4',4''-substituted 3alpha-(diphenylmethoxy)tropane analogs for the treatment of adhd

Description of equivalent WO 2004062610 A2

4',4"-SUBSTITUTED 3α-(DIPHENYLMETHOXY) TROPANE ANALOGS FOR TREATMENT OF MENTAL DISORDERS

Frank P. Zemlan

CROSS REFERENCE TO RELATED APPLICATIONS

[001] The present application is based upon and claims priority from U.S.

Provisional Patent Application Nos. 60/438,981, filed January 9, 2003, and

60/451,357, filed March 3, 2003, both of which are incorporated herein by reference.

TECHNICAL FIELD

[002] The present invention relates to pharmaceutically active compositions

consisting of 4',4"-substituted 3 -(diphenylmethoxy) tropane analogs which are used

in a method for treating specific psychiatric disorders including narcolepsy, attention

deficit hyperactivity disorder (ADHD), conduct disorder, alcohol addiction, tobacco addiction, nicotine addiction, inhalation disorders, Parkinsonism including Parkinson's disease, female and male orgasmic disorders, female and male sexual

arousal disorders, hypoactive sexual desire disorder, and disorders characterized by

anxiety and/or depression.

BACKGROUND OF THE INVENTION

[003] The brain consists of a vast network of neurons that communicate with each

other via chemical messengers. Each neuron generates neurochemicals or

neurotransmitters which act at sites referred to as receptors on the cellular membranes

of neurons. One group of neurotransmitters, referred to as the monoamine

neurotransmitters, includes serotonin, dopamine and noradrenaline. Monoamine

neurotransmitters are released into the synaptic cleft between neurons in order to

stimulate post-synaptic receptor activity. The removal (or inactivation) of monoamine neurotransmitters occurs mainly by a reuptake mechanism into the pre-synaptic

terminals. By inhibiting the reuptake, an enliancement of the physiological activity of

monoamine transmitters occurs.

[004] The serotonergic neural system of the brain has been shown to influence a variety of physiologic functions, and compounds having dopamine reuptake-

inhibiting activity have been shown to have the ability to treat in mammals, including

humans, a variety of disorders associated with this neural system, for example, eating

disorders, depression, cocaine addiction, dementia of aging, memory dysfunction in

aging, and attention deficit hyperactivity disorder.

[001] However, the use of dopamine transport inhibitors to treat such conditions frequently brings along with it a number of undesirable side effects. For example,

benztropine (COGENTIN™) is a high affinity dopamine transport (DAT) inhibitor

that increases dopamine activity in the brain. This material has been in continuous

clinical use for over forty years. Benztropine's inhibition of the dopamine transporter

is responsible for its clinical effectiveness for treating idiopathic Parkinson's disease,

a clinical indication for which it is FDA approved. Unfortunately, the clinical

usefulness of benztropine has been severely limited by its anticholinergic properties

which result from benztropine's high affinity binding to Ml cholinergic receptors.

Benztropine's anticholinergic side effects, as documented in the Physician's Desk Reference, include tachycardia, constipation, vomiting, confusion, disorientation, memory impairment and hallucinations.

[006] The present invention provides the therapeutic benefits of dopamine transport

inhibitors while demonstrating low affinity for Ml cholinergic receptors. The compounds described herein, therefore, retain benztropine's clinical utility for treating

disorders associated with dopamine insufficiency in the brain while demonstrating reduced anticholinergic side effects due to limited Ml cholinergic binding.

[007] U.S. Patent 5,792,775, Newman, et al., issued August 1 1, 1998, describes the

family of 4',4"-substituted 3α-(diphenylmethoxy) tropane analogs utilized in the

present invention and teaches their use for the treatment of cocaine addiction and for

the diagnosis and/or monitoring (but not the treatment of) neurodegenerative

disorders, such as Parkinson's disease.

