KR20090089439A - Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors - Google Patents

Abstract

This invention relates to novel chromen-2-one derivatives of Formula (I) useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention. ® KIPO & WIPO 2009

Description

Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

The present invention relates to novel chromen-2-one derivatives useful as monoamine neurotransmitter reuptake inhibitors.

In another aspect, the invention relates to the use of these compounds in a method of treatment and to pharmaceutical compositions comprising the compounds of the invention.

Serotonin selective reuptake inhibitors (SSRI) are currently efficacious in the treatment of several CNS disorders, including depression and panic disorder. SSRIs have generally been recognized to be effective, well tolerated and easily administered to psychiatrists and primary care physicians. However, they are associated with a number of undesirable properties.

Thus, compounds with an optimized pharmacological profile with respect to the activity for reuptake of the monoamine neurotransmitter serotonin, dopamine and noradrenaline, such as the ratio of serotonin reuptake to noradrenaline and dopamine reuptake activity, are still strongly required Is saved.

WO 2006/035034 and WO 2007/093604, each of which applicants are NeuroSearch A / S, describe their use as chroman-2-one derivatives and monoamine neurotransmitter reuptake inhibitors.

The gist of the invention

It is an object of the present invention to provide novel compounds that show activity as monoamine neurotransmitter reuptake inhibitors.

In a first aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

In Formula I,

R ¹ and Q are described later.

In a second aspect, the invention provides a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers, excipients or diluents. It provides a pharmaceutical composition comprising.

In a further aspect, the present invention is directed to preparing a pharmaceutical composition for treating, preventing or alleviating a disease, disorder or condition in response to inhibition of monoamine neurotransmitter reuptake in the central nervous system of a mammal, including humans. , Compounds of the present invention, stereoisomers thereof, mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof.

In yet another aspect, the invention provides a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof to a living animal body, including a person in need thereof. A method of treating, preventing or alleviating a disease, disorder or condition in response to inhibition of monoamine neurotransmitter reuptake in the central nervous system of a living animal body, including humans.

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

Chromen 2-one derivative

In a first aspect of the invention there is provided a compound of formula (I), a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

Formula I

In Formula I,

Q is a chromen-2-on-yl group,

The chromen-2-one-yl group is a heteroaryl group wherein the heteroaryl group is halo, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, hydroxy, alkoxy, cycloalkoxy, Optionally substituted with one or more substituents independently selected from the group consisting of methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl),

The chromen-2-one-yl group is halo, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, hydroxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and Optionally further substituted with one or more substituents independently selected from the group consisting of alkynyl,

R ¹ is hydrogen or alkyl,

The alkyl is independently from the group consisting of halo, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, hydroxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl Optionally substituted with one or more substituents selected.

In one embodiment of the compound of formula (I), R ¹ is hydrogen or alkyl. In certain embodiments, R ¹ is hydrogen.

In a further embodiment of the compound of formula (I), Q is a substituted chromen-2-one-7-yl group.

In yet further embodiments of compounds of Formula (I), Q is a 3- (optionally substituted heteroaryl) -chromen-2-one-yl group.

In a further embodiment of the compound of formula (I), Q is a compound which is chromen-2-one-7-yl substituted with furanyl or benzofuranyl group. In certain embodiments, Q is chromen-2-one-7-yl substituted with furanyl, such as furan-2-yl or furan-3-yl. In a further particular embodiment, Q is chromen-2-one-7yl substituted with benzofuranyl, such as benzofuran-2-yl.

In certain embodiments, compounds of the invention are exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-furan-2-yl -Chromen-2-one; Exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-furan-3-yl-chromen-2-one; Exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-benzofuran-2-yl-chromen-2-one; Or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the aspects as described above is included within the scope of the present invention.

Definition of substituents

In the context of the present invention, halo is fluoro, chloro, bromo or iodo.

In the context of the present invention, an alkyl group is a monovalent saturated, straight or branched hydrocarbon chain. And the hydrocarbon chain preferably containing from 1 to 6 carbon atoms, including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl (C _{1 -6} - alkyl). In a preferred embodiment, the alkyl is C _{1 -4,} including butyl, isobutyl, sec-butyl and tert-alkyl groups. In a further preferred embodiment of the invention, alkyl is C _{1 -3} which can be in particular methyl, ethyl, propyl or isopropyl-alkyl group.

In the context of the present invention, alkenyl groups represent carbon chains containing one or more double bonds, including di-enes, tri-enes and poly-enes. In preferred embodiments, the alkenyl group of the invention comprises one or more double bonds and containing 2 to 6 carbon atoms (C _{2 -6} - alkenyl). In the most preferred embodiment, alkenyl groups of the invention are ethenyl; 1- or 2-propenyl; 1-, 2- or 3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4- or 5-hexanyl, or 1,3-hexadienyl, or 1,3,5-hexatrienyl.

In the context of the present invention, alkynyl groups represent carbon chains containing one or more triple bonds, including di-phosphorus, tri-phosphorus and poly-phosphorus. In preferred embodiments, the alkynyl group of the invention comprises a containing at least one triple bond and 2 to 6 carbon atoms (C _{2 -6} - alkynyl). In the most preferred embodiment, the alkynyl group of the invention is ethynyl; 1- or 2-propynyl; 1-, 2- or 3-butynyl, or 1,3-butadiinyl; 1-, 2-, 3-, 4-pentynyl, or 1,3-pentadiinyl; 1-, 2-, 3-, 4- or 5-hexynyl, or 1,3-hexadiinyl or 1,3,5-hexatriinyl.

In the context of the invention, cycloalkyl groups are preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl cyclic alkyl group containing 3 to 7 carbon atoms, including (C _{3 -7} - cycloalkyl Alkyl).

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

Cycloalkoxy is O-cycloalkyl, where cycloalkyl is as defined above.

Cycloalkylalkyl is cycloalkyl as described above and alkyl as described above, for example cyclopropylmethyl.

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

In the context of the present invention, heteroaryl groups represent aromatic monocyclic or bicyclic heterocyclic groups having one or more heteroatoms in the ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S).

Preferred monocyclic heteroaryl groups of the invention include aromatic 5- and 6-membered heterocyclic monocyclic groups, for example oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, 1 , 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, triazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadia Zolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl, thienyl, pyridyl, pyrimidyl or pyridazinyl.

Preferred acyclic heteroaryl groups of the invention are, for example, indolinyl, indolyl, isoindoleyl, indazolyl, benzofuranyl, benzo [b] thienyl, benzimidazolyl, benzoxazolyl, Benzooxadiazolyl, benzothiazolyl, benzo [d] isothiazolyl, furinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthy Include, but are not limited to, lidinyl, putridinyl, and indenyl.

Pharmaceutically acceptable salts

The compounds of the present invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (ie physiologically) acceptable salts of the compounds of the invention, and predrug or prodrug forms.

Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts, including, for example, hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, Ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, emborate, enanthate, fumarate, glatamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene -2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate and the like. Such salts are well known and can be formed by procedures described in the art.

Other acids, such as oxalic acid, which cannot be considered pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Examples of pharmaceutically acceptable cationic salts of the compounds of the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, ricinium and ammonium of the compounds of the invention containing anionic groups. It includes salt. Such cationic salts can be formed by processes that are well known and described in the art.

In the context of the present invention, "onium salts" of N-containing compounds are also considered to be pharmaceutically acceptable salts. Preferred "onium salts" include alkyl-onium salts, cycloalkyl-onium salts and cycloalkylalkyl-onium salts.

Examples of predrug or prodrug forms of the compounds of the invention include examples of suitable prodrugs of materials according to the invention, including compounds modified in one or more reaction groups or derived groups of the invention. Of particular interest are compounds modified from carboxyl groups, hydroxyl groups or amino groups. Examples of suitable derivatives are esters or amides.

The compounds of the present invention may be provided in soluble or insoluble form with pharmaceutically acceptable solvents such as water, ethanol and the like. Soluble forms may also include hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like. In general, the soluble forms are considered to correspond to the insoluble forms for the purposes of the present invention.

Stereoisomer

Those skilled in the art will appreciate that compounds of the present invention may exist in different stereoisomeric forms, including enantiomers, diastereomers and cis-trans-isomers.

For example, the group -O-Q of formula I can in particular be an exo or endo coordination with an azabicyclic ring.

The present invention includes all such stereoisomers and any mixtures thereof, including racemic mixtures.

Racemic forms can be resolved into optical antipodes by known methods and techniques. One method of separating the enantiomeric compounds (including enantiomeric intermediates) is for the compounds that are chiral acids-using optically active amines and freeing the diastereomericly dissolved salts by acid treatment. . Another method of resolving racemates into optical counterparts is based on chromatography on an optically active matrix. Thus, the racemic compounds of the present invention can be resolved into their optical counterparts by, for example, fractional crystallization of D- or L- (tartrate, mandelate, or camphor-sulfonate) salts.

The compounds of the present invention may also be derived from optically active activated carboxylic acids such as (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) campanic acid. Compounds) to form diastereomeric amides, or compounds of the present invention to react with optically active chloroformates and the like to form diastereomeric carbamates.

Additional methods of resolving optical isomers are known in the art. Such methods include those described in the literature (Jaques J, Collet A, & Wilen S in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981)).

Optically active compounds can also be prepared from optically active starting materials.

Labeled  compound

The compounds of the present invention can be used in labeled or unlabeled form. In the context of the present invention, the labeled compound has one or more atoms replaced by atoms having an atomic mass or mass number that is different from the atomic mass or mass number generally found in nature. The labeling will allow easy quantitative determination of the compound.

The labeled compounds of the present invention are useful as diagnostic tools, radiotracers or monitoring agents in various diagnostic methods and may be useful for in vivo receptor imaging.

The labeled compounds of the present invention preferably contain one or more radionuclides as labels. Positron emitting radionuclides are all candidates for use. In the context of the present invention, the radionuclide is preferably selected from ² H (deuterium), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹³¹ I, ¹²⁵ I, ¹²³ I and ¹⁸ F.

Physical methods for detecting labeled compounds of the invention include positron emission tomography (PET), single photon imaging computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computer axial X- Tomography (CAT), or a combination thereof.

Manufacturing method

The compounds of the present invention can be prepared by conventional methods for chemical synthesis, for example by the methods described in the working examples. Starting materials of the methods described herein are known or can be readily prepared by conventional methods from commercially available chemicals.

In addition, one compound of the present invention can be converted to another compound of the present invention using conventional methods.

The final product of the reactants described herein can be separated by conventional techniques, for example by extraction, crystallization, distillation or chromatography.

Biological activity

Compounds of the invention are tested for their ability to inhibit the reuptake of monoamine dopamine, noradrenaline and serotonin in synaptosomes, as described, for example, in WO 97/30997 (Applicant: Neutroch A / S). Can be. Based on the balanced activity observed in these tests, the compounds of the present invention can be used to treat, prevent or alleviate diseases, disorders or conditions in response to inhibition of monoamine neurotransmitter reuptake in the central nervous system of mammals, including humans. Is considered useful. In certain embodiments, the compounds of the present invention may be used in the treatment of mood disorders, depression, atypical depression, depression secondary to pain, major depressive disorder, mood swing disorder, bipolar disorder, type I bipolar disorder, type II bipolar disorder, cyclic mood Disorders, mood disorders due to general medical conditions, substance-induced mood disorders, pseudo dementia, Ginger syndrome, obsessive compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without panic disorder history, Panic attack, memory deficit, memory loss, attention deficit hyperactivity disorder, obesity, anxiety, general anxiety disorder, eating disorder, Parkinson's disease, Parkinson's disease, dementia, aging dementia, senile dementia, Alzheimer's disease, Down syndrome, AIDS Syndrome, memory dysfunction at aging, specific phobias, social phobia, social anxiety disorder, post-traumatic stress disorder, acute stress disorder, chronic Tress disorders, drug addiction, drug abuse, drug abuse tendencies, cocaine abuse, nicotine abuse, tobacco abuse, alcoholic addiction, alcoholism, pathological walls, withdrawal syndrome due to discontinuation of use of toxic substances, pain, chronic pain, inflammatory pain, Neuropathic pain, diabetic neuropathic pain, migraine, tension headache, chronic tension headache, depression-related pain, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, cancer pain, irritable bowel pain, irritable bowel syndrome, postoperative pain , Post mastectomy pain syndrome (PMPS), post-stroke pain, drug-induced neuropathy, diabetic neuropathy, pain sustained by the sympathetic nervous system, trigeminal neuralgia, toothache, facial muscle pain, annular pain, anorexia, premenstrual syndrome, Premenstrual discomfort disorders, late progesterone syndrome, post-traumatic syndrome, chronic fatigue syndrome, persistent plant conditions, urinary incontinence, stress incontinence, urge incontinence, Liver incontinence, sexual dysfunction, premature ejaculation, erectile dysfunction, erectile dysfunction, premature female orgasm, restless leg syndrome, cyclic limb motor disorder, eating disorders, anorexia nervosa, sleep disorders, general developmental disorders, autism, asperger disorders, let disorders, Childhood collapsing disorders, learning disorders, motor impairment, narcosis, hair growth, narcolepsy, post-stroke depression, stroke-induced brain injury, stroke-induced nerve damage, Gilles de la Tourette disease, tinnitus, tic disorders, dysmorphic disorders, It is considered useful for treating, preventing or alleviating hostile oppositional disorders or post-stroke disorders. In a preferred embodiment, the compound is considered useful for treating, preventing or alleviating depression.

Currently, suitable dosages of the active pharmaceutical ingredient (API) are in the range of about 0.1 to about 1000 mg API, more preferably about 10 to about 500 mg API, most preferably about 30 to about 100 mg API per day, but such The range is contemplated depending on the exact mode of administration, the form administered, the instructions considered, the weight of the subject, particularly the subject concerned, and further preferences and experiences of the attending physician or veterinarian.

Preferred compounds of the invention exhibit biological activity in the range of micromolar and micromolar, i.e., less than 1 μM to about 100 μM.

Pharmaceutical composition

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

The therapeutic compounds of the invention may be administered in the form of source compounds, but the active ingredient in the pharmaceutical composition may optionally be in the form of one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional agents in the form of physiologically acceptable salts. Administration with a pharmaceutical adjuvant is preferred.

In a preferred embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or derivative thereof with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic components known and used in the art. It provides a pharmaceutical composition comprising. The carrier (s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical compositions of the present invention can be used orally, rectally, bronchial, intranasally, lung, topical (including buccal and sublingual), transdermal, intravaginal or parenteral (skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracranial, Compositions suitable for administration (including intraocular injection or infusion) or compositions in a form suitable for administration by inhalation or aeration or by a sustained release system, including powder and liquid aerosol administration. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing a compound of the present invention, which matrices may be in the form of shaped articles, eg films, or microcapsules.

Accordingly, the compounds of the present invention may take the form of pharmaceutical compositions and unit dosage forms thereof in combination with conventional adjuvants, carriers or diluents. These forms are solid (especially in tablets, filled capsules, powders and pellets), liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, emulsions, and capsules filled with them) that are each oral dosage form, and for rectal administration. Suppositories, and parenteral sterile injectable solutions. 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 be any suitable for the intended daily dosage range to be used. It may contain a suitable effective amount of the active ingredient.

The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention as an active ingredient.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier can be solid or liquid. Solid dosage formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can also act as diluents, fragrances, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

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

In tablets, the active ingredient 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 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term “formulation” refers to the formulation of an active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by a carrier with or without a carrier. Detergents and lozenges include Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, low melting waxes such as mixtures of fatty acid glycerides or cocoa butter are first melted and the active ingredient is homogeneously dispersed therein by stirring. The molten homogeneous mixture was then solidified by pouring into a mold of convenient size and cooling.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, blowing agents or sprays which contain, in addition to the active ingredient, carriers known to be suitable in the art.

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

Thus, the compounds according to the invention can be formulated for parenteral administration (eg by injection, for example by cyclic injection or continuous infusion), and in ampoules, prefilled syringes, small dose infusions or in multidose containers It may be provided in unit dosage form with added preservatives. The compositions may take such formulations as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. In addition, the active ingredient may be obtained by preservative separation of sterile solids or by lyophilization from solution to be composed with a suitable vehicle, eg, sterile pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners, if desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well known suspending agents.

Also included are solid form preparations which will be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, such preparations may include colorants, fragrances, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

For topical administration to the epidermis, the compounds of the present invention may be formulated as ointments, creams or lotions, or as transdermal patches. 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 can be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents.

Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in an aromatic substrate, generally sucrose and acacia or tragacanth; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

The solution or suspension is administered directly to the nasal cavity by conventional means, for example by dropper, pipette or spray. The composition may be provided in single or multiple dosage forms.

Administration to the airways can also be accomplished by aerosol formulations, wherein the active ingredient is chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane And pressurized packs with a suitable propellant such as, carbon dioxide, or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. Drug dosage can be adjusted by providing a metered valve.

The active ingredients may also be selected from the group consisting of anhydrous powders of the compounds, such as lactose, starch, starch derivatives (e.g. hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP)) It may be provided in the form of a powder mixture. Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be provided in unit dosage form, for example in a capsule or cartridge of gelatin, or in a unit dosage form in a blister pack in which the powder may be administered by an inhaler.

In compositions for airway administration, including nasal compositions, the compounds will generally have a small particle size (eg, about 5 microns or less). Such particle size can be obtained by methods known in the art, for example by fine powder.

If desired, compositions adapted for sustained release of the active ingredient can be used.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit dosages containing appropriate amounts of the active ingredient. Such unit dosage forms can be packaged preparations, packages containing discrete amounts of preparations (eg, packaged tablets, capsules), and powders in bottles or ampoules. In addition, the unit dosage form may be a capsule, tablet, casein, or lozenge itself, or may be any of a suitable number of packaged forms.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

More details on formulation and administration techniques can be found in the latest edition of the following literature (Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.)).

A therapeutically effective amount refers to the amount of active ingredient that ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, such as ED ₅₀ and LD _50, can be measured by standard pharmacological procedures in cell culture or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and can be expressed as the ratio LD ₅₀ / ED ₅₀ . Pharmaceutical compositions with high therapeutic indices are preferred.

The dosage to be administered should be carefully adjusted to the age, weight and condition of the individual to be treated, as well as the route of administration, dosage form and treatment and the desired outcome, and the precise dosage should of course be determined by the practitioner.

The actual dosage will depend on the nature and severity of the disease to be treated, at the discretion of the physician, and may vary by titration of the dosage for the particular situation of the invention to provide the desired therapeutic effect. However, it is currently contemplated that pharmaceutical compositions containing from about 0.1 to about 500 mg, preferably from about 1 to 100 mg, most preferably from about 1 to about 10 mg of active ingredient per individual dose are suitable for therapeutic treatment.

The active ingredient may be administered in one or several doses per day. Satisfactory results can be obtained in dosages as low as 0.1 μg / kg intravenously and 1 μg / kg orally. The upper limit of the dosage range is currently considered to be about 10 mg / kg intravenous and 100 mg / kg orally. Preferred ranges are about 0.1 μg / kg to about 10 mg / kg / day for intravenous administration and about 1 μg / kg to about 100 mg / kg / day for oral administration.

How to treat

In another aspect, the invention comprises a method of administering an effective amount of a compound of the invention to a living animal body, including a human in need thereof, wherein the monoamine neurotransmitter in the central nervous system of the living animal body, including the human Methods of treating, preventing or alleviating a disease, disorder or condition in response to inhibition of reuptake are provided.

Currently, suitable dosage ranges range from 0.1 to 1000 mg, 10 to 500 mg per day, depending on the exact mode of administration, the form administered, the direction of administration, the subject concerned, the weight of the subject concerned, and additionally the preferences and experience of the attending physician or veterinarian, and In particular 30 to 100 mg.

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

Produce Example

All reactions involving air sensitive reagents or intermediates are carried out in anhydrous solvents under nitrogen. Magnesium sulfate was used as a drying agent in the workup process and the solvents were evaporated under reduced pressure.

Example  One

Endo-benzoic acid 8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl ester

Benzoylchloride (84.3 g, 600 mmol) was added to a mixture of tropin (70.6 g, 500 mmol), potassium tert-butoxide (67.3 g, 600 mmol) and THF (500 mL) at <30 ° C. for 30 minutes. The mixture was stirred at rt for 2 h. Water (1 L) was added, followed by extraction with diethyl ether (2 x 500 ml). The organic phase was washed twice with water (2 x 200 ml) and then with a solution of saturated aqueous sodium chloride (200 ml). The ether phase was dried and hydrochloric acid (170 ml, 3M) in ethanol was added. Precipitated hydrochloride was filtered off and washed with diethyl ether. Excess aqueous ammonia solution was added and then extracted with a mixture of ethyl acetate and diethyl ether to give a free base. Yield 66.8 g (54%).

Endo-benzoic acid 8-aza-bicyclo [3.2.1] oct-3-yl ester

2,2,2-trichloroethylchloroformate (75.0 ml, 544 mmol) was added to endo-benzoic acid 8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl ester (66.8 g, 272 mmol). To the mixture was added dropwise to anhydrous toluene (500 ml). The mixture was stirred at room temperature for 1 hour and then at 100 ° C. for 15 hours. Water (250 ml) was added and stirred for 1 hour. The phases were separated and the organic phase was washed twice with water (2 x 200 ml). The mixture of intermediate 3-benzoyloxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid trichloromethyl ester was dried and evaporated. Acetic acid (350 ml) was added followed by zinc (53.4 g, 817 mmol) over 3 hours. Water (100 ml) was added, ice was added to cool, alkalinized by addition of concentrated aqueous ammonia solution (about 400 ml), and the mixture was extracted with dichloromethane (2 x 300 ml). Yield 44.5 g (61%).

Endo-3-benzoyloxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Di-tert-butyl-dicarbonate (39.9 g, 183 mmol) in THF (100 ml) was endo-benzoic acid 8-aza-bicyclo [3.2.1] oct-3-yl ester (44.5 g, 166.4 mmol), triethylamine (67.4 g, 666 mmol) and THF (250 ml) were added to the stirred mixture and then stirred for 1 hour. Water (1 L) was added and the mixture was extracted with diethyl ether (2 x 300 ml). The collected ether phases were washed twice with water (2 x 200 ml) and dried and then evaporated. Yield 60.1 g (100%).

Endo-3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

Endo-3-benzoyloxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (55.0 g, 166 mmol), potassium hydroxide (11.2 g, 199 mmol) and ethanol (99%, 400 ml ) Was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethyl ether (200 ml) was added, residual potassium benzoate was separated by filtration and the filtrate was evaporated. The product was polished with petroleum. Yield 30.0 g (80%). Melting point 139.5-140.8 ° C.

Exo-7- (8-tert-butoxycarbonyl-8-aza-bicyclo [3.2.1] oct-3-yloxy) -chromen-2-one

Triphenylphosphine (7.5 g, 28.6 mmol) was dissolved in dioxane (70 ml) and cooled to 8 ° C. Diethylazodicarboxylate (5.0 g, 28.6 mmol) was added to the mixture below 15 ° C and stirred for 15 minutes. Endo-3-hydroxy-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (5.0 g, 22.0 mmol) and 7-hydroxycoumarin (4.3 g, 26.4 mmol) To the mixture. The temperature increased due to the exothermic reaction. The mixture was stirred at rt for 15 h. Water (200 ml) was added, followed by extraction with diethyl ether (2 × 100 ml). The mixture was dried and evaporated. Chromatography on silica gel using dichloromethane and 5% methanol as solvent. The crude product was dissolved in diethyl ether (200 ml) and washed with aqueous sodium hydroxide solution (3 × 200 ml, 1M). The product was dried and evaporated. Yield 5.32 g (65%).

Exo-7-[(1S, 3S, 5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-bromo-chrome Ment-2-one

Bromine (1.38 ml, 27.0 mmol) was dissolved in exo-7- (8-tert-butoxycarbonyl-8-aza-bicyclo [3.2.1] oct-3-yloxy) -chromen-2-one ( 7.8 g, 21.0 mmol), acetic acid (150 ml) and sodium acetate (5.2 g, 63.0 mmol) were added to the mixture. The mixture was stirred at rt for 90 min. Water (100 ml) was added. The resulting precipitate was filtered and washed with water (10 ml), methanol (5 ml) and diethyl ether (20 ml). Yield 7.5 g (79%).

Method A

Exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-furan-2-yl-chromen-2-one hydrochloride

Exo-7-[(1S, 3S, 5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-bromo-chrome Men-2-one (2.0 g, 4.0 mmol), 2-furanboronic acid (0.89 g, 8.0 mmol), potassium carbonate (1.66 g, 12.0 mmol), 1,2-dimethoxyethane (20 ml) and water (10 ml ) Was stirred and sparged with argon for 10 minutes. Paladacycle (94 mg, 0.1 mmol) and Pd (PPh ₃ ) ₄ (115 mg, 0.1 mmol) were added and then stirred at reflux for 2 hours. The mixture was cooled to room temperature. Water (25 ml) was added and the precipitated solid was filtered off. The mixture of solid and hydrogen chloride in acetic acid (20 ml, 1M) was stirred for 3 hours. The mixture was alkalized by addition of aqueous ammonia solution. The product precipitated out. Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia solution as solvent gave pure pure base. The compound was converted to the corresponding salt by stirring in hydrogen chloride in acetic acid (5 ml, 1 M). Yield 150 mg (12%). LC-ESI-HRMS of [M + H] + is as follows: 338.1389 Da. Calc. 338.139234 Da, dev. 1 ppm.

Exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-furan-3-yl-chromen-2-one hydrochloride

Exo-7-[(1S, 3S, 5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-bromo-chrome The title compound was prepared according to Method A from ment-2-one and 3-furanboronic acid. LC-ESI-HRMS of [M + H] + shows the following: 338.1406 Da. Calc. 338.139234 Da, dev. 4 ppm.

Exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-benzofuran-2-yl-chromen-2-one hydrochloric acid salt

Exo-7-[(1S, 3S, 5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-bromo-chrome The title compound was prepared according to Method A from ment-2-one and 2-benzofuranboronic acid. LC-ESI-HRMS of [M + H] + is as follows: 388.1554 Da. Calc. 388.154884 Da, dev. 1.3 ppm.

Test Example

In vitro inhibitory activity

A number of compounds have been tested for their activity of inhibiting reuptake of monoamine neurotransmitters dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in synaptosomes as described in WO 97/16451. It was.

The test value is given by IC ₅₀ (concentration of test substance (μM) that inhibits up to 50% of specific binding of ³ H-DA, ³ H-NA or ³ H-5-HT).

The test results obtained by testing certain compounds of the present invention are shown in the table below.

Test compound 5-HT-Absorbing IC ₅₀ (μM) DA-Absorbing IC ₅₀ (μM) NA-Absorbing IC ₅₀ (μM)  First compound of Method A: exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] -oct-3-yl) oxy] -3-furan-2-yl- Chromen-2-one  0.0077  0.034  0.0043  Second compound of Method A: Exo-7-[(1S, 3S, 5R)-(8-Aza-bicyclo [3.2.1] -oct-3-yl) oxy] -3-furan-3-yl- Chromen-2-one  0.010  0.0099  0.00048  Third compound of Method A: exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] -oct-3-yl) oxy] -3-benzofuran-2-yl Chromium 2-on  0.0091  0.70  0.84

Claims (13)

A compound of formula (I), a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. Formula I

In Formula I, Q is a chromen-2-on-yl group, The chromen-2-one-yl group is a heteroaryl group wherein the heteroaryl group is halo, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, hydroxy, alkoxy, cycloalkoxy, Optionally substituted with one or more substituents independently selected from the group consisting of methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl), The chromen-2-one-yl group is halo, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, hydroxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and Optionally further substituted with one or more substituents independently selected from the group consisting of alkynyl, R ¹ is hydrogen or alkyl, The alkyl is independently from the group consisting of halo, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, hydroxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl Optionally substituted with one or more substituents selected. The compound of claim 1, wherein R ¹ is hydrogen or alkyl. The compound of claim 1 or 2, wherein Q is a substituted chromen-2-one-7-yl group. The compound of any one of claims 1-3, wherein Q is a 3- (optionally substituted heteroaryl) -chromen-2-one-yl group. The compound of any one of claims 1-4 wherein Q is chromen-2-one-7-yl substituted with a furanyl or benzofuranyl group. The compound of claim 1, wherein the exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-furan-2-yl-chromen 2-one; Exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-furan-3-yl-chromen-2-one; Exo-7-[(1S, 3S, 5R)-(8-aza-bicyclo [3.2.1] oct-3-yl) oxy] -3-benzofuran-2-yl-chromen-2-one; Or a pharmaceutically acceptable salt thereof. A therapeutically effective amount of a compound according to any one of claims 1 to 6, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof is one or more pharmaceutically acceptable carriers, excipients or diluents. Including with, a pharmaceutical composition. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. The use of claim 8 for preparing a pharmaceutical composition for treating, preventing or alleviating a disease, disorder or condition in response to inhibition of monoamine neurotransmitter reuptake in the central nervous system of a mammal, including humans. The method of claim 9, wherein the disease, disorder or condition is mood disorder, depression, atypical depression, depression secondary to pain, major depressive disorder, mood depressive disorder, bipolar disorder, type I bipolar disorder, type II bipolar disorder , Circulatory mood disorders, mood disorders due to general medical conditions, substance-induced mood disorders, pseudo dementia, Ginger syndrome, obsessive compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, panic disorder history No agoraphobia, panic attack, memory deficit, memory loss, attention deficit hyperactivity disorder, obesity, anxiety, general anxiety disorder, eating disorder, Parkinson's disease, Parkinson's disease, dementia, aging dementia, senile dementia, Alzheimer's disease, Down syndrome, Acquired immunodeficiency dementia complex, memory dysfunction at aging, specific phobias, social phobia, social anxiety disorder, post traumatic stress disorder, acute stress Child, chronic stress disorder, drug addiction, drug abuse, drug abuse tendency, cocaine abuse, nicotine abuse, tobacco abuse, alcoholic addiction, alcoholism, morbidity, withdrawal syndrome, pain, chronic pain, Inflammatory pain, neuropathic pain, diabetic neuropathy pain, migraine, strain headache, chronic strain headache, depression-related pain, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, cancer pain, irritable bowel pain, irritable bowel syndrome , Postoperative pain, post mastectomy pain syndrome (PMPS), stroke pain, drug-induced neuropathy, diabetic neuropathy, pain sustained by the sympathetic nervous system, trigeminal neuralgia, toothache, facial muscle pain, annular pain, anorexia, physiology Pre-syndrome, premenstrual discomfort disorders, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, persistent plant conditions, urinary incontinence, stress incontinence, urgency Urinary incontinence, night incontinence, sexual dysfunction, premature ejaculation, erection difficulty, erectile dysfunction, premature female orgasm, restless leg syndrome, periodic limb movement disorder, eating disorders, anorexia nervosa, sleep disorders, general developmental disorders, autism, asperger disorder, let Disorders, childhood disruptive disorders, learning disorders, motor impairment, narcosis, hair growth, narcolepsy, post-stroke depression, stroke-induced brain injury, stroke-induced nerve damage, Gilles de la Tourette disease, tinnitus, tic disorders, body dysplasia For people with disabilities, hostile opposition disorders or post stroke strokes. A therapeutically effective amount of a compound according to any one of claims 1 to 6, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, in a living animal body, including a person in need thereof. A method of treating, preventing, or alleviating a disease, disorder, or condition in response to inhibition of monoamine neurotransmitter reuptake in the central nervous system of a living animal body, including human, comprising administering. A compound according to any one of claims 1 to 6, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament. The method according to any one of claims 1 to 6, for use in treating, preventing or alleviating a disease, disorder or condition in response to inhibition of monoamine neurotransmitter reuptake in the central nervous system of a mammal, including humans. The compound, stereoisomer thereof, mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.