WO2001028977A1

WO2001028977A1 - Method for treating parkinson's disease by administering (-)-5-keto-2-n,n-di-n-propylamino-tetrahydrotetralin

Info

Publication number: WO2001028977A1
Application number: PCT/US2000/028685
Authority: WO
Inventors: Durk Dijkstra; Leonard Theodore Meltzer; Bastiaan Johan Venhuis; Hakan Vilhelm Wikstrom; Lawrence David Wise; David Juergen Wustrow
Original assignee: Warner-Lambert Company
Priority date: 1999-10-20
Filing date: 2000-10-17
Publication date: 2001-04-26
Also published as: SV2001000202A; PE20010746A1; AU1209501A; CO5251402A1; AR026086A1; GT200000182A; PA8505301A1

Abstract

Parkinson's disease is treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Description

METHOD FOR TREATING PARKINSON'S DISEASE BY ADMINISTERING (-)-5-KETO-2-N,N-DI-N-PROPYLAMINO-TETRAHYDROTETRALLN

FIELD OF THE INVENTION

The present invention is directed to a method for treating Parkinson's disease by administering (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin.

BACKGROUND OF THE INVENTION

Neurodegenerative diseases are becoming more prevalent with the aging population. One particular neurodegenerative disease which typically has its onset between the ages of 50 and 80 years of age is Parkinson's disease. Parkinson's disease is a disorder of the brain which is characterized by tremor and difficulty with walking, movement, and coordination.

Parkinson's disease appears to be caused by a progressive deterioration of dopamine-containing neurons in the substantia nigra zona compacta of the brain. Dopamine is a chemical neurotransmitter which is utilized by brain cells to transmit impulses to control or modulate peripheral muscle movement. The loss of the dopamine-containing neurons results in reduced amounts of dopamine available to the body. Insufficient dopamine is thought to disturb the balance between dopamine and other neurotransmitters such as acetylcholine. When such dopamine levels are reduced, nerve cells cannot properly transmit impulses, resulting in a loss of muscle control and function.

Currently, there is no known cure for Parkinson's disease. Treatments are typically aimed at controlling the symptoms of Parkinson's disease, primarily by replacing the dopamine, with either L-DOPA which is metabolized to dopamine, or by administering chemical agents that stimulate dopamine receptors. Current treatments to slow the progression of the disease include compounds such as deprenyl (selegiline), a selective monoamine oxidase inhibitor, and amantadine, a compound that appears to decrease dopamine reuptake into presynaptic neurons. Certain hydroxy substituted dipropylamino tetralines (OH-DPATs) are known to have useful dopaminergic activity. However, their clinical use is limited because they have little or no bioavailability. An object of this invention is to provide a prodrug that is uniquely metabolized in vivo to a OH-DPAT that is a potent dopamine receptor agonist.

Applicants have now discovered that Parkinson's disease can be treated with (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin ((-)-5-keto-DP ATT) (Formula I) or a pharmaceutically acceptable salt thereof:

The compound of Formula I is unexpectedly converted to (-)5,6-diOH- aminotetralin (5,6-diOH-DPAT), (Formula II), in vivo in the central nervous system. The (-)5,6-diOH-DPAT is a potent dopamine D1/D2 receptor agonist, whereas the (-)-5-keto-DPATT does not itself bind to dopamine receptors in in vitro experiments

The (-)5,6-diOH-DPAT of Formula II appears in the brain cells of animals following oral administration of the (-)-5-keto-DPATT of Formula I. Surprisingly, no 5,6-diOH-DPAT is observed in brain cells following oral administration of the (+)enantiomer, namely (+)-5-keto-DPATT. Therefore, in accord with the present invention, applicants have found that (-)-5-keto-2-N,N-di-n-propylamino- tetrahydrotetralin is an effective dopamine D1/D2 agonistic prodrug for treatment of Parkinson's disease, as it is converted or metabolized, in vivo, into (-)5,6-diOH- DPAT, which lodges in brain cells and is an effective dopamine D1/D2 agonist. SUMMARY OF THE INVENTION

The present invention provides a compound which is (-)5-keto-2-N,N~di- n-propylamino-tetrahydrotetralin or a pharmaceutically acceptable salt thereof, and method for treating Parkinson's disease comprising administering to a patient in need of treatment an effective amount of the compound. This compound is selectively converted into (-)-5,6-dihydroxy-N,N-di-n-propyl-2-aminotetralin in vivo, and therapeutic amounts thereof are deposited in brain tissue, resulting in the effective treatment of Parkinson's disease. The invention additionally provides a process for preparing the 5-keto compound.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds having the Formula I

known as (-)-5-keto-2-N,N-di-N-propylamino-tetrahydrotetralin, ((-)-5-keto- DPATT), and the pharmaceutically acceptable salts thereof. The term "patient" as used herein means all animals including humans.

