CA2172605A1 - Transdermal device containing (e)-2-(p-fluorophenethyl)-3-fluoroallylamine for the treatment of alzheimer's disease - Google Patents

Abstract

The present invention relates to a method of treatment for Alzheimer's disease in a patient in need thereof comprising transdermally administrating 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 for administration of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

Description

-~WO9J/~X3~ 2 ~ 7~ 6 ~ 5 PCT/US94/09517 TRANSDE~MAL DEVICE CONTAINING (E)-2-(P-FW OROPHENETHYL)-3-FLUOROALLyLAMINE
FOR THE TREATMENT OF A UHEIMER'S DISEASE

.

BACKGROUND OF T~E INVENTION

The class of compounds known as monoamine oxidase (MAO) inhibitors have long been utilized for the treatment of depression. 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. Among the 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 (e.g. o-tyramine, phenethylamine, tele-N-methylhistamine) and (c) tyramine.

Biochemical and pharmacological studies indicate that the MAO enzyme exists in two forms known as "MAO Type A"
(MAO-A) and "MAO Type B" (MAO-B). The two forms differ in -W095/08325 PCT~S94/09517 their distribution in body organs, in their substrate specificity and in their sensitivity to inhibitors. In general, MAO-A selectively oxidizes the so-called "neurotransmitter" monoamines (epinephrine, norepinephrine and 5-hydroxytryptamine), while 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. However, in man, dopamine has been shown to be a preferred substrate for MAO-B. MAO-A and MAO-B also differ 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" o 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. For example, 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.

There is now evidence that patients with Alzheimer's disease have higher cerebral MAO-B activity than healthy, elderly people. Monoamines are known to play a fundamental role in the cognitive processes linked to memory and learning, and it has been shown that patients with Alzheimer's disease have reduced activity of different neurotransmission systems mediated by monoamines such as dopamine, noradrenaline and 5-hydroxytryptamine. Finally, the MAO-B inhibitor L-deprenyl now appears to be an effective treatment for patients with Alzheimer's disease.
35 [See Mangoni et al., Eur. Neurol. 31, lO0 (l99l)].

c c t ~ f r ~ ~ ~ ~ c 2 6 0 5 / r r ~ ~ c c The compound (E)-2-(p-fluorophenethyl)-3-fluoroallylamine is a known selective inhibitor of MAO-B
with activity as an antiparkinsonian agent.

SUMMARY OF TEE INVENTION

The present invention provides a transdermal device for administration of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable saltthereof.

DETAILED DESCRIPTION OF T~E INVENTION

The compound (E)-2-(p-fluorophenethyl)-3-fluoroallylamine 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)-3-20 fluoroallylamine is specifically disclosed in European Patent Application Publication No. 0 295 604, published December 21, 1988.

Pharmaceutically acceptable salts are such organic and 25 inorganic salts of the compound (E)-2-~p-fluorophenethyl)-3-fluoroallylamine which are non-toxic and allow for bioavailability. For example, the following salts are pharmaceutically acceptable: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, 30 benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, madelic, cinnamic, palmitic, itaconic and benzenesulfonic.

AMENDE~ S~IEI~

5~

W095/08325 2 t 7 2 6 0 5~ PCT~S94/09~17 In general, (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.

In general, (E)-2-(p-fluorophenethyl)-3-fluoroallylamine may be prepared by procedures wherein adiester 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.

Following difluoromethylation, it is preferred to selectively remove one of the ester groups by acid hydrolysis. To accomplish selective cleavage 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 '; ' ~?l~F- 1~ r-~

~ W095/08325 2 1 7 ~ 6 ~ ~ PCT~S94/09517 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. When one ester group bears benzyl, diphenylmethyl, or triphenylmethyl and the other is a straight-chain Cl-C4 alkyl group, 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 l to 48 hours. As will be apparent to those skilled in the art, the ester groups can be chosen so that both groups can be cleaved simultaneously by acid-hydrolysis or catalytic hydrogenolysis.

