MXPA05011809A - Aminocyclohexyl ether compounds and uses thereof - Google Patents

Abstract

Aminocyclohexyl ether compounds are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses uses for the compounds and compositions, including the treatment of arrhythmia.

Description

AMINOCICLOHEXIL-ETER COMPOUNDS AND USES OF THEM TECHNICAL FIELD The present invention is directed to aminocyclohexyl ether compounds, pharmaceutical compositions and methods for the synthesis of aminocyclohexyl ether compounds, and therapeutic uses thereof.

BACKGROUND OF THE INVENTION Ion channels are ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Its critical functions include the control of the electrical potential through the membrane, the mediation of the ionic and fluid balance, the facilitation of neuromuscular and neuronal transmission, the rapid transmembrane signal transduction, and the regulation of secretion and contractility. For example, cardiac ion channels are proteins that reside in the cell membrane and control the electrical activity of cardiac tissue. In response to external stimuli, such as potential changes through the cell membrane, these ion channels can form a pore through the cell membrane and allow the movement of specific ions in and out of the cell. The integrated behavior of thousands of ion channels in a single cell results in an ionic current, and the integrated behavior of many of these ion currents constitutes the characteristic cardiac action potential. Arrhythmia is a variation of the normal rhythm of the heartbeat and usually represents the end product of an abnormal structure, number or function of the ion channel. Both atrial and ventricular arrhythmias are known. The main cause of the victims of cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the United States alone, more than one million citizens will have a new or recurrent coronary attack each year (defined as myocardial infarction or fatal coronary heart disease). Approximately 650,000 of these will be first attacks and 450,000 will be recurrent attacks. Approximately one third of the people who experience these attacks will die from them. At least 250,000 people a year die from coronary heart disease within 1 hour of the onset of symptoms and before they reach a hospital. These are sudden deaths caused by cardiac arrest that usually results from ventricular fibrillation. Atrial fibrillation (AF) is the most common arrhythmia observed in clinical practice and is a cause of morbidity in many individuals (Pritchett E. L, N. Engl. J. Med. 327 (14): 1031, October 1 1992, exhibit 1031-2, Kannel and Wolf, Am. Heart J. 123 (1): 264-7, January 1992).

Its frequency is likely to increase as the population ages, and it is estimated that 3-5% of patients over 60 years of age have AF (Kannel WB, Abbot RD, Savage DD, McNamara PM, N. Engl. J. Med. 306 (17): 1018-22, 1982, Wolf PA, Abbot RD, Kannel WB, Stroke 22 (8): 983-8, 1991). Although AF is rarely fatal, it can impair cardiac function and is a major cause of stroke (Hinton RC, Kistler JP, Fallon JT, Friedlich AL, Fisher CM, American Journal of Cardiology 40 (4): 509-13, 1977; Wolf PA, Abbot RD, Kannel WB, Archives of Intemal Medicine 147 (9): 1561-4,1987; Wolf PA, Abbot RD, Kannel WB Stroke 22 (8): 983-8, 1991; Cabin HS, Clubb KS , Hall C, Perlmutter RA, Feinstein AR, American Journal of Cardiology 65 (16): 1112-6, 1990). WO 95/08544 describes a class of aminocyclohexyl ester compounds which are useful in the treatment of arrhythmias. WO 93/19056 discloses a class of aminocyclohexylamides which are useful in the treatment of arrhythmia and in the induction of local anesthesia. WO 99/50225 describes a class of aminocyclohexyl ether compounds which are useful in the treatment of arrhythmias. Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia. For exampleClass I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias. The treatment of ventricular arrhythmia is very important since said arrhythmia can be fatal. Serious ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) occur more often in the presence of ischemia or myocardial infarction. Ventricular fibrillation frequently occurs in the setting of acute myocardial ischemia, before the infarction develops completely. At present, there is no satisfactory pharmacotherapy for the treatment and prevention of ventricular fibrillation during acute ischemia. In fact, many class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction. Antiarrhythmic drugs of class I, I, and III have been used to convert the recent onset of AF into sinus rhythm and to prevent the occurrence of arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs 48 (3): 345-71, 1994). However, pharmacological therapy is often limited by adverse effects, which include the possibility of increased mortality and inadequate efficacy (Feld GK, Circulation, 83 (6): 2248-50, 1990; Copien SE, Antman E. ., Berlin JA, Hewitt P., Chalmers TC, Circulation, 1991; 83 (2): 714, and Circulation, 82 (4): 1106-16, 1990; Flaker GC, Blackshear JL, McBride R., Kronmal RA, Halperin JL, Hart RG, Journal of the American College of Cardiology 20 (3): 527-32, 1992, CAST, N. Engl. J. Med. 321: 406, 1989, Nattel S., Cardiovascular Research, 37 (3 ): 567-77, 1998). The conversion rates of class I antiarrhythmics vary between 50% and 90% (Nattel S., Hadjis T., Talajic M., Drugs, 48 (3): 345-71, 1994, Steinbeck G., Remp T. , Hoffmann E., Journal of Cardiovascular Electrophysiology, 9 (8 Suppl): S104-8, 1998). Class III antiarrhythmics seem to be more effective in terminating atrial flutter than for AF, and are generally considered less effective than class I drugs for the termination of FA (Nattel S., Hadjis T., Talajic M., Drugs, 48 (3): 345-71, 1994, Capucci A., Aschieri D., Villani GQ, Drugs &Aging 13 (1): 51-70, 1998). Examples of such drugs include ibutilide, dofetilide and sotalol. The conversion rates of these drugs vary between 30% and 50% for the recent onset of AF (Capucci A., Aschieri D., Villani GQ, Drugs &Aging, 13 (1): 51-70, 1998), and also are associated with the risk of induction of ventricular tachyarrhythmias of Torsades de Pointes. In the case of ibutilide, the risk of ventricular proarrimia is estimated at ~ 4.4%, with ~ 1.7% of patients requiring cardioversion for refractory ventricular arrhythmias (Ko ey PR, VanderLugt JT, Luderer JR, American Journal of Cardiology 78 (8A) : 46-52, 1996). Such events are particularly tragic in the case of FA because this arrhythmia is rarely fatal on its own. In this field there is still a need to identify new antiarrhythmic treatments, both for ventricular arrhythmias and for atrial arrhythmias. The present invention covers this need and also provides other related advantages.

BRIEF DESCRIPTION OF THE INVENTION In one embodiment, the present invention provides a compound of formula (IA), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug of it: wherein R3, 4 and 5 are independently selected from hydrogen, hydroxy and C.sub.1 -C.sub.2 alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, with the proviso that R3, R and R5 can not be all hydrogen In one embodiment, the present invention provides a compound of formula (IB), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug of it: wherein R3, R and R5 are independently selected from hydrogen, hydroxy and alkoxy of CrC6, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, with the proviso that R3, R4 and R5 can not all be hydrogen . In one embodiment, the present invention provides a compound of formula (IC), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug of it: wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C.sub.1 -C.sub.2 alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, with the proviso that R3, R4 and R5 can not be all hydrogen In one embodiment, the present invention provides a compound of formula (ID), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug of it: wherein R3, R4 and 5 are independently selected from hydrogen, hydroxy and alkoxy of C.-Ce, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, with the proviso that R3, R4 and R5 can not be all hydrogen In one embodiment, the present invention provides a compound of formula (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug of it: wherein R4 and R5 are independently selected from hydrogen, hydroxy and C-i-Cd alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, with the proviso that R and R5 can not all be hydrogen.

In another embodiment, the present invention provides a compound or any salt thereof, or any solvate thereof, or a mixture comprising one or more said compounds or any salt thereof or any solvate thereof, selected from the group it consists of: In another embodiment, the present invention provides a composition that includes one or more of the compounds indicated in the table above, or includes a pharmaceutically acceptable solvate or salt of one or more of the compounds indicated in the previous table. The composition may or may not include additional components as described in detail elsewhere in this patent. In one embodiment, the present invention provides a compound, or a mixture comprising compounds, or any solvate thereof, selected from the group consisting of: Comp. Structure Chemical name # (1R, 2R) -2- [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane monohydrochloride (1S, 2S) -2- [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane monohydrochloride Monohydrochloride of (1 R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane Monohydrochloride of (1 R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1 - (3,4-dimethoxyphenethoxy) -cyclohexane In another embodiment, the present invention provides a composition that includes one or more of the compounds indicated in the preceding table, or includes a solvate of one or more of the compounds indicated in the preceding table. The composition may or may not include additional components as described in detail elsewhere in this patent. In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, the free base or any salt thereof, or any solvate thereof. In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, the free base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound that is (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, the free base or any salt thereof, or any solvate thereof. In one embodiment, the present invention provides a compound that is (1S, 2S) -2 - [(3S) -hydroxypropyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, the free base or any salt thereof. , or any solvate thereof. In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxypheneneoxy) -cyclohexane monohydrochloride, or any solvate of! same. In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane monohydrochloride, or any solvate thereof. In one embodiment, the present invention provides a compound that is (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane monohydrochloride, or any solvate thereof. In one embodiment, the present invention provides a compound that is (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane monohydrochloride, or any solvate thereof. The present invention also provides protonated versions of all the compounds described in this patent. That is, for each compound described in this patent, the invention also includes the protonated quaternary amine form of the compound. These protonated quaternary amine forms of the compounds may be present in solid phase, for example in crystalline or amorphous form, and may be present in solution. These protonated quaternary amine forms of the compounds may be associated with pharmaceutically acceptable anionic counterions, including without limitation those described for example in: "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from any of the compounds described in this patent, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers , and mixtures thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient, and furthermore, a method of manufacturing said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester , amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, stereoisomer , stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or meiabolium thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) monohydrochloride -cyclohexane, or any solvate thereof; in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method of making said composition or medicament. In other embodiments, the present invention provides one or more compounds of the present invention, such as those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt , ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above, for use in methods for modulating the activity of the ion channel in a warm-blooded animal, or for modulating the activity of the ion channel in vitro. In a version of this embodiment, the warm-blooded animal in which the activity of the ion channel is modulated is a mammal; in one version, the warm-blooded animal is a human being; In one version, the warm-blooded animal is a farm animal. As described in the present invention, a variety of cardiac pathological conditions can be treated or prevented using one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof , including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. Without wishing to be bound by theory, the inventors consider that the compounds of the present invention are ion channel modulator compounds which, individually or together with one or more additional compounds, are capable of selectively modulating some ionic currents. The ionic currents referred to herein are generally cardiac currents and, more specifically, are sodium currents and early repolarization currents. Throughout this patent the inventors describe means by which they consider that the compounds described in this patent can act. Such descriptions are not considered to be limiting, but represent the belief of the inventors as to the way in which the compounds can act. The pathological conditions that can be treated or prevented by the present invention can include, without limitation, various cardiovascular diseases. Cardiac pathological conditions that can be treated or prevented by the present invention can include without limitation arrhythmias, such as the various types of atrial and ventricular arrhythmias, for example atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter. In another embodiment, the present invention provides ion channel modulator compounds that can be used to selectively inhibit cardiac currents of early repolarization and cardiac sodium currents, under conditions where an "arrhythmogenic substrate" is present in the heart. An "arrhythmogenic substrate" is characterized by a reduction in the duration of the cardiac action potential or changes in the morphology of the action potential, premature action potentials, high cardiac frequencies, and may also include greater variability in time between the potentials of action and an increase in heart acidity due to ischemia or inflammation. Changes such as these are observed during conditions of ischemia or inflammation of the myocardium and the conditions that precede the appearance of arrhythmias such as atrial fibrillation. In other embodiments, the present invention provides a method for modulating the activity of the ion channel in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. In other embodiments, the present invention provides a method for modulating the activity of the ion channel in an in vitro environment, comprising administering in vitro an effective amount of one or more compounds of the present invention, such as those of the formula (IA) , (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, precursor metabolic or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. In other modalities, the present invention provides a method for blocking / inhibiting the activity / conductance of the ion channel in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention , such as those of formula (IA), (IB), (! C), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, isomer geometric, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. In other embodiments, the present invention provides a method for modulating the activity of the potassium ion channel in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention. invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, isomer geometric, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. In other embodiments, the present invention provides a method for modulating the activity of cardiac sodium currents in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention. invention, such as those of formula (IA), (IB), (1C), (ID), or (IE), or a pharmaceutically acceptable solvate, sai, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, isomer geometric, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. In other embodiments, the present invention provides a method for modulating the ion channel activity of early repolarization cardiac currents and cardiac sodium currents in a warm-blooded animal, which comprises administering the warm-blooded animal in need thereof. an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide , complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. In other embodiments, the present invention provides a method for the treatment or prevention of arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable sai, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or mixture of compounds described above. In other embodiments, the present invention provides a method for the treatment or prevention of arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, as those selected from the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, base free or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxy? Irrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3R) -hydroxy? Irrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; or a composition or medicament including said compound or mixture of compounds described above. In other embodiments, the present invention provides a composition or medicament that contains one or more compounds of the present invention, such as those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures of the same, as described above, in an amount effective to treat a disease or condition in a warm-blooded animal that suffers or has the disease or condition, or to prevent a disease or condition in a warm-blooded animal that would otherwise would occur; and further contains a pharmaceutically acceptable carrier, diluent or excipient.