SUMMARY OF THE INVENTION

[008] The present invention relates to a method for treating a condition selected

from narcolepsy, attention deficit hyperactivity disorder (ADHD), conduct disorders,

alcohol addiction, tobacco addiction, nicotine addiction, inhalation disorders,

Parkinsonism including Parkinson's disease, female and male orgasmic disorders, female and male sexual arousal disorders, hypoactive sexual desire disorder, and

disorders characterized by anxiety and/or depression, comprising administering to a

patient in need of such treatment a safe and effective amount of a compound havin₀

the formula

<img file="WO2004062610A2_D0001.tif" /> in which R is selected from hydrogen, alkyl, alkoxy, arylalkyl, aryloxyalkyl, cinnamyl and acyl; and

R¹ and R² are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halogen, cyano, amino and nitro;

1 with the proviso that if R is methyl, R and R are not both hydrogen.

[009] A preferred compound of the formula given above is one in which R is methyl

and R¹ and R² are both fluorine. Further, it is preferred that the compounds be

administered to the patient at from about 0.05 to about 1000 mg per day (more

preferably from about 0.1 to about 75 mg per day).

[010] All percentages, proportions and ratios set forth herein are "by weight," unless

otherwise specified.

[Oil] All patents and publications described herein are incorporated by reference

herein.

DETAILED DESCRIPTION OF THE INVENTION

[012] The compounds used in the present invention are described in U.S.

Patent 5,792,775, Newman, et al., issued August 11, 1998, incorporated herein by

reference, as well as pharmaceutically acceptable salts of those compounds. The

method of making those compounds is also described in the Newman, et al. patent.

These referenced 4',4"-substituted 3α-(diphenylmethoxy) tropane analogs

demonstrate high affinity for the dopamine transporter and inhibit dopamine uptake,

while also exhibiting relatively limited Ml cholinergic binding. The preferred compound for use in the present invention is N-allyl-4',4"-difluoro-3α-diphenyl-

methoxytropane.

[013] The present invention relates to methods of treating specific diseases using compounds having the following formula:

<img file="WO2004062610A2_D0002.tif" />

[014] In Formula I, R is a functional group including, but not limited to, hydrogen, alkyl, alkoxy, arylalkyl, aryloxyalkyl, cinnamyl and acyl. In Formula I, R^l and R² are

independently selected and are functional groups including, but not limited to,

hydrogen, alkyl, alkoxy, hydroxy, halogen, cyano, amino and nitro. In these

compounds, when R is methyl, R and R cannot both be hydrogen.

[015] The term "independently selected" is used herein to indicate that the R¹ and R²

groups can be identical or different (e.g., R¹ and R² may both be methoxy, or R¹ may be methoxy and R² may be halogen).

[016] The term "alkyl" is used herein to refer to a branched or unbranched, saturated

or unsaturated, monovalent hydrocarbon radical containing from 1-8 carbons,

cycloalkyls (3-7 carbons), cycloalkyl methyls (3-8 carbons) and arylalkyls. Suitable

alkyl radicals include, for example, methyl, ethyl, n-propyl, i-propyl, 2-propenyl (or allyl), n-butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, n-

amyl, hexyl, etc. As used herein, the term "alkyl" encompasses "substituted alkyl."

The term "substituted alkyl" refers to alkyls as just described above including one or

more functional groups such as lower alkyl, aryl, aralkyl, acyl, halogen (i.e.,

haloalkyls, e.g., CF₃), hydroxyl, amino, acylamino, acyloxy, alkoxyl, mercapto, and

the like. These groups may be attached to any carbon atom in the alkyl moiety.

[017] The term "alkoxy" is used herein to refer to the — OR group, where R is a

lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl, or substituted,

aralkyl. Suitable alkoxy radicals include, for example, methoxy, ethoxy, phenoxy,

t-butoxy, etc.

[018] The term "aryl" refers to an aromatic substituent which may be a single ring or multiple rings which are fused together, linked covalently, or linked to a common

group such as an ethylene or methylene moiety. The aromatic ring(s) may include

phenyl, naphthyl, biphenyl, biphenylmethyl, 2,2-diphenyl-l -ethyl, and may contain a

heteroatom, such as thienyl, pyridyl and quinoxalyl. The aryl group may also be

substituted with halogen atoms or other groups, such as nitro, carboxy, alkoxy,

phenoxy, and the like. Additionally, the aryl group may be attached to other moieties

at any position on the aryl radical which would otherwise be occupied by a hydrogen

atom (such as 2-pyridyl, 3-pyridyl, and 4-ρyridyl). As such, the terms "aralkyl" and "aryloxyalkyl" refer to an aryl radical attached directly to an alkyl group (e.g., 3(2-

pyridyl)propyl)) or an oxygen which is attached to an alkyl group, respectively. [019] The term "cinnamyl" is used herein to refer to the 3-phenyl-2-propenyl radical

(i.e., Ph.CH:CH.CH₂ — ). The phenyl group may be substituted with halogen atoms or

other groups (e.g., nitro, hydroxy, amino, etc.).