Examples of patients include humans, rodents, and monkeys.

Those skilled in the art are easily able to identify patients having Parkinson's disease. For example, patients who exhibit symptoms which include, but are not limited to, tremor and/or shaking and difficulty with walking, other movement, and coordination.

A "therapeutically effective amount" is an amount of a compound of Formula I, that when administered to a patient, ameliorates a symptom of Parkinson's disease.

The compounds of the present invention can be administered to a patient either alone or as part of a pharmaceutical composition of the compounds admixed with a pharmaceutically acceptable carrier, diluent, or excipient. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.

A preferred route of administration is oral, although parenteral and transdermal administration are also contemplated. Controlled release formulations, particularly in the form of skin patches and the like, are particularly well-suited for treating elderly patients. Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils

(such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be controlled by addition of any of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Oral delivery of the invention compounds is preferred, given the typical age of the patient population and the condition being treated. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be used in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Controlled slow release formulations are also preferred, including osmotic pumps and layered delivery systems.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahyclrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxtyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention. The term "pharmaceutically acceptable salts" as used herein refers to those amino acid addition salts of the compound of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxiciry, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of Formulas I and π. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphtylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J Pharm. Sci., 1977; 66:1-19 which is incorporated herein by reference.)

In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.

In addition, it is intended that the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as through metabolism. The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way.

The (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin utilized in the method of the present invention is ideally suited for several reasons. First, the compound is stable, making it an excellent candidate for oral administration. Second, the compound is long acting, thereby enabling effective treatment with fewer dosings which is of significant importance for elderly patients. Third, the compound serves as a prodrug which is converted or metabolized into the biologically active (-)-5,6- dihydroxy-N,N-dipropyl-2-aminotetralin, thereby reducing the peripheral side effects associated with administering the active compound itself to the patient. Fourth, the compound of the present invention has excellent oral bioavailability. Additionally, the compound of the present invention is unexpectedly selectively converted to (-)-5,6-diOH-DPAT in vivo in the central nervous system.

The following detailed examples illustrate the general synthetic techniques utilized for preparing the compound, along with some of the biological assays employed to establish the efficacy of the compound of the present invention.

EXAMPLE 1 The following scheme illustrates a preferred method for making (-)-5-keto-

DPATT (also referred to as (-)-PD 148903).

^reS0luti0n. (-)-5-ketc-DPATT

A mixture of 23.1 g (0.2 mol) 1,3-cyclohexadione, 6.0 g (0.2 mol) paraformaldehyde and 28.8 mL of dipropylamine (0.2 mol) in 200 mL of toluene was stirred for 1 hour with 60 g powdered molecular sieves (4 A) at a reaction temperature of 85°C.

After 1 hour 15 mL of acetone was added, and the mixture was stirred at 85°C for a further 2 hours. The color was changing from yellow to red. After cooling, the reaction mixture was filtered through celite and concentrated under reduced pressure giving a dark-red oil.

To the oil, dissolved in a mixture of 250 mL of THF and 12 mL of acetic acid and cooled in an ice-bath, was added in small portions, 5 g of sodium cyanaborohydride. The reaction mixture was stirred overnight at room temperature. Ninety percent of the solvent was evaporated. Ether (200 mL) was added, and the reaction mixture was made alkaline with saturated sodium bicarbonate solution. The aqueous layer was extracted 3 times with 50 mL of ether. The combined organic layer was washed with brine and dried over sodium sulfate. Concentrated under reduced pressure gave 40 g of a red oil. The oil was dissolved in 150 mL of boiling isopropyl acetate and, dropwise, a solution of 15.4 g (0.04 mol) (-)-ditoluyltartaric acid was added. The precipitate was collected by suction filtration and dried in vacuum dessicator. The mixture of diastereomeric salts (21 g, 16.5%) was recrystallized 3 times from 300 mL of ethanol (90%) yielding 5 g salt with [a] = -146° (c-0.05 methanol) and was then salt basified with NaHCO3 solution and the free base converted into the hydrochloride salt. Yield

2.0 g (3.5%) of (-)-(5)-keto-DPATT. [a] = -152.4°(c = 0.1, MeOH), cc >99%, mp 148-150°C.

EXAMPLE 2

Determination of Prodrug Enantiomers, (-)-5-keto-DPATT and (+)-5-keto- DP ATT, and Active Metabolite 5,6-di-OH-DPAT in the CNS by Brain

Microdialysis

Methods

Brain Guide Cannula Procedure:

Each of four study rats was anesthetized with ketamine (30 mg/kg), xylazine (6 mg/kg), and sodium pentobarbital (50 mg/kg) administered intramuscularly. The anesthetized rat was placed in the stereotaxic frame, securing the head, while its body rested on a heating pad to maintain body temperature at 37°C. A 2-3 cm midline incision was made on the top of the head exposing the skull. With the skin retracted laterally, the skull was abraded with cotton swabs and any bleeding was controlled using a small vessel cauterizer (Fine Science Tools, Inc. #18000-00). A dental drill, secured to the stereotaxic frame, was aligned with Bregma once the surface of the skull was cleaned. A hole was drilled 0.8-1.0 mm deep +0.7 mm rostral and -3.1 mm lateral from Bregma in order to insert the guide cannula into the skull. One additional hole was drilled 0.4 mm in depth in the opposite quadrant of the skull for insertion of a stainless steel anchoring screw. With the help of an electrode manipulator, the guide cannula was lowered into the predrilled hole leading to the brain. To secure the guide in position, the surface of the skull was scored and dental cement applied. The skin was closed around the cannula using 4-0 silk suture. A stylet was placed inside the guide cannula hole securing access until the study day. Each rat was given 10 mL of Lactated Ringer's solution subcutaneously, then placed on a heating pad for post-surgical recovery. Once ambulatory, the rat was transferred to a suspended wire cage with food and water given ad libitum.

Vascular Cannulation Procedures:

The morning before the study, under isoflurane anesthesia, each microdialysis rat was implanted with a jugular cannula for blood sampling. The jugular vein was ligated and the cannula inserted through a small incision into the vessel. The cannula was routed subcutaneously to a position in the midscapular region where it was exteriorized. Cannula patency was maintained with 17 units/mL of heparin in a 0.9% saline solution, then held in place over the back by a Velcro jacket until accessed for the study. Following surgical recovery, the rats were returned to their suspended wire cage with food and water given ad libitum.

Probe Insertion and Calibration: The evening before the study, the rats were anesthetized for probe insertion with

Diprivan (10 mg/mL) at a dose of 10 to 15 mg/kg TV. The stylet was removed from the intercerebral guide and the dura punctured with a 27-gauge needle. A Harvard flexible loop microdialysis probe with 3 mm-membrane tip (Cat. #59-7006) was inserted through the guide into the caudate putamen and locked in position. Each rat was again supplemented with 10 mL of Lactated Ringer's solution given subcutaneously. Following probe insertion, the rats were placed in a BAS Raturn System (Bioanalytical Systems, Inc.) consisting of a turntable, housing bowl, and balance arm. This system allows for free movement of the rat while preventing probe line and cannula entanglement. Probe lines were secured to the rat probe and perfused with artificial cerebrospinal fluid (ACSF) at 1 μL/min using a syringe pump (CMA/102 Microdialysis Pump). The rats remained in the Raturn systems from this point throughout the duration of the study with water given ad libitum. One hour prior to dosing, the calibrator (PD 0166871 200 ng/mL) was added to the ACSF and three dialysate samples collected for analysis.

Dosing and Sampling: Following a pre-dose blood sample, four prepared rats were dosed with (-)-5-keto-

DPATT at 10 mg/kg via oral gavage, and 3 fasted rats were dosed 2 mg/kg via IV bolus. The same number of prepared rats were dosed with the same amounts of (+)- 5-keto-DPATT. Dosing vehicle for both studies were: 5% dextrose for IV bolus and HPLC grade H2O for oral dose.

Oral dosed blood samples were collected through the jugular cannula at 45, 75, 105,

135, 165, 225, 285, 345, 405, and 480 minutes, and ACSF was collected with continuous flow (1 μL/min) at 30-minute intervals using a CMA/142 Microfraction collector for automated collection. The first ACSF collection at 30 minutes post- dose represents 0 through 30 minutes for an average at 15 minutes thus matching the time point of blood sampling. IV dosed blood samples were collected through the jugular cannula at 0, 0.08, 0.25, 0.5, 1, 2, 4, 6, and 8 hours. Each blood sample was placed directly into a serum separator collection tube for centrifugation and decanting of serum. Upon final sample, brain probes were removed from oral dosed rats euthanized by intravenous overdose of sodium pentobarbital. Brain samples were collected and parenchyma separated from capillaries by a depletion technique using 6 mL of Hepes buffer and 8 mL of 26% dextran/Hepes buffer to homogenize the brain sample immediately, then centrifuge the homogenate to separate supernatant (parenchyma) and pellet (capillaries).

Analysis: Individual samples of (-)-5-keto-DPATT and (+)-5-keto-DPATT in serum and brain tissue samples were prepared by liquid/liquid extraction with a 2 mL methyl t-butyl ether, 100 μL 0.1% HAC and analyzed by LC/MS/MS. Chromatographic conditions were isocratic ( acetonitrile:0.1% formic 60:40) reverse-phase, 2.1 x 100 mm x 3μ YMC basic column, 0.2 mL/min flow rate. Samples were analyzed by multiple-reaction monitoring (MRM) using a Micromass Quattro II triple quadrupole mass spectrometer with Z-spray ionization source operating with positive ion electrospray. Brain microdialysis samples were analyzed by direct injection using similar LC/MS/MS conditions as described above.

Standard curves were prepared in rat serum, brain homogenate, and artificial cerebrospinal fluid (ACSF) separately. Injection volumes were 5 μL and a post- column divert valve was used.

All sample concentrations were rounded to 3 significant figures using the validated computer program PKBASE Version 1.1 (CPL #49). Pharmacokinetic parameters were determined by noncompartmental analysis of individual rat- serum and ACSF Concentration-time data using WinNonlin Version 1.5

(CPL #54). Mean, standard deviation (SD), and percent relative standard deviation (%RSD) were calculated using Microsoft Excel, Version 7 (Microsoft Corporation).

CONCLUSION: The active metabolite of racemic 5-keto-DPATT, (-)-5,6-di-OH-DPAT, was observed in brain following administration of the active

(-) enantiometer, (-)-5-keto-DPATT, but not the inactive (+) enantiomer, (+)-5-keto- DPATT.

RESULTS/CONCLUSIONS: As shown in Table I and illustrated in Chart I, serum and brain ECF (microdialysis probe in striatum) concentrations of (-)-5-keto- DP ATT were significantly lower than the concentrations for the inactive enantiometer (+)-5-keto-DPATT following a 10 mg/kg PO dose to rats. However, only the active metabolite was present in brain ECF following administration of (-)-5-keto-DPATT. This demonstrates involvement of CNS tissue in the conversion of (+)-5-keto-DPATT to 5,6-di-OH-DPAT. Enantio-selective delivery of the active metabolite to the CNS renders the present compound high efficacious for the treatment of Parkinson's disease. Table 1. Mean Serum and Brain Concentrations of (-)-5,6-diOH-DPAT and

(+)-5,6-diOH-DPAT Following a 10 mg/kg PO Dose to Rats of (-)-5- keto-DPATT and (+)-5-keto-DPATT, Respectively

Compound Tmax Cmax AUClast tV₂

(hr) (ng/mL) (ng-hr/mL) (hr)

(-)-5-keto-DPATT 0.8 10.6 11.7 1.1

Serum

(-)-5,6-diOH-DPAT 1.6 4.9 28.2 42.5

(-)-5-keto-DPAT 2.0 16.2 50.2 3.0

Brain ECF

(-)-5,6-diOH-DPAT 2.5 4.76 7.73 NDT

(+)-5-keto-DPATT 0.8 480.8 418 1.2

Serum

(+)-5,6-diOH-DPAT 10.93 55 70.1

(+)-5-keto-DPAT 1.5 345 448

Brain ECF

(+)-5,6-diOH-DPAT ND ND ND ND

Brain ECF (extracellular fluid) concentrations (n = 3) were determined using a microdialysis probe placed in the striatum. ND = not detected, NDT = not determined. Cmax is maximum concentration level. AUC last means area under the dose response curve.

Chart l

Metabolic Transformations

DP AT means N,N-di-n-propylaminotetralin.

DP ATT means N-N-di-n-propylaminotetrahydrotetralin.

EXAMPLE 3

The effects of per os (PO) delivery of (-)-5-keto-2-N,N-di-n-propylamino- tetrahydrotetralin and (+)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin in a standard anti-Parkinson's animal assay was carried out as follows:

Adult male Sprague-Dawley rats (250-300 g) were pretreated as follows: The animals were first anesthetized with chloral hydrate. Unilateral lesions of the nigrostriatal dopamine system were produced by infusing 8 μg of 6-hydroxydopamine HBr (6-OHDA) into the right medial forebrain system. Rats were pretreated 30 minutes before surgery with desipramine HCl, 25 mg/kg IP, to protect noradrenergic neurons, and with pargyline, 25 mg/kg EP, to potentiate the effects of 6-OHDA. A minimum of 3 weeks after surgery, the rotational behavior induced by apomorphine HCl (a known dopamine D1/D2 agonist), 50 μg/kg SC, was assessed. Rotational behavior was measured using an automated rotometer system (Rotorat Rotational system, MED Associates, Georgia, VT). Only rats demonstrating more than 100 contraversive turns per hour in response to apomoφhine were used for assaying test compounds, as this demonstrates a rodent condition resembling human Parkinson' s disease. Anti-Parkinson activity was assessed by the ability of test compounds to produce contraversive turning in these unilateral 6-OHDA lesioned rats. This is an accepted method of testing anti- Parkinson drugs (see Hudson et al., Brain Research, 1993;626:167-174).

Table 2. Comparison of (-)-5-keto-DPATT and (+)-5-keto-DPATT, on Total Contraversive Rotations for 12 Hours in Unilateral 6-OHDA Lesioned Rats

Dose (mg/kg PO) Compound

(-)-5-keto-DPATT (+)-5-keto-DPATT

0.03 2230 ± 877 (8) not tested

0.1 7151 ± 1634 (7) 958 ± 397 (8)^a

Data are the mean + S.E.M. of contraversive rotations. Group size is (8-16). ^a P <0.05 vs same dose of (-)-5-keto-DPATT, Student's t-test.

The foregoing results establish that (-)-5-keto-DPATT is useful for producing an anti-Parkinson effect, whereas (+)-5-keto-DPATT caused only minimal effect. EXAMPLE 4

Tablet Formulation

(-)-5-keto-2-N,N-di-n-propylamino- tetrahydrotetralin 100 mg

Magnesium stearate 10 mg

Hydroxypropylmethylcellulose 20 mg

Talc 50 mg

Total 180 mg

The above ingredients are blended to uniformity and pressed into a tablet. Such tablets are administered from 1 to 4 times each day for effective treatment of Parkinson's disease.

EXAMPLE 5

Capsule Formulation

(-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin 80 mg

Titanium dioxide 5 mg

Sodium starch glycolateulose 15 mg

Total lO mg

The above ingredients are blended to uniformity and filled into a soft gelatin capsule. Such capsules are administered orally to a patient at the rate of from 1 to 6 per day.

EXAMPLE 6

Suppository Formulation

(-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin 600 mg hydrochloride

Theobroma oil 50 mg

Glycerinated gelatin 1000 mg

Glycerin 150 mg

Total 1800 mg The ingredients are blended to uniformity at 60°C and poured into tapered molds to produce a rectal suppository weighing 1.8 grams. Such suppository is administered once every 4 to 8 days.

EXAMPLE 7 Preparation for Parenteral Solution

Twenty grams of (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin maleate is dissolved in a mixture of 700 mL of propylene glycol and 200 mL of water for injection. The pH is adjusted to 6.0 by addition of dilute hydrochloric acid, and the volume is made up to 1000 mL by addition of water. The formulation is sterilized and filled into 5.0 mL ampoules, each containing 2.0 mL (representing

40 mg of drug) and sealed under nitrogen.

Claims

CLAIMSWhat is claimed is:

1. A compound that is (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin.

2. A method for treating Parkinson's disease in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin or a pharmaceutically acceptable salt thereof.

3. A method according to Claim 2, wherein the compound administered is (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin hydrochloride.

4. A method according to Claim 2, wherein the compound is administered orally.

5. A method for producing (-)-5,6-dihydroxy-2-N,N-di-n-propylaminotetralin in a mammal comprising administering to the mammal an effective amount (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin or a pharmaceutically acceptable salt thereof.

6. A method according to Claim 5, wherein the compound administered is (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin hydrochloride.

7. A method according to Claim 6, wherein the compound is administered orally.

8. A method for treating Parkinson's disease in a patient in need thereof comprising delivering (-)-5,6-dihydroxy-2-N,N-di-n-propyl-aminotetralin to the brain of the patient by administering to the patient a therapeutically effective amount of (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin or a pharmaceutically acceptable salt thereof.

9. A method according to Claim 8, wherein the compound administered is (-)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin hydrochloride.

10. A method according to Claim 9, wherein the compound is administered orally.

11. A process for preparing a (-)-isomer of a compound of the formula

said process comprising the steps of: reacting 1,3-cyclohexadione, paraformaldehyde, and dipropylamine at approximately 85°C; adding acetone to the reaction mixture; treating the reaction mixture with sodium cyanoborohydride to produce the compound of the Formula A

treating the compound of Formula A with boiling isopropyl acetate and (-)ditoluyltartaric acid to form diastereomeric salts; and crystallizing the salts of the compound having Formula A to yield the (-)-isomer of the compound of Formula I.

12. A method according to Claim 11 , wherein said reacting step further comprises stirring said mixture in the presence of 4 A molecular sieves.