Morita, Yuzurihara, Weintraub, "Identification of magnolol and honokiol as anxiolytic agents in extracts of saiboku-to, an oriental herbal medicine," J. Nat. Prod, 61(1):135-138, 1998. Narita H, "Use of Kampo medicine in psychiatry," Jpn. J. Neuropsychopharmacol. 12:165-172 (In Japanese), 1990. Watanabe, Watanabe, Goto, Yamaguichi, Yamamoto, Hagine, "Pharmacological properties of magnolol and honokiol extracted from Magnolia officinalis: central depressant effects," Planta Med., 49:103-108, 1983. Yu and Chang, "Submicron polymer membrane hemoglobin nanocapsules as potential blood substitutes: preparation and characterization," Artif Cells Blood Substit. Immobil Biotechnol, 24(3):\69 %3, 1996.

Claims: WHAT IS CLAIMED IS: 1. A compound having the formula: wherein R is -CH 2 -CH=CH 2 , -CH=CH-CH 3 or -CH 2 -CH 2 CH 3 and X is independently 5'-CH=CH 2 . 5'-CH 2 -CH 3 . 5'-CH=CH 2 , 3'-OH; 5'-CH 2 - CH=CH 2 .5'-CH 2 -CH 2 -CH 3; 5'-CH 2 -CH=CH 2 , 3'-OH; 5'-CH 2 -CH 2 -CH 3 , 3'-OH; 5'-CH 2 -CH=CH 2 , 3'-OCH 3; 5'-CH 2 -CH 2 -CH 3 , 3'-OCH 3; 5'- CH=CH-CH 3 , 3'-OH; 5'-CH=CH-CH 3 , 3'-OCH 3 .5'-CH 3; 5'-CH(CH 3 ) 2 .5'- CH 2 CH(CH 3 ) 2; 5'-C(CH 3 ) 3; 5'-CH(CH 3 ) 2 C 2 H 5; 5'-(l-adamantyl); 5'- CH(CH 3 ) 2 , 6 -CH 3; 5'-CH(CH 3 ) 2> 4 -CH 3; 5'-C(=O)-CH 3; 5'-C(-OH)-CH 3; 5'-CH 2 -C(=O)-CH 3; 5'-CH 2 .C(-OH)-CH 3 .5'-CH 2 -COOH; 5'-CH 2 CH 2 - COOH; 5'-CH 2 CH 2 CH 2 -COOH; 5'-CH 2 -COOH, 3-OH; 5'-OH; 5'-OCH 3 ; 3'-F; 4'-F; 5'-F; 3'-F, 5'-CH 3 ; 3'-F, 5'-CH 2 -CH 3 ; 3'-F, 5'-CH 2 -OH; 3'-F, 5'- CH 2 -CH 2 -OH; 3'-F, 5'-COOH; 3'-F, 5'-CH 2 -COOH; 3'-F, 5'-CH=CH- CH 3 ; 3'-F, 5'-CH 2 -CH 2 -CH 3 ; 3'-F, 5'-CH 2 -CH=CH 2 ; 3'-F, 5'-CH 2 -CHF- CH 3 ; 3'-F, 5'-CH 2 -CHF-CH 2 F; 4'-F, 5'-CH 3 ; 4'-F, 5'-CH 2 -OH; 3'-F, 5'- CH 2 -CH 3 ; 6'-F, 5'-CH 2 -CH 3 ; 6'-F, 5'-CH 2 -OH or 6 f -F, 5'-COOH. The compound in claim 1 having the formula: A compound having the formula: wherein R is -CH 2 -CH=CH 2 , -CH=CH-CH 3 , or -CH 2 -CH 2 CH 3 and dependently 3-CH 3 .3-CH 2 -CH 3 .3-CH 2 -CH=CH 2 .3-CH 2 -CH 2 -CH 3; 3-CH 2 - CH=CH 2 , 5-OH; 3-CH 2 -CH 2 -CH 3 , 5-OH; 3-CH 2 -CH=CH 2 , 5-OCH 3; 3- CH 2 CH 2 CH 3 , 5-OCH 3; 3-CH=CH-CH 3; 3-CH 3> 6-CH(CH 3 ) 2; 3,5 di-CH 3 .2,6 di- CH 3; 3-CH(CH 3 ) 2; 3-CH(CH 3 ) 2> 6-CH 3; 3-CH 2 CH(CH 3 ) 2; 3-C(=O)-CH 3; 3-C(-OH)- CH 3 .3-CH 2 .C(=O)-CH 3; 3-CH 2 .C(-OH)-CH 3 .3-COOH, 6-OH; 2-COOH; 3-OCH 3; 3-CH 2 COOH; 3-CH 2 CH 2 COOH; 3-CH=CHCOOH; 3-CHO, 2-OH; 3-CH 2 OH, 2- OH; 3-CHO, 5-OCH 3; 3-CH 2 OH, 5-OCH 3 .3-CHO, 5-CH 3 .3-CH 2 OH, 5-CH 3 , 3-F; 2F; 2-F, 3-CH 3 ; 6-F, 3-CH 3 ; 5-F, 3-CH=CH-CH 3 ; 5-F,3-CH 2 -CH 2 -CH 3 ; 5-F, 3- CH 2 -CH=CH 2 ; 5-F, 3-CH 2 -CHF-CH 3 , or 5-F, 3-CH 2 -CHF-CH 2 F. The compound in claim 3 having the formula: 5. A composition comprising the compound of claim 1. 6. A composition comprising the compound of claim 3. 7. A composition comprising 3-n.-propyl-5'-(2-propenyl)-l,l '-biphenyl-2',4-diol and 5'-n.-propyl-3-(2-propenyl)-l,l'-biphenyl-2',4-diol. 8. The composition of claim 1 or claim 3, further comprising a pharmaceutical excipient. 10. A method of reducing anxiety in a mammal, comprising administering to said mammal a therapeutically effective amount of a composition comprising at least one of the compounds of claim 1. 11. A method of reducing anxiety in a mammal, comprising administering to said mammal a therapeutically effective amount of a composition comprising at least one of the compounds of claim 3. 12. The method of claim 9, wherein said compound has the formula: wherein R is -CH 2 -CH=CH 2 , -CH=CH-CH 3 or -CH 2 -CH 2 CH 3 and X is independently 5'-CH=CH 2 . 5'-CH 2 -CH 3; 5'-CH=CH 2 , 3'-OH; 5'-CH 2 - CH=CH 2; 5'-CH 2 -CH 2 -CH 3; 5'-CH 2 -CH=CH 2 , 3'-OH; 5'-CH 2 -CH 2 -CH 3 , 3'-OH; 5'-CH 2 -CH=CH 2 , 3'-OCH 3 .5'-CH 2 -CH 2 -CH 3 , 3'-OCH 3; 5'- CH=CH-CH 3 , 3'-OH; 5'-CH=CH-CH 3 , 3'-OCH 3; 5'-CH 3 .5'-CH(CH 3 ) 2; 5'- CH 2 CH(CH 3 ) 2 .5'-C(CH 3 ) 3 .5'-CH(CH 3 ) 2 C 2 H 5 .5'-(l-adamantyl); 5'- CH(CH 3 ) 2 , 6 -CH 3 .5'-CH(CH 3 ) 2> 4 -CH 3; 5'-C(=O)-CH 3 .5'-C(-OH)-CH 3 . 5'-CH 2 -C(=O)-CH 3; 5'-CH 2- C(-OH)-CH 3; 5'-CH 2 -COOH; 5'-CH 2 CH 2 - COOH; 5'-CH 2 CH 2 CH 2 -COOH; 5'-CH 2 -COOH, 3-OH; 5'-OH; 5'-OCH 3 ; 3'-F; 4'-F; 5'-F; 3'-F, 5'-CH 3 ; 3'-F, 5'-CH 2 -CH 3 ; 3'-F, 5'-CH 2 -OH; 3'-F, 5'- CH 2 -CH 2 -OH; 3'-F, 5'-COOH; 3'-F, 5'-CH 2 -COOH; 3'-F, 5'-CH=CH- CH 3 ; 3'-F, 5'-CH 2 -CH 2 -CH 3 ; 3'-F, 5'-CH 2 -CH=CH 2 ; 3'-F, 5'-CH 2 -CHF- CH 3 ; 3'-F, 5'-CH 2 -CHF-CH 2 F; 4'-F, 5'-CH 3 ; 4'-F, 5'-CH 2 -OH; 3'-F, 5'- CH 2 -CH 3 ; 6'-F, 5'-CH 2 -CH 3 ; 6'-F, 5'-CH 2 -OH or 6'-F, 5'-COOH. 14. The method of claim 13 wherein said composition has the formula: OH wherein R is -CH 2 -CH=CH 2 , -CH=CH-CH 3 , or -CH 2 -CH 2 CH 3 and X' is independently 3-CH 3 .3-CH 2 -CH 3; 3-CH 2 -CH=CH 2; 3-CH 2 -CH 2 -CH 3 .3-CH 2 - CH=CH 2 , 5-OH; 3-CH 2 -CH 2 -CH 3 , 5-OH; 3-CH 2 -CH=CH 2 , 5-OCH 3; 3- CH 2 CH 2 CH 3 , 5-OCH 3 .3-CH=CH-CH 3 .3-CH 3; 6-CH(CH 3 ) 2 . 3,5 di-CH 3; 2,6 di- CH 3; 3-CH(CH 3 ) 2; 3-CH(CH 3 ) 2> 6-CH 3; 3-CH 2 CH(CH 3 ) 2; 3-C(=O)-CH 3; 3-C(-OH)- CH 3 .3-CH 2 .C(=O)-CH 3 .3-CH 2 .C(-OH)-CH 3 .3-COOH, 6-OH; 2-COOH; 3-OCH 3; 3-CH 2 COOH; 3-CH 2 CH 2 COOH; 3-CH=CHCOOH; 3-CHO, 2-OH; 3-CH 2 OH, 2- OH; 3-CHO, 5-OCH 3 .3-CH 2 OH, 5-OCH 3; 3-CHO, 5-CH 3; 3-CH 2 OH, 5-CH 3 , 3-F; 2F; 2-F, 3-CH 3 ; 6-F, 3-CH 3 ; 5-F, 3-CH=CH-CH 3 ; 5-F,3-CH 2 -CH 2 -CH 3 ; 5-F, 3- CH 2 -CH=CH 2 ; 5-F, 3-CH 2 -CHF-CH 3 , or 5-F, 3-CH 2 -CHF-CH 2 F. 15. The method of claim 11 wherein the composition comprises: 16. The method of claim 13 wherein the composition comprises: 17. A process for preparing a compound of the formula: comprising the steps of hydrogenating tris-(Triphenylphosphine) rhodium(I) chloride in toluene; adding the honokiol to said solution; separating the desired mixture; obtaining said compound from said mixture. 18. A process for preparing a compound of the formula: comprising the steps of hydrogenating tris-(Triphenylphosphine) rhodium(I) chloride in toluene; adding the honokiol to said solution; separating the desired mixture; obtaining said compound from said mixture. 