[020] The term "acyl" is used herein to refer to the group — C(O)R, where R is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, as defined above.

[021] The term "cyano" is used herein to refer to the group — CN.

[022] The term "halogen" is used herein to refer to fluorine, bromine, chlorine, and

iodine atoms.

[023] The term "hydroxyl" is used herein to refer to the group — OH.

[024] The term "nitro" is used herein to refer to the group — NO₂.

[025] The term "amino" is used herein to refer to the group — NRR', where R and R'

may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl or acyl.

[026] Within the scope of Formula I, certain embodiments are preferred, namely

those in which R is methyl; R¹ is methoxy; and R² is selected from H and methoxy.

Also preferred are compounds in which R is methyl; R^l is nitro; and R² is H. Also preferred are compounds in which R is methyl; R¹ is cyano; and R² is H. Also

preferred are compounds in which R is methyl; R¹ is Br; and R² is selected from H,

Br, Cl and F. Also preferred are compounds in which R is methyl; R¹ is F; and R² is

selected from H, Br, F and Cl. Also preferred are compounds in which R is methyl; R¹

is an alkyl selected from methyl, ethyl, propyl, butyl, i-butyl, t-butyl, pentyl and

hexyl; and R is selected from H and alkyl. Also preferred are compounds in which R is methyl; R¹ is hydroxy; and R² is selected from H, hydroxy, Br, Cl or F. Also preferred are compounds in which R is alkyl; and R¹ and R² are independently

selected from Br, Cl, F and I. Also preferred are compounds in which R is

n-cinnamyl; and R¹ and R² are independently selected from Br, Cl, F and I. Also

preferred are compounds in which R is arylalkyl; and R¹ and R² are independently

selected from Br, Cl, F and I. Particularly preferred are compounds in which R is

methyl and both R¹ and R² are fluorine atoms.

[027] The compounds of Formula I can be prepared using the synthetic scheme set

forth in the Newman, et al. patent (U.S. Patent 5,792,775). Briefly, 4',4"-substituted

benzhydrols are converted to benzhydrochlorides in refluxing thionyl chloride. Benzhydrochlorides are then added, neat or in a minimal volume of anhydrous diethyl

ether, to tropine at 160°C, to form 4' or 4',4"-substituted 3 -(diphenylmethoxy)

tropane analog 3α-(diphenylmethoxy) tropane analogs of the present invention. This

second step, i.e., the melt reaction, can be carried out rapidly and without the use, or alternatively with the minimal use, of solvent.

[028] The compounds described above are administered to a patient having a condition selected from narcolepsy, attention deficit hyperactivity disorder, conduct

disorder, alcohol addiction, tobacco addiction, nicotine addiction, Parkinsonism

including Parkinson's disease, female and male orgasmic disorders, female and male

sexual arousal disorders, hypoactive sexual desire disorder, and disorders

characterized by anxiety and/or depression. A primary focus of the present invention is the treatment of attention deficit hyperactivity disorder (ADHD) and Parkinson's

disease. These are all conditions which are known to be tied in with the dopamine

receptors. The compounds of the present invention not only treat those conditions, but also, because of their decreased affinity for the Ml receptor, are accompanied by

minimized anticholinergic side effects. The connection between the diseases treated in

the present invention and the dopamine receptors are discussed in, for example, the

following references (all of which are incorporated herein by reference):

[029] Alcohol Addiction

— Eiler 2" _ et al. Dl dopamine receptor regulates alcohol-motivated behaviors in the

bed nucleus of the stria terminalis in alcohol-preferring (P) rats. Synapse. 2003

Apr;489(l):45-56.

— Tupala, et al. Dopamine receptors and transporters in the brain reward circuits of

type 1 and 2 alcoholics measured with human whole hemisphere radiography.

Neuroimage. 2003 May;19(l): 145-55.

