WO2002094827A1

WO2002094827A1 - Fused tropane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

Info

Publication number: WO2002094827A1
Application number: PCT/DK2002/000345
Authority: WO
Inventors: Bjarne H. Dahl; Alex Haahr Gouliaev
Original assignee: Neurosearch A/S
Priority date: 2001-05-23
Filing date: 2002-05-23
Publication date: 2002-11-28

Abstract

This invention relates to fused tropane derivatives. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the optically active isomer of the invention. A compound of the general formula (I).

Description

FUSED TROPANE DERIVATIVES AND THEIR USE AS MONOAMINE NEUROTRANSMITTER RE-UPTAKE INHIBITORS

TECHNICAL FIELD

This invention relates to fused tropane derivatives. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the optically active isomer of the invention.

BACKGROUND ART

WO 97/16451 describes fused tropane-derivatives and their use as mixed monoamine neu retransmitter re-uptake inhibitors. The document specifically discloses a number of (1S,2S,4S,7R)-8-azatricyclo[5.4.0.0^4,8]undecan derivatives and (1 S,3S,4S,8R)-7-azatricyclo[5.3.0.0⁴'⁸]decan derivatives.

However, there is a continued strong need to find compounds with an optimised biochemical profile as regards the activity on reuptake of the monoamine neurotransmitters serotonin, dopamine and noradrenaline, such as the ratio of the serotonin reuptake versus the noradrenaline and dopamine activity.

Furthermore, there is a strong need to find effective compounds, which structurally and synthetically wise are unrelated to ***e.

SUMMARY OF THE INVENTION

Therefore, in its first aspect, the invention provides a compound of general formula I,

or a pharmaceutically acceptable addition salt thereof or the N-oxide thereof.

In its second aspect the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention together with at least one pharmaceutically-acceptable carrier, excipient or diluent. In a further aspect the invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to inhibition of monoamine neu retransmitter re-uptake in the central nervous system (CNS), which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of the invention.

Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

In its first aspect, the invention provides a compound of general formula I,

or a pharmaceutically acceptable addition salt thereof or the N-oxide thereof wherein

X and Y together forms =O, =S, =NOR², =CR³R⁴, =N-CN, =N-NR⁷R⁸, -(CH₂)_m-, or

-W'-(CH₂)_P-W"-, or one of X and Y is hydrogen and the other is -OR⁵, -SR⁵, or -NR⁵R⁶ Z is hydrogen, -COOR⁹;

R³ and R⁴are independently hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, or -(CH₂)_q-COOR² ;

R², R⁵ and R⁶are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl, -CO-alkyl, or -S0₂-alkyl; R⁷ and R⁸ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl;

R⁹ is alkyl, alkenyl or alkynyl;

R¹ is alkyl, alkenyl, alkynyl, aryl, or arylalkyl; where said aryl groups may be substituted one or more times with substituents selected from the group consisting of halogen, CF₃, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino and nitre;

W and W" are each independently O or S; n is 1 , 2, 3, or 4; m is 2, 3, 4, or 5; p is 1 , 2, 3, 4, or 5; and q is O, 1 , 2, 3, or 4.

In its second aspect, the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.

In a further aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to inhibition of monoamine neurotransmitter reuptake in the central nervous system.

In a still further aspect, the invention relates to a method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of the invention.

In a further aspect, the invention relates to for the preparation of the compounds of the invention comprising forming a fused ring having the formula

wherein n and R¹ is are defined as above, by ring-closure of a compound having the formula

_/ (^CH ₂)n — COOalkyl

wherein n and R¹ is as defined above and thereafter optionally converting the compound obtained to another compound of the invention using conventional methods, and/or optionally forming a pharmaceutically acceptable salt thereof. In one embodiment, X and Y together form =0, =S, =NOR², or =CR³R⁴, or one of X and Y is hydrogen and the other is -OR⁵, -SR⁵, or -NR⁵R⁶;

Z is hydrogen;

R³ and R⁴are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, or -(CH₂)_q-COOR² ;

R², R⁵ and R⁶are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl, -CO-alkyl, or -S0 -alkyl;

R⁷ and R⁸ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl; R¹ is aryl; where said aryl group may be substituted one or more times with substituents selected from the group consisting of halogen, CF₃, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino and nitre; n is 1 , 2, or 3; m is 2, 3, 4, or 5; p is 1 , 2, 3, 4, or 5; and q is O, 1 , 2, 3, or 4.

In a special embodiment, the invention relates of (1 R,2R,4R,7S)-8- azatricyclo[5.4.0.0^4,8]undecan derivates of formula I. In a further special embodiment, the invention relates to (1 R,3R,4R,8S)-7-azatricyclo[5.3.0.0^4,8]decan derivatives of formula I. In a still further special embodiment, the invention relates of

(1 R,3R,4R,5R,8S)-7-azatricyclo[5.3.0.0⁴'⁸]decan derivates of formula I. In a further special embodiment, the invention relates to (I R.SR^R.δS.δS)^- azatricyclo[5.3.0.0^4,8]decan derivatives of formula I. In a further embodiment, X and Y forms =O. In a still further embodiment, one of X and Y is hydrogen and the other is -OR⁵, wherein R⁵ is as defined above

In a further embodiment, R⁵ is hydrogen. In a still further embodiment, R⁵ is alkyl, such as methyl or ethyl.

In a further embodiment, R¹ is aryl, which aryl group may be substituted one or more times with halogen. In a still further embodiment, R¹ is phenyl substituted once with halogen, such as chlorine. In a further embodiment, R¹ is phenyl substituted twice with halogen, such as chlorine.

In a still further embodiment, Z is hydrogen. In a further embodiment, n is 1. In a still further embodiment, n is 2. In a further embodiment, X and Y together form =0, or one of X and Y is hydrogen and the other is -OR⁵;

Z is hydrogen;

R⁵ is hydrogen;

R¹ is aryl; where said aryl group may be substituted one or more times with substituents selected from the group consisting of halogen; and n is 1 , or 2.

In a further embodiment, X and Y together form =0, or one of X and Y is hydrogen and the other is -OR⁵;

Z is hydrogen;

R⁵ is hydrogen or alkyl.

R¹ is phenyl, substituted once or twice with halogen; and n is 1. In a special embodiment, R¹ is phenyl substituted once or twice with chlorine. In a further special embodiment, R¹ is 4-chlorophenyl. In a still further special embodiment, R¹ is 3,4-dichlorophenyl.

In a special embodiment, the compound of general formula I is selected from: (1 R,3R,4R,8S)-3-(3,4-Dichloropehnyl)-7-azatricyclo[5.3.0.0⁴'⁸]decan-5-one,

(1 R₎3R.4R,5R,8S)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-ol₎

(1 R,3R,4R,5S,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]decan-5-ol,

(1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-5-ethoxy-7-azatricyclo-[5.3.0.0⁴'⁸]decane,

(1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-5-methoxy-7-azatricyclo-[5.3.0.0^4,8]decane, and pharmaceutically acceptable addition salts thereof.

Definition of Substituents

In the context of this invention halogen represents a fluorine, a chlorine, a bromine or an iodine atom.

Alkyl means a straight chain or branched chain of one to six carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl; methyl, ethyl, propyl and isopropyl are preferred groups.

Cycloalkyl means cyclic alkyl of three to seven carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

Alkenyl means a group of from two to six carbon atoms, including at least one double bond, for example, but not limited to ethenyl, 1 ,2- or 2,3-propenyl, or 1 ,2-, 2,3-, or 3,4-butenyl.

Alkynyl means a group of from two to six carbon atoms, including at least one triple bond, for example, but not limited to ethynyl, 1 ,2-, 2,3-propynyl, or 1 ,2-, 2,3- or 3,4-butynyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Acyl is -CO-alkyl wherein alkyl is as defined above.

Cycloalkoxy means O-cycloalkyl, wherein cycloalkyl is as defined above. Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaning for example, cyclopropylmethyl.

Amino is NH or NH-alkyl or N-(alkyl)₂, wherein alkyl is as defined above.

Aryl is a carbocyclic aromatic ring system such as phenyl or naphthyl (1- naphthyl or 2-naphthyl).

The compounds of this invention may exist in unsolvated as well as in 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 this invention. It will be appreciated by those skilled in the art that some compounds of the present invention contain chiral centres and that such compounds exist in the form of isomers. Examples of such isomers are the 5R- and the 5S-isomers of the (1S,3S,4S,8R)-7-azatricyclo[5.3.0.0^4,8]decan derivatives. The invention includes all such isomers and any mixtures thereof including racemic mixtures. Methods for the resolvation of optical isomers, known to those skilled in the art may be used, and will be apparent to the average worker skilled in the art. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).

The compounds of the invention may be prepared in numerous ways. The compounds of the invention and their pharmaceutically acceptable derivatives may thus be prepared by any method known in the art for the preparation of compounds of analogous structure, and as shown in the representative examples which follow.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulphonate derived from methane sulphonic acid, the naphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the succinate derived from succinic acid, the tartrate derived from tartaric acid, the toluene-p-sulphonate derived from p-toluene sulphonic acid, and the like. Such salts may be formed by procedures well known and described in the art.

Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt. Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.

In the context of this invention the "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

The chemical substance according to the invention may be administered as such or in the form of a suitable prodrug.

The term "prodrug" denotes a compound, which is a drug precursor and which, following administration and absorption, release the drug in vivo via some metabolic process.

Particularly favoured prodrugs are those that increase the bioavailability of the compounds of the invention (e.g. by allowing an orally administrered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a specific biological compartment (e.g. the brain or lymphatic system).

Thus examples of suitable prodrugs of the substances according to the invention include compounds modified at one or more reactive or derivatizable groups of the parent compound. Of particular interest are compounds modified at a carboxyl group, a hydroxyl group, or an amino group. Examples of suitable derivatives are esters or amides.

The chemical compound of the invention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvents such as water, ethanol, and the like. Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.

Labelled Compounds The compounds of the invention may be used in their labelled or unlabelled form. In the context of this invention "label" stands for the binding of a marker to the compound of interest that will allow easy quantitative detection of said compound.

The labelled compounds of the invention may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo re- ceptor imaging.

The labelled isomer of the invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage.

In the context of this invention the radionuclide is preferably selected from H

(deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹³¹l, ¹²⁵l, ¹²³l, and ¹⁸F. The physical method for detecting the labelled isomer of the present invention may be selected from Position Emission Tomography (PET), Single Photon

Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy

(MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography

(CAT), or combinations thereof.

Methods of Preparation

The compounds of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.

Also one compound of the invention can be converted to another compound of the invention using conventional methods, such as those described in

WO 97/16451. The end product of the reaction described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.

Biological Activity The compounds of the invention may be tested for its ability to inhibit the reuptake of the monoamine neurotransmitters in synaptosomes, eg such as described in WO 97/16451. Based on the balanced activity observed in these tests the compound of the invention is considered useful for combating diseases, disorders or conditions associated with the dopaminergic, noradrenalinergic and/or serotonergic neural system.

The diseases, disorders or conditions contemplated in this context are eating disorders, obesity, anorexia nervosa, disorders of sleep, panic disorders, social phobia, dementia, senile dementia, pre-senile dementia, memory deficits, memory loss, Alzheimer's disease, chronic fatigue syndrome, anxiety, pseudodementia, Ganser's syndrome, narcolepsy, drug addiction or misuse, alcoholism, tobacco abuse, panic disorder, post-traumatic syndrome, migraine, pain, attention deficit hyperactivity disorder, autism, mutism, trichotillomania, Parkinson's disease, depression, attention, alertness, arousal, vigilance, premature ejaculation, and erectile dysfunction.

The compounds of the invention are considered particularly useful for the treatment, prevention or alleviation of depression, pseudodementia, Ganser's syndrome, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety and eating disorders.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention.

While a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

Pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral 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. The chemical compound of the present invention 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 chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention. For preparing pharmaceutical compositions from a chemical compound of the present invention, 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, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component.

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.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, 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.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.

Compositions 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. Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose 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 formulation agents such as suspending, stabilising 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, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.

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.

Also included are solid form preparations, intended for conversion shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component such preparations may comprise colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, tnchlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the 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 dose 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. In compositions intended for administration to the respiratory tract, including intranasal compositions, 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.

When desired, compositions adapted to give sustained release of the active ingredient may be employed.

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 a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. 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.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred. The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.

The actual dosage depend on the nature and severity of the disease being treated and the route of administration, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 0.01 to about 500 mg of active ingredient per individual dose, preferably of from about 0.1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses per day. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.01 μg/kg i.v. and 0.1 μg/kg p.o. The upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10 mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy In another aspect the invention provides a method for the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system (CNS), and which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of the optically active isomer of the invention.

In a more preferred embodiment the invention provides a method of combating depression, pseudodementia, Ganser's syndrome, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety and eating disorders.

It is at present contemplated that suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of the dosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about 10 mg/kg p.o.

Any possible combination of two or more of the embodiments described herein is comprised within the scope of the present invention.

EXAMPLES

The invention is further illustrated with reference to the following examples which are not intended to be in any way limiting to the scope of the invention as claimed.

Example 1

(-)-2-Carbomethoxytropinone: Was prepared by a known procedure (J. F. Casale, Forensic Science International, 33 (1987) 275-298).

Example 2

(+)-Ecgonine ethylester: (-)-2-Carbomethoxytropinone (37.4g) in methyl alcohol (1.5L) was stirred at -45°C, sodium borohydride (37g) was added in small portions, while keeping the temperature between - 45°C and - 35°C, the reaction mixture was stirred at - 45°C for 2 hours, while keeping the temperature at - 45°C hydrochloric acid (120mL) was added drop wise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated to a volume of approximately 120mL, added water (500mL) and washed with diethyl ether (3X100mL). The water phase was added 25% ammonia (aq.) until pH= 0.6 and ex- tracted with dichloromethane (4X200mL), the organic phases was dried (sodium sul- fate). The organic phases was evaporated to an oil. The oil was dissolved in ethyl acetate (370m L), a solution of sodium ethoxide (from 7g of sodium) was added, the resulting solution was heated at reflux for 3 hours. The reaction mixture was evaporated to an oil, the residue was added toluene (0.5L) and evaporated to an oil, this was repeated. The product 30 g (79%) is an oil.

Example 3

(1S,2S,3R,5R)-3-(3,4-Dichlorophenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2- carboxylic acid methyl ester: Magnesium turnings (7.8g) in diethyl ether was added with stirring bromo-3,4-dichlorobenzene, the mixture was heated at reflux for 1 hour. The reation mixture was cooled to - 20°C. (+)-Ecgonine ethylester (30g) in diethyl ether (400mL) and toluene (400mL) was added, the mixture was stirred at -15°C for 2 hours. The reaction mixture was added water (0.75L) and 4M hydrochloric acid (130mL) until pH = 1. The phases was separated, the aqueous phase was added 25% ammonia (aq.) until pH = 11 , the mixture was extracted first with diethyl ether (2X200mL) then with dichloromethane (2X200mL). The organic phases was mixed and dried with magnesium sulfate and evaporated to an oil. The oil was added 2M sodium methoxide in methyl alcohol, the mixture was stirred under reflux for 17 hours and evaporated to an oil. The oil was dissolved in diethyl ether (0.45L) and washed with water (80mL, 5°C), dried with magnesium sulfate and evaporated to an oil. Yield 13.4g. Example 4

(1S,2S,3R,5R)-3-(3,4-Dichlorophenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2- carboxylic acid methyl ester fumarate: (1S,2S,3R,5R)-3-(3,4-Dichlorophenyl)-8- methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester (0.5g) was dissolved in ethyl alcohol and added fumaric acid (0.18g), the solution was evaporated to a foam. Yield 0.57g (84%) MP185-187°C.