In addition, the invention provides methods of treating a disease or condition in a warm-blooded animal suffering from or having the disease or condition, or preventing the emergence of a disease or condition in a warm-blooded animal, where it is administered to the animal. hot-blooded animal in need thereof a therapeutically effective amount of one or more compounds of the present invention, such as those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures of the same; or a composition or medicament including said compound or mixture of compounds described above. By way of illustration and not limitation, the following are examples of some of the diseases, disorders and conditions for which the compounds, compositions, medicaments and methods of the present invention have application: arrhythmia, atrial arrhythmia; ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, central nervous system diseases, convulsion, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory diseases, cystic fibrosis, ast cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, irritable bowel syndrome, cardiovascular diseases, cerebral or myocardial ischemia, hypertension, prolonged QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's disease, myasthenia gravis, paramyotonia congenita , malignant hyperthermia, hyperkalemic periodic paralysis, myotonia of Thomsen, autoimmune disorders, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease or other mental disorders and alopecia. In one embodiment, the compounds of the present invention can be used to treat or prevent arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, or ventricular flutter; in another version, the compounds can be used to treat arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, or ventricular flutter, in another version, the compounds can be used to prevent arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, or ventricular flutter. In other embodiments, the present invention provides a composition or medicament containing an amount of one or more compounds of the present invention, such as those of formula (IA), (IB), (IC), (ID), or (IE) ), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof as described above, effective to produce analgesia or local anesthesia in a warm-blooded animal in need thereof, and a pharmaceutically acceptable carrier, diluent or excipient. The invention further provides a method for producing analgesia or local anesthesia in a warm-blooded animal, which includes administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline form or amorphous, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, or a composition or medicament including said compound or mixture of compounds described above. These compositions, medicaments and methods can be used to alleviate or prevent the sensation of pain in a warm-blooded animal. In other embodiments, the present invention provides a composition or medicament containing an amount of one or more compounds of the present invention, such as those of formula (IA), (IB), (IC), (ID), or (IE) ), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof as described above, effective to increase libido in a warm-blooded animal in need thereof, and a pharmaceutically acceptable carrier, diluent or excipient. The invention further provides a method for increasing libido in a warm-blooded animal, which includes administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those of the formula ( IA), (IB), (IC), (ID), or (lE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geomorphic isomer, chrysalis or amorphous form, mebolic , meiabolic precursor or prodrug thereof, including its enaniomeric, diastereomeric and isolated geomeric isomers, and mixtures thereof, or a composition or medicament including said compound or mixture of compounds described above. Such compositions and methods can be used, for example, to eradicate sexual dysfunction, for example, impoeence in males, or to increase the sexual desire of a patient without sexual dysfunction. As another example, the therapeutically effective amount may be administered to a bull (or other breeding stock) to promote an increase in semen ejaculation, where the ejaculated semen is collected and stored for use as required to inseminate the semen. females in a breeding program.

The compounds of the present invention are effective anolyarmic agents. It has been found that the compounds according to the present invention exhibit a low toxicity to the central nervous system (CNS), at the same time receiving an alpha-nervous acrylity. In another embodiment, the present invention provides methods of synthesizing the compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), and in particular methods for the synisis of the following compounds: (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimeloxifene-oxy) -cyclohexane, the free base and the monohydrochloride correspond; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphene-oxy) -cyclohexane, the free base and the monohydrochloride correspond; (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, the free base and the monohydrochloride correspond; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, the free base and the monohydrochloride correspond; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenefoxy) -cyclohexane, the free base and the monohydrochloride correspond; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, the free base and the monohydrochloride correspond; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxy-pheneioxy) -cyclohexane, the free base and the corresponding monohydrochloride. Some general synthetic processes for aminocyclohexyl esters are described in WO 99/50225 and references cited therein. These and other modalities of the present invention will become evident by reference to the following description, reaction schemes and examples. DETAILED DESCRIPTION OF THE INVENTION As indicated above, the present invention is directed to aminocyclohexyl ether compounds of formula (IA), (IB), (IC), (ID) or (IE), methods of manufacturing thereof, pharmaceutical compositions conforming the compounds of aminociclohexil-éíer, and several uses of the compuesíos and the compositions. Such uses include the irradiation of arriimies, the modulation of the ion channel and other uses described herein. For the understanding of the present invention, the following definitions and the explanation of the conventions used in the present invention may be of assistance: The aminocyclohexyl ether compounds of the invention have an oxygen atom of ether in the 1-position of a cyclohexane ring and a niinogen atom of amine in position 2 of the cyclohexane ring, with the other positions listed in the corresponding order as shown in the following section (A): 4 (A) The bonds of the ring of cyclohexane with the atoms of 1-oxygen and 2-nihirogen in the above formula, may be relative dispositions in cis or trans relation. In a preferred embodiment of the present invention, the stereochemistry of the amine and ether subsides of the cyclohexane ring is (R, R) -trans or (S, S) -trans. In another preferred embodiment, the stereochemistry is (R, S) -c / s or (S, R) -c / s. A wavy bond of a subscript to the cylcohexane ring indicates that this group may be located on either side of the plane of the central ring. When a corrugated bond is shown intersecting a ring, it indicates that the indicated target group may be linked at any position in the susceptory ring to the target group, and that the target group may be above or below the plane of the ring system. to the one who is united. Following the descriptive practice of the standard chemical guideline and as used in the paiennium, a wedge link in bold means above the plane of the ring, and a striped wedge link means below the plane of the ring; a confinuous line link and a disconfinuous line link (esius is, -), means a trans configuration, while two conical line links or two discontinuous line links mean a cis configuration. In the formulas represented in the present, a link with a susíiuuyenie or a link that unites a molecular fragment with the rest of a compound, can be seen by inler- sizing one or more links in a ring esírucíura. Esio indicates that the bond may be attached to any of the atoms that constitute the ring's expression, provided that in that atom another hydrogen atom may be present. Where a substitute is not identified in a particular position of a structure, then there is hydrogen in that position. For example, the compounds of the invention that belong to group (B): CB). where (B) encompasses groups in which any atom of the ring would otherwise be bonded with hydrogen, can be substituted by hydrogen instead of R 3, R 4 or R 5, with the proviso that each of R 3, R 4 and R 5 one and only once in the ring. Ring atoms which are not sus fi rified with any of R3, R4 or R5, are bonded with hydrogen. In those cases where the invention specifies that a non-aromatic ring is suspended with one or more functional groups, and the functional groups are shown attached to the non-aromatic ring with bonds that bisect the ring bonds, then the functional groups may be present in different atoms of the ring or in the same ring of the ring, provided that the ring could be suspended in a different way with a hydrogen atom. The compounds of the present invention contain at least two asymmetric carbon atoms and therefore exist as enantiomers and diastereomers. Unless otherwise indicated, the present invention includes all the enantiomeric and diastereomeric forms of the aminocyclohexyl ether compounds of the invention. Pure stereoisomers, mixtures of enaniomers or diastereomers, and mixtures of different compounds of the invention, are included in the present invention. Thus, the compounds of the present invention can occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers, unless a specific enantiomer or diastereomer stereoisomer is identified, all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers. Unless stated otherwise, the phrase "pure stereoisomerism" generally refers to the asymmetric carbon atoms that are described or illus- trated in the formulas for that compound. As an example, and in no way limiting the generality of the former, a compound designated by the formula: includes at least chiral rings (the carbon of cyclohexyl bonded to oxygen, the carbon of cyclohexyl attached to the nihologen and the carbon of pyrrolidinyl bound to oxygen), and therefore has at least eight separate stereoisomers, which are: (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (pheneioxy susidined with R3, R4 and R5) - cyclohexane; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (phenetoxy susíiuuido with R3, R4 and R5) -cyclohexane; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (phenetoxy substituted with R3, R4 and R5) -cyclohexane; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (phenetoxy susiiuuide with R3, R4 and R5) -cyclohexane; (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (pheneioxy substituted with R3, 4 and Rd) -cyclohexane; (1 R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (pheneioxy susiiuuide with R3, R and R5) -cyclohexane; (1S, 2R) -2 - [(3R) -hydroxypyridinyl] -1- (phenetoxy substituted with R3, R4 and R5) -cyclohexane; and (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl-1- (pheneioxy substituted with R3, R4 and RsJ-cyclohexane, and unless the context makes otherwise apparent, as used in this patent, a compound of the formula: means a composition that includes a component that is any of the eight pure enanimeric forms of the indicated compound, or is a mixture of any two or more of the pure enanimeric forms, wherein the mixture may include any number of the enanimeric forms in any proportion. As an example, and in no way limiting the generality of the former, unless the context makes evident another thing, as it is used in this patent, a compound designated with the chemical formula (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxy? -rolidolidinyl] -1- (3,4-dimethoxyphene-1-yl) -cyclohexane means a composition that includes a component that is any of the two pure enaniomeric forms of the indicated compound (i.e., (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane or (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane), or is a racemic mixture of the two pure enaniomeric forms, wherein the racemic mixture can include any kind Relative of the two enaniomers. The phrase "independent in each occurrence" means (i) when any variable occurs more than once in a compound of the invention, the definition of that variable in each occurrence is independent of its definition in all the occurrences; and (ii) the identity of any of two different variables (for example R-i in the group of R-i and R2) is selected without considering the identity of the other member of the group. However, combinations of subscripts or variables are permissible only if the combinations produce compounds that do not violate the standard rules of chemical valence. According to the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise: "Acid addition salts" refers to those salts that retain effectiveness biological and the properties of the free bases, and that are not undesirable either biologically or otherwise, which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitrile acid, phosphoric acid, and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, puruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, aric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, epanosulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, and includes, without limitation, those described for example in "Handbook of Pharmaceuíical Salís, Properties, Selecíion, and Use", P. Heinrich Slahl and Camille G. Wermuíh (Eds.), published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002. "Alcoxi" refers to an oxygen atom (O) substituted with an alkyl group; for example, alkoxy can include, without limitation, methoxy, which can also be denoted as -OCH3, -OMe or C-alkoxy. "Modular" with respect to the activity of an ion channel means that the activity of the ion channel it can be increased or decreased in response to the administration of a compound or composition or method of the present invention. In this way, the ion channel can be acyivated, in order to transport more ions, or can be blocked (inhibited) so that fewer ions are transported, or not transported, through the channel. "Pharmaceutically acceptable carriers" for therapeutic use are well known in pharmaceutical practice and are described, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co. (A. R. Gennaro, 1985). For example, saline and sterile phosphate buffer saline can be used at physiological pH. Preservatives, stabilizers, colorants and even flavoring agents can be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and p-hydroxybenzoic acid esters can be added as preservatives (id, page 1449). In addition, antioxidants and suspension agents (id.) Can be used. "Pharmaceutically acceptable salts" refer to the salts of the compounds of the present invention derived from the combination of said compounds and an organic or inorganic acid (acid addition salts), or an organic or inorganic base (addition salts of base). Examples of pharmaceutically acceptable salts include, without limitation, those described for example in "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wennuth (Eds.), Published by VHCA (Switzerland). ) and Wiley-VCH (FRG), 2002. The compounds of the present invention can be used in the free base or salt forms, both considered within the scope of the present invention. The "therapeutically effective amount" of a compound of the present invention will depend on the route of administration, the type of warm-blooded animal and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determine this amount are well known to experts in medical practice. This amount and method of administration can be adjusted to optimize efficacy, but will depend on factors such as weight, diet, concurrent medication, and other factors that will be recognized by experts in medical practice. The compositions described herein as "containing a compound, for example of the formula (IA)", encompass compositions containing more than one compound of the formula (IA).

Compounds of the present invention In one embodiment, the present invention provides a compound of formula (IA), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof: (ÍA) wherein, R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-Cd alkoxy, including their enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, with the proviso that R3, R4 and R5 do not they can all be hydrogen. In one embodiment, the present invention provides a compound of formula (IA), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IA), or a solvate, or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently selected from hydroxy and Ci-Cβ alkoxy, including their enantiomeric, diastereomeric isomers and geometric isolated, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IA), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enaniomeric, diastereomeric and geometric isomers, and mixtures thereof, wherein R3 is hydrogen, R4 and R5 are independently selected from hydroxy and C6-C6 alkoxy.

In one embodiment, the present invention provides a compound of formula (IA), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 are independently selected from alkoxy In one embodiment, the present invention provides a compound of formula (IA), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enaniomeric, diastereomeric and geometric isomers, and mixtures thereof, wherein R3 is hydrogen, and R and R5 are independently selected from Ci-Ce alkoxy. In one embodiment, the present invention provides a compound of formula (IA), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 are C-alkoxy. In one embodiment, the present invention provides a compound of formula (IA ), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, wherein R3 is hydrogen, and R and R5 are C-alkoxy. In another embodiment, the present invention provides a compound of formula (IB), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer etric, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof: wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C1-C6 alkoxy, including their enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IB), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enanliomeric, diastereomeric and geometric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IB), or a solvate, or pharmaceutically acceptable salt thereof, wherein R4 and R5 are independently selected from hydroxy and Ci-Cd alkoxy, including its enantiomeric, dereomeric and geometric isolated isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IB), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, dereomeric and geometric isomers, and mixtures thereof, wherein R3 is hydrogen, and R and R5 are independently selected from hydroxy and C.C. alkoxy. In one embodiment, the present invention provides a compound of formula (IB), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, dereomeric and geometric isolated isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 are independently selected from CI-CT alkoxy. In one embodiment, the present invention provides a compound of formula (IB), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, dereomeric and geometric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 are independently selected from Ci-Cβ alkoxy. In one embodiment, the present invention provides a compound of formula (IB), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enaniomeric, dereomeric and geomeric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 are C-alkoxy. In one embodiment, the present invention provides a compound of formula (IB ), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enaniomeric, dereomeric and geomethyric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 are Ci alkoxy. In another embodiment, the present invention provides a compound of formula (IC), or a solvap, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geomelic isomer, chylaaline or amorphous form, meiabolium, meiabolic precursor or prodrug of it: wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-Ce alkoxy, including their enanliomeric, diastereomeric and geometiric isolates, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IC), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enaniomeric, diastereomeric and geometiric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IC), or a solvate, or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently selected from hydroxy and alkoxy.

C-i-Cβ, including its enanliomeric, diastereomeric and isolated geomyric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IC), or a solvate, or pharmaceutically acceptable salt of! same, including its isolated enanfiomeric, diastereomeric and geomethyric isomers, and mixtures thereof, wherein R3 is hydrogen, R and R5 are independently selected from hydroxy and C-i-Cβ alkoxy. In one embodiment, the present invention provides a compound of formula (IC), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometiric isomer, crystalline or amorphous form, metabolite, meiabolic precursor or prodrug thereof, including its enaniomeric, diastereomeric, and isolated geomeric isomers, and mixtures thereof, wherein R3 is hydrogen, and R and R5 are independently selected from C.sub.6 -alkoxy. In one embodiment, the present invention provides a compound of formula (IC), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometiric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 are independently selected from C.sub.6-alkoxy. In one embodiment, the present invention provides a compound of formula (IC), or a solvap, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, spherical mixture, geomeric isomer, crystalline or amorphous form, meiabolium, mephabolic precursor or prodrug thereof, including its isolated enaniomeric, diastereomeric and geomeric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and Rs are C-alkoxy. In one embodiment, the present invention provides a compound of formula (IC ), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, wherein R3 is hydrogen, and R and R5 are Ci alkoxy. In another embodiment, the present invention provides a compound of formula (ID), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, meiabolic precursor or prodrug of it: wherein R3, R4, and R5 are independently selected from hydrogen, hydroxy, and C-? -C6 alkoxy, including their enaniomeric, diastereomeric, and isolated geomeric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula. (ID), or a solvage, or acceptable pharmaceutically acceptable salt thereof, including its enaniomeric, diastereomeric, and isolated gelmethyl isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (ID), or a soivate, or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently selected from hydroxy and alkoxy.

Ci-Cd, including its isolated enanfiomeric, diasphereomeric and geomeric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (ID), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof., wherein R3 is hydrogen, and R4 and R5 are independently selected from hydroxy and C.sub.6 -alkoxy. In one embodiment, the present invention provides a compound of formula (ID), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometiric isomer, crystalline or amorphous form, mephabolite, mephabolic precursor or prodrug thereof, including its enaniomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, wherein R3 is hydrogen, and R and R5 are independently selected from alkoxy.

In one embodiment, the present invention provides a compound of formula (ID), or a solvate, or pharmaceutically acceptable salt thereof, including its enantiomeric, diasphereomeric, and isolated geomeric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 independently selected from C.-C.sub.be. alkoxy. In one embodiment, the present invention provides a compound of formula (ID), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, spheresisomer, geomeric isomer, crystalline or amorphous form, mephabolyl, meiabolic precursor or prodrug thereof, including its isolated enaniomeric, diastereomeric and geomeric isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 C-alkoxy. In one embodiment, the present invention provides a compound of formula (ID). ), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enanliomeric, diastereomeric and geomelic isomers, and mixtures thereof, wherein R3 is hydrogen, and R4 and R5 C-alkoxy. In another embodiment, the present invention provides a compound of formula (IE), or a solvap, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture rich, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof: wherein R and Rs independently selected from hydrogen, hydroxy and C.sub.1 -C.sub.2 alkoxy, including their enantiomeric, diastereomeric and isolated geometiric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IE), or a solvate, or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IE), or a solvate, or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 independently selected from hydroxy and Ci-Cβ alkoxy, including their enantiomeric, diastereomeric isomers and geometric isolated, and mixtures thereof. In one embodiment, the present invention provides a compound of formula (IE), or a solvate, or pharmaceutically acceptable salt thereof, including its enaniomeric, diasphereomeric, and isolated geomeric isomers, and mixtures thereof, wherein R4 and Rs selected independently of hydroxy and alkoxy of C.-C3.

In one embodiment, the present invention provides a compound of formula (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, wherein R4 and R5 independently selected from C1-C6 alkoxy. In one embodiment, the present invention provides a compound of formula (IE), or a solvate, or pharmaceutically acceptable salt thereof, including its enanfiomeric, diasphereomeric, and isolated geometrical isomers, and mixtures thereof, wherein R4 and R5 selected independently of C1-C3 alkoxy. In one embodiment, the present invention provides a compound of formula (IE), or a solva, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, wherein R4 and R5 C-alkoxy. In one embodiment, the present invention provides a compound of formula (IE), or a solvate or pharmaceutically acceptable salt thereof, including its isolated enaniomeric, diastereomeric and geomethyric isomers, and mixtures thereof, wherein R4 and R5 C-alkoxy.

In another embodiment, the present invention provides a compound or any salt thereof, or any solvate thereof, or a mixture comprising one or more of said compounds, salts or solvates, selected from the group consisting of: In another embodiment, the present invention provides a composition that includes one or more of the compounds indicated in the above table, or includes a solvage or a pharmaceutically acceptable salt of one or more of the compounds indicated in the preceding table. The composition may or may not include additional components as described in detail elsewhere in this patent. In another embodiment, the present invention provides a compound, or a mixture comprising compounds, or any solvate thereof, selected from the group consisting of: In another embodiment, the present invention provides a composition that includes one or more of the compounds indicated in the preceding table, or includes a solvate of one or more of the compounds indicated in the preceding table. The composition may or may not include additional components as described in detail elsewhere in this patent. In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, the free base or any salt thereof, or any solvation thereof. In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxypheneloxy) -cyclohexane, the free base or any salt thereof, or any solvate of it. In one embodiment, the present invention provides a compound that is (1S, 2S) -2 - [(3R) -hydroxy-pyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, the free base or any salt thereof , or any solvate thereof.

In one embodiment, the present invention provides a compound that is (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimeloxifenefoxy) -cyclohexane, the free base or any salt thereof, or any solvation thereof. In one embodiment, the present invention provides a compound that is monohydrochloride of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimefoxifene-oxy) -cyclohexane, or any solvate thereof. In one embodiment, the present invention provides a compound that is monohydrochloride of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenenoxy) -cyclohexane, or any solvate thereof. In one embodiment, the present invention provides a compound that is monohydrochloride of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, or any solvate thereof. In one embodiment, the present invention provides a compound which is (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxypheneloxy) -cyclohexane monohydrochloride, or any solvate thereof. The present invention also provides protonated versions of all the compounds described in this patent. That is, for each compound described in this patent, the invention also includes the quaternary amine form proimlated from the compound. These quaternary amine forms of the compounds can be present in solid phase, for example in crystalline or amorphous form, and can be present in solution. These quaternary amine forms of the compounds may be associated with pharmaceutically acceptable anionic conirations, including without limitation those described, for example, in: "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", P. Heinrich Siahl and Camille G. Wermufh (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002.

DESCRIPTION OF THE METHOD OF PREPARING THE COMPOUNDS OF THE INVENTION The aminocyclohexyl-ether compounds of the present invention contain amino and ether functional groups disposed in an arrangement 1, 2 in a cyclohexane ring. Accordingly, the amino and ether functional groups may be disposed in cis or trans relation to one another and to the plane of the cyclohexane ring as shown on the page in a two-dimensional representation. The present invention provides a syn- theic methodology for the preparation of the aminociclohexyl-efer compounds according to the present invention described herein. The aminociclohexyl ether compounds described in the present can be prepared from amino alcohols and alcohols, following the general methods described below and illustrated in the examples. Some general syngeneic procedures for aminocyclohexyl esters are described in WO 99/50225 and references cited therein. Other procedures that may be used to prepare the compounds of the present invention are described in the following provisional U.S. patent applications: US 60 / 476,083, US 60 / 476,447, US 60 / 475,884, US 60 / 475,912 and US 60 / 489,659, and references cited therein. The trans compounds of the present invention can be prepared analogously to the known synthetic methodology. In one method, illustrated in Reaction Scheme 1, the compounds are prepared by a syn- thesis of Williamson's son (Feuer, H., Hooz, J., "Meyhods of Formation of the Efher Linkage", in Patai, Wiley: New York, 1967, pp. 445-492) enire an acivated form of the 4R aminoalcohol with the alkoxide of the 3,4-dimethoxyphenethyl alcohol, in a polar solvent such as dimethoxy manganese (dimethyl glycol ether DME) (reaction scheme 1), which provides the corresponding 5R aminoel with alio yield. The subsequent resolution of the diastereomers, for example by chromatographic separation (for example HPLC) to produce 5RRR and 5SSS, followed by hydrogenolysis, yields compound 1 and compound 2, respectively. The reaction scheme 1 illustrates a reaction sequence by means of which the following aminocyclohexyl ether compounds of the present invention can be synthesized: (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4 -dimeíoxifeneíoxi) -cyclohexane, free base; monohydrochloride of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane (compound 1); (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base; monohydrochloride of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphene-oxy) -cyclohexane (compound 2); (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base; monohydrochloride of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxy-pyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane (Compound 3); (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenehoxy) -cyclohexane, free base; monohydrochloride of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimeloxifeneloxy) -cyclohexane (compound 4); (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenehoxy) -cyclohexane, free base; monohydrochloride of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -l- (3,4-dimethoxyphenetoxy) -cyclohexane (Compound 5); (1 R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base; monohydrochloride of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane (compound 6); (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphene-oxy) -cciohexane, free base; monohydrochloride of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dylmeloxyphenexy) -cyclohexane (compound 7).

Reaction Scheme 1 HL ".OH (B ° C) 2 °: > AN ^ a) NaH, THF, reflux L TH THF (95%) L>" OH b, ßziBr. Bu_, Nl (cat.) (> 9S%) ~ ° • Ote! 1R 2R (mez The free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxypheneloxy) cyclohexane and its corresponding monohydrochloride (compound 6), and the free base of (1S, 2S) - 2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane and its corresponding monohydrochloride (compound 7), are bound using a similar synthetic sequence but starting with 3- (S) -hydroxypyrrolidine. Hydrogenolysis of (1R, 2R) / (1S, 2S) -2 - [(3R) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane (5R) gave the free base of (1R, 2R) / ( 1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane, and the corresponding monohydrochloride (Compound 4). Similarly, starting with 3- (S) -hydroxypyrrolidine instead of 3- (R) -hydroxypyrrolidine and following the same synthetic sequence, (1R, 2R) / (1S, 2S) -2 - [(3S) -benzyloxypyrrolidinyl will be produced. ] -1 - (3,4-dimethoxyphenetoxy) cyclohexane. This by hydrogenolysis will yield the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane and the corresponding monohydrochloride (compound 5). The free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane and the corresponding monohydrochloride (compound 3) ) can also be synthesized by a similar procedure, starting with racemic 3-hydroxypyrrolidine. The reaction scheme 2 shows a second general methodology by which the compounds of the present invention can be prepared. The compounds of formula (1A), (IB), (IC), (ID), or (IE), can be prepared by reduction of the corresponding cetopyrrolidinylcyclohexyl ether with NaBH in 2-propanol. The preparation of the initial aminoalcohol 2e requires the preparation of the amine 1e, for which a method of preparation is illustrated in the reaction scheme 3. The 3-hydroxypyrrolidine 1a was protected in the N by carbamoylation with benzyl chloroformate, to give 1b; oxidation of Swem (Mancuso, AJ; Swern, D. "Acivated Dimethyl Sulfoxide: Useful Reagents for Synthesis", Synthesis 1981, 165-185) to him, followed by ketalization with ethylene glycol, gave Id, which was then hydrogenated to give .

Reaction scheme 2 Synthetic methodology for preparing a trans-aminocyclohexyl ether compound of the present invention rOH Reaction scheme 3 Synthetic methodology for preparing the amine 1e required for the formation of the aminoalcohol 2e (shown in reaction scheme 2) no Reaction Scheme 4 Synthetic sequence for preparing a cis-aminocciohexyl ether compound of the present invention, as the compound or The present invention provides syngeneic processes with which compounds of formula (57) with configuration (1R, 2R) for the ether and amino functional groups can be prepared in a stereoisomerically pure form. The compounds of the formulas (66), (67), (69) and (71) are some of the examples represented by the formula (57). The present invention also provides synnemic procedures with which the compounds of formulas (52), (53) and (55) can be syntheiZed in a stereoisomerically pure form. The compounds (61), (62) and (64) are examples of the formulas (52), (53) and (55) respectively. As described in reaction scheme 5, the preparation of a stereoisomerically pure frans-aminocyclohexyl ether compound of formula (57) can be carried out following a process starting with a monohalobenzene (49), wherein X can be be F. Cl, Br or I.

Reaction Scheme Process for preparing a stereoisomerically pure trans- (1R.2R) -aminochexyl ether ether compound of formula (57) (49) (50) (51) In a first step, the compound (49) is transformed by means of a well established microbial oxidation in the c / s-cyclohexandienodiol (50) in a stereo-isomerically pure form (T. Hudlicky y oíros, Aldrichimica Acta, 1999, 32, 35; and references cited there). In a separate step, the compound (50) can be selectively reduced under suitable conditions to give the compound (51) (eg, H2-Rh / Al2? 3; Boyd and others, JCS Chem. Commun. 1996, 45- 46; Ham and Coker, J. Org. Chem. 1964, 29, 194-198, and references cited therein). In another separate step, the least hindered hydroxy group of formula (51) is converted selectively under the appropriate conditions into a spiked form, represented by formula (52). An "activated form" as used herein, means that the hydroxy group is converted into a good leaving group (-O-J), which by reaction with an appropriate nucleophile will result in a substitution production with inversion of the stereochemical configuration. The outgoing group can be a mesylate group (MsO-), Iosilalo (TsO-) or nosy (NsO-) or another good group equivalent. The hydroxy group may also be converted to other suitable leaving groups according to well-known procedures. In a typical reaction for the formation of a tosilaio, the compound (52) was brought with a hydroxyalumination reactive such as osyl chloride (TsCl) in the presence of a base such as pyridine or и lilylamine. In general, the reaction is carried out satisfactorily at approximately 0 ° C, but can be adjusted as necessary to maximize the yield of the desired product. An excess of the hydroxy activating reagent (for example, tosyl chloride) can be used with respect to the compound (52), in order to convert the hydroxy group to the maximum form in the active form. In a separate step, the transformation of the compound (52) into the compound (53) can be done by hydrogenation and hydrogenolysis in the presence of a catalyst under the appropriate conditions. Palladium on activated carbon is an example of the catalysts. Hydrogenolysis of alkyl or alkenyl halide as (52) can be done under basic conditions. The presence of an alkaline base such as sodium oxide, sodium bicarbonate, sodium acetate or calcium carbonate is possible in some examples. The base can be added in a portion or incrementally during the reaction. In a separate step, the alkylation of the free hydroxy group of the compound (53) to form the compound (55) is carried out under appropriate conditions with the compound (54) wherein -O-Q represents a good leaving group, by reaction with a hydroxy function with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound. Trichloroacetimidate is an example of the -O-Q function. For some compounds (54) it may be necessary to introduce appropriate protecting groups before performing this step. Suitable protecting groups are described, for example, in Greene, "Protective Groups in Organic Chemistry," John Wiley &; Sons, New York, NY (1991). In a separate step, the resulting compound (55) is treated under suitable conditions with an amino compound of formula (56) to form the compound (57) as a product. The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (57) at a suitable rate. An excess of the amino compound (56) can be used to convert the compound (55) to the product (57) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to substantial completion, the product is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified accordingly. The protecting groups can be removed at the appropriate stage of the reaction sequence. Suitable methods are described, for example, in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The above-described reaction sequence (reaction scheme 5) generates the compound of formula (57) as the free base. If desired, the free base can be converted into the sa! monohydrochloride by the known methods or, if desired, alternately in addition acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. The acid addition salts can also be prepared meiosymely by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt. All publications and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication or patent application was specifically and individually incorporated as a reference. In one embodiment, the present invention provides a process for the preparation of a stereoisomerically pure compound of formula (57): (57) wherein Ri and R2, when taken together with the nitrogen atom to which they are directly attached in the formula (57), form a ring denoted by the formula (II): (H) and R3, R4 and Rs are independently selected from hydrogen, hydroxy and C-Ce alkoxy, with the proviso that R3, R4 and R5 can not all be hydrogen; comprising the steps of starting with a monohalobenzene (49), wherein X can be F, Cl, Br or I; and following a reaction sequence as summarized in the reaction scheme under the appropriate conditions, wherein -OQ represents a good leaving group, by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of a compose of éer; and -O-J represents a good leaving group by reaction with a nucleophilic reagent, with inversion of the stereochemical configuration as shown in reaction scheme 5, and all the formulas and symbols are as described above. In another embodiment, the present invention provides a process for the preparation of a pure stereoisomeric compound of formula (66), comprising the steps shown in reaction scheme 6, under the appropriate conditions, wherein all the formulas and symbols are as is described above. As summarized in reaction scheme 6, the preparation of a pure stereoisomeric transferamino-cyclohexyl ether compound (66) can be carried out beginning with a biotransformation of chlorobenzene (58) to compound (59), with a microorganism such as Pseudomonas putida 39 / D. Experimental conditions for biotransformation are well established (Organic Synthesis, Vol. 76, 77, and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35, and references cited therein). In a separate step, compound (59) is selectively reduced under suitable conditions to give compound (60) (eg H2-Rh / AI2O3; Boyd et al., JCS Chem. Commun. 1996, 45-46; Coker, J. Org. Chem. 1964, 29, 194-198, and references cited therein). In another separate step, the least hindered hydroxy group of formula (60) is converted selectively under the appropriate conditions in a positive form, such as the εylation (TsO-) of formula (61) (eg TsCI in the presence of pyridine) . In a separate step, the compound (61) is converted to the compound (62) by reduction, such as hydrogenation and hydrogenolysis, in the presence of a catalyst and under the appropriate conditions. Palladium on activated carbon is an example of the catalysts. The reduction of the compound (61) can be done under basic conditions, for example in the presence of a base such as sodium oxide, sodium bicarbonate, sodium acetate or calcium carbonate. The base can be added in a portion or incrementally during the reaction. In another separate step, the free hydroxy group of the compound (62) is alkylated under the appropriate conditions to form the compound (64). The trichloroacetylimide (63) is easily prepared from the corresponding alcohol, 3,4-dimethoxyphenethylalcohol, which is available commercially (for example, from Aldrich), for example with ichloroaceyoniiryl. The alkylation of the compound (62) with the trichloroacetimidate (63) can be done in the presence of a Bronsid acid or a Lewis acid such as HBF4. In a separate step, the osylate group of formula (64) is displaced by an amino compound such as 3R-pyrrolidinol (65), with inversion of the configuration. 3R-pyrrolidinol (65) is commercially available (eg, from Aldrich), or can be prepared according to the published procedure (eg Chem. Ber. / Recueil 1997, 130, 385-397). The reaction can be carried out with or without a solvent, and at an appropriate temperature scale that allows the formation of the product (66) at a suitable rate. An excess of the amino compound (65) can be used to convert the compound (64) to the product (66) as much as possible. The reaction can be done in the presence of a base that facilitates the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to the substantial completion, the desired product is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified in accordance.

Reaction Scheme 6: Process for preparing a stereochemically pure frans- (1R.2R) -aminocyclohexyl ether compound of formula (66) TsCl (66) The above-described reaction sequence (reaction scheme 6) generally produces the compound of formula (66) as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatively in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metastasically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt. In another embodiment, the preparation of a stereochemically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 7, which comprises the steps starting with chlorobenzene (58) and proceeding with a reaction sequence analogous to the applicable portion (ie, of the compound (58) to the compound (64)) which is described in reaction scheme 6 above, yielding the compound of the formula (64). This is reacted under suitable conditions with an amino compound of formula (65A) wherein Bn represents a benzyl protecting group of the hydroxy function of 3R-pyrrolidinol, to form the compound (67). The compound (65A) is commercially available (for example from Aldrich) or can be prepared according to published literature (for example, Chem. Ber./Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperalure scale which allows the formation of the product (67) at a suitable speed. An excess of the amino compound (65A) can be used to convert the compound (64) to the product (67) as much as possible. The reaction can be done in the presence of a base that can facilitate production formation. Generally the additional base is not nucleophilic in its chemical reactivity. The benzyl protecting group (Bn) of the compound (67) can be removed by a standard procedure (for example, hydrogenation in the presence of a catalyst under the appropriate conditions). Palladium on activated carbon is an example of the catalysts. You will hear proper conditions described in Greene, "Proactive Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The product is a compound of stereochemically pure rans-aminocyclohexyl ether of formula (66) and is generally formed as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatively in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metasystically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme 7 Procedure for preparing a trans ~ compound. { R, 2R) -stereochemically pure aminocyclohexyl ether of formula (66) TsCI In another embodiment, the preparation of a stereochemically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 8, which comprises the steps of starting with chlorobenzene (58), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 6 above, yielding the compound of formula (64). This is reacted with an amino compound of formula (68). The compound (68), 3S-pyrrolidinol, is commercially available (for example, from Aldrich) or can be prepared according to a published procedure (for example, Chem. Ber./Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (69) at a suitable rate. An excess of the amino compound (68) can be used to convert the compound (64) to the maximum in the production (69). The reaction can be done in the presence of a base that can facilitate production formation. Generally the additional base is not nucleophilic in its chemical reactivity. The product is a compound of pure eschereochemically fraps-aminociclohexyl-eneer of formula (69) and is generally formed as the free base. If desired, the free base can be converted to the monohydrochloric salt by means of the known methods or, if desired, allymerically in further acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. The acid addition salts can also be prepared meiostatically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme 8 Process for preparing a stereoisomerically pure fraps- (1R, 2R) -aminocyclohexyl ether compound of formula (69) (58) (59) (60) TsCl (69) In another embodiment, the preparation of a stereochemically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 9, comprising the steps of starting with chlorobenzene (58), and proceeding with a reaction sequence analogous to the applicable portion described in reaction scheme 7 above, yielding the compound of formula (64). This is reacted with an amino compound of formula (70) wherein Bn represents a benzyl protecting group of the hydroxy function of 3S-pyrrolidinol, to form the compound (71). The compound (70) is commercially available (for example, from Aldrich) or can be prepared according to a published procedure (for example, Chem. Ber./Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperature scale which allows the formation of the product (71) at a suitable speed. An excess of the amino compound (70) can be used to convert the compound (64) to the product (71) as much as possible. The reaction can be carried out in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. The benzyl protecting group (Bn) of the compound (71) can be removed by a standard procedure (for example, hydrogenation in the presence of a catalyst under the appropriate conditions). Palladium on activated carbon is an example of the catalysts. Other suitable conditions are described in Greene, "Proteclive Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The product is a stereochemically pure frans-aminocyclohexyl ether compound of formula (69) and is generally formed as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatively in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metastasically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme 9 Process for preparing a stereoisomerically pure trans- (AR, 2R) -aminocyclohexyl ether compound of formula (69) (58) (59) (60) TsCl In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 10, which comprises the steps of starting with the compound of formula (50), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 5, wherein all the formulas and symbols are as described above.

Reaction Scheme 10 Process for preparing a trans-ClR, 2R) -aminocyclohexyl ether stereoisomerically pure compound of formula (57) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 11, which comprises the steps of starting with the compound of formula (59), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 6, wherein all the formulas and symbols are as described above. The 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of formula (59) is a commercially available product (eg, from Aldrich), or is synthesized according to a published procedure (for example, Organic Synthesis, Vol. 76, 77 and T. Hudiicky et al., Aldrichimica Acta, 1999, 32, 35, and references cited therein).

Reaction Scheme 11 Principle for preparing a trans = R, 2 R) = stereisoisomerically pure aminocyclohexyl ether of formula (66) TsC? In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 12, which comprises the steps of starting with the compound of formula (59), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 7, wherein all the formulas and symbols are as described above.

Reaction Scheme 12 Process for preparing a stereoisomerically pure fra /? S- (1? .2 /?) - aminocyclohexyl ether compound of formula (66) TsCl o- "'« OcBp? OHMte In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 13, which comprises the steps of starting with the compound of formula (59), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 8, wherein all the formulas and symbols are as described above.

Reaction Scheme 13 Process for preparing a trans-C? R, 2R) -aminocyclohexyl ether stereoisomerically pure compound of formula (69) TaCI HN- "? In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 14, which comprises the steps of starting with the compound of formula (59), and proceeding with a reaction sequence analogous to the applicable portion described in FIG. reaction scheme 9, where all the formulas and symbols are as described above.

Reaction Scheme 14 Process for preparing a stereochemically pure trans-1R, 2R) -aminocyclohexyl ether compound of formula (69) TsCl In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 15, which comprises the steps of starting with the compound of formula (51), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 5, wherein all the formulas and symbols are as described above.

Reaction Scheme 15 Process for preparing a stereoisomerically pure compound of trans- (1 2 -ffl-aminocyclohexyl ether of formula (57) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 16, which comprises the steps of starting with the compound of formula (60), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 6, wherein all the formulas and symbols are as described above.

Reaction Scheme 16 Process for preparing a stereoisomerically pure compound of trans- (1ff.2ff) -aminocyclohexyl ether of formula (66) TsCl In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 17, which it comprises the steps of starting with the compound of formula (60), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 7, wherein all the formulas and symbols are as described above.

Reaction Scheme 17 Process for preparing a stereoisomerically pure compound of trans-M 2R) -aminocyclohexyl ether of formula (66) TsCl In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 18, which comprises the steps of starting with the compound of formula (60), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 8, where all the formulas and symbols are as described above.

Reaction Scheme 18 Process for preparing a stereoisomerically pure compound of • frans- (1 .2i%) - aminociclohsxi étsr of formula (69) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 19, which comprises the steps of starting with the compound of formula (60), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 9, wherein all the formulas and symbols are as described above.

Reaction Scheme 19 Process for preparing a stereoisomerically pure compound of frans- (1 2ff) -aminocyclohexyl ether of formula (69) ci A H A.üp TsCl In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 20, which comprises the steps of starting with the compound of formula (52), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 5, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of trans- (1 2-f-arninocycloryexy-ether of formula (57) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 21, which comprises the steps of starting with the compound of formula (61), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 6, wherein all the formulas and symbols are as described above.

Reaction Scheme 21 Process for preparing a stereoisomerically pure compound of trans- (1 2ff) -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 22, which comprises the steps of starting with the compound of formula (61), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 7, wherein all the formulas and symbols are as described above.

Reaction Scheme 22 Process for preparing a stereoisomerically pure compound of trans- (1f?, 2R) -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a pure trans-aminociclohexyl ether esfereoisoméricamenie compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 23, which comprises the steps of starting with the compound of formula (61), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 8, where all the formulas and symbols are as described above.

Reaction Scheme 23 Process for preparing a stereoisomerically pure compound of frans- (1 2 R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 24, which comprises steps to start with the compound of formula (61), and proceed with a reaction sequence analogous to the applicable portion that is described in reaction scheme 9, where all the formulas and symbols are as described above.

Reaction Scheme 24 Process for preparing a stereoisomerically pure compound of frans- (1 2R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 25, which comprises the steps of starting with the compound of formula (53), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 5, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1. 2 R) -aminocyclohexyl ether of formula (57) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 26, which comprises the steps of starting with the compound of formula (62), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 6, wherein all the formulas and symbols are as described above.

Reaction Scheme 26 Process for preparing a stereoisomerically pure compound of frans- (1-R2ff) -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 27, comprising the steps starting with the compound of formula (62), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 7, wherein all the formulas and symbols are as described above.

Reaction Scheme Process for preparing a stereoisomerically pure compound of trans- (1R2R> -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 28, which comprises the steps of starting with the compound of formula (62), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 8, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of fraps- (1R2R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 29, which comprises the steps of starting with the compound of formula (62), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 9, wherein all the formulas and symbols are as described above.

Reaction Scheme 29 Process for preparing a stereoisomerically pure compound of fraps- (1 R2R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 30, comprising the steps starting with the compound of formula (55), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 5, wherein all the formulas and symbols are as described above.

Reaction Scheme Process for preparing a stereoisomerically pure compound of frans- (1 R2R) -aminocyclohexyl ether of formula (57) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 31, which comprises the steps of starting with the compound of formula (64), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 6, wherein all the formulas and symbols are as described above.

REACTION SCHEME 31 Process for preparing a stereoisomerically pure compound of frans- (1 R2R) -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a pure stereoisomeric compound of frar / s-arninocyclohexyl ether of formula (66) can be carried out under suitable conditions, by means of a process as summarized in the reaction scheme. , comprising the steps of starting with the compound of formula (64), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 7, wherein all formulas and symbols are as described above .

Reaction Scheme 32 Process for preparing a stereoisomerically pure compound of frans- (1-R2R-amidocyclohexyl ether of formula (66) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 33, which comprises the steps of starting with the compound of formula (64), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 8, wherein all the formulas and symbols are as described above.

Reaction Scheme 33 Process for preparing a stereoisomerically pure compound of trans-11 R2R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a pure stereoisomeric trans-aminocciohexyl ether compound of formula (69) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 34, comprising the steps starting with the compound of formula (64), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 9, wherein all the formulas and symbols are as described above.

Reaction Scheme 34 Process for preparing a stereoisomerically pure compound of frans- (1R2fl) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 35, which comprises the steps of starting with the compound of formula (67), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 7, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of fraps- (1R2f?) - aminociclohexyl ether of formula (66) In olra modality, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 36, comprising the steps of start with the compound of formula (71), and proceed with a reaction sequence analogous to the applicable portion that is described in reaction scheme 9, wherein all formulas and symbols are as described above.

Reaction Scheme 36 Process for preparing a stereoisomerically pure compound of > fra / 7S- (1R2R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure compound of formula (55) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 37, comprising the steps of starting with the compound of formula (49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 5, wherein all formulas and symbols are as described above.

Reaction Scheme 37 Process for preparing a stereoisomerically pure compound of formula (55) In another embodiment, the preparation of a stereoisomerically pure compound of formula (64) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 38, comprising the steps of starting with the compound of formula (58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 6, wherein all formulas and symbols are as described above.

Reaction Scheme 38 Process for preparing a stereoisomerically pure compound of formula (64) TsCl In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (67) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 39, which comprises the steps of starting with the compound of formula (58), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 7, wherein all the formulas and symbols are as described above.

Reaction Scheme 39 Process for preparing a stereoisomerically pure compound of formula (67) Tsa In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (71) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 40, which comprises the steps of starting with the compound of formula (58), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 9, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (71) TsCl In another embodiment, the preparation of a stereoisomerically pure compound of formula (53) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 41, which comprises the steps of starting with the compound of formula (49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 5, wherein all formulas and symbols are as described above.

Reaction Scheme 41 Process for preparing a stereoisomerically pure compound of formula (53) In another embodiment, the preparation of a stereoisomerically pure compound of formula (62) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 42, which comprises the steps of starting with the compound of formula (58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 6, wherein all formulas and symbols are as described above.

Reaction Scheme 42 Process for preparing a stereoisomerically pure compound of formula (62) TsCi In another embodiment, the preparation of a stereoisomerically pure compound of formula (52) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 43, comprising the steps of starting with the compound of formula (49), and follow with a reaction sequence analogous to the applicable portion which is described in reaction scheme 5, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (52) In another embodiment, the preparation of a stereoisomerically pure compound of formula (61) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 44, comprising the steps of starting with the compound of formula (58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 6, wherein all the formulas and symbols are as described above.

Reaction Scheme 44 Process for preparing a stereoisomerically pure compound of formula (61) TsCl In another embodiment, the present invention provides a compound of formula (52), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (53), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (54), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that R3, R and R5 do not They can be hydrogen mud. In another embodiment, the present invention provides a compound of formula (55), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that when R3, R and R5 they are all hydrogen, then J is not a methanesulfonyl group. In another embodiment, the present invention provides a compound of formula (61), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (62), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (64), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (67), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides synthetic methods with which the compounds of formula (75), with fra / 7s- (1S, 2S) configuration for the ether and amino functional groups, can be prepared in a stereoisomerically pure manner. The compounds of the formulas (79), (80), (81) and (82) are some of the examples represented by the formula (75). The present invention also provides synthetic methods by which the compounds of formulas (72), (73) and (74) can be synthesized in stereoisomerically pure form. The compounds (76), (77) and (78) are examples of the formulas (72), (73) and (74), respectively. As summarized in the reaction scheme 45, the preparation of a pure stereoisomeric α-cyclohexyl ether compound of formula (75) can be carried out following a process starting with a monohalobenzene (49), wherein X can be F, Cl, Br or I.

Reaction Scheme Method for preparing a stereoisomerically pure compound of trans-ii S.2 S) -aminocydohexyl ether of formula (75) In a first step, the compound (49) is transformed by means of a well established microbial oxidation in the c / 's-cyclohexandienodiol (50) in a stereo-isomerically pure form (T. Hudiicky et al., Aldrichimica Acta, 1999, 32, 35, and references cited therein). In a separate step, compound (50) can be selectively reduced under suitable conditions to give compound (51) (e.g., H2-Rh / AI2O3; Boyd et al., JCS Chem. Commun. 1996, 45-46; Ham and Coker, J. Org. Chem. 1964, 29, 194-198, and references cited therein). In another separate step, the compound (51) is converted to the compound (72) by reaction with the compound (54) under the appropriate conditions, wherein -OQ represents a good leaving group, by reaction with a hydroxy function with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound. Trichloroacetimidate is an example of the -O-Q function. For some compounds (72) it may be necessary to introduce appropriate protective groups before performing this step. Suitable protecting groups are described, for example, in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York, NY (1991). In a separate step, the transformation of the compound (72). in the compound (73) it can be carried out by hydrogenation and hydrogenolysis in the presence of a catalyst and under the appropriate conditions. Palladium on activated carbon is an example of the catalysts. The hydrogenolysis of alkyl or alkenyl halide such as (72) can be done under basic conditions. The presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetamide or calcium carbonate is possible in some examples. The base can be added in a portion or incrementally during the reaction. In another separate step, the hydroxy group of the compound (73) is selectively converted under the appropriate conditions into a acylated form, represented by the compound (74). A "acylated form" as used herein, means that the hydroxy group is converted into a good leaving group (-O-J), which by reaction with an appropriate nucleophile will result in a substitution product with reversal of the stereochemical configuration. The leaving group can be a mesylate group (MsO-), tosylate (TsO-) or nosyllalo (NsO-). The hydroxy group may also be converted to other suitable leaving groups according to well-known procedures. In a typical reaction for the formation of an ionosylation, the compound (73) was admixed with a hydroxyalivative reagent such as fosyl chloride (TsCl) in the presence of a base (e.g., pyridine or eryrylamine). In general, the reaction is performed satisfactorily at about 0 ° C, but can be adjusted as necessary to maximize the yield of the desired product. An excess of the hydroxy activating reagent (for example, osyl chloride) can be used with respect to the compound (73), to convert the hydroxy group to the activated form as much as possible. In a separate step, the resulting compound (74) is treated under suitable conditions with an amino compound of formula (56) to form the compound (75) as a product. The reaction can be carried out with or without solvency and at an appropriate temperature scale which allows the formation of the product (75) at a suitable speed. An excess of the amino compound (56) can be used to convert the compound (74) to the product (75) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to substantial completion, the product is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified accordingly. The protecting groups can be removed in the appropriate step of the reaction sequence. Suitable methods are described, for example, in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The above-described reaction sequence (reaction scheme 45) generates the compound of formula (75) as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatingly in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metasystically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt. All publications and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication or country application was specifically and individually incorporated as a reference. In one embodiment, the present invention provides a method for the preparation of a pure stereo.someric compound of formula (75): (75) where R-i and R2, when taken together with the niologen atom to which they are directly attached in the formula (75), form a ring denoted by the formula (ll): CD} and R3, R4 and R5 are independently selected from hydrogen, hydroxy and alkoxy of C.-C6, with the proviso that R3, R4 and R5 can not be hydrogen ions; comprising the steps of starting with a monohalobenzene (49), wherein X can be F, Cl, Br or I; and continuing with a reaction sequence like the one summarized in the reaction scheme 45 under the right conditions, where -O-Q represented a good leaving group, by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound; and -O-J represents a good leaving group by reaction with a nucleophilic reagent, with inversion of the stereochemical configuration as shown in reaction scheme 45, and all formulas and symbols are as described above. In another embodiment, the present invention provides a process for the preparation of a pure stereoisomeric compound of formula (79), comprising the steps shown in reaction scheme 46, under the appropriate conditions, wherein all the formulas and symbols are as is described above. As summarized in reaction scheme 46, the preparation of a stereoisomerically pure iraps-aminocyclohexyl-ether compound (79) can be carried out starting with a biotransformation of chlorobenzene (58) to compound (59), with a microorganism such as Pseudomonas putida 39 / D. The experimental conditions for biotransformation are well established (Organic Synthesis, Vol. 76, 77, and T. Hudiicky and Oíros, Aldrichimica Acta, 1999, 32, 35, and references cited therein). In a separate step, compound (59) is selectively reduced under suitable conditions to give compound (60) (eg, H2-Rh / AI2O3; Boyd et al., JCS Chem. Commun. 1996, 45-46; Ham; and Coker, J. Org. Chem. 1964, 29, 194-198, and references cited therein). In another separate step, the compound (60) is converted to the compound (76) by reaction with the compound (63) under the appropriate conditions. The trichloroacetimidate (63) is easily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (for example, from Aldrich), by treatment with trichloroaceloniyryl. The alkylation of the compound (60) with .alpha.-chloroacetylimide (63) can be done in the presence of a Bronsid acid or a Lewis acid such as HBF.sub.4. The reaction femperairy can be adjusted as necessary to maximize the yield of the desired product. In a separate step, the compound (76) is converted to the compound (77) by reduction, for example by hydrogenation and hydrogenolysis in the presence of a calychator and under the appropriate conditions. Palladium on activated carbon is an example of the catalysts. The reduction of the compound (76) can be done under basic conditions, for example in the presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetate or calcium carbonate. The base can be added in a portion or incrementally during the reaction. In another separate step, the hydroxy group of compound (77) is converted under suitable conditions into a spiked form, such as the losilay (TsO-) of formula (78) (eg, TsCI in the presence of pyridine). In a separate step, the iosylate group of formula (78) is displaced by an amino compound such as 3f? -pyrrolidinol (65), with inversion of the configuration. 3R-pyrroidinol (65) is commercially available (eg, from Aldrich), or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil 1997, 130, 385-397). The reaction can be carried out with or without a solvent, and at an appropriate temperature scale that allows the formation of the production (79) at a suitable rate. An excess of the amino compound (65) can be used to convert the compound (78) to the maximum in the production (79). The reaction can be done in the presence of a base that facilitates the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to substantial completion, the desired product is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified accordingly.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1S.2S) -aminocyclohexyl ether of formula (79) (77) (76) The above described reaction sequence (reaction scheme 46) generally produces the compound of formula (79) as the free base. If desired, the free base can be converted to the monohydrochloric salt by known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid under the appropriate conditions. Acid addition salts can also be prepared metasystically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt. In another embodiment, the preparation of a pure stereoisomeric compound of trans-aminocyclohexyl ether of formula (79) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 47, which comprises steps of starting with the chlorobenzene (58), and proceeding with a reaction sequence analogous to the applicable portion (i.e., of the compound (58) to the compound (78)), which is described in reaction scheme 46 above, yielding the compound of formula (78). This is reacted under suitable conditions with an amino compound of formula (65A), wherein Bn represents a benzyl protecting group of the hydroxy function of 3S-pyrrolidinol, to form the compound (80). The compound (65A) is commercially available (for example, from Aldrich) or can be prepared according to a published procedure (for example, Chem. Ber./Recueil 1997, 130, 385-397). The reaction can be carried out with or without a solvent and at an appropriate scale of time to allow production of the product (80) at an adequate rate. An excess of the amino compound (65A) can be used to convert the compound (78) to the product (80) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. The benzyl protecting group (Bn) of the compound (80) can be removed by a standard procedure (for example, hydrogenation in the presence of a calychator under the appropriate conditions). Palladium on activated carbon is an example of the catalysts. Other suitable conditions are described, for example, in Greene, "Protecive Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The product is a pure stereoisomeric frans-aminocyclohexyl ether compound of formula (79) and is generally formed as the free base. If desired, the free base can be converted to the monohydrochloric salt by known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid under the appropriate conditions. Acid addition salts can also be prepared melasically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme 47 Process for preparing a stereoisomerically pure compound of trans' (1S, 2S) -aminocyclohexyl ether of formula (79) (78) (80) (79) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by means of a procedure as summarized in reaction scheme 48, comprising the steps starting with chlorobenzene (58), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 46 above, yielding the compound of formula (78). This is reacted with an amino compound of formula (68). The compound (68), 3S-pyrrolidinol, is commercially available (for example, from Aldrich) or can be prepared according to a published procedure (e.g., Chem. Ber. / Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperalure scale which allows the formation of the product (81) at a suitable speed. An excess of the amino compound (68) can be used to convert the compound (78) to the product (81) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. The product is a pure stereoisomeric, trans-aminocyclohexyl ether compound of formula (81) and is formed as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid under the appropriate conditions. Acid addition salts can also be prepared metasystically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme Method for preparing a stereoisomerically pure trans- compound. { ? S, 2S) -aminocyclohexyl ether of formula (81) (77) (76) (78) (SI) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by means of a procedure such as that it summarizes in reaction scheme 49, which comprises the steps of starting with a chlorobenzene (58), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 47 above, yielding the compound of formula ( 78). That is reacted with an amino compound of formula (70) wherein Bn represented a benzyl protecting group of the hydroxy function of 3S-pyrroidinol, to form the compound (82). The compound (70) is commercially available (for example, from Aldrich) or can be prepared according to a published procedure (for example, Chem. BerJRecueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (82) at a suitable rate. An excess of the amino compound (70) can be used to convert the compound (78) to the product (82) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. The benzyl protecting group (Bn) of the compound (82) can be removed by a standard procedure (for example, hydrogenation in the presence of a catalyst under the appropriate conditions). Palladium on activated carbon is an example of the catalysts. Other suitable conditions are described, for example, in Greene, "Protecive Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The product is a pure stereoisomeric ether-aminocyclohexyl ether compound of formula (81) and is generally formed as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid, under the appropriate conditions. Acid addition salts can also be prepared metasystically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme 49 Process for preparing a stereoisomerically pure compound of frans- (1S.2S) -aminocyclohexyl ether of formula (81) (YES) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under the appropriate conditions by means of a process as summarized in reaction scheme 50, which comprises steps of starting with the compound of formula (50), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 45, where all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1S, 2S) -aminocyclohexyl ether of formula (75) .

In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 51, comprising the steps starting with the compound of formula (59), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 46, wherein all the formulas and symbols are as described above. The 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of formula (59) is a commercially available product (for example, from Aldrich) or is synthesized according to a published procedure ( example, Organic Synthesis, Vol. 76, 77, and T. Hudiicky and oíros, Aldrichimica Acta, 1999, 32, 35, and references cited therein).

Reaction Scheme 51 Process for preparing a stereoisomerically pure compound of frans- (1S.2S) -aminocyclohexyI-ether of formula (79) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a procedure as summarized in reaction scheme 52, which comprises the steps of starting with the compound of formula (59), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 47, wherein all formulas and symbols are as described above.

Reaction Scheme 52 Process for preparing a stereoisomerically pure frans- (1S, 2S) -aminocyclohexyl ether compound of formula (79) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether of formula (81) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 53, which comprises the steps of starting with the compound of formula (59), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 48, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S, 2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions, by means of a procedure as summarized in reaction scheme 54, which comprises the steps of starting with the compound of formula (59), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 49, wherein all the formulas and symbols are as described above.

Reaction Scheme Process for preparing a stereoisomerically pure compound of frans- (1S.2S) -aminocyclohexyl ether of formula (81) TsCI ror? In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 55, which comprises the steps of starting with the compound of formula (51), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 45, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure frans- (1S.2S) -aminocyclohexyl ether compound of formula (75) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 56, which comprises the steps of starting with the compound of formula (60), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 46, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S, 2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 57, which comprises the steps of starting with the compound of formula (60), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 47, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of f r / S- (1 S 2 S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a pure trans-aminocyclohexyl ether stereoisomeric compound of formula (81) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 58, which comprises the steps of starting with the compound of formula (60), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 48, where all the formulas and symbols are as described above.

Reaction Scheme 58 Process for preparing a stereoisomerically pure compound of fra /? S- (1S, 2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 59, which comprises the steps of starting with the compound of formula (60), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 49, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frar7s- (1S.2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 60, which comprises the steps of starting with the compound of formula (72), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 45, wherein all the formulas and symbols are as described above.

Reaction Scheme 60 Process for preparing a stereoisomerically pure compound of fra;? S- (1S.2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 61, which comprises the steps of starting with the compound of formula (76), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 46, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a sterra-purely fraps- (1 S 2 S) -aminocyclohexyl ether compound of formula (79) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 62, which comprises the steps of starting with the compound of formula (76), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 47, wherein all the formulas and symbols are as described above.

Reaction Scheme 62 Process for preparing a stereoisomerically pure compound of frans- (1 S.2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 63, which comprises the steps of starting with the compound of formula (76), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 48, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S, 2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 64, which comprises the steps of starting with the compound of formula (76), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 49, wherein all the formulas and symbols are as described above.

Reaction Scheme 64 Process for preparing a stereoisomerically pure compound of frans-d S.2 S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 65, comprising the steps starting with the compound of formula (73), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 45, wherein all formulas and symbols are as described above.

Reaction Scheme Method to prepare a stereoisomerically pure trans- compound. { ? S.2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 66, which comprises the steps of starting with the compound of formula (77), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 46, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S, 2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 67, which comprises the steps of starting with the compound of formula (77), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 47, wherein all formulas and symbols are as described above.

Reaction Scheme 67 Process for preparing a stereoisomerically pure compound of trans-C? 2S) -aminocylohexyl ether of formula (79) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 68, comprising the steps starting with the compound of formula (77), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 48, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S.2S) -aminocyclohexyl ether of formula (81) TsCl H? R In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 69, comprising the steps of starting with the compound of formula (77), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 49, wherein all formulas and symbols are as described above.

Reaction Scheme 69 Process for preparing a stereoisomerically pure compound of trans- (S, 2S) -aminocyclohexyl ether of formula (81) In another modality, the preparation of a pure trans-aminociclohexyl-esfferapheneisomeric compound of formula (75) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 70, comprising the steps of start with the compound of formula (74), and proceed with a reaction sequence analogous to the applicable portion that is described in reaction scheme 45, where all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S.2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 71, which comprises the steps of starting with the compound of formula (78), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 46, where all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S, 2S) -aminocyclohexyl ether of formula (79) V »OH In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 72, which comprises the steps of starting with the compound of formula (78), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 47, wherein all the formulas and symbols are as described above.

Reaction Scheme 72. Method for preparing a stereoisomerically pure compound of trans ?? S.2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a pure trans-aminocrylohexyl ether esteriferous ester of formula (81) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 73, which comprises the steps of starting with the compound of formula (78), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 48, where all the formulas and symbols are as described above.

Reaction Scheme 73 Process for preparing a stereoisomerically pure trans- compound. { ? S.2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 74, which comprises the steps of starting with the compound of formula (78), and continuing with a reaction sequence analogous to the applicable portion which is described in reaction scheme 49, where all the formulas and symbols are as described above.

Reaction Scheme Process for preparing a stereoisomerically pure compound of fra / is-d S_2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 75, which comprises the steps of starting with the compound of formula (80), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 47, where all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S, 2 S) -aminocyclohexy I-ether of formula (79) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 76, which comprises the steps of starting with the compound of formula (82), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 49, wherein all formulas and symbols are as described above. 2 Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S 2 S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a pure stereoisomeric compound of formula (74) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 77, comprising the steps of starting with the compound of formula (49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 45, wherein all the formulas and symbols are as described above.

Reaction Scheme 77 Process for preparing a stereoisomerically pure compound of formula (74) In another embodiment, the preparation of a pure stereoisomeric compound of formula (78) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 78, which comprises the steps of starting with the compound of formula (58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 46, where all the formulas and symbols are as described above.

Reaction Scheme 78 Process for preparing a stereoisomerically pure compound of formula (78) In an embodiment, the preparation of a pure stereoisomerically pure trans-aminociclohexyl ether of formula (80) can be carried out under the appropriate conditions, by means of a procedure as summarized in reaction scheme 79, which it comprises the steps of starting with the compound of formula (58), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 47, wherein all the formulas and symbols are as described above.

Reaction Scheme 79 Process for preparing a stereoisomerically pure compound of formula (80) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (82) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 80, which comprises the steps of starting with the compound of formula (58), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 49, where all the formulas and symbols are as described above.

Reaction Scheme 80 Procedure for preparing a stereoisomerically pure compound of formula (82) In another embodiment, the preparation of a stereoisomerically pure compound of formula (73) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 81, comprising the steps of starting with The compound of formula (49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 45, where all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (73) In another embodiment, the preparation of a stereoisomerically pure compound of formula (77) can be carried out under suitable conditions by means of a procedure as summarized in reaction scheme 82, which comprises the steps of starting with the compound of formula (58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 46, wherein all the formulas and symbols are as described above.

Reaction Scheme 82 Method for preparing a stereoisomerically pure compound of formula (77) In another embodiment, the preparation of a stereoisomerically pure compound of formula (72) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 83, which comprises the steps of starting with the compound of formula (49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 45, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (72) In another embodiment, the preparation of a stereoisomerically pure compound of formula (76) can be carried out under suitable conditions by means of a process as summarized in reaction scheme 84, which comprises the steps of starting with the compound of formula (58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 46, wherein all formulas and symbols are as described above.

Reaction Scheme 84 Method for preparing a stereoisomerically pure compound of formula (76) In another embodiment, the present invention provides a compound of formula (72), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (73), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (73), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that R3, R4 and Rs are not they can all be hydrogen. In another embodiment, the present invention provides a compound of formula (74), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that when R3, R4 and R5 they are all hydrogen, then J is not a methanesulfonyl group. In another embodiment, the present invention provides a compound of formula (76), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (77), or a pharmaceutically acceptable salt or solvate thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (78), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (80), or a solvap or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. The present invention provides synthetic procedures by which the compounds of formula (57) can be prepared in a stereoisomerically pure form, with a trans-R, 2R configuration for the ether and amino functional groups. The compound of the formula (66) is an example represented by the formula (57). The present invention also provides synthetic methods by which the compounds of formula (75) can be prepared in a stereoisomerically pure form, with an iaA7S- (1S, 2S) configuration for the ether and amino functional groups. The compound of formula (79) is an example represented by formula (75). The present invention also provides synnemic procedures with which the compounds of formulas (85), (86), (55) and (74) can be synthesized in a stereoisomerically pure manner. The compounds (62) and (90) are examples of the formula (85). Compounds (87) and (89) are examples of formula (86). The compound (64) is an example of the formula (55). The compound (78) is an example of the formula (74). The aminocyclohexyl ethers of the present invention can be used for medical applications including, for example, cardiac arrhythmia such as atrial arrhythmia and ventricular arrhythmia. As summarized in Reaction Scheme 85, the preparation of a pure stereoisomeric transferamino-cyclohexyl ether compound of formula (57) can be carried out following a procedure starting with a racemic mixture of meso-c / sl, 2- cyclohexanediol (83). Compound (83) is commercially available (eg, from Sigma-Aldrich, Yes. Louis, Missouri) or can be easily synthesized according to published methods (eg, JE Taylor et al., Org. Process Res. &Dev. , 1998, 2, 147; Organic Syntheses, CV6, 342).

Reaction Scheme Method for preparing a stereoisomerically pure compound of fra /? S- (1R2R> -aminocyclohexyl ether of formula (57) (meso) (racemate) Resolution In a first step, one of the hydroxy groups of the compound (83) is converted under the appropriate conditions into an activated form represented by the racemic mixture comprising the formulas (53) and (84).

An "activated form" as used herein, means that the hydroxy group is converted into a good leaving group (-O-J), which by reaction with an appropriate nucleophile will result in a production of susíiution with inversion of the stereochemical configuration. The leaving group can be any suitable leaving group by reaction with a known nucleophilic reagent with inversion of the stereochemical configuration, including without limitation the compounds described in MB Smiíh and J. March in "March's Advanced Organic Chemisfry", fifth edition, Chapter 10 , John Wiley & Sons, Inc., New York, NY (2001). Specific examples of the leaving groups include a mesylate group (MsO-), an ionosyl group (TsO-), a 2-bromophenylsulphone group, a 4-bromophenylsulphone group or a nosyiate group (NsO-). The hydroxy group can also be converted to other suitable leaving groups according to known procedures, using any suitable activating agent, including those described in M.B. Smith and J. March in "March's Advanced Organic Chemistry", fifth edition, Chapter 10, John Wiley & Sons, Inc., New York, NY (2001). In a typical reaction for the formation of a tosylation, the compound (83) is prepared with a conjugated amount of hydroxy activating reactive, such as osyl chloride (TsCl), in the presence of a base such as pyridine or triethylamine. The reaction can be monitored and generally performed satisfactorily at approximately 0 ° C, but the conditions can be adjusted as necessary to maximize the yield of the desired product. Reagent elements can be advantageously added to facilitate the formation of mono-monolayers (for example, MJ Martinelli and others, "Selective monosulfonylation of infernal 1, 2-diols calalyzed by di-n-buylylide oxide" Tetrahedron Letters, 2000, 41, 3773) . The racemic mixture comprises the formulas (53) and (84) and is then subjected to a resolution process by which the two optically active isomers are separated into products which are substantially purely stereoisomerically, such as (85) and (86). ), where G and G. are independently selected from hydrogen, acyl C.-Ca, or any other suitable functional group that is introduced as part of the resolution process necessary for the separation of the two isomers. In some situations it may be appropriate for the resolution process to produce the compounds (85) and (86) with sufficient optical purity for their application in the subsequent steps of the synthetic process. Methods for the resolution of racemic mixtures are well known (for example, E. L. Eliel and S. H. Wilen, in "Stereochemisfry of Organic Compounds," John Wiley &Sons: New York, 1994, Chapter 7, and references cited therein). Examples of suitable methods that can be applied are enzymatic resolution (for example mediated by lipase) and chromatographic separation (for example HPLC with chiral stationary phase or simulated moving bed technology). For the compound (85), when G is hydrogen, (85) is equal to the compound (53), and in a separate reaction step is carried out, under the appropriate conditions, the alkylation of the free hydroxy group of the compound (85). ) with the compound (54), to form the compound (55), wherein -OQ represents a good leaving group by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound. The leaving group can be any known suitable leaving group, which includes the compounds described in Greene, "Proteclive Groups in Organic Chemistry", John Wiley &; Sons, New York NY (1991). Specific examples of -O-Q groups include trichloroaceimidate. For some compounds (54), it may be necessary to introduce appropriate protection groups before performing this step. Suitable protecting groups are given for example in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). For the compound (85) when G is not hydrogen, suitable methods are used to convert (85) into the compound (53). For example, when G is an acyl function of C2, a soft base catalyzed melanolysis (G. Zemplen and Oros, Ber., 1936, 69, 1827) can be used to transform (85) into (53). The latter can then be subjected to the same reaction with (54) to produce (55) as described above. In a separate step, the resulting compound (55) was run under suitable conditions with an amino compound of formula (56) to form the compound (57) as a product. The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (57) at a suitable speed. An excess of the amino compound (56) can be used to convert the compound (55) to the product (57) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to substantial completion, the product is recovered from the reaction mixture by means of conventional techniques of organic chemistry and purified in accordance. The protecting groups can be removed at the appropriate stage of the reaction sequence. Suitable methods are described, for example, in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The reaction sequence described above (scheme of reaction 85) generates the compound of formula (57) as the free base. Whether If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatively in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metastasically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt. In one embodiment, the present invention provides a method for the preparation of a stereoisomerically compound pure formula (57): (57) and R3, R4 and R5 are independently selected from hydrogen, hydroxy and C1-C6 alkoxy. with the proviso that R3, R4 and R5 can not all be hydrogen; comprising the steps of starting with a monohalobenzene (49), wherein X can be F, Cl, Br or I; and following a reaction sequence as summarized in the reaction scheme under the appropriate conditions, wherein -OQ represents a good leaving group, by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound; and -OJ represents a good leaving group by reaction with a nucleophilic reagent, with inversion of the stereochemical configuration as shown in reaction scheme 45, and all the formulas and symbols are as described above, comprising the steps of starting with a compound of formula (83), and follow with a reaction sequence as summarized in reaction scheme 85, under the appropriate conditions, wherein: wherein G and G-? they are independently selected from hydrogen, C-C8 acyl, or any other suitable functional group which is introduced as part of the resolution process necessary for the separation of the two isomers; -OQ represents a good leaving group, by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound, which includes those described in "Proiecive Groups in Organic Chemisfry", John Wiley & Sons, New York NY (1991); and -O-J represented a good leaving group by reaction with a nucleophilic reagent, with reversal of the stereochemical configuration, including without limitation, those described in "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991), and as shown in reaction scheme 85, and all formulas and symbols are as defined above. In another embodiment, the present invention provides a method for the preparation of a pure stereoisomeric compound of formula (66), which comprises carrying out under the appropriate conditions the steps shown in reaction scheme 86, where all the formulas and symbols are used. They are as described above. As summarized in reaction scheme 86, the preparation of a trans-aminocyclohexyl ether pure stereoisomeric compound of formula (66) can be carried out starting with the monosylation of c / s-1,2-cyclohexanediol (83) with TsCI, in the presence of Bu2SnO and triethylamine, under the appropriate conditions (MJ Martinelli, and other "Selective monosulfonylation of intemal 1,2-diols catalyzed by di-n-bufylfin oxide", Tetrahedron Letters, 2000, 41, 3773). Initial non-optimized yields of 80-90% have been obtained and a greater opfimization is being sought. The resulting racemic hydroxyosilase mixture comprising the compounds (62) and (87) is subjected to a lipase-mediated resolution procedure under the appropriate conditions, such as treatment of the racemates (62) and (87) with vinyl acetamide (88) in the presence of a lipase derived from Pseudomonas sp. (N. Boaz and Oíros, Tetra, Asymmetry, 1994, 5, 153), to give the compilation (62) and (89). In a separate step, the stereoisomerically pure compound of formula (62), obtained from the resolving process, is alkylated under the appropriate conditions by treatment with the trichloroacefimidafo (63) to form the compound (64). Initial non-optimized yields of 60-70% have been obtained and further optimization is being sought. The trichloroacefimide (63) is easily prepared from the corresponding alcohol, 3,4-dirneuroxyphenethylalcohol, which is commercially available (for example, from Sigma-Aldrich, Yes. Louis, Missouri), by tramadol with ichloroaceyoniiril. The alkylation of the compound (62) by means of friction or acetylimid (63) can be carried out in the presence of a Lewis acid, such as HBF4.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1-R2R-aminocyclohexyl-ether of formula (66) (66) (64) In another separate step, the iosylate group of formula (64) is displaced by an amino compound, such as 3R-pyrrolidinol (65), with configuration inversion. 3R-pyrrolidinol (65) is commercially available (eg, from Sigma-Aldrich, St. Louis, Missouri), or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (66) at a suitable rate. An excess of the amino compound (65) can be used to convert the compound (64) to the product (66) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to substantial completion, the desired product is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified accordingly. Initial non-optimized yields of approximately 40% have been obtained and further optimization is being sought. In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 87, which comprises performing under the appropriate conditions the steps shown in the reaction scheme 87, wherein all the formulas and symbols are as described above. As summarized in reaction scheme 87, the preparation of a stereoisomerically pure i / ans-aminocyclohexyl ether compound of formula (66) can be carried out starting with the monotosylation of c / s-1,2-cyclohexanediol (83). ) with TsCI in the presence of Bu2SnO and triethylamine, under the appropriate conditions (MJ Martinelli, and others "Selective monosulfonylation of internal 1, 2-diols catalyzed by di-n-butyltin oxide" Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxitosylates comprising the compounds (62) and (87) is subjected to a lipase-mediated resolution procedure under the appropriate conditions, such as bringing the racemates (62) and (87) with vinyl acetate ( 88), in the presence of a lipaea derived from Pseudomonas sp. (N. Boaz and Oros, Tetra, Asymmetry, 1994, 5, 153) to provide the compounds (90) and (87).

Reaction Scheme Method for preparing a stereoisomerically pure compound of fra /? S- (1R2R> -aminocyclohexyl ether of formula (66) (66) (54) In a separate step, the pure stereoisomeric compound of formula (90) obtained from the resolution process is subjected to a methanolysis catalyzed by a soft base (G. Zemplen et al., Ber., 1936, 69, 1827) to form the compound (62). This is rented under the appropriate conditions by irrigation with the richer (63) to form the compound (64). The ichloroacetylimid (63) is easily prepared from the corresponding alcohol, 3,4-dimethioxyphenethyl alcohol, which is commercially available (for example, from Sigma-Aldrich, Yes. Louis, Missouri), by fractionation with ichloroacefoniiril. The alkylation of the compound (88) with .alkyl aceaceimide (63) can be carried out in the presence of a Lewis acid, such as HBF. In another separate step, the ionosyl group of formula (64) is displaced by an amino compound, as 3R-pyrro! idinol (65), with inversion of the configuration. 3R-pyrrolidinol (65) is commercially available (eg, from Sigma-Aldrich, St. Louis, Missouri), or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (66) at a suitable speed. An excess of the amino compound (65) can be used to convert the compound (64) to the product (66) as much as possible. The reaction can be done in the presence of a base that can facilitate production formation. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to the substantial completion, the product is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified in accordance. In another embodiment, the present invention provides a process for the preparation of a stereoisomerically pure compound of formula (66), which comprises performing under the appropriate conditions the steps shown in reaction scheme 88, wherein all the formulas and symbols are as is described above. As summarized in reaction scheme 88, the preparation of a pure stereoisomeric compound of trans-aminocyclohexyl ether of formula (66) can be carried out starting with the monophosylation of c / s-1,2-cyclohexanediol (83) with TsCl, in the presence of Bu2SnO and eryrylamine, under the appropriate conditions (MJ Maríinelli and others, "Selecíive monosulfonylaíion of internal 1, 2-diols caíalyzed by di-n-buíyllin oxide", Tetrahedron Letters, 2000, 41, 3773). The racemic mixture resulting from hydroxyphosilates comprising the compounds (62) and (87) is subjected to a chromatographic resolution process under the appropriate conditions, such as HPLC with an appropriate chiral stationary phase and simulated moving bed technology, to provide the compounds (62) and (87) substantially in stereoisomerically pure form.

Reaction Scheme 88 Process for preparing a stereoisomerically pure trans- compound. { R2f?) - aminocyclohexyl ether of formula (66) In a separate step, the stereoisomerically pure compound of formula (62) obtained from the resolving process is alkylated under the appropriate conditions by treatment with the .lichloroacetylimide (63), to form the compound (64). The trichloroacetylimide (63) is easily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (eg, from Sigma-Aldrich, Yes. Louis, Missouri), by irradiation with trichloroacetonitrile. The alkylation of the compound (62) with trichloroacetylimide (63) can be carried out in the presence of a Lewis acid as HBF4. In another separate step, the losylate group of formula (64) is displaced by an aminoalonal compound such as 3R-pyrrolidinol (65), with inversion of the configuration. 3R-pyrrolidinol (65) is commercially available (eg, from Sigma-Aldrich, St. Louis, Missouri), or can be prepared according to a published procedure (eg, Chem. Ber./Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperalure scale which allows the formation of the product (66) at a suitable speed. An excess of the amino compound (65) can be used to convert the compound (64) to the product (66) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to its substantial completion, the desired production is recovered from the reaction mixture by means of conventional organic chemistry techniques, and purified accordingly. The above-described reaction sequences (reaction schemes 86, 87 and 88) generally produce the compound of formula (66) as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid under the appropriate conditions. Acid addition salts can also be prepared metastasically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt. In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 89, which comprises the steps of starting with a racemic mixture comprising formulas (53) and (84), and proceeding with a reaction sequence analogous to the applicable portion described in reaction scheme 85, wherein all formulas and symbols are as described above. 90 Reaction Scheme Method for preparing a stereoisomerically pure compound of fra /? S- (1R2R> -aminocyclohexy-ether of formula (57) (racemate) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 90, which comprises the steps of starting with a racemic mixture comprising formulas (62) and (87), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 86, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of trans- (1R2ffl-aminocyclohexyl ether of formula (66) (racemaio) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 91, which comprises the steps of starting with a racemic mixture comprising formulas (62) and (87), and proceeding with a reaction sequence analogous to the applicable portion described in reaction scheme 87, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of trans? R2R1-aminocyclohexyl ether of formula (66) (racemate) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 92, which comprises the steps of starting with a racemic mixture comprising formulas (62) and (87), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 88, wherein all formulas and symbols are as described above.

Reaction Scheme 92 Process for preparing a stereoisomerically pure compound of trans-C R2R) -aminocyclohexyl ether of formula (66) Chromatographic resolution In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (57) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 93, which comprises the steps of starting with a compound of formula (85) wherein G is not hydrogen, and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 85, wherein all the formulas and symbols are as is described above.

Reaction Scheme 93 Process for preparing a stereoisomerically pure compound of fra /? S- (1R2R? -aminocyclohexyl ether of formula (57) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 94, which comprises the steps of starting with a compound of formula (90), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 87, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure trans- compound. { ? R2R) -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a pure stereoisomeric compound of formula (55) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 95, comprising the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 85, wherein all formulas and symbols are as described above.

Reaction Scheme 95 Method for preparing a stereoisomerically pure compound of formula (55) (racemate) CCAA In another embodiment, the preparation of a stereoisomerically pure compound of formula (55) can be carried out under the appropriate conditions, by means of a process such as that summarized in reaction scheme 96, comprising the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion which is described in reaction scheme 85, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (55) Resolution In another embodiment, the preparation of a stereoisomerically pure compound of formula (64) can be carried out under the appropriate conditions, by means of a procedure as summarized in reaction scheme 97, which comprises the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 86, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (64) (racemate) In another embodiment, the preparation of a pure stereoisomeric compound of formula (64) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 98, comprising the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 87, wherein all formulas and symbols are as described above.

Reaction Scheme 98 Process for preparing a stereoisomerically pure compound of formula (64) (racemate) In another embodiment, the preparation of a pure stereo-isomeric compound of formula (64) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 99, which comprises the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 88, wherein all formulas and symbols are as described above.

Reaction Scheme 99 Process for preparing a stereoisomerically pure compound of formula (64) (racemate) In another embodiment, the preparation of the stereoisomerically pure compounds of formulas (85) and (86) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 100, which comprises the steps of starting with the compound of formula (83), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 85, wherein all the formulas and symbols are as described above.

Reaction Scheme 100 Process for preparing stereoisomerically pure compounds of formulas (85) v (86) (racemate) Resolution In another embodiment, the preparation of the pure stereoisomeric compounds of the formulas (62) and (89), can be carried out under the appropriate conditions by means of a procedure as summarized in reaction scheme 101, which comprises the steps of starting with the compound of formula (83), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 86, wherein all the formulas and symbols are as described above.

Reaction Scheme 101 Process for preparing stereoisomerically pure compounds of formulas (62) v (89) A? .and > H Bu_SnO, r? 0H rA- "'TsCl, Et3N l CAot, * AAWS I (meso) (racemate) In another embodiment, the preparation of pure stereoisomeric compounds of the formulas (90) and (87), can be carried out under suitable conditions by means of a process as summarized in reaction scheme 102, comprising the steps starting with the compound of formula (83), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 87, wherein all the formulas and symbols are as described above.

Reaction Scheme 102 Process for preparing stereoisomerically pure compounds of formulas (87) v (90) Resolution mediated by lipase O in the presence of a lipase) In another embodiment, the preparation of pure stereoisomeric compounds of the formulas (62) and (87) can be carried out under the appropriate conditions by means of a process as summarized in reaction scheme 103, which comprises steps of starting with the compound of formula (83), and proceeding with a reaction sequence analogous to the applicable portion which is described in reaction scheme 88, wherein all formulas and symbols are as described above.

Reaction Scheme 103 Process for preparing stereoisomerically pure compounds of formulas (62) and (87) (racemate) In another embodiment, the present invention also provides synthetic methods with which the compounds of formula (75) can be prepared in substantially pure stereoisomerically manner., with an ipsp- (1S, 2S) configuration for the ether and amino functional groups. As summarized in reaction scheme 104, the preparation of a pure stereoisomeric era / α-aminocyclohexyl ether compound of formula (75) can be carried out following a procedure starting with a racemic mixture of 77eso-c / s-1,2-cyclohexanediol (83). Compound (83) is commercially available (eg, from Sigma-Aldrich, St. Louis, Missouri) or can be easily synthesized by published methods (eg, J. E. Taylor et al., Org. Process Res. &; Dev., 1998, 2, 147; Organic Syntheses, CV6, 342).

Reaction Scheme 104 Process for preparing a stereoisomerically pure compound of f r / s- (1 S 2 S) -aminocyclohexyl ether of formula (75) (meso) (racemate) Resolution In a first step, one of the hydroxy groups of the compound (83) is converted under the appropriate conditions into an activated form represented by the racemic mixture comprising the formulas (53) and (84). An "activated form" as used herein, means that the hydroxy group is converted into a good leaving group (-O-J), which by reaction with an appropriate nucleophile will result in a substitution product with inversion of the stereochemical configuration. The leaving group can be any suitable leaving group by reaction with a known nucleophilic reagent with inversion of the stereochemical configuration, including without limitation the compounds described in M.B. Smith and J. March in "March's Advanced Organic Chemistry", fifth edition, Chapter 10, John Wiley & Sons, Inc., New York, NY (2001). Specific examples of such leaving groups include a mesylate group (MsO-), an isosyl group (TsO-), a 2-bromophenylsulfonate group, a 4-bromophenylsulphone group or a nosylate group (NsO-). The hydroxy group may also be converted to other suitable leaving groups according to known procedures, using any suitable activating agent, including, without limitation, those described in M.B. Smiíh and J. March in "March's Advanced Organic Chemisíry", fifth edition, Chapter 10, John Wiley & Sons, Inc., New York, NY (2001). In a typical reaction for the formation of a tosylate, the compound (83) was brought with a coniralated amount of hydroxy activating reactive, such as osyl chloride (TsCl), in the presence of a base such as pyridine or triethylamine. The reaction can be monitored and generally performed satisfactorily at about 0 ° C, but the conditions can be adjusted as necessary to maximize the yield of the desired product. Other reagents can be advantageously added to facilitate the formation of monotosylates (for example, MJ Martinelli and others, "Select monosulfonylation of internal 1, 2-diols cayalyzed by di-n-buylylide oxide" Tetrahedron Letters, 2000, 41, 3773) . The racemic mixture comprises the formulas (53) and (84) and is then subjected to a resolving process by which the two optically active isomers are separated into products that are substantially stereoisomerically pure in form, such as (85) and (86). ), where G and G-? they are independently selected from hydrogen, C-i-Cs acyl, or any other suitable functional group which is introduced as part of the resolution process necessary for the separation of the two isomers. In some situations it may be appropriate for the resolution process to produce the compounds (85) and (86) with sufficient optical purity for their application in the subsequent steps of the synthetic process. Methods for the resolution of racemic mixtures are well known (for example, E.L. Eliel and S.H. Wilen, in "Stereochemislry of Organic Compounds," John Wiley &Sons: New York, 1994, Chapter 7, and references cited therein). Examples of suitable methods that can be applied are enzymatic resolution (for example mediated by lipase) and chromatographic separation (for example HPLC with chiral stationary phase or simulated moving bed technology). For the compound of formula (86), when Gi is hydrogen, (86) is equal to the compound (84), and in a separate reaction step is carried out, under the appropriate conditions, the alkylation of the free hydroxy group of the compound (86) with the compound (54), to form the compound (74), wherein -OQ represents a good leaving group by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of a compound ether. The leaving group can be any known suitable leaving group, including, without limitation, the compounds described in Greene, "Protective Groups in Organic Chemistry," John Wiley &; Sons, New York NY (1991). The ichloroacetyimide is an example of the -O-Q function. For some compounds (54), it may be necessary to initiate appropriate protection groups before performing this step. Suitable pro-void groups are given for example in Greene, "Proiecive Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). For the compound (86) when G-. it is not hydrogen, suitable methods are used to convert (86) into the compound (84). For example, when G. is an acyl function of C2, a base-catalyzed soft methanolysis (G. Zemplen et al., Ber., 1936, 69, 1827) can be used to transform (86) to (84). The latter can then be subjected to the same reaction with (54) to produce (74) as described above. In a separate step, the resulting compound (74) was run under the appropriate conditions with an amino compound of formula (56) to form the compound (75) as a product. The reaction can be carried out with or without solvency and at an appropriate temperature scale which allows the formation of the product (75) at a suitable speed. An excess of the amino compound (56) can be used to convert the compound (74) to the product (75) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to substantial completion, the production is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified accordingly. The protecting groups can be removed at the appropriate stage of the reaction sequence. Suitable methods are described, for example, in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991). The above-described reaction sequence (reaction scheme 104) generates the compound of formula (75) as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatively in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metastasically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt. In one embodiment, the present invention provides a process for the preparation of a stereoisomerically pure compound of formula (75): wherein Ri and R2, when taken together with the nitrogen atom to which they are directly attached in the formula (75) , form a ring denoted by the formula (II): and R3, R and R5 are independently selected from hydrogen, hydroxy and C.sub.1 -C.sub.2 alkoxy, with the proviso that R.sup.3, R.sup.4 and R.sup.5 can not all be hydrogen; comprising the steps of starting with a compound of formula (83), and continuing with a reaction sequence as summarized in reaction scheme 104, under the appropriate conditions, wherein G and G-? are independently selected from hydrogen, C-i-Cβ acyl, or any other suitable functional group which is introduced as part of the resolution process necessary for the separation of the two isomers; -OQ represents a good leaving group by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound, including, without limitation, those described in "Protective Groups in Organic Chemistry" , John Wiley & Sons, New York NY (1991); and -O-J represents a good leaving group by reaction with a nucleophilic reagent, with reversal of the stereochemical configuration, including, without limitation, those described in "Protective Groups in Organic Chemistry," John Wiley & Sons, New York NY (1991), as shown in reaction scheme 104, and all formulas and symbols are as described above. In another embodiment, the present invention provides a process for the preparation of a stereoisomerically pure compound of formula (79), which comprises performing under the appropriate conditions the steps shown in reaction scheme 105, wherein all the formulas and symbols are as is described above. As summarized in reaction scheme 105, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79), can be carried out starting with the monotosylation of c / s-1,2-cyclohexanediol (83) with TsCl, in the presence of Bu2SnO and triethylamine under the appropriate conditions (MJ Martinelli et al. "Selective monosulfonylation of internal 1, 2-diols catalyzed by di-n-butyltin oxide" Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxitosylates comprising the compounds (62) and (87), is subjected to a lipase-mediated resolution procedure under the appropriate conditions, such as treatment of the racemates (62) and (87) with vinyl acetate (88), in the presence of a lipase derived from Pseudomonas sp. (N. Boaz et al., Tetra, Asymmetry, 1994, 5, 153) to provide compounds (87) and (90). In a separate step, the pure stereoisomeric compound of formula (87), obtained from the resolution process, is alkylated under the appropriate conditions by treatment with trichloroacetimidafo (63) to form the compound (78). The trichloroacetimide (63) is easily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (eg, from Sigma-Aldrich, Yes. Louis, Missouri), by friction with acetonitrile. The alkylation of the compound (87) with .alichloroