Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
  • A61K9/7061—Polyacrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• MAO monoamine oxidase
• MAO is an enzyme which plays an important role in the metabolic regulation of naturally occurring monoamines. MAO catalyzes the biodegradation of monoamines through oxidative deamination.
• physiologically active monoamines which are known substrates for MAO are: (a) the so-called “neurotransmitter” monoamines, such as the catecholamines (e.g. dopamine, epinephrine and norepinephrine) and the indoleamines (e.g. tryptamine and 5-hydroxytryptamine), (b) the so-called "trace” amines
• MAO-A MAO Type A
• MAO-B MAO Type B
• the two forms differ in their distribution in body organs, in their substrate specificity and in their sensitivity to inhibitors.
• MAO-A selectively oxidizes the so-called “neurotransmitter” monoamines (epinephrine, norepinephrine and 5-hydroxytryptamine)
• MAO-B selectively oxidizes the "trace” monoamines (o-tyramine, phenethylamine and tele-N-methylhistamine) .
• Both MAO-A and MAO-B oxidize tyramine, tryptamine and dopamine.
• dopamine has been shown to be a preferred substrate for
• MAO-B differs in their sensitivity to inhibition, and thus can be selectively inhibited depending upon the chemical structure of the inhibitor and/or the relative concentrations of the inhibitor and the enzyme. It should be observed that the "selectivity" of an MAO inhibitor arises because the inhibitor has a greater affinity for one form of the enzyme over the other. Thus the selectivity of an inhibitor for MAO-A or MAO-B will be dose-dependent, selectivity being lost as the concentration of inhibitor is increased.
• L-deprenyl,3 is a selective inhibitor of MAO-B in vivo at lower doses but becomes a non-selective inhibitor of both MAO-A and MAO-B as the dose is increased.
• the present invention provides a method of treatment for Alzheimer's disease in a patient in need thereof comprising administering to said patient a therapeutically effective amount of (E)-2-(p-fluorophenethyl)-3- fluoroallylamine or a pharmaceutically acceptable salt thereof. Also provided is a transdermal device fo administration of (E)-2-(p-fluorophenethyl)-3- fluoroallylamine or a pharmaceutically acceptable salt thereof.
• the compound (E)-2-(p-fluorophenethyl)-3- fluoroallyla ine is generically disclosed in U.S. Patent No. 4,454,158, issued June 12, 1984, as an MAO-B inhibitor. This patent is incorporated herein by reference in its entirety.
• the compound (E)-2-(p-fluorophenethyl)-3- fluoroallylamine is specifically disclosed in European Patent Application Publication No. 0 295 604, published December 21, 1988.
• salts are such organic and inorganic salts of the compound (E)-2-(p-fluorophenethyl)- 3-fluoroallylamine which are non-toxic and allow for bioavailability.
• the following salts are pharmaceutically acceptable: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, madelic, cinnamic, palmitic, itaconic and benzenesulfonic.
• (E)-2-(p-fluorophenethyl)-3- fluoroallylamine may be prepared by procedures which are well known and appreciated in the art such as the procedures described in U.S. Patent No. 4,454,158, issued June 12, 1984, and European Patent Application Publication No. 0 295 604, published December 21, 1988.
• (E)-2-(p-fluorophenethyl)-3- fluoroallylamine may be prepared by procedures wherein a diester of p-fluorophenylethylbutyric acid is difluoromethylated in a known manner by first treating the diester with a strong base to produce the corresponding carbanion and then contacting the carbanion with a suitable halomethylating agent.
• the strong base must be non- nucleophilic and be of sufficient strength to remove a proton from the methine moiety adjacent to the carboxy group of the starting ester.
• Suitable bases are known in the art, such as are disclosed in European Patent Application Publication No. 0 295 604, published December 21, 1988.
• ester groups Following difluoromethylation, it is preferred to selectively remove one of the ester groups by acid hydrolysis.
• acid hydrolysis it is preferred to have a mixed diester wherein one ester group is easily cleaved (e.g. one ester group bears t-butyl, benzyl, diphenylmethyl or triphenylmethyl) while the other bears a straight chain alkyl (e.g. methyl, ethyl, propyl or n-butyl).
• the easily cleaved ester group can be selectively hydrolyzed by treatment with an organic or inorganic acid, either with or without an added solvent, using a temperature range of about 0° to about 25° C and a reaction time of about 1 to 10 hours. Ambient temperature is preferred.
