AU684545B2 - Transdermal device containing (E)-2-(P-fluorophenethyl)-3-fluoroallylamine for the treatment of Alzheimer's disease - Google Patents

Description

OPI DATE 10/04/95 AOJP DATE 01/06/95 APL.ID 76364/94 ii1111 111Ili(iili l ii111 PCT NUMBER PCT/US94/09517 liiI1111111 11111ii11iii1. m1: niourn lull INI111 AU9476364 (51) International Patent Clasiication 6. (11) International Publication Number: WO 95108325 A61 3113, /70Al (43) International Publication Date: 30 March 1995 (30.03.95) (21) International Application Number: (22) International Filing Date: 2 Priority Data: 08/127,190 24 Septemb Parent Application or Grant (63) Related by Continuation us Filed on PCT/US94/09517 3 August 1994 (23.08.94) er 1993 (24.09.93) US 08/269.339 (CON) 30 June 1994 (30.06.94) (74) Agent. PAYNE, Helen;, Marion Merrell Dow Inc., 2110 East Galbraith Road, P.O. Box 156300, Cincinnati, OH 45215-6300 (US).

(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CE, CN, C7, DE, DK, ES, FL GB, 3E, HU, JP, ICE, KG, KP, KR, K, LK, LT, LU, LV, MD, MG, MN, MW, NL, NO, NZ PL, PT, RO, RU, SD, SE, SI, SK, Ti, 'iT, UA, US, U7, VN, European patent (AT, BE, CE, DE, DK, ES, FR, GB, GR, IE- IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CL, CM, GA, GN, ML, MR, NE, SN, TD, TG), ARWPO patent (KE, MW, SD).

Published With irnernational search report.

(71) Applicant (for all designated States except US): MERRELL PHARMACEUTICALS INC. P.O. Box 56300, 2110 East Galbraith Road, Cincinnati, OH 45215- 6300 (US).

(72) Inventors; and Inventors/Applicants (for US only): McDONALD, in, A.

[AU/US]; 4722 Shadwell Place, San Diego, CA 92130 (US).

PALFREYMAN, Michael, G. [GB/US]; 11515 Applejack Court, Cincinnati, OH 45249 YUJ, Daniel, H-S.

[US/US]; 15303 West 85th Street, Lenexa, KS (U) 68454

A

*C,1,o 'litle: TRANSDERMAL DEVICE CONTAINING (BP)-2-(P-FLUOROPHENETHYL)-3-FLUOROALLYLAMINE FOR TE TREATMIENT OF ALZHEIER'S DISEASE (57) Abstract 'Me present invention relates to 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. Also provided is a transdermal device for administration of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

WO 95/08325 PCT/US94/09517 -1- TRANSDERMAL DEVICE CONTAINING (E)-2-(P-FLUOROPHENETHYL)-3-FLUOROALLYLAMINE FOR THE TREATMENT OF ALZHEIMER'S DISEASE BACKGROUND OF THE 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: the so-called "neurotransmitter" monoamines, such as the catecholamines dopamine, epinephrine and norepinephrine) and the indoleamines tryptamine and 5-hydroxytryptamine), the so-called "trace" amines o-tyramine, phenethylamine, tele-N-methylhistamine) and 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 L_ I WO 95/08325 PCTUS94/09517 -2their 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" 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. 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.

[See Mangoni et al., Eur.Neurol. 31, 100 (1991)].

I I The compound (E)-2-(p-fluorophenethyl)-3- fluoroallylamine is a known selective inhibitor of MAO-B with activity as an antiparkinsonian agent.

SUMMARY OF THE INVENTION The present invention provides a transdermal device for administration of fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

According to a preferred aspect of the present invention there is provided a transdermal device comprising a support matrix, a backing member, and fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps.

0 eoe e* o a MC'r oC ED MC C:\VN ORDVMAALC'NCDELEmDh'fP73fig40 CC -sll 11-g-II~ M01675E r C r -3- The compound (E)-2-(p-fluorophenethyl)-3fluoroallylamine is a known selective inhibito f MAO-B with activity as an antiparkinsonian age SUMMARY OFallE' INVENTION The present I-vention provides a transdermal device for administr 'on of (E)-2-(p-fluorophenethyl)-3flu allylamine or a pharmaceutically acceptable salt thereof.

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

Pharmaceutically acceptable salts are such organic and 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, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, madelic, cinnamic, palmitic, itaconic and benzenesulfonic.

CI) AMENDED SHEET 4; WO 95/08325 PCTIUS94/09517 -4- In general, (E)-2-(p-fluorophenethyl)-3fluoroallylamine 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.