Example 5

(1S,2S,3R,5R)-3-(3,4-Dichlorophenyl)-8-(methoxycarbonyl methyl)-8-aza- bicyclo[3.2.1]octane-2-carboxylic acid methyl ester: (1S,2S,3R,5R)-3-(3,4- Dichlorophenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester (13g) and 1 -chloroethyl chloroformate (8.5mL) was mixed in Xylene (40mL), the reaction mixture was heated at reflux for 3.5 hours, then stirred at room temperature overnight. Methyl alcohol (50mL) was added, and the mixture was heated at reflux for 2 hours, then a Dean Stark apparatus was added, and approximately (75mL) of distillate was collected and removed. The resulting mixture was added, 4 M sodium hydox- ide (aq.) (50mL), bride (10mL) and xylene (60mL). The organic phase was separated and dried with sodium sulfate, after filtration the filtrate was evaporated to an oil. The oil (14.5g) in xylene (50mL) was added triethylamine (10.3mL) and methyl bromoace- tate (6.8mL), the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtrated, the precipitate was washed with xylene and toluene, the filtrate was evaporated to an oil. Yield 14 g (78.5%). Example 6

(1R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0⁴'⁸]decan-5-one: Sodium (1g) was dissolved in methyl alcohol (20mL), xylene (50mL) was added and (1 S,2S,3R,5R)-3-(3,4-dichlorophenyl)-8-(methoxycarbonyl methyl)-8-aza- bicyclo[3.2.1]octane-2-carboxylic acid methyl ester (14g) in xylene (30mL). The reaction mixture was heated at reflux for 4 hours and then cooled to room temperature added water (50mL) and concentrated hydrochloric acid (15mL), then heated at reflux overnight. The reaction mixture was distillated until only one phase was left (water was added occasionally), the residue was added 25% ammonia (aq.), the precipitate was isolated by filtration and air dried on the filter. Yield 6.2g (58%). MP 192-194°C.

Example 7

(1R,3R.4R,5R,8S)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0⁴'⁸]decan-5-ol fumarate: (1 R,3R,4R,8S)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]-decan-5-one (5.2g) was suspended in methyl alcohol (50mL) and added sodium borohydride (3g), the reaction mixture was stirred at room temperature for 1.5 hour, then added water (100mL), the precipitate was isolated by filtration. The precipitate was added to a hot solution of fumaric acid (1.8g) in water (200mL), the solution was heated at reflux for 10 minutes, then cooled to 5°C, a brown gum separated and was isolated by decanting of the liquid, the brown gum was added ethyl alcohol (96%) (50mL) and water (20mL), the mixture was heated at reflux for 10 minutes and cooled to 5°C, a solid crystallized out, and was isolated by filtration. The precipitate was washed with cold (5°C) ethyl alcohol (2mL) and air dried on the filter. Yield 2.5 g (34%) MP 255- 257°C. Example 8

(IR.SR^R.SS^SH-tS^-Dichlorophenyl -azatricyclo-tδ.S.O.O^-decan-δ-ol

The isomer is produced as follows: To a -10°C stirred solution of triphenylphosphine (4.71 g; 18 mmol) in THF (125mL), a solution of diethylazodicarboxylate (2.82 ml) in THF (25 mL) is added drop-wise, during which reaction the temperature is kept at - 10°C by external cooling.

Solid (1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]- decan-5-ol (4.45 g) is now added in one portion. Stirring is continued for two hours, during which period the temperature is allowed to rise to 0°C.

Benzoic acid (2.19 g) is added, and stirring is continued overnight at room temperature. The reaction mixture was evaporated in vacuo, and the residue treated with diethylether/1 N HCI (100 mL). The organic phase is discharged, and the aqueous phase is basified with aqueous ammonia. This afforded a precipitate of the crude product, which is subsequently extracted with diethyl ether. The organic phase is dried and evaporated to dryness. Yield: crude intermediate benzoate.

This intermediate is purified by SiO₂ column purification in EtAc:MeOH:acetone (4:1 :1), and subsequently treated with EtOH/4N NaOH for 3 hours at room-temperature. Addition of water to the reaction mixture gives a precipitate of (1 R,3R,4R,5S,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]- decan-5-ol, which is recrystallised from EtOH to give a crystalline product.

Example 9

(1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0⁴'⁸]-decan-5-ethoxy fumarate (1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0⁴'⁸]-decan-5- ol (2.0 g; 6.7 mmol) in THF (40 mL) was added potassium fert.butoxide (2.4 g; 21 mmol), the solution was stirred for one hour, when cooled to -60°C by external cooling. The mixture was added diethyl sulfate (1.1 g, 7 mmol). The reaction mixture was 5 stirred at 8 hours at -40°C, then at room temperature overnight.

The reaction mixture was added water and extracted 3 times with diethyl ether, the collected ether phases was washed with water and dried, then evaporated to an oil.

The oil was dissolved in ethyl alcohol (approximately 25 ml) and added fu- 10 marie acid (0.82 g; 7 mmol), the mixture was heated on a hot plate until the solution was clear, then cooled on an ice/water bath. (1 R,3R,4R,5R,8S)-3-(3,4- dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]-decan-5-ethoxy fumarate precipitated and was isolated by filtration. Upon standing more (1 R,3R,4R,5R,8S)-3-(3,4- dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]-decan-5-ethoxy fumarate precipitated from 15 the filtrate, this was also isolated by filtration. The precipitates was united and stirred in a mixture of ethyl acetate and diethyl ether. Yield 1.78 g (52 %) MP 174-175°C.

Example 10

(IR.SR^R.δR.βSJ-S-tS^-DichlorophenylJ-T-azatricyclo-IS.S.O.O^l-decan-δ- methoxy fumarate

(1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0⁴'⁸]-decan-5-ol (7.43 g;

25 25 mmol) in THF (150 mL) was added potassium fe/ .butoxide (8.4 g; 75 mmol), the solution was stirred at room temperature for 1 hour, then cooled external to -75°C, over 15 min was added dimethyl sulfate (3.2 g; 25 mmol) in THF (10 mL), while the temperature was kept below -65°C.

The reaction mixture was stirred for 2 hours, then allowed to warm to room

30 temperature and poured into water (200 mL). The mixture was extracted twice with diethyl ether (2 X 200 mL). The organic phases was collected, dried and then evaporated to an oil.

The oil was added ethyl alcohol and fumaric acid (3.2 g; 27.5 mmol). The mixture heated to reflux and became a clear solution. Upon cooling on an ice/water

35 bath (1 R,3R,4R,5R,8S)-3-(3,4-dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]-decan-5- methoxy fumarate precipitated and was isolated by filtration. The solid was washed with cold ethyl alcohol and after that diethyl ether and dried. Yield 8.5 g (79 %) MP 208-209°C.

Example 11

The following two compounds is prepared analogously from (1 R,3R,4R,5S₎8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]-decan-5-ol using the methods as described in examples 9 and 10.

(1 R,3R,4R,5S,8S)-3-(3,4-Dichlorophenyl)-5-ethoxy-7-azatricyclo-[5.3.0.0^4,8]-decan, and (1 R,3R,4R,5S,8S)-3-(3,4-Dichlorophenyl)-5-methoxy-7-azatricyclo-[5.3.0.0^4,8]-decan.

Example 12

The following compounds are prepared analogously using the methods as described above and in WO 97/16451.

1 R,2R,4R,7S)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.0^4,8]undecan-11 -one, 1 R,2R,4R,7S)-2-(3,4-Dichlorophenyl)-8-azatricyclo[5.4.0.0⁴'⁸]undecan-11 -ol, 1 1 RR.,33FR,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0⁴'⁸]decan-5-one O-methyl- oxime,

1 R,2R,4R,7S)-2-(4-Chlorophenyl)-8-azatricyclo[5.4.0.0^4,8]undecan-11 -one, 1 R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-aza-tricyclo[5.3.0.0^4,8]dec-5-yl acetate, 1 R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0⁴'⁸]dec-5-yl methane sulphate,

1 R,3R,4R,8S)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-one, 1 R,3R,4R,8S)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-ol, 1 R,3R,4R,8S)-3-(4-Chlorophenyl)-5-ethoxy-7-azatricyclo[5.3.0.0^4,8]decane, 1 R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0⁴'⁸]decan-5-one O-benzyl- oxime,

1R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-one O-allyl- oxime,

1 R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-one oxime, 1 R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-one O-tet .- butyl-oxime,

1 R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-one O-ethyl- oxime, 1 R,3R,4R,8S)-5-Allyloxy-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decane, Ethyl (1 R,3R,4R,8S)-2-[3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0⁴'⁸]dec-5- ylidenjacetate,

(1 R,3R,4R,8S)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-one oxime, N1-(1 R,3R,4R,8S)-3-(4-chlorophenyl)-7-azatricyclo[5.3.0.0^4,8]dec-5-yl]acetamide, (1 R,3R,4R,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo[5.3.0.0^4,8]dec-5-yl amine, and pharmaceutically acceptable addition salts thereof.