• the choice of the acid for the hydrolysis is not critical, except that the acid should be chosen so that it can be easily removed after the hydrolysis stage. Trifluoroacetic acid is preferred since its low boiling point permits it to be easily removed from the hydrolysis product.
• the easily cleaved ester group can also be selectively cleaved by subjecting the mixed diester to catalytic hydrogenolysis using conventional procedures: for example, by treatment under a hydrogen atmosphere in the presence of a catalyst (e.g., Pd/C) at ambient temperature for 1 to 48 hours.
• a catalyst e.g., Pd/C
• the ester groups can be chosen so that both groups can be cleaved simultaneously by acid hydrolysis or catalytic hydrogenolysis.
• the difluoromethylated monoester is converted to its acrylate ester by treatment with a base.
• the reaction can be performed using an aqueous or non-aqueous solvent with strong bases such as sodium hydroxide and the like, or with weak bases, such as triethylamine or sodium bicarbonate. With strong bases, care must be exercised to avoid using an excess of base to prevent interaction with the double bond.
• strong bases care must be exercised to avoid using an excess of base to prevent interaction with the double bond.
• the choice of the base, the reaction solvent and reaction conditions will be apparent to those skilled in the art.
• a preferred procedure is to use aqueous sodium hydroxide in THF at ambient temperature. In general, a temperature range of 0° to 25°C and a reaction time of 15 minutes to 2 hours can be used.
• the acrylate ester is reduced to yield the allyl alcohol.
• the reducing agent employed for this transformation can be any reagent which is known in the art to be capable of selectively reducing an ester function or carboxylic acid function to the corresponding carbinol in the presence of a double bond.
• a preferred reducing agent is diisobutylaluminum hydride (DIBAL-H) in hexane, THF, diethyl ether, dichloromethane, or mixtures thereof.
• a solution of the acrylate methyl ester in THF is cooled to about 0° to -78°C (preferably -60 to -70°C), the DIBAL-H dissolved in hexane is added, and the temperature of the mixture is allowed to rise to ambient temperature.
• the reaction time can be about 2 to 24 hours.
• the allyl alcohol can be converted to the desired allyl primary amine using procedures known in the art to be useful for replacing an allylic hydroxyl group by an allylic primary amino group.
• a preferred laboratory method involves the direct formation of an imido derivative, preferably the phthalimide, and subsequent cleavage of the imido group to generate the primary amino group.
• the imido derivative can be prepared conveniently by treating the allyl alcohol with the appropriate imide (i.e., phthalimide, succinimide, or maleimide) in the presence of a triarylphosphine (e.g., triphenylphosphine) or a trialkylphosphine and diethyl azodicarboxylate in an aprotic organic solvent (e.g., THF or dioxane).
• aprotic organic solvent e.g., THF or dioxane.
• the reaction can be performed using a temperature range of about 0° to 70°C and a reaction time of about 1 to 24 hours. Ambient temperature is preferred.
• the imido derivative can be cleaved, preferably by reaction with hydrazine in an organic solvent, such as an alkanol (e.g., ethanol) at reflux temperature (50° to 100°C) and a reaction time of about 30 minutes to 10 hours. It is preferable to add an acid (e.g., hydrochloric acid) after the hydrazine treatment to convert the product to the acid addition salt.
• an acid e.g., hydrochloric acid
• Other reagents can be used to cleave the imido function.
• the imide can be heated with a strong mineral acid (e.g., hydrochloric or sulfuric acid) or a mixture of hydrochloric acid and acetic acid. Acids such as hydrobromic acid which are reactive towards olefins usually cannot be used.
• the final products are conveniently purified and isolated as the acid addition salt using conventional purification methods.
• Step A Ethyl 2-(tert-butoxycarbonyl)-p-fluorophenyl ⁇ butyrate
• Step B Ethyl 2-(tert-butoxycarbonyl)-2-(difluoromethyl)- p-fluorophenylbutyrate
• Step D (E)-2-(p-Fluorophenethyl)-3-fluoroallyl alcohol
• Step E (E)-l-Fluoro-2-(p-fluorophenethyl)-3- phthalimidopropene
• Step F (E)-(p-Fluorophenethyl)-3-fluoroallylamine HC1
• the present invention provides a method of treatment for Alzheimer's disease in a patient in need thereof comprising administering to said patient a therapeutically effective amount of (E)-2-(p-fluorophenethyl)-3- fluoroallylamine or a pharmaceutically acceptable salt thereof.