Tn general, (E)-2-(p-fluorophenethyl)-3fluoroallylamine 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 nonnuc)eophilic 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 one ester group bears t-butyl, benzyl, diphenylmethyl or triphenylmethyl) while the other bears a straight chain alkyl methyl, ethyl, propyl or ?0 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 250 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_ _U I_ WO 95/08325 PCT/US94/09517 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 C]-C 4 alkyl group, the easily cleaved ester group can also be selectively cleaved by subjecting the mixed diester to catalytic hydrogenolysis .sing conventional procedures: for example, by treatment under a hydrogen atmosphere in the presence of a catalyst Pd/C) at ambient temperature for 1 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 hydrooenolysis.

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 .e 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 0 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 Gf 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, IIBP1 ii WO 95/08325 PCT/US94/09517 -6diethyl ether, dichloromethane, or mixtures thereof. In a preferred procedure, a solution of the acrylate methyl ester in THF is cooled to about 00 to -78°C (preferably to -700( 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 phthalimide, succinimide, or maleimide) in the presence of a triarylphosphine triphenylphosphine) or a trialkylphosphine and diethyl azodicarboxylate in an aprotic organic solvent THF or dioxane). The reaction can be performed using a temperature range of about 00 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 ethanol) at reflux temperature (500 to 1000C) and a reaction time of about 30 minutes to 10 hours. It is preferable to add an acid 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 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 ~P WO 95/08325 PCT/US94/09517 -7conveniently purified and isolated as the acid addition salt using conventional purification methods.

The foregoing procedures may be illustrated by the following example.

EXAMPLE 1 (E)-(p-Fluorophenethyl)-3-fluoroallylamine HC1 Step A: Ethyl 2-(tert-butoxycarb. .yl)-p-fluorophenylbutvrate 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. PouL 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 nbutyl lithium (143.7mL) in THF (200mL), cool to -78 0 C and slowly add a solution of tert-butyl p-fluorophenylbutyrate (26.76g) in THF (100mL). After 1 hour, add a solution of ethyl chloroformate (12.19g) in THF (100mL) and continue stirring at ambient temperature for 24 hours. Then pour the mixture into water, neutralize with dilute aqueous HC1 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)-pfluorophenylbutyrate (32.14g) in THF (400mL), add sodium tert-butoxide (19.81g). Stir the mixture for 1 hour, then heat to 450C and add CICHF 2 gas rapidly for about minutes. Continue stirring for 1 hour under an atmosphere of CICHF 2 and allow the temperature to fall to ambient.

WO 95/08325 PCTIUS94/09517 -8- Pour the reaction mixture into water/brine and isolate the crude product by ether extraction to give an orange oil (34.55g).

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 e.iporation. 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)-3fluoroacrylate (15.70g) in hexane (350mL) to -10°C 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 10 0 C and treat consecutively with methanol (196mL) and 6M aqueous HC1 (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)-3phthalimidopropene Cool a solution of (E)-2-(p-fluorophenethyl)-3fluoroallyl alcohol (11.36g), phthalimide (8.43g) and M01675E in THF (50mL). Continue stirring at ambient temperature r C r rC r -9triphenylphosphine (15.3g) in THF (400m) to 0°C, and treat slowly with a solution of diethyl azodicarboxylate (9.99g) in THF (50mL). 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 HC1 Reflux a mixture of (E)-l-fluoro-2-(p-fluorophenethyl)- 3-phthalimidopropene (0.26g) and hydrazine hydrate in ethanol (5mL) for 2.5 hours. Add 6N HC1 (1.2mL) and evaporate the mixture to dryness. Dissolve the residue in NaOH (10mL) and isolate the crude amine by ether extraction. Dissolve in THF (10mL) and treat with di-tertbutyl 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 HCl-saturated ether (12mL) and allow to stand overnight. Filter to dive the title product (30mg) as colorless plates 1310C).

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 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 Dementia of k the Alzheimer's Type (SDAT), is a form of presenile AMENDED SHEET WO 95/08325 PCT/US94/09517 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 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 fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically acceptable salt thereof, can be ?eadily 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 M01675E C c I C C r r C c i f r r r fr c r r c c r -11therapeutically effective amount or dose, 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 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.

In effecting treatment of a patient afflicted with Alzheimer's disease, the compound 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 AMENDED

SHEET

M01675E 1 f t r I c r rr i I r r r t r r f V t -12selected, 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.

AMENDED

SHEET

Iln WO 95108325 PCT/US94/09517 -13- 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

T

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 _pe, 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.

I WO 95/08325 PCT/US94/09517 -14- 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; antibac:erial 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 acuomplished 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, transderwal 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 II I lsl I WO 95/08325 PCT/US94/09517 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 'in 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 mate-ial 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.

r C~F- WO 95108325 PCTIUS94/09517 -16- 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 fluorophenethyl)-3-fluoroallylamine. These examples are I WO 95/08325 PCT/US94/09517 -17understood 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 indicated: refers to grams, "jg" refers to micrograms, "mmol" refers to millimoles, "mL" refers to milliliters, refers to degrees Celsius, "HPLC" refers to high performance liquid chromatography, "pL" refers to microliters, "cm" refers to centimeters, "cm 2 refers to centimeters squared, "mm" refers to millimeters, refers to molar, "nm" refers to nanometers, "hr" refers to hour.

EXAMPLE 2 (E)-(p-Fluorophenethyl)-3-fluoroallylamine Combine (E)-(p-fluorophenethyl)-3-fluoroallylamine HC1 (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 MgSO 4 filter, and evaporate in vacuo to give 22.38 g of the title compound as an oil. 1

H

NMR (CDC1 3 8 1.20 2H), 2.45 2H), 2.73 2H), 3.13 2H), 6.55 J=80.0, 1H), 6.97 2H), 7.16 2H); 13C NMR (CDC13) 8 161.31 JC,F= 2 4 145.36 (d, JC,F=255.2), 137.15 JC,F=2.8), 129.65 JC,F=8.3), 123.50 JC,F= 3 115.01 Jc,F=20.4), 41.58 (d, JC,F=9.

2 33.40 Jc,F=2.8), 26.83 JC,F= 3 EXAMPLE 3 Preparation of transdermal devices containing fluorophenethyl)-3-fluoroallylamine.

Combine (E)-(p-fluorophenethyl)-3-fluoroallylamine and a matrix, National Starch Duro-Tak 1074; 10%, 20%, and 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 50 0 C for 15 minutes. Place a substrate layer on top of the drug/adhesive coat and apply a roller to remove air _1 WO 95/08325 PCTIUS94/09517 -18bubbles to give sheets from which transdermal devices containing 10%, 20%, 30%, 40%, and 50% drug/matrix) can be cut.

EXAMPLE 4 Skin permeation studies of (E)-(p-fluorophenethyl)-3fluoroallylamine.

Skin permeation of (E)-(p-fluorophenethyl)-3fluoroallylamine was conducted at 37 0 C 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. ofControlledRelease 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 100pL, 1501L, and 200pL of a saturated solution of (E)-(p-fluorophenethyl)-3-fluoroallylamine in water.

The saturated solution of (E)-(p-fluorophenethyl)-3fluoroallylamine 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. 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.

I_ I WO 95108325 PCT/US94/09517 -19- Drug permeation at 100 pL Drug permeation at 150 pL Drug permeation at 200 pL (pg/cm 2 (pg/cm 2 (pg/cm 2 time(hr) sample sample sample sample sample sample sample sample sample time1 2 3 1 2 3 1 2 3 4 4798.10 4592.82 4508.32 6391.68 5464.09 4582.53 6234.36 6256.11 5723.97 8 9626.69 8763.95 8688.90 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 2188835 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 permeation 974.06 859.01 815.96 976.51 796.97 773.67 903.37 956.15 893.90 rate (pg/cm2hr) average ±standard 883.01 81.74 849.05 111.00 917.81 33.54 deviation (pg/cnm 2 /hr) EXAMPLE Skin permeation studies of transdermal devices containing (E)-(p-fluorophenethyl)-3-fluoroallylamine.

Skin permeation study of transdermal devices containing 20%, 30%, 40%, and 50% drug/matrix) of fluorophenethyl)-3-fluoroallylamine was conducted at 37 0

C

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 et al, J. of Controlled Release 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 (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 I-p WO 95/08325 PCT/US94/09517 permeation rate were determined. The results are summarized in Table 2.

Table 2 drug/m x Skin Permeation Rate Standard deviation drug/matrix (pg/cm2/hr) 7.60 0.87 36.73 2.11 96.78 8.55 181.16 10.35 249.16 15.04

_I

Claims (16)

1. A transdermal device comprising a support matrix, a backing member, and (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof, having a skin permeation rate greater than 6.73 Vig/cm 2 /hr.

2. The transdermal device according to Claim 1, wherein the pharmaceutically acceptable 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 15 fluorophenethyl)-3-fluoroallylamine hydrochloric acid. A transdermal device comprising a backing member, permeable layer, a reservoir, and (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof, having a skin permeation rate greater than 6.73 20 pg/cm 2 /hr. o S: 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 fluorophenethyl-3-fluoroallylamine hydrochloric acid. 119~ I I -22-

7. A transdermal device when used 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, having a skin permeation rate greater than 6.73 p.g/cm2/hr.

8. The transdermal device according to Claim 8, wherein the pharmaceutically acceptable acid addition salt is selected from the group consisting of hydrochloric, hydrobromic, s Ifonic, 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 fluorophenethyl)-3-fluoroallylamine hydrochloric acid. :o 10. A transdermal device when used for the treatment of Alzheimer's disease comprising a backing member, permeable layer, a reservoir, and fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof, having a skin permeation rate greater than 6.73 ig/cm 2 /hr. S 0 011. 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 fluorophenethyl-3-fluoroallylamine hydrochloric acid.

13. The transdermal device according to claim 1, wherein the skin permeation rate is greater than 34.62 rpg/cm /hr. II -23-

14. The transdermal device according to claim 1, wherein the skin permeation rate is greater than 88.23 [Ig/cm 2 /hr. The transdermal device according to claim 1, wherein the skin permeation rate is greater than 170.81 pg/cm2/hr.

16. The transdermal device according to claim 1, wherein the skin permeation rate is greater than 234.12 pg/cm2/hr.

17. The transdermal device according to claim 4, wherein the skin permeation rate is greater than 34.62 tg/cm2/hr.

18. The transdermal device according to claim 4, wherein the skin permeation rate is greater than 88.23 tg/cm2/hr.

19. The transdermal device according to claim 4, wherein the skin permeation rate is greater than 170.81 pg/cm2/hr. *00 The transdermal device according to claim 4, wherein the skin permeation 20 rate is greater than 234.12 .g/cm 2 /hr.

21. A transdermal device according to any one of claims 1, 4, 7 or 10 as substantially as hereinbefore described with reference to any one of the examples. DATED: 31 July 1997 PHILLIPS ORMONDE FITZPATRICK Attorneys for: MERRELL PHARMACEUTICALS INC cl INu A A i~ A I AUONAL blLARC REPORIT in Inl Applluton No PCT/US 94/09517 A. CLASSIFICATION OF SUDJECT MATERR IPC 6 A61K31/135 A61K9/70 According to Internatonal Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classtfication system followed by classification symbols) IPC 6 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. P,X WO,A,93 24120 (MERRELL DOW PHARMACEUTICALS 1-14 INC.) 9 December 1993 see the whole document Y DEMENTIA 1-14 vol. 1, no. 6 1990 pages 323 348 DARRYL KABINS ET AL. 'Potential applications for monoamine oxidase B inhibitors' see abstract see page 337, right column, paragraph 4 page 339, right colum, paragraph 1; figure 2; table 6 S] Further documents are listed in the continuation of box C. Patent family members are listed in annex. SSpecial categories of cited documents 'T later document published after the international filing date or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the prnciple or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international "X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on pnonty claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the pnority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 2 December 1994

29. 2. A Name and mailing address of the ISA Authonzed officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31-70) 340.2040, Tx. 31 651 eponi, Tzschoppe D Fax 31-70) 340-3016 Form PCT/ISA/210 (second shet) (July 1992) page 1 of 2 IN'QTWNA'JIONAL SEARCH REPORT lnt onal AppliCAtio1 No PCT/US 94/09517 C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of' document, with indication, where appropriate, of the relevant pasSages Relevant to claim No. PROG. DRUG. RES. vol. 38 1992 pages 171 297 ANDREA M. CESURA ET AL. 'The new generation of monoiamine oxidase inhiblitors' see page 269, paragraph 3 -page 271, paragraph 2 see page 277, paragraph 4 EP,A,0 406 488 (SOMERSET PHARMACEUTICALS INC) 9 January 1991 see page 2, paragraph 1; example 3 1-14 1-14 Form PCTIISA/216 (continuation of Second sheet) (July 1992) page 2 of 2 I INTEIRNA'A lONAL bILM.Mt. IKVr%nA a Infonaton O P~~r~tfamy meber mn onal Application No Inforoaionon atet fmil mebeI PCT/US 94/09517 Patent document Publication IPatent family Publication cited in search report date member(s) Idate- WO-A-9324120 09-12-93 AU-B- 3978293 30-12-93 EP-A-0406488 09-01-91 US-A- 4861800 29-08-89 AU-B- 628340 17-09-92 AU-A- 3502289 22-11-90 US-A- 4868218 19-09-89 US-E- RE34579 05-04-94 Farm PCT/ISAN210 (pitent family anntx) (JUly 1992)