19. A process for preparing the compound of claim 4 comprising the steps of: passing hydrogen gas for two h with stirring in a solution of tris-(Triphenylphosphine) rhodium(I) chloride (10 mg) in toluene (4 ml) at room temperature; then dissolving honokiol (20 mg) in toluene (1 ml); adding the honokiol slowly into the reaction flask with stirring; passing the hydrogen gas for another 10 min after the complete addition of honokiol solution; stirring the reaction mixture overnight at room temperature; passing the reaction mixture through a column of florisil (5 gm); washing said reaction mixture with 50 ml of dry diethyl ether; evaporating the solvents to get crude residue; resuspending the crude residue in aforesaid HPLC eluant and injecting the suspension in the HPLC system for analysis; collecting peak 2, having a retention time- 11 min, m/z 268; NMR(CDC1 3 ): δ: 0.994 (t,3H), 1.663 (dt,3H), 2.629 (t,2H), 3.347 (d,2H), 5.03-5.11 (m,2H), 5.90-6.04 (m,lH), 6.88-7.20 (m, 6H) with small shoulders (approximately 8% of total peak 2) at δ 2.55, 3.45 and 5.13; and isolating the small shoulder of peak 2, eluting at about 12 minutes,with preparative HPLC purification. 20. A pharmaceutical composition which comprises an effective amount of the compound according to claim 1 ; and a pharmaceutically acceptable carrier. 21. The compound X; or a pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition which comprises an effective amount of the compound according to claim X; and a pharmaceutically acceptable carrier. 23. A pharmaceutical composition for the treatment of anxiety, comprising an effective amount of a compound according to claim X or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 24. A method of treatment or prophylaxis of anxiety in mammals, which comprises administration to a mammal in need of such treatment an effective amount of a compound according to claim X. 25. A method of treating a person suffering from depression which comprises administration to said person X or a pharmaceutically acceptable salt thereof in an amount sufficient to alleviate said depression. 26. A method of treating an anxiety-related disorder comprising administering to a patient in need of such treatment an amount of the compound X, or a pharmaceutically acceptable salt thereof, effective in preventing or alleviating anxiety and the symptoms associated with such disorder. 27. A method according to claim X, wherein said anxiety-related disorder is selected from the group consisting of panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, posttraumatic stress disorder, obsessive-compulsive disorder, and avoidant personality disorder. 28. A method for inhibiting onset of or treating anxiety in a mammal, which comprises administering to a mammalian specie in need of such treatment an anxiolytic effective amount of an angiotensin converting enzyme inhibitor, alone or in combination with a calcium channel blocker.

Inventors: SATSANGI NEERA, SATSANGI RAJIV K, STAVINOHA WILLIAM B, SATSANGI, NEERA, SATSANGI, RAJIV, K., STAVINOHA, WILLIAM, B.
Applicants: SATSANGI NEERA, SATSANGI RAJIV K, STAVINOHA WILLIAM B, UNIV TEXAS, BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM, SATSANGI, NEERA, SATSANGI, RAJIV, K., STAVINOHA, WILLIAM, B.
Application year: 1998
Main classification: C07C39
IPC codes: A61K31, A61P25, C07C39, C07C59, C07C63