Following selective hydrolysis, 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. 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 25C 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, W095/08325 2 1 7 2 6 ~ 5 -6- PCT~S94/09517 diethyl ether, dichloromethane, or mixtures thereof. In a preferred procedure, a solution of the acrylate methyl ester in THF is cooled to about 0 to -78C (preferably -60 to -70C), 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). The reaction can be performed using a temperature range of about 0 to 70C and a reaction time of about l to 24 hours. Ambient temperature is preerred. 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 100C) and a reaction time of about 30 minutes to lO 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. Other reagents can be used to cleave the imido function. For example, 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 ~ W095/08325 2 1 7 2 6 0 5 PCT~S94/09517 conveniently purified and isolated as the acid addition salt using conventional purification methods.

The foregoing procedures may be illustrated by the following example.

(E)-(p-Fluorophenethyl)-3-fluoroallylamine HCl Step A: Ethyl 2-(tert-butoxycarbonyl)-p-fluorophenyl-butyrate Treat a solution of p-fluorophenylbutyric acid (25g) in tert-butyl acetate (349mL) with perchloric acid (1.77mL) and then stir at ambient temperature for 1.5 hours. Pour the solution into water (350mL) containing NaOH (48g) and isolate the tert-butyl ester by ether extraction to give a pale yellow oil. Prepare a solution of lithium diisopropylamide from diisopropylamine (22.74g) and 1.6M n-butyl lithium (143.7mL) in THF (200mL), cool to -78C and slowly add a solution of tert-butyl p-fluorophenylbutyrate (26.76g) in THF (lOOmL). After 1 hour, add a solution of ethyl chloroformate (12.19g) in THF (lOOmL) and continue stirring at ambient temperature for 24 hours. Then pour the mixture into water, neutralize with dilute aqueous HCl and isolate the product by ether extraction to give an orange oil (32.27g).

Step B: Ethyl 2-(tert-butoxycarbonyl)-2-(difluoromethyl)-p-fluorophenylbutyrate To a solution of crude ethyl 2-(tert-butoxycarbonyl)-p-fluorophenylbutyrate (32.14g) in THF (400mL), add sodium tert-butoxide (19.81g). Stir the mixture for 1 hour, then heat to 45C and add ClCHF2 gas ra`pidly for about 15 minutes. Continue stirring for 1 hour under an atmosphere of ClCHF2 and allow the temperature to fall to ambient.

W095/08325 2 ~ 7 ~ 6 0 5 PCT~S9~/09517 ~

Pour the reaction mixture into water/brine and isolate the crude product by ether extraction to give an orange oil t34 55g)~

Step C: (E)-Ethyl 2-(p-fluorophenethyl)-3-fluoroacrylate Stir a solution of ethyl 2-(tert-butoxycarbonyl)-2-(difluoromethyl)-p-fluorophenylbutyrate (30.28g) in trifluoroacetic acid (168mL) for 1 hour and then remove the excess trifluoroacetic acid by evaporation. Dissolve the residual oil (25.82g) in THF (230mL) and slowly treat with 2M NaOH (80mL) so that the pH does not rise above 7.02.
After completion of addition of the solution, stir the solution for another 15 minutes and then extract the product into ether. Evaporate the ether and filter the residue through a short column of silica using 5% ethyl acetate in light petroleum as the solvent. Evaporate the solvent to give an essentially pure product as a pale orange oil (15.75g).

Step D: (E)-2-(p-Fluorophenethyl)-3-fluoroallyl alcohol Cool a solution of (E)-ethyl 2-(p-fluorophenethyl)-3-fluoroacrylate (15.70g) in hexane (350mL) to -10C and then slowly treat with a solution of diisobutylaluminum hydride in hexane (lM solution, 196mL). Stir at ambient temperature for 90 minutes, then cool to 10C and treat consecutively with methanol (196mL) and 6M a~ueous HCl (245mL). Add water and isolate the product by ether extraction followed by distillation of the solvents to give almost pure alcohol (11.36g).