[030] Nicotine Addiction

— Bal k et al. Dopamine Dl and D2 receptor mRNA up-regulation in the caudate-

patamen and nucleus accumbens of rat brains by smoking. Prog

Neuropsycholpharmaeol Biol Psychiatry. 2002 Oct;26(6): 1095-104.

— Geracioti, et al. Low CSF concentrations of a dopamine metabolite in tobacco

smokers. Am J. Psychiatry. 1999 Jan; 156(1): 130-2.

[031] Drug Addiction

— Campiani, et al. Synthesis and pharmacological evaluation of potent and highly

selective D3 receptor ligands: inhibition of cocaine-seeking behavior and the role of

dopamine D3/D2 receptors. J Med Chem. 2003 Aug 28;46(18):3822-39. — Chartoff, et al. Dopamine-dependent increases in phosphorylation ofcAMP

response element binding protein (CREB) during precipitated morphine withdrawal in primary cultures ofrat striatum. J Neurochem. 2003 Oct;38(l):107-18.

— O'Shea, et al. Is frequent dosing with ecstasy a risky business ofdopamine- containing neurons? Trends Pharmacol Sci. 2003 Jun;24(6):272-4.

[032] Sexual Dysfunction (F/M Or asmic Disorder. F/M Sexual Arousal Disorders.

Hvpoactive Sexual Desire Disorder)

— Earle et al. Biochemical screening in the assessment of erectile dysfunction: what

tests decide future therapy? Urology. 2003 Oct;62(4):727-31.

— Giuliano, et al. Dopamine and male sexual function. Eur Urol. 2001 Dec;40(6):601-

8. Review.

[033] Sleep Disorders (Narcolepsv/Cataplexy)

— Wisor et al. Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001

Mar l;21(5):1787-94.

— Honda, et al. Dopamine D3 agonists into the substantia nigra aggravate cataplexy

but do not modify sleep. Neuroreport. 1999 Nov 26; 10(17):3713-24.

[034] Parkinsonism including Parkinson's Disease

— Moore. Organization ofmidbrain dopamine systems and the pathophysiology of

Parkinson 's disease. Parkinsonism Relat Disord. 2003 Aug;9 Suppl 2:S65-71.

Review.

— Stocchi, et al. Dual dopamine agonist treatment in Parkinson 's disease. J Neurol.

2003 Jul;250(7):822-6.

[035] ADHD/Conduct Disorders

— Young, et al. Dopamine transporter polymorphism associated with externalizing

behavior problems in children. Am J Med Genet. 2002 Mar 8; 114(2): 144-9. — Seeman, et al. Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis. Behav Brain Res. 2002 Mar 10;130(l-2):79-83.

— Solanto. Dopamine dysfunction in AD/HD: integrating clinical and basic

neuroscience research. Behav Brain Res. 2002 Mar 10;130(l-2):65-71. Review

— Swanson et al. Pharmacokinetic and pharmacodynamic properties of stimulants:

implications for the design of new treatments for ADHD. Behav Brain Res. 2002 Mar

10;130(l-2):73-8. Review.

[036] Depression Anxiety/Stress Disorders

— Wall, et al. Infralimbic D2 receptor influences on anxiety-like behavior and active memory/attention in CD-I mice. Prog Neuropsychopharmacol Biol Psychiatry. 2003

May;27(3):395-410.

— Laasko, et al. Personality traits and striatal dopamine synthesis capacity in healthy

subjects. Am J Psychiatry. 2003 May;160(5):904-10.

— Lawford, et al. D2 dopamine receptor gene polymorphism: paroxetine and social

functioning in posttraumatic stress disorder. Eur Neuropsychopharmacol. 2003

Oct;13(5):313-20.

— Buller, et al. Systemic apomorphine alters HP A axis responses to interleukin-1 beta administration but not sound stress. Psychoneuroendocrinology. 2003 Aug;28(6):715-

32.

— Brunswick, et al. Greater availability of brain dopamine transporters in major

depression shown by [99m TcJTRODAT-1 SPECT imaging. Am J Psychiatry. 2003

Oct; 160(10): 1836-41.

— Kondo, et al. Combination of dopamine D2 receptor gene polymorphisms as a possible predictor of treatment-resistance to dopamine antagonists in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Sep;27(6):921-6.

[037] The compounds used in the present invention may be administered by any

conventional route, such as orally, transdermally, subcutaneously, parenterally, intramuscularly, intravenously, intraperitoneally, or via inhalation. Oral, parenteral

and subcutaneous administration are preferred. The compounds used in the present

invention may be administered alone or in combination with other therapies

conventionally known for treating attention deficit hyperactivity disorder (ADHD),

conduct disorder, alcohol addiction, tobacco addiction, nicotine addiction, inhalation

disorders, Parkinsonism including Parkinson's disease, female and male orgasmic

disorders, female and male sexual arousal disorders, hypoactive sexual desire

disorder, as well as conventional therapies for treating anxiety and/or depression.

[038] The active compounds are administered to a patient in a "safe and effective

amount," i.e., an amount which provides the desired clinical benefit based on size,

weight, age, physical and mental condition of the patient, and severity of the condition

being treated, while minimizing any undesirable side effects. The precise dosages i

be administered will be determined based on the judgment of the treating physician.

Typical dosages for administration of the active compounds are from about 0.05 to

about 1000 milligrams (mg) per day, more preferably from about 0.1 to about 100 mg

per day, more preferably from about 0.1 to about 75 mg/day, more preferably from about 0.1 to about 50 mg/day, most preferably from about 5 to about 10 mg/day. The desired dosage may be administered in one, two or three subdoses at suitable times

during the day. The subdoses may consist of 0.05 to 1000 mg per subdose, preferably

0.1 to 100 mg per subdose, most preferably 0.5 to 10 mg per subdose. The desired dosage will depend on the particular compound to be utilized, the disease to be

treated, the severity of the disease, the route of administration, the weight and health

of the patient, and the judgment of the treating physician. The active compound may

be administered in a timed or delayed release dosage form thereby allowing treatment

over an extended period of time.

[039] For oral administration, conventional solid carriers for the active compound

may be employed, such as pharmaceutical grades of cellulose, glucose, lactose,

mannitol, magnesium stearate, sodium saccharin, sucrose, talcum or similar solid

carriers. A pharmaceutically acceptable dosage for oral administration may be

manufactured incorporating any customary nontoxic pharmaceutical excipient, such

as those excipients described above, and generally about 5% to about 95% of the

active compound, more preferably about 25% to 75% of the active compound.

[040] The compounds described herein, together with a conventional pharmaceutically acceptable adjuvant, carrier or diluent, may thus be placed into the

form of a pharmaceutical composition and unit dosages thereof, and in such form may

be employed as solids, such as tablets or filled capsules, or liquids, such as solutic ,

suspensions, emulsions, elixirs or capsules filled with the same, all for oral use; in the

form of suppositories for rectal administration; or in the form of sterile injectable

solutions for parenteral (including subcutaneous) use. Such pharmaceutical

compositions and unit dosage forms thereof may comprise conventional ingredients in

conventional proportions, with or without additional active compounds or principles,

and such unit dosage forms may contain any suitable effective amount of the active

ingredient commensurate with the intended daily dosage range to be employed. [041] The compounds described herein can be administered in a wide variety of oral

and parenteral dosage forms. It will be obvious to those skilled in the art that the

following dosage forms may comprise, as the active component, either a compound

described herein or a pharmaceutically acceptable salt of such a compound.

[042] For preparing pharmaceutical compositions of the compounds described

herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form

preparations include powders, tablets, pills, capsules, cachets, suppositories, and

dispersible granules. A solid carrier can be one or more substances which may also

act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders,

preservatives, tablet disintegrating agents, or an encapsulating material.

[043] In powders, the carrier is a finely divided solid admixed with the finely divided active component.

[044] In tablets, the active component is mixed with the carrier having the necessary

binding capacity in suitable proportions and compacted in the shape and size desired.

[045] The powders and tablets typically contain from about 5 or 10% to about 70

of the active compound. Suitable carriers include, for example, magnesium carbonate,

magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,

methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and

the like. The description herein is intended to include the formulation of the active

compound with an encapsulating material as carrier providing a capsule in which the

active compound, with or without additional carriers, is surrounded by the

encapsulating material, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be

used as solid forms suitable for oral administration.