Claims

CLAIMS:

1. A compound of the general formula (I),

X and Y together forms =O, =S, =NOR², =CR³R⁴, =N-CN, =N-NR⁷R⁸, -(CH₂)_m-, or -W'-(CH₂)_P-W"-, or one of X and Y is hydrogen and the other is -OR⁵, -SR⁵, or -NR⁵R⁶

Z is hydrogen, -COOR⁹;

R², R⁵ and R⁶are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl, -CO-alkyl, or -SO₂-alkyl;

R⁷ and R⁸ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl;

R⁹ is alkyl, alkenyl or alkynyl;

W' and W" are each independently O or S; n is 1 , 2, 3, or 4; m is 2, 3, 4, or 5; p is 1 , 2, 3, 4, or 5; and q is O, 1 , 2, 3, or 4.

2. The compound according to claim 1 , wherein

X and Y together form =O, =S, =NOR², or =CR³R⁴, or one of X and Y is hydrogen and the other is -OR⁵, -SR⁵, or -NR⁵R⁶;

Z is hydrogen;

R³ and R⁴are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, or -(CH₂)_q-COOR² ; R², R⁵ and R⁶are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl, -CO-alkyl, or -SO₂-alkyl;

R⁷ and R⁸ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, or arylalkyl; R¹ is aryl; where said aryl group may be substituted one or more times with substituents selected from the group consisting of halogen, CF₃, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino and nitro; n is 1, 2, or 3; m is 2, 3, 4, or 5; p is 1 , 2, 3, 4, or 5; and q is O, 1 , 2, 3, or 4.

3. The compound according to claims 1 or 2, wherein X and Y together form =O, or one of X and Y is hydrogen and the other is -OR⁵; Z is hydrogen; R⁵ is hydrogen or alkyl.

R¹ is phenyl, substituted once or twice with halogen; and n is 1.

4. The compound according to any one of claims 1 -3, wherein R¹ is phenyl substituted once or twice with chlorine.

5. A compound of any one of claims 1-4 which is

(1 R,3R,4R,8S)-3-(3,4-Dichloropehnyl)-7-azatricyclo[5.3.0.0^4,8]decan-5-one, (1 R,3R.4R,5R,8S)-3-(3,4-dichlorophenyl)-7-azatricyclo[5.3.0.0⁴'⁸]decan-5-ol, (1 R,3R,4R,5S,8S)-3-(3,4-Dichlorophenyl)-7-azatricyclo-[5.3.0.0^4,8]-decan-5-ol, (1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-5-ethoxy-7-azatricyclo-[5.3.0.0^4,8]-decan, (1 R,3R,4R,5R,8S)-3-(3,4-Dichlorophenyl)-5-methoxy-7-azatricyclo-[5.3.0.0^4,8]-decan, or a pharmaceutically acceptable addition salt thereof.

6. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of any one of claims 1-5, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.

7. The use of a compound according to any one of claims 1 -5, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system.

8. The use according to claim 7, wherein the disease, disorder or condition is depression, pseudodementia, Ganser's syndrome, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety and eating disorders.

9. A method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to inhibition of monoamine neurotransmitter re-uptake in the central nervous system, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound according to any one of the claims 1-5.

10. The method of claim 9, wherein the disease, disorder or condition is depression, pseudodementia, Ganser's syndrome, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety and eating disorders.

11. A method for the preparation of the compounds of any one of claims 1-5 comprising forming a fused ring having the formula

wherein n and R¹ is are defined in claim 1 , by ring-closure of a compound having the formula

_/ (^CH ₂)n-COOalkyl

wherein n and R¹ is as defined in claim 1 and thereafter optionally converting the compound obtained to another compound of the invention using conventional methods, and/or optionally forming a pharmaceutically acceptable salt thereof.