Step E: (E)-l-Fluoro-2-(p-fluorophenethyl)-3-phthalimidopropene Cool a solution of (E)-2-(p-fluorophenethyl)-3-fluoroallyl alcohol (11.36g), phthalimide (8.43g) and L-~ V V ~
~ f ' C S~ ~ C ~ C
c ~ e ~ c ~ c 2 1 7 ~ 6 ~ 5 9 r ~ r i triphenylphosphine (15.3g) in THF (40QmL) to 0C, and treat slowly with a solution of diethyl azodicarboxylate (9.99g) in TEF (SOmL~. Continue stirring at ambient temperature overnight, then evaporate the solution to leave an orange paste (30g). Separate the pure product by using chromatography on silica (20% ethyl acetate in petroleum ether as eluant) to give a pale yellow solid (13.9g).

Step F: (E)-(p-Fluorophenethyl)-3-fluoroallylamine ~Cl Reflux a mixture of (E)-l-fluoro-2-(p-fluorophenethyl)-3-phthalimidopropene (0.26g) and hydrazine hydrate (80mg) in ethanol (5mL) for 2.5 hours. Add 6N HCl (1.2mL) and evaporate the mixture to dryness. Dissolve the residue in NaO~ (lOmL) and isolate the crude amine by ether extraction. Dissolve in T~F (lOmL) and treat with di-tert-butyl dicarbonate (194mg). Reflux the solution for 2 hours and then isolate the crude N-Boc derivative by ether extraction. Purify by silica chromatography (25% ethyl acetate in petroleum ether) to give pure material (180mg) as an almost colorless oil. Dissolve in HC1-saturated ether (12mL) and allow to stand overnight. Filter to dive the title product (30mg) as colorless plates (m.p. 131C).
The present invention provides a method of treatment for Alzheimer's disease in a patient in need thereof comprising transdermally administering to said patient a therapeutically effective amount of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof. As used herein, the term "patient" refers to a warm-blooded animal, such as a human, which is afflicted with Alzheimer's disease. The term "patient in need thereof" refers to a patient in need of treatment for Alzheimer's disease.

Alzheimer's disease, also known as Senile Dementiz of the Alzheimer's Type (SDAT), is a form of presenile W095/08325 2 1 7~605 PCT/US94/09S17 degenerative dementia due to atrophy of frontal and occipital lobes of the brain. 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.

In effecting treatment according to the present invention, 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. In determining the ~ ~ t ~ ~ J . ~ i r L~l U ' U / J .L:-2 1 7 ;~ ~i O ~ c~ r ~ c ~ r r therapeutically effective amount or d~se, a number offactors 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.
lQ
A therapeutically effective amount of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically acceptable salt thereof, will vary from about 0.001 mg/Rg/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.

In effecting treatment of a patient afflicted with Alzheimer's disease, 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. 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 AME~GEDS
5~

~-~ v ~ v ~
2 1 7 2 6 05 1~ -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, increase~ 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.

Al~IIENDED SHEE~

~ogs/08325 2 1 7~60~ PCT~S94/09517 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, Primogel~, corn starch and the like; lubricants such as magnesium stearate or Sterotex~; 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. 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. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, 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.

For the purpose of parenteral therapeutic administration, such as intramuscular, intravenous, and subcutaneous, 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.

W095/08325 2 1 7 ~ 6 ~ ~ PCT~S94/09517 ~

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.

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.

In general, 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 ~ W095/08325 2 1 7 ~ 6 ~ 5 PCT~S94/09517 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.

The proper choice of a backing member is well known and appreciated in the art. Backing members are usually impermeable to the compound and thereby define one face of the transdermal device.

The reservoir, the compound containing portion of the transdermal device, 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.
.
Examples of transdermal devices are described in U.S.
Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894.

WO 95/08325 2 ~ 7 ~ 6 0 5 PCT/US94/09517 ~

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. Alternatively, 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. In the case of microcapsules, 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.

An example of a 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.
The following examples present the preparation of a transdermal device for administration of (E)-(p-fluorophenethyl)-3-fluoroallylamine. These examples are 095/08325 2 1 7 ~ 6 OS PCT~S94/09517 understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in these examples, the following terms have the meanings 5 indicated: "g" refers to grams, "~g" refers to micrograms, "mmol" refers to millimoles, "mL" refers to milliliters, "C" refers to degrees Celsius, "HPLC" refers to high performance liquid chromatography, "~L" refers to microliters, "cm" refers to centimeters, "cm2" re~ers to 10 centimeters squared, "mm" refers to millimeters, "M" refers to molar, "nm" refers to nanometers, "hr" refers to hour.

(E)-(p-Fluorophenethyl)-3-fluoroallylamine Combine (E)-(p-fluorophenethyl)-3-fluoroallylamine HCl (26.5 g, 0.113 mmol) and water. Make the solution basic with sodium hydroxide and extract with hexane. Combine the organic layers, dry over MgSO4, filter, and evaporate ~n vacuo to give 22.38 g of the title compound as an oil. lH
NMR (CDC13) ~ 1.20 (s, 2H), 2.45 (m, 2H), 2.73 (m, 2H), 3.13 (m, 2H), 6.55 (d, J=80.0, lH), 6.97 (m, 2H), 7.16 (m, 2H);
13C NMR (CDC13) ~ 161.31 (d, JC,F=243.2), 145.36 (d, JC,F=255.2), 137.15 (d, JC,F=2.8), 129.65 (d, JC,F=8.3), 123.50 (d, JC,F=3-7)~ 115.01 (d, JC,F=20.4), 41.58 (d, JC.F=9.2), 33.40 (d, JC,F=2-8)~ 26.83 (d, JC,F=3-7)-Preparation of transdermal devices containinq (E)-(p-fluorophenethyl)-3-fluoroallylamine.

Combine (E)-(p-fluorophenethyl)-3-fluoroallylamine and - a matrix, National Starch Duro-Tak 1074; 10%, 20%, 30%, 40%, and 50~ (w/w) to form a drug/matrix. After drug solubilization, coat drug/matrix on a sheet of polyethylene using a Lab Hand Coater. Dry the coated sheets in an oven at 50C for 15 minutes. Place a substrate layer on top of the drug/adhesive coat and apply a roller to remove air W095/08325 2 i 7 2 6 0 5 PCT~S94/09517 bubbles to give sheets from which transdermal devices containing 10%, 20%, 30%, 40%, and 50% (w/w, drug/matrix) can be cut.

Skin permeation studies of (E)-(p-fluorophenethyl)-3-fluoroallylamine.

Skin permeation of (E)-(p-fluorophenethyl)-3-fluoroallylamine was conducted at 37C by Franz diffusion cells (model FDC-400, Crown Glass Co.) using hairless mouse skins and water (pH=7.0) as dissolution medium, according to the method of M. Mahjour el al, J. of ControlledRele~e 14, 243-252, (1990). Hairless mouse skins were harvested from six-week old hairless mice (Charles River Co.) and fitted over the diffusion cell. The dermal side of the skin was loaded with lOO~L, 150~L, and 200~L of a saturated solution of (E)-(p-fluorophenethyl)-3-fluoroallylamine in water.
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 W detector. A DuPont Zorbax Rx C8 column, 4.6 mm by 25 cm, was used with isocratic elution, 78% 0.05M sodium phosphate adjusted to pH 2.9 with phosphoric acid and 22~ acetonitrile. Flow rate of 1.5 mL/minute and detection at 265 nm.
Table 1 summarizes the results of the skin permeation study of (E)-(p-fluorophenethyl)-3-fluoroallylamine.

~ W095/08325 2 1 7 2 6 0 5 PCT~S94/09517 Drug permeation at 100 ~L Drug permeation at 150 ~L Drug permeation at Z00 I~L
(~J9/cm2) (~9/cm2) (I~g/cm2) time (hr) sample sample sample sample sample sample sample sample sample 4 4798.10 4592.82 4508.32 6391.68 5464.09 4582.53 6234.36 6256.11 5723.97 8 9626.69 8763.95 ~688.90 10014.32 9400.18 8276.54 10874.62 11033.97 10298.52 12 14828.55 13221.46 12931.25 15103.49 13509.45 12146.41 15447.40 15865.07 14819.10 24 24613.43 21888.35 21243.21 25527.66 21762.32 20271.37 24634.65 25613.63 23934.88 28 29029.84 25982.51 24795.02 30164.52 25183.02 23683.37 28760.30 30068.48 27996.68 skin p . t , 974.06 859.01 815.96 976.51 796.97 773.67 903.37 956.15 893.90 rate (~Jg/cmZ/hr) ;Iverage +standard 883.01 + 81.74 849.05 +111.00 917.81 +33.54 deviation (~Jg/an21hr) Skin permeation studies of transdermal devices containinq (E)-(p-fluorophenethyl)-3-fluoroallylamine.

Skin permeation study of transdermal devices containing 10%, 20%, 30%, 40~, and 50% (w/w, drug/matrix) of (E)-(p-fluorophenethyl)-3-fluoroallylamine was conducted at 37C
by Franz diffusion cells (model FDC-400, Crown Glass Co.) using hairless mouse skins and water tpH=7.0) as dissolution medium, according to the method of M. Mah]our et al, J. of Controlled Releo~e 14, 243-252, (1990). Hairless mouse skins were harvested from six-week old hairless mice (Charles River Co.) and fitted over the diffusion cell.
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 wos5l~32s 2 1 7 2 6 0 5 PCT~S94/09517 permeation rate were determined. The results are summarized in Table 2.

S Table 2 drug/matrix(w/w) (~g/crn2/hr) 10% 7.60 + 0.87 l 20% 36.73 + 2.11 30% 96.78 + 8.55 40% 181.16 + 10.35 50% 249.16 + 15.04

Claims (12)

WHAT IS CLAIMED IS:

1. A transdermal device comprising a support matrix, a backing member, and (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

2. The transdermal device according to Claim 1, wherein the pharmaceutically aceptable acid addition salt is selected from the group consisting of 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.

3. The transdermal device according to Claim 2, comprising (E)-2-(p-fluorophenethyl)-3-fluoroallylamine hydrochloric acid.

4. A transdermal device comprising a backing member, permeable layer, a reservoir, and (E)-2-(p-fluorophen-ethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

5. The transdermal device according to claim 4, wherein the salt is selected from the group consisting of 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.

6. The transdermal device according to claim 5 wherein the salt is (E)-2-(p-fluorophenethyl-3-fluoroallylamine hydrochloric acid.

7. A transdermal device for the treatment of Alzheimer's disease comprising a support matrix, a backing member, and (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

8. The transdermal device according to Claim 8, wherein the pharmaceutically aceptable acid addition salt is selected from the group consisting of 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.

9. The transdermal device according to Claim 8, comprising (E)-2-(p-fluorophenethyl)-3-fluoroallylamine hydrochloric acid.

10. A transdermal device for the treatment of Alzheimer's disease comprising a backing member, permeable layer, a reservoir, and (E)-2-(p-fluorophen-ethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

11. The transdermal device according to claim 10, wherein the salt is selected from the group consisting of 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.

12. The transdermal device according to claim 11 wherein the salt is (E)-2-(p-fluorophenethyl-3-fluoroallylamine hydrochloric acid.