[046] For preparing suppositories, a low melting wax, such as an admixture of fatty

acid glycerides or cocoa butter, is first melted and the active material is dispersed

homogeneously therein, as by stirring. The molten homogeneous mixture is then

poured into convenient sized molds, allowed to cool, and thereby to solidify.

[047] Formulations suitable for vaginal administration may be presented as

pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the

active ingredient, such carriers as are known in the art to be appropriate.

[048] Liquid form preparations include solutions, suspensions, and emulsions, for

example, water or water-propylene glycol solutions. Parenteral injection liquid

preparations can be formulated as solutions in, for example, aqueous polyethylene

glycol solution.

[0491 The compounds described above may be formulated for parenteral

administration (e.g., by injection, for example, bolus injection or continuous infus i)

and may be presented in unit dosage form in ampoules, pre-filled syringes, small

volume infusion or in multi-dose containers with an added preservative. The

compositions may take such forms as suspensions, solutions, or emulsions in oily or

aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing

and/or dispersing agents. Alternatively, the active ingredient may be in powder form,

obtained by aseptic isolation of sterile solid or by lyophilization from solution, for

constitution with a suitable vehicle, e.g., sterile, pyro gen-free water, before use. [050] Aqueous solutions suitable for oral use can be prepared by dissolving the

active compound in water and adding suitable colorants, flavors, preservatives,

stabilizing and/or thickening agents, as desired.

[051] Aqueous suspensions suitable for oral use can be made by dispersing the

finely divided active component in water with viscous material, such as natural or

synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other

well-known suspending agents.

[052] Also included within the scope of this invention are solid form preparations

which are intended to be converted, shortly before use, to liquid form preparations for

oral administration. Such liquid forms include solutions, suspensions, and emulsions.

These preparations may contain, in addition to the active component, colorants,

flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners,

solubilizing agents, and the like.

[053] For topical administration to the epidermis, the compounds described above

may be formulated as ointments, creams or lotions, or as a transdermal patch.

Ointments and creams may, for example, be foraiulated with an aqueous or oily base

with the addition of suitable thickening and/or gelling agents. Lotions may be

formulated with an aqueous or oil base and will in general also contain one or more

art-known emulsifying agents, stabilizing agents, dispersing agents, suspending

agents, thickening agents, or coloring agents.

[054] Formulations suitable for topical administration in the mouth include lozenges comprising active component in a flavored base, usually sucrose and acacia or

tragacanth; pastilles, comprising the active component in an inert base such as gelatin or glycerin; and mouthwashes comprising the active component in a suitable liquid carrier.

[055] Solutions or suspensions are applied directly to the nasal cavity by

conventional means, for example, with a dropper, pipette or spray. The formulations

may be provided in single or multidose form. In the case of a dropper or pipette, this

may be achieved by the patient administering an appropriate, predetermined volume

of the solution or suspension. In the case of a spray, the active component may be

administered, for example, by means of a metering atomizing spray pump.

[056] Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active component is provided in a pressurized pack with a suitable propellant, such as a chlorofluorocarbon, for example,

dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane. carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a

surfactant, such as lecithin. The dosage of drug may be controlled by provision of a

metered valve.

[057] Alternatively, for nasal administration, the active ingredient may be provided

in the form of a dry powder, for example, a powder mix of the therapeutic compound

in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example, in capsules or cartridges of, e.g., gelatin,

or blister packs from which the powder may be administered by means of an inhaler. [058] In formulations intended for administration to the respiratory tract, including

intranasal formulations, the compound will generally have a small particle size, for

example of the order of 5 microns or less. Such a particle size may be obtained by

means known in the art, for example by micronization.

[059] When desired, formulations adapted to give sustained release, timed release or

delayed release of the active component may be employed.

[060] The pharmaceutical preparations are preferably in unit dosage forms. In such

form, the preparation is subdivided into unit doses containing appropriate quantities of

the active component. The unit dosage form can be packaged, the package containing

discrete quantities of preparation, such as a packeted tablet, capsule or powders in a

vial or ampoule. Also, the unit dosage form can be a capsule, tablet, cachet, or

lozenge itself, or it can be the appropriate number of any of these in packaged form.

[061] Tablets or capsules for oral administration and liquids for intravenous

administration are preferred pharmaceutical compositions for use in the method of the

present invention.

1062] What is claimed is: