UA79484C2 - Piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors - Google Patents

Abstract

This invention relates to novel piperidine derivatives 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.

Description

Description of the invention

This invention relates to novel piperidine derivatives useful as monoamine 2 neurotransmitter resorption inhibitors.

According to other aspects, the invention relates to the use of these compounds in therapy and pharmaceutical compositions containing the compounds of the invention.

Reshkprom ei ai. |Re(kpom R A, 2papa y), KogikomuzKi A R, MMapd S2.Mem R, doppzop KM and Teiia 5 K; in). Honey.

Spent 2002 45 3161-3170) describe 5AK studies of piperidine-based cocaine analogs. 70 ЮМУО 00/20390 (Seogdemp ОМпимегею)) describes monomeric and dimeric heterocycles and their therapeutic use.

MO 98/51668 (Mepygobeagsp A/5)| describes 3-alkoxyimidomethyl-piperidine derivatives active as neurotransmitter resorption inhibitors. Examples 1 and 2 describe mixtures of two intermediates, (α3-cis/trans-1-methyl-3-methoxycarbonyl-4-(3,4-dichlorophenyl)-piperidine and 12(-3-cis/trans-1-methyl-3 -Hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine No pharmacological application of a mixture of these two intermediates has been disclosed.

However; there remains a strong need to find compounds with an optimized biochemical profile that relates to the reuptake activity of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine, such as the ratio of reuptake activity for serotonin versus activity for noradrenaline and dopamine.

In addition, there is a strong need to find effective compounds that are structurally and synthetically unrelated to cocaine.

According to the first aspect, the invention relates to piperidine derivatives of the formula I: c () o "a so" or any of their isomers or any mixture of their isomers, or their pharmaceutically acceptable salts, where Me) zv KK", VZ and B " is defined below. M

According to the second aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of the invention, or any of its isomers or a mixture thereof. isomers, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.

According to yet another aspect, the invention relates to the use of a compound of the invention, or any of its isomers or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment, prevention or amelioration of a disease, disorder or condition in a mammal, involving a human , if this "" disease, disorder or condition is dependent on the inhibition of resorption of monoamine neurotransmitters in the central nervous system.

According to another aspect, the invention relates to a method of treating, preventing or ameliorating a disease, disorder or condition of an animal, involving a human, if this disorder, disease or condition is dependent on the inhibition of resorption of monoamine neurotransmitters in the central nervous system, the method comprising the step of o applying a therapeutically effective amount of a compound of the invention, or any of its isomers or a mixture of isomers, or a pharmaceutically acceptable salt thereof, to such an organism of an animal in need thereof.

The following objects of the invention should be apparent to those skilled in the art from the following detailed description and examples. со Piperidine derivatives "from" According to the first aspect, the presented invention relates to a piperidine derivative of the formula ()

F) ime) 60 a of any of its isomers or a mixture of its isomers, or its pharmaceutically acceptable salt, where in! represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl;

ВЗ represents -С(-0)-О-Б2 or -СНо-О-82; for where KO represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl;

B represents where B2 and B? independently of each other represent halogen or trifluoromethyl; provided that the mixture of isomers is not (y-cis/trans-1-methyl-3-methoxycarbonyl-4-(3,4-dichlorophenyl)-piperidine or (--cis/trans-1-methyl-3-hydroxymethyl -4-(3,4-dichlorophenyl)-piperidine.

In one embodiment, v represents hydrogen or alkyl.

In the second incarnation of KU and E? independently of each other represent halogen.

In a special embodiment, KU represents chlorine.

In the next incarnation 2? represents chlorine.

In yet another embodiment, 2 represents chlorine and ER represents chlorine.

In the next embodiment, EZ represents -С(-0)-О-Б2,

In the next incarnation of B? represents -CH»-O-HB2,

In yet another embodiment, CO is hydrogen, alkyl, or cycloalkylalkyl.

In the next embodiment, KO represents hydrogen or alkyl.

In yet another embodiment, K7 is alkyl or cycloalkylalkyl.

In a special embodiment, CO represents hydrogen. see

In the next embodiment, K- represents alkyl, such as methyl or ethyl. at

In yet another embodiment, K7 is cycloalkylalkyl, such as cyclopropylmethyl.

In the next embodiment, compounds of formula I, B! represents hydrogen, alkyl or cycloalkylalkyl; B 9 represents hydrogen or alkyl; and B2 and VE? independently of each other represent halogen. « zo In another embodiment of compounds of formula I, B! represents hydrogen or alkyl; B represents hydrogen or alkyl; and B2 and 2? independently of each other represent halogen. co

In the next embodiment of compounds of formula I, EK! represents hydrogen or alkyl; KZ represents -СНо-О-В2; Co "I represents alkyl or cycloalkylalkyl; and KU and RE? independently of each other represent halogen. b

In a special embodiment, the chemical compound of the invention is 1-methyl-4-(3,4-dichlorophenyl)-piperidine-3-carboxylic acid methyl ester; - 1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine; 1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; "1-methyl-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; - 3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; "Z-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; "Z-cyclopropylmethoxymethyl'4-(3,4-dichlorophenyl)-piperidine; or any of their isomers or mixtures of isomers thereof, or a pharmaceutically acceptable salt thereof.

In the following special embodiment, the chemical compound of the invention is -i (--Cys-1-methyl-4-(3,4-dichlorophenyl)-piperidine-3-carboxylic acid methyl ester; co (--Trans-1-methyl-4- (3,4-dichlorophenyl)-piperidine-3-carboxylic acid methyl ester; (-)-Cys-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine; o (3-Trans-1 -methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine; o 20 (-3-Cys-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-U -Cis-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine; t" (-3-Trans-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine (--Trans-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-Cys-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine (-)-Cys-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine;

HF) (-)-Trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; with (-)-Trans-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-Cys-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; in 5 (4)-Cys-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl )-piperidine; (-)-Cys-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (α43-Cys-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4- dichlorophenyl)-piperidine; (-U-Cys-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-U-Cys-1-methyl-3-isobutoxymethyl-4-(3, 4-dichlorophenyl)-piperidine; 65 (-3-Trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-U-Trans-1-methyl-3Z-ethoxymethyl-4- (3,4-dichlorophenyl)-piperidine;

(4-3-Trans-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (--Trans-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)- piperidine; (--Trans-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 5(-)U-Trans-1-methyl-3-isobutoxymethyl-4-(3,4- dichlorophenyl)-piperidine; (43-Cys-1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (4)-Trans-1-methyl-3-isobutoxymethyl-4-(3,4 -dichlorophenyl)-piperidine; (-3-Trans-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-U-Cys-1-methyl-33-ethoxymethyl-4-(3 ,4-dichlorophenyl)-piperidine; 70 (4-3-Cys-33-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-U-Cys-3-ethoxymethyl-4-(3,4-dichlorophenyl )-piperidine; (-3-Cys-33-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-Y-Cys-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (4 -3-Cys-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-U-Cys-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-Trans-3Z -ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (--Trans-33-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine N; (-3-Trans-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (--Trans-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (--Trans-3- cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-Trans-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (α43-Cys-3-isobutoxymethyl-4-(3, 4-dichlorophenyl)-piperidine; (-U-Cys-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (43-Trans-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; сч (-U-Trans-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; or their pharmaceutically acceptable salt. i)

Any combination of two or more embodiments described above is within the scope of the present invention.

In the context of the present invention, halogen is fluorine, chlorine, bromine or iodine. In the context of the present invention, alkyl denotes a monovalent saturated, linear or branched hydrocarbon chain. The hydrocarbon chain preferably has from one to six carbon atoms (C. alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred embodiment, alkyl is C 1-4 alkyl, including butyl, isobutyl, secondary butyl, and tertiary butyl. In another preferred embodiment of the present invention, alkyl is C 4 alkyl, which may, in particular, be methyl, ethyl, propyl or Me

From Isopropyl. M

In the context of the present invention, alkenyl denotes a carbon chain containing one or more double bonds, including dienes, trienes, and polyenes. In the best embodiment, the alkenyl of the invention contains from two to six carbon atoms (Co. valkenyl), involving at least one double bond, in the best embodiment, the alkenyl of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or 3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4- or « 5-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatrienyl. z c In the context of the present invention, alkynyl denotes a carbon chain containing one or more triples. bonds, involving di-ins, tri-ins and poly-ins. In the best embodiment, the alkynyl of the invention contains from two to six carbon atoms (Co valkynyl), involving at least one triple bond, in the best embodiment, the alkynyl 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-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatrienyl. -I In the context of the present invention, cycloalkyl denotes cyclic alkyl, preferably containing from three to seven carbon atoms (C3-7cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. and, Pharmaceutically acceptable salts thereof. The chemical compound of the invention may be presented in any form suitable for the intended use. so 50 Suitable forms include pharmaceutically (ie, physiologically) acceptable salts, and pre- or pro-pharmaceutical forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts such as chloride, hydrochloric acid derivative, bromide, bromic acid derivative, nitrate, nitric acid derivative, perchlorate, perchloric acid derivative, phosphate, phosphate dv Acids, sulfate, derivative of sulfuric acid, formate, derivative of formic acid, acetate, derivative of acetic acid, asonate, derivative of aconitic acid, ascorbate, derivative of ascorbic acid, benzenesulfonate, derivative (F. of benzenesulfonic acid, benzoate, derivative of benzoic acid, cinnamate , derivative of cinnamic acid, citrate, derivative of citric acid, embonate, derivative of embonic acid, enanthate, derivative of enanthic acid, fumarate, derivative of fumaric acid, glutamate, derivative of glutamic acid, glycolate, derivative of glycolic acid, bo lactate, derivative of non-lactic acid, maleate, maleic acid derivative, malonate, malonic acid derivative, mandelate, almond derivative Acids, methanesulfonate, derivative of methanesulfonic Acids, naphthalene-2-sulfonate, derivative of naphthalene-2-sulfonic acid, phthalate, derivative of phthalic acid, salicylate, derivative of salicylic acid, sorbate, derivative of sorbic acid, stearate, derivative of stearic acid, succinate, derivative of succinic acid acids, tartrate, derivative of tartaric acid, p-toluenesulfonate, derivative b5 of p-toluenesulfonic acid, etc. Such salts can be formed by methods well known and 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 the preparation of the chemical compound of the invention and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of the chemical compound of the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, and ammonium salts, etc., of the chemical compound of the invention containing an anionic group. Such cationic salts can be formed by methods well known and described in the art.

In the context of the present invention, "onium salts" of M-containing compounds are also considered as pharmaceutically acceptable 7/o pain relievers. Preferred "onium salts" include alkyl onium salts, cycloalkyl onium salts and cycloapalkylalkyl onium salts.

Examples of pre- or prodrug forms of a chemical compound of the invention include examples of suitable prodrugs according to the invention, which include compounds modified by one or more reactive or derivatizable groups of the original compound. Compounds modified by the carboxyl, hydroxyl or amino group are of special interest. Examples of suitable derivatives are esters or amides.

The chemical compound of the invention can be presented in soluble or insoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol, etc. Soluble forms also include hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc., soluble forms are considered equivalent to insoluble forms for the purposes of this invention.

Steric Isomers

The chemical compounds of the present invention can exist as enantiomers in (g) and (-) forms, as well as in racemic forms (4). The racemates of these isomers and the individual isomers themselves are within the scope of the present invention.

Racemic forms can be separated into optical antipodes by known methods. One way to separate the isomeric salts is to use an optically active acid and separate the optically active amine compound with base treatment. Another method of separating racemates into optical antipodes is chromatography on an optically active matrix. The racemic compounds of the present invention can thus be separated into their optical antipodes, for example, by fractional crystallization of a4- or I- (for example, tartrates, mandelates or camphorsulfonates).

The chemical compounds of the present invention can also be separated by the formation of diastereomeric amides by the reaction of the chemical compounds of the present invention with optically active activated carboxylic acids such as derivatives (7) or (-) phenylalanine, (t) or (-) phenylglycine, (Ж) or (- camphanic acid, or by the formation of diastereomeric carbamates by the reaction of the chemical compound of the presented invention with optically active chloroformate "phe" or similar.

Additional methods for separating optical isomers are known in the art. Such methods include (described in

Зз5 Chadchtsev U, Sopeig A, 8 UMiep Z in "Epapiotegv, Kasegpayev, and Kezoitsiope", Wopp UMPeu and zopv, Mem Hogk (1981). uh-

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

In addition, the compounds of the present invention can exist in cis- or trans-configurations, as well as in a mixture thereof. Substituent BO and substituent B" of the piperidine skeleton of formula 1 can, in particular, be in the cis- or "trans-configuration relative to each other. In one embodiment of the invention, the substituents BEZ and B! are in the trans-configuration. In the second embodiment of the invention, the substituents Z and KE" is in the cis configuration. The invention covers all such isomers and any mixtures thereof. involving racemic mixtures. "» Labeled Compounds " The compounds of the invention can be used in labeled or unlabeled form. In the context of the present invention, "labeled" refers to the attachment of a marker to the desired compound, which will allow easy quantification of the specified compound. and Labeled compounds of the invention may be useful as diagnostic tools, radioisotope tracers,

Gee! or by means of monitoring in various diagnostic methods, and for receptor mapping of ip mimo.

The labeled isomer of the invention preferably contains at least one radionuclide as a label. All positron-emitting and radionuclides are candidates for application. In the context of the present invention, the radionuclide is preferably selected from the 070 group: "H (deuterium), ЗН (tritium), С, с, 1911,125),123) and ВЕ,

The physical method of determining the labeled isomer of the presented invention can be selected from Positional T emission tomography (PET), Computed tomography with single photon imaging (5PEST),

Magnetic Resonance Spectroscopy (MAK5), Magnetic Resonance Imaging (MRI), and Computed X-ray Tomography (CRT), or their combinations. 29 Methods of obtaining

F! Chemical compounds of the invention can be obtained by conventional methods of chemical synthesis, for example, described in the examples. The starting materials described in the presented application are known or can be easily obtained by conventional methods from commercially available reagents.

Also, one compound of the invention can be converted into another compound of the invention using conventional methods. because the final products of the reactions described here can be isolated by conventional methods, such as extraction, crystallization, distillation, chromatography, etc.

Biological activity

Compounds of the invention can be tested for their ability to inhibit the resorption of the monoamines dopamine, norepinephrine and serotonin in synaptosomes, for example as |(described in UMO 97/309971. bo Thus, according to the next aspect based on the proportional activity observed in these tests,

the compounds of the invention are considered useful in the treatment, prevention, or amelioration of a disease, disorder, or condition in a mammal, involving a human, when the disease, disorder, or condition is dependent on inhibition of the resorption of monoamine neurotransmitters in the central nervous system.

The end products of the reactions described here can be isolated by conventional methods, such as extraction, crystallization, distillation, chromatography, etc.

Biological activity

Compounds of the invention can be tested for their ability to inhibit the resorption of the monoamines dopamine, norepinephrine, and serotonin in synaptosomes, for example, as |(described in UMO 97/309971. 70 Thus, according to the next aspect, based on the proportional activity observed in these tests, the compounds of the invention are considered useful in the treatment, prevention, or amelioration of a disease, disorder, or condition in a mammal, involving a human, when the disease, disorder, or condition is dependent on the inhibition of reuptake of monoamine neurotransmitters in the central nervous system.

In a particular embodiment, the compounds of the invention are considered useful for the treatment, prevention or alleviation of /5 mood disorder, depression, atypical depression, major depressive disorder, psychodepressive disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, mood disorder due to a general medical condition , substance-induced mood disorder, pseudodementia, syndrome

Hanser's, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, panic attack, memory deficits, 2o memory loss, attention deficit hyperactivity disorder, obesity , anxiety, generalized anxiety disorder, eating disorder, Parkinson's disease, parkinsonism, dementia, dementia with aging, senile dementia, Alzheimer's disease, dementia complex with acquired immunodeficiency syndrome, memory dysfunction with aging, social phobia, post-traumatic stress disorder , acute stress disorder, drug addiction, drug abuse, cocaine abuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism, pain, inflammatory pain, neuropathic pain, migraine pain, tension headache, chronic headache type with tension, pain associated with depression, fibromyalgia, and) arthritis, osteoarthritis, rev rheumatoid arthritis, back pain, cancer pain, inflammatory bowel pain, inflammatory bowel syndrome, post-operative pain, post-attack pain, drug-induced neuropathy, diabetic neuropathy, sympathetically mediated pain, trigeminal neuralgia, toothache, "E zo Myofascial pain, phantom limb pain, bulimia, premenstrual cycle syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, urinary incontinence, stress incontinence, urge incontinence, nocturnal incontinence, premature ejaculation, difficulties with " Erectile dysfunction, anaphylactic anorexia, sleep disorders, autism, mutism, trichotillomania, narcolepsy, post-stroke depression, stroke-induced brain damage, stroke-induced neuronal damage, or Gilles de la Tourette's disease, in a preferred embodiment, the compounds are believed to be useful for treating, prevention or relief of depression.

A suitable dosage of the active pharmaceutical ingredient (API) can be expected to be in the range of about 0.1 to about 100 ug ARI per day, more preferably from about 10 to about 50 ug ARI per day, most preferably from about 30 to about 100 mg ARI per day, depending, however, on the correct method of application, "

Forms in which it is used, weighted indications, the person, and in particular, the person's body weight, and in addition /7-From the experience of a doctor or veterinarian. . Preferred compounds of the invention exhibit biological activity in the sub-micromolar and micromolar ranges, i.e. from below 1 to about 100 µM.

Pharmaceutical compositions

According to another aspect, the invention relates to new pharmaceutical compositions containing a therapeutically effective amount of a chemical compound of the invention.

Given that the chemical compounds of the invention for use in therapy can be used in the form of an unprocessed chemical compound, it is better to introduce the active ingredient, as an option, in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or more adjuvants, fillers, carriers , buffers, diluents, and/or other conventional pharmaceutical excipients. In a preferred embodiment, the invention relates to pharmaceutical compositions containing a chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients known and used in the art. levels of technology. Carriers must be "acceptable" in the sense of compatibility with other ingredients in the Composition and harmless to their recipient.

Pharmaceutical compositions of the invention can be suitable for oral, rectal, bronchial,

F) nasal, pulmonary, local (including buccal and sublingual), transdermal, vaginal or parenteral (including dermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) application, or in the form , suitable for use by inhalation or inhalation, involving the use of powders and liquid aerosols, or continuous release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing a compound of the invention, the matrices may be in the form of molded articles such as films or microcapsules.

The chemical compound of the invention, together with a conventional adjuvant, carrier or diluent, can thus be created in the form of pharmaceutical compositions and their unit doses. Thus, forms include solid products, in particular tablets, filled capsules, powders and granules, and liquid products, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled therewith, all for oral use, rectal suppositories , and sterile solutions for injections for parenteral use.

Such pharmaceutical compositions and unit doses thereof may contain conventional ingredients in conventional proportions,

With or without additional active compounds or ingredients, and such unit doses may contain any suitable effective amounts of the active ingredient consistent with the prescribed daily dosage limits.

The chemical compound of the present invention can be used in a very wide variety of oral and parenteral dosage forms. Those skilled in the art will understand that the following dosage forms may contain as an active ingredient a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention. 70 For obtaining pharmaceutical compositions from the chemical compound of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid preparations include powders, tablets, pills, capsules, wafers, suppositories and dispersible granules. The solid carrier may be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating material.

In powders, the carrier is a finely divided solid product mixed with a finely divided active ingredient.

In tablets, the active ingredient is mixed with a carrier having the required binding capacity in a suitable proportion and compressed to the desired size and shape.

Powders and tablets preferably contain from 5 or 10 to about 7095 active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc. The term "preparation" encompasses the composition of an active compound with an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without a carrier, is surrounded by a carrier which is thus in association therewith. Wafers are involved in a similar way. Tablets, powders, capsules, pills, and wafers can be used as a solid product suitable for oral administration.

To obtain suppositories, a low-melting wax, such as a mixture of glyceride of fatty acids or cocoa butter, i) is first melted and the active component is homogeneously dispersed by stirring. The molten homogeneous mixture is then poured into a mold of suitable size, allowed to cool and harden.

Compositions suitable for vaginal use 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 acceptable. co

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

A chemical compound of the present invention can thus be formulated for parenteral administration (eg by injection, eg by bolus injection or continuous infusion) and can be presented as a unit dose in ampoules, pre-filled syringes, low volume infusions, or in a multi-dose container with an added preservative. The compositions may take forms such as suspensions, solutions, or emulsions in oil or water carriers, and may contain forming agents such as suspending agents, stabilizers, and/or dispersants. Alternatively, the active ingredient may be in the form of a powder, suture) obtained by aseptic isolation of a sterile solid product or lyophilization from a solution, for reconstitution with a suitable excipient, for example, 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 dyes, flavors, stabilizers and thickeners as needed. -I Aqueous suspensions suitable for oral use can be obtained by dispersing the finely divided active component in water with a viscous material, such as natural or synthetic gums, resins, and methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Also covered is the solid form of drugs intended to be converted immediately before use into a liquid form of drugs for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component, such preparations may contain dyes, flavors, stabilizers, buffers, artificial and natural sugar substitutes, dispersants, thickeners, solubilizers, etc.

For local application, the chemical compound of the invention can be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can, for example, be formulated with a water or oil base with the addition of suitable thickeners and/or gelling agents. Lotions can be formulated with an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, co-suspending agents, thickeners, or dyes.

Compositions suitable for topical application in the mouth include lozenges containing the active agent in a flavored base, usually sucrose and gum arabic or gum tragacanth; lozenges containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are injected directly into the nasal cavity by conventional means, for example from a dropper, pipette or spray. The compositions can be offered in the form of single or multiple doses. 65 Application to the respiratory tract can also be achieved by aerosol formulations in which the active ingredient is packaged under pressure with a suitable propellant such as chlorofluorocarbon (CFC).

for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or another suitable gas. An aerosol can also contain a surfactant such as lecithin. The dose of medication can be adjusted with a dosing valve.

Alternatively, the active ingredients may be provided in dry powder form, for example a mixture of powder compounds in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PMP). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in the form of a single dose, for example, in capsules or cartridges, for example, from gelatin, or blister packs, from which the powder can be used by means of 7/o inhalation.

In compositions intended for application to the respiratory tract, involving intranasal compositions, the compound usually has a small particle size, for example, on the order of 5 microns or less. This particle size can be obtained by means known in the art, for example, micronization.

If desired, compositions adapted for continuous release of the active 7/5 Ingredient may be used.

Pharmaceutical preparations are mostly single doses. In this form, the drugs are divided into single doses containing acceptable amounts of the active component. A unit dose can be a packaged drug, a package containing a discrete amount of the drug, such as packaged tablets, capsules, and powders in glasses or ampoules. Also, a unit dose may be a capsule, tablet, wafer, or cake, or may be an acceptable number of any of these packaged forms.

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

The following data regarding the creation and application can be found |in the latest edition of Ketipdiops'z

ERagtaseciisa! Zsiepsez (Maask Rybiizpipd So., Eaviop, RA)). high school

A therapeutically effective dose refers to the amount of an active ingredient that improves a symptom or condition.

Therapeutic effectiveness and toxicity, for example, EDvo and IDvbo, can be determined by standard i) pharmacological methods in cell cultures or on experimental animals. The ratio of doses between therapeutic and toxic effects is a therapeutic index, which can be expressed as a ratio of ID so/EDrvo.

Pharmaceutical compositions exhibiting large therapeutic indices are preferred. "The applied dose should definitely be carefully set with regard to the age, weight and condition of the person being treated, as well as the route of administration, dosage form and dosage regimen and the desired result, the correct dosage should definitely be determined by the doctor. "Mr

The actual dosage depends on the nature and severity of the disease being treated and on the caution of the physician, and can be differentiated by titration of the dosage for individual cases of application of the present invention for b"

From obtaining the desired therapeutic effect. However, M pharmaceutical compositions containing from about 0.1 to about 500 mg of active ingredient per individual dose, preferably from about 1 to about 100 mg, preferably from about 1 to about 10 mg, may be expected to be suitable for therapeutic treatment.

The active ingredient can be used in one or several doses per day. And a satisfactory result can "

In some cases, be obtained at a dosage as low as 0.1mcg/kg intravenously and mcg/kg with s orally. The upper limits of the dosage limits are now considered to be approximately 10mg/kg IV and 10Omg/kg. orally Preferred ranges are from about 0.1 µg/kg to about 1 µg/kg/day intravenously, and from about 1 µg/kg to about 10 µg/kg/day orally.

Methods of therapy

According to another aspect, the invention relates to a method of treating, preventing, or ameliorating a disease or disorder or condition in an animal, involving a human, if the disease, disorder, or condition is dependent on inhibiting the resorption of a monoamine neurotransmitter in the central nervous system, the method being and, applying to such an animal organism, involving a person in need of it, an effective amount of a chemical compound of the invention.

It can be expected that suitable dosage limits are 0.1-100Omg/day, 10-B0Omg/day, and especially 30-10Omg/day, depending, as usual, on the correct method of application, the form used, the indication for which application is directed, the subject involved and the body weight of the subject involved, and furthermore the choice and experience of the physician or veterinarian.

Examples 5B The invention is further illustrated by the following examples, which do not limit the scope of the claimed invention. o Example 1 ime) i" ' bo ny i -k-k che 0) shi. b5 (--Cys-1-methyl-4-(3,4-dichlorophenyl)-piperidine-3-carboxylic acid methyl ester (1 ) and

(--Trans-1-methyl-4-(3,4-dichlorophenyl)-piperidine-3-carboxylic acid methyl ester (2)

A solution of 1-bromo-3,4-dichlorobenzene (29g, 130 mmol) in diethyl ether (1500 ml) is added to a suspension of magnesium flakes (3.4 g, 142 mmol) in diethyl ether (20 ml) while stirring. The mixture is heated at reflux for 20 minutes and then cooled at -402C. A solution of aresoline (10 g, ppmmol) in toluene (100 mL) is added slowly while keeping the internal temperature between -402C and -302C. The reaction mixture is stirred at -202С for 6 hours, and then 4H HCl (50 ml) is added. The phases are then separated and ammonia (aq.) is added to the aqueous phase to basic pH and extracted with dichloromethane (4x1O0Oml), dried over magnesium sulfate and evaporated to an oil. Isomers (1) and (2) are separated by column chromatography (petroleum ether 70, ether, triethylamine 70:25:5), obtaining 5.0 g (2596) (1) (m.p. 70-750C) and 2.0 g (1096) (2) (oil).

Example 2 Method A1 (-3-Cys-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine (3)

GiAIN is added to solution (1) (500g, 1/mmol) in tetrahydrofuran (5Oml) at -502С7; (0.50g, 1Zmmol). stirred at -302C for 3 hours, then quenched by adding water and evaporated to a solid product. c 29 The residue is dissolved in dichloromethane, dried with magnesium sulfate and evaporated to dryness. Output: 4, bg (3) (100965). at

T.pl. 127-12996. . (4) Solution (2) (2.0g, b,bmmol ) is reduced by method (A1), obtaining 1.9 g (10095) of product (4). Melting point 109-11196, "

Method (a)

The racemate can be separated into individual enantiomers by mandelate precipitation. - c (-3-Cys-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine (5) Mixture (3) (23.8 g, 86 b, mmol) and (-) h mandelic acid (6.6g, 43.4mmol) in absolute ethanol (bOml) is heated until the solution is clear. The reaction mixture is evaporated to dryness and recrystallized once from toluene (10Oml) and once from toluene (100ml) and absolute ethanol (12ml). The precipitate is isolated and poured into water (7/bml). Concentrated ammonia (aq) was added to basic pH and the mixture was extracted with ethyl acetate (3x75ml). The combined organic phases were dried over sodium sulfate and - evaporated to dryness. Yield: 8.2g (69965) (5) , m.p. 94.5-96.59C, A?5 -679. (Ce) (-3-Cys-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate, m .pl. 147-149960, AB -nvVe. i" Method (B) (-)-Cys-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine (b) (ee) 50 U toluene from recrystallization in method (a), add water (/bml) and concentrated ammonia (aq.) to

GT" basic pH. The mixture is extracted with ethyl acetate (2 x 75 ml). The combined organic phases are dried over sodium sulfate and evaporated to dryness. The residue is dissolved in absolute ethanol (bOml) and mandelic acid (6.6g, 43 A4mmol) is added (t). Further, the method is carried out by method (a) yield: 7.4g (62965) (6), m.pl. 95-979C, dv --65e, (-U-Cys-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate, m.p. 148-1502C, Ag --679, o Method A?

The pure enantiomers, (-)- and (-)-Trans-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine, can be obtained by isomerization (5) and (6). (i)-trans-7-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine (7) and Solution (5) (10.0g, Zbmmol) and potassium tert-butoxide (12.0g, 1.08 mmol) in dimethylformamide (75 ml) was stirred overnight. Sasi" (75 ml, ZM) is added and the reaction mixture is extracted with ethyl acetate (2 x 200 ml).

The combined organic phases are dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from ethyl acetate (7 ml). Exit: 6, Zg (63905) (7), t.pl. 137-1382C, A?5 -k399, (--Trans-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine (8) b5 (8) is synthesized from (6) (2.0g , 7.mmol) by method (Ag), obtaining 1.4g (70905) (8), mp 137-1399С, dB --38".

(--Trans-1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate, m.p. 138-1402C, A25 --25e,

Example C Method B1 and d

(-)-Cys-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine (9) To a solution of (3) (24g, 8.mmol) in tetrahydrofuran (40ml) is added 6095 Mann (0.69g, 17mmol) and stirred at room temperature for one hour. Diethyl sulfate (1.4ml, 11mmol) was added and the reaction mixture was stirred overnight. Water was added and the reaction mixture was extracted with diethyl ether (3x40ml). The combined organic phases were dried magnesium sulfate and evaporated to dryness Column chromatography using a mixture of dichloromethane, methanol and ammonia (aq) (9:1:195) afforded 1.5g (56905) of product (9) (oil).

In a similar way: (-3-Cys-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine (10) is obtained by methylation (3) with dimethylsulfate (oil).

C) t (22) with (-)-trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine (11) "and (11) is synthesized from (4) (1.8g, b,bmmol) by method (B1), obtaining 0.83g (4395) of product (11) (oil).

Similarly, the following is obtained: (-)-Trans-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine (12) by methylation (4) with dimethyl sulfate (oil). « 20 Method B2 -o s " ;»

(-3-Cys-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (13)

Potassium tert-butoxide (13.3 g, 120 mmol) is added to solution (5) (11.0 g, 4 mmol) in tetrahydrofuran (15 mmol).

The reaction mixture is stirred for one hour and cooled to 52C. Diethyl sulfate (5.7 mL, 44 mmol) was added and the reaction mixture was stirred overnight. Saturated sodium chloride (15Oml) and water (5Oml)

Ge) is added and the reaction mixture is extracted with ethyl acetate (2x8Oml), dried with sodium sulfate and evaporated to dryness. Output: 12g (9995) (13). T.pl. 72.5-742C, A?5 -659,

Analogously, the following is obtained: (4-3-Cys-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine (14) by alkylation (5) with dimethyl sulfate (oil). (-U-Cys-1- methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine (15) by alkylation (6) with dimethyl sulfate (oil). (4-3-Cis-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4 -dichlorophenyl)-piperidine fumarate (16) by alkylation (5) with (bromomethyl)cyclopropane. M.p. 187-188.52С, AB -nvZe, (--Cys-1-methyl-3-cyclopropylmethoxymethyl-4-( 3,4-dichlorophenyl)-piperidine fumarate (17) by alkylation (b)

(bromomethyl)cyclopropane. T.pl. 184.5-187.62С, А?5..--662, (--Cys-1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (18) by alkylation (/(" ((6) 1-bromo-2-methylpropane. M.pl. 181-1832C, A?5.--6495, (-3-Trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl )-piperidine (19) by alkylation (7) with diethyl sulfate (oil). (oil). -Trans-1-methyl-33-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (22) by alkylation (/(:(8) with dimethyl sulfate. M.p. 50-702C (hygroscopic), a?5 --239, (-Trans-1-methyl-33-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (23) by alkylation (8) 75. (bromomethyl)cyclopropane. M.p. 180-1822С, A25 --3192, (--Trans-1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (24) by alkylation (8) with 1-bromo-2-methylpropane. M.p. 162 -1642C, A?9 --299,

Analogously obtained: (4)-Cys-1-methyl-3-isobutoxymethyl-4-(3,4-diporphenyl)-piperidine fumarate (43-Trans-1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl )-piperidine fumarate (4-3-Trans-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4-dichlorosrenyl)-piperidine and fumarate

Example 4 Method C

The racemate (-)-Cys-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine (9) can be separated into individual enantiomers as dibenzoyltartrates. high school

Method (a) He) (4-3-Cys-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine bromide (13) (--Cys-1-methyl-33-ethoxymethyl-4 -(3,4-dichlorophenyl)-piperidine (9) (1.1 g, 3.1 mmol) and (-)-dibenzoyltartaric acid (0.48 g, 1.0 mmol) were dissolved in 9995 ethanol (1 mL) and evaporated to dryness. The evaporated residue is crystallized from toluene (3ml). Recrystallization from a mixture of toluene (1Oml) and ethanol (1Oml). The precipitate is isolated and dissolved in a mixture of 4H Mahon (5ml) and diethyl ether (1Oml). The diethyl ether is separated and dried (ee) with magnesium sulfate yield: 0.25g (4595) of the product as the free base. Bromic acid (0.20ml, 1.7mmol) is added and the mixture is evaporated to dryness. The residue is recrystallized from ethanol (2ml) and diethyl ether (10ml) to yield: 0 ,20g (2896) (13), mp 183-1852C, (a) -62.82, (c-14mg/ml in 99905 ethanol). (o)

Method (B) im (-U-Cys-1-methyl-3-ethoxymethyl-4-(3,4-diporphenyl)-piperidine bromide (25)

Toluene from recrystallization in method (a) is added 4N Mahon (B5ml) and extracted with diethyl ether (3x25ml), dried with magnesium sulfate and evaporated to dryness. The residue is dissolved in 9995 ethanol (1 Oml) and (t-dibenzoyltartaric acid (0.67g, 1.9mmol) is added. Then method (a) is repeated, yield: 0.14g (2095) (25), mp 183 « 400 -1859C, A?5 --66.12, (c-14 mg/ml in 9996 ethanol) - c (4)-Trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine bromide (19) and "from (--Trans-i -methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine bromide (20) " (19) and (20) are separated from (11) (0 .83g, 2.9mmol) by the method used in method C yield: 0.16g (3090) (19), mp 2229-2249, AB ZA, oo (c-1Omg/ml in 99956 ethanol); and 0 ,14g (2695) (20), mp 2199-22120, - 395 25 --32.72 (c-10mg/ml in 9996 ethanol). (43-Cys-1-methyl-3-methoxymethyl-4 -(3,4-dichlorophenyl)-piperidine bromide (14) and is), (--Cys-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine bromide (15) and" (14 ) and (15) are separated from (10) by the method C. A?5 -652, t.pl., 212-2159C for (14) and A 25.--659, t.pl. 850 0212-2159 for (15) Example 5

ЧТ» (а4)-Cys-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine (26b)

The mixture (13) of 0.70 g and 1-chloroethyl chloroformate (2.5 ml) is stirred at 1009C for 2 days, after which 4H Mason (25 ml) is added. The mixture is stirred under reflux overnight. After cooling, the mixture is extracted with toluene. The organic phase was dried and evaporated to give an oil which was column chromatographed (500, methylene chloride, Meon, ammonia 9:1:195) to give the product as pale crystals.

T. pl. 68-7026. o (-3-Cys-33-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate, m.p. 149-151960. AB u-nvVe.

Analogously obtained: 60 (--Cys-33-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine bromide (27), mp, 182-1842C, d2B o --75e, (4-3-Cys- 3-Methoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (28), mp 154.5-1562С, AB -nvvo. (-U-Cys-3-methoxymethyl-4-(3,4 -dichlorophenyl)-piperidine fumarate (29), mp 147-14990, dB -- 689. (4-3-Cys-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (30), mp 172-173,590, 65 dg5 -t6Ze,

(-Y-Cys-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (31), mp 175-176,596,

AB --652, (-3-Trans-3Z-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine (32), (oil), A?5 nave, (--Trans-3Z-ethoxymethyl-4- (3,4-dichlorophenyl)-piperidine fumarate (33), mp, 140-14290, dB --37". (-3-Trans-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine ( 34), (oil), B AB ad, (--Trans-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (35), m.p. 140-1429C, dB --319, ( --Trans-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (36), mp 153.5-155.590,

AB --37",

In a similar way: (4-3-Trans-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (43-Cys-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (- -Cis-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (4)-Trans-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine fumarate (--Trans-3-isobutoxymethyl- 4-(3,4-dichlorophenyl)-piperidine fumarate.

Claims (1)

The formula of the invention 1. Piperidine derivative of formula I: 23) Ф и в и 25. ST Y ai « or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, where so in! represents hydrogen or alkyl; VZ represents -СН»-О-22; "where is KE? represents alkyl or cycloalkylalkyl; Ge») vi represents m Fa 7 t - with a. ouch! . where K" and K" independently of each other represent halogen. "» 2. The compound according to claim 1, where v! represents hydrogen. Q. The compound according to claim 1, where in! represents alkyl. 4. The compound according to any of claims 1-3, where K7 represents alkyl. Sh- 5. The compound according to any of claims 1-3, where K7 represents cycloalkylalkyl. (Se) 6. The compound according to any of claims 1-5, where KZ represents chlorine and 2? represents chlorine. 7. The compound according to claim 1, which is 1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (oo) 250 1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 1-methyl-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; eat"! feet 1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; C-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; GF) or any of their isomers, or any mixture of their isomers, or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1, which is (4)-cis-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-)-cis-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 60th ()-trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (4)-trans-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-cis-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-cis-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)- piperidine; 65 (-)-cis-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-cis-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4- dichlorophenyl)-piperidine; (-)-cis-1-methyl-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-N-cis-1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; ()-trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine (-)-trans-1-methyl-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-)-trans-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl) )-piperidine; (-)U-trans-1-methyl-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-)U-trans-1-methyl-3-diclopropylmethoxymethyl-4-(3 ,4-dichlorophenyl)-piperidine; (-N-trans-1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; 70 (i)-cis-1-methyl-3-isobutoxymethyl-4 -(3,4-dichlorophenyl)-piperidine; (1)-trans-1-methyl-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; ()-trans-1-methyl-3-cyclopropylmethoxymethyl- 4-(3,4-dichlorophenyl)-piperidine; (-)-cis-1-methyl-33-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-cis-3-ethoxymethyl-(3 ,4-dichlorophenyl)-piperidine; (-)-cis-33-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-cis-3-methoxymethyl-4-(3,4-dichlorophenyl)- piperidine; (-)-cis-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-3-cis-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl )-piperidine; (-)-cis-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (i)-trans-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-)-trans-3-ethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (i-3-trans-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-)U-trans-3-methoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (-)U -trans-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; ch (i-3-trans-3-cyclopropylmethoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (i)-cis-3 -isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; i) (-U-cis-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; (1)-trans-3-isobutoxymethyl-4 -(3,4-dichlorophenyl)-piperidine; (-N-trans-3-isobutoxymethyl-4-(3,4-dichlorophenyl)-piperidine; "Ezo or their pharmaceutically acceptable salt. 9. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1-8, or any of its isomers, or any mixture of its isomers, or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, filler or diluent. 10. Use of the compound according to any of claims 1-8 or any of its isomers, or any mixture of its Me Z isomers, or its pharmaceutically acceptable salt for the production of a medication. M 11. Use according to claim 10, for the production of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or disorder or condition of a mammal, including a human, if this disease, disorder or condition is dependent on the inhibition of monoamine neurotransmitter resorption in the central nervous system. 12. Use according to claim 11, where the disease, disorder or condition is a mood disorder, depression, atypical depression, "major depressive disorder, psychodepressive disorder, bipolar disorder, bipolar disorder |, with bipolar II disorder, cyclothymic disorder, mood disorder due to general medical condition, . substance-induced mood disorder, pseudodementia, Hanser's syndrome, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, panic attack, memory deficits, memory loss, Hyperactivity and attention deficit disorder, obesity, anxiety, generalized anxiety disorder, -And eating disorder, Parkinson's disease, parkinsonism, dementia, senile dementia, Alzheimer's disease, dementia complex with acquired immunodeficiency syndrome, dysfunction and, pam for aging, social phobia, post-traumatic stress disorder, acute stress disorder, drug addiction, drug abuse, cocaine abuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism, pain, inflammatory pain, neuropathic pain, pain with migraine, tension headache, chronic headache, e.g pain associated with depression, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, cancer pain, inflammatory bowel pain, inflammatory bowel syndrome, post-operative pain, post-attack pain, drug-induced neuropathy, diabetic neuropathy, sympathetic sustained pain, trigeminal neuralgia, toothache, myofascial pain, phantom limb pain, bulimia, premenstrual cycle syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, F) urinary incontinence, stress incontinence, urge incontinence , bedwetting, premature ejaculation, erectile dysfunction, anaphylactic anorexia, sleep disorders, autism, mutism, trichotillomania, narcolepsy, post-stroke depression, stroke-induced brain damage, stroke-induced neuronal damage or Gilles de la Tourette disease. 13. A method of treating, preventing, or ameliorating a disease or disorder or condition of an animal, including a human, if this disorder, disease, or condition is dependent on inhibiting the resorption of a monoamine neurotransmitter in the central nervous system, in which such animal organism in need is administered a therapeutically effective amount of a compound according to any of claims 1-8, or any of its isomers, or any b5 mixture of its isomers, or a pharmaceutically acceptable salt thereof. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 9, 25.06.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. со « со « (22) m. shi s z -I se) sh» oo 50 s» F) ime) 60 b5