• patient refers to a warm-blooded animal, such as a human, which is afflicted with Alzheimer's disease.
• patient in need thereof refers to a patient in need of treatment for Alzheimer's disease.
• Alzheimer's disease also known as Senile Dementia of the Alzheimer's Type (SDAT)
• SDAT Senile Dementia of the Alzheimer's Type
• Alzheimer's disease involves a progressive loss of memory, deterioration of intellectual functions, apathy, speech and gait disturbances and disorientation. The course of the disease may take a few months to four to five years to progress from the early stages to a complete loss of intellectual function.
• An attending diagnostician as one skilled in the art, can identify those patients who are afflicted with Alzheimer's disease on the basis of standard diagnostic procedures and tests.
• Alzheimer's disease in a patient will be controlled so that the progressive loss of memory, deterioration of intellectual functions, apathy, speech and gait disturbances and disorientation will be slowed, interrupted, arrested or stopped. Treatment will not necessarily result in total elimination of the disease or in regression of the disease to a normal cognitive state.
• a therapeutically effective amount of (E)-2-(p- fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically acceptable salt thereof is an amount which is effective, upon single or multiple dose administration to the patient, in controlling the Alzheimer's disease so that the progressive loss of memory, deterioration of intellectual functions, apathy, speech and gait disturbances and disorientation will be slowed, interrupted, arrested or stopped.
• a therapeutically effective amount of (E)-2-(p- fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically acceptable salt thereof can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
• the attending diagnostician a number of factors are considered by the attending diagnostician, including, but not limited to: the patient's size, age and general health; the severity of the disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
• a therapeutically effective amount of (E)-2-(p- fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically acceptable salt thereof will vary from about 0.001 mg/Kg/day to about 1.0 mg/Kg/day. Preferred amounts are expected to vary from about 0.01 mg/Kg/day to about 0.25 mg/Kg/day.
• the compound (E)-2-(p- fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically acceptable salt thereof can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
• the compound can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like.
• Oral administration is generally preferred.
• Transdermal administration is also preferred.
• One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the stage of the disease, and other relevant circumstances.
• the compounds can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
• the compounds of the invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crystallization, increased solubility and the like.
• the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
• the carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
• the pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, transdermal device or the like.
• the compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
• the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
• These preparations should contain at least 0.1% of the compound of the invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 0.5% to about 20% of the weight of the unit.
• the amount of the compound present in compositions is such that a suitable dosage will be obtained.
• compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 0.05-25 milligrams of a compound of the invention.
• the tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, PrimogelTM, corn starch and the like; lubricants such as magnesium stearate or SterotexTM; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
• binders such as microcrystalline cellulose, gum tragacanth or gelatin
• excipients such as starch or lactose, disintegrating agents such as alginic acid, PrimogelTM, corn starch and the like
• lubricants such
• the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.
• a liquid carrier such as polyethylene glycol or a fatty oil.
• Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
• tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
• a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
• the compounds of the present invention may be incorporated into a solution or suspension.
• These preparations should contain at least 0.01% of a compound of the invention, but may be varied to be between 0.01 and about 50% of the weight thereof.
• the amount of the inventive compound present in such compositions is such that a suitable dosage will be obtained.
• Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 10 milligrams of the compound of the invention.
• the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
• the compounds of this invention can also be administered topically. This can be accomplished by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients'. Preferred topical administration is by a transdermal device.
• a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients'.
• Preferred topical administration is by a transdermal device.
• Factors to be considered in the use of transdermal devices are well known in the art and include: the optimum level of pharmaceutically active compound necessary to obtain the desired therapeutic response, inherent restrictions on the physical and chemical properties of the delivery system materials dictated by the desired application, the kinetics and mechanism of the delivery of pharmaceutically active compound from the delivery system, and the mechanism and rate of removal of the pharmaceutically active compound from the patient.
• transdermal devices are a combination of the compound to be administered and a excipient, commonly a polymeric material, arranged to allow delivery of the pharmaceutically active compound at controlled rate over a specified period of time.
• Transdermal devices are a laminate consisting of a backing member, a reservoir containing the compound, and an adhesive layer or a means for maintaining the device in contact with the skin or mucosa.
• Backing members are usually impermeable to the compound and thereby define one face of the transdermal device.
• the reservoir encompasses a broad class of structures capable of fulfilling the function.
• Reservoirs may be walled containers containing the compound as a liquid, solid, suspension, solution, or in a polymeric matrix.
• the compound may be contained in a matrix that controls the rate of delivery either by microporous flow or by diffusion.
• a reservoir may consist of a plurality of microcapsules containing the compound disbursed throughout a matrix which is either solid or microporous.
• a reservoir may consist of the compound adsorbed onto a polymeric matrix.
• a reservoir may be formed of permeable material or have permeable material on one face of the reservoir to permit passage of the compound.
• a reservoir may take the form of the compound surrounded by release controlling materials, such as by encapsulation, layers, or containers.
• a transdermal device may have a permeable membrane which determines the rate of delivery of the compound, such membranes are well known and appreciated in the art. Membranes may control the delivery of the compound by microporous flow, diffusion through the membrane, or by pressure induced viscous flow.
• transdermal devices are described in U.S. Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generally contain a backing member which defines one of its face surfaces, a compound permeable adhesive layer defining the other face surface and at least one reservoir containing the compound interposed between the face surfaces.
• the compound may be contained in a plurality of microcapsules distributed throughout the permeable adhesive layer. The compound is delivered continuously from the reservoir or microcapsules through a membrane which is either; directly in contact with the skin or mucosa of the recipient, or into an active agent permeable adhesive which is in contact with the skin or mucosa of the recipient.
• the encapsulating agent may also function as the membrane. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
• transdermal device which requires no membrane is described in U.S. Pat. No. 3,921,636 and comprises the pharmaceutically active compound contained in a support matrix from which it is delivered in a desired gradual, constant and controlled rate. At least two types of release are possible in these systems.
• the support matrix is permeable to the release of the compound through diffusion or microporous flow.
• the release is rate controlling. Release by diffusion occurs when the support matrix is non-porous.
• the pharmaceutically effective compound dissolves in and diffuses through the support matrix itself. Release by microporous flow occurs when the pharmaceutically effective compound is transported through a liquid phase in the pores of the support matrix.
• the rate of release controls the amount of compound administered to a patient.
• g refers to grams
• ⁇ g refers to micrograms
• mmol refers to millimoles
• mL refers to milliliters
• °C refers to degrees Celsius
• HPLC high performance liquid chromatography
• ⁇ L refers to microliters
• cm refers to centimeters
• cm 2 refers to centimeters squared
• mm refers to millimeters
• M refers to molar
• nm refers to nanometers
• hr refers to hour.
• the saturated solution of (E)-(p-fluorophenethyl)-3- fluoroallylamine in water had a density of 1.124 g/mL.
• Concentration of drug in dissolution medium was measured at 4, 8, 12, 24, and 28 hours, using HPLC.
• HPLC was conducted on a Waters 845 system with a Waters WISP 712 autoinjector, Waters 600E pump, and Waters 486 UV detector.
• Table 1 summarizes the results of the skin permeation study of (E)-(p-fluorophenethyl)-3-fluoroallylamine.
• Transdermal devices containing 10%, 20%, 30%, 40%, and 50% (w/w, (E)-(p-fluorophenethyl)-3-fluoroallylamine/matrix) were applied to the dermal side of the skin.
• the concentration of drug in the dissolution medium was measured by HPLC as taught above in Example 4 and the permeation rate were determined. The results are summarized in Table 2.

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• 1994
  • 1994-08-23 EP EP94926566A patent/EP0720475A1/en not_active Withdrawn
  • 1994-08-23 AU AU76364/94A patent/AU684545B2/en not_active Ceased
  • 1994-08-23 HU HU9600725A patent/HUT75877A/hu unknown
  • 1994-08-23 CA CA002172605A patent/CA2172605A1/en not_active Abandoned
  • 1994-08-23 JP JP7509764A patent/JPH09505276A/ja active Pending
  • 1994-08-23 CN CN94193473A patent/CN1131390A/zh active Pending
  • 1994-08-23 WO PCT/US1994/009517 patent/WO1995008325A1/en not_active Application Discontinuation
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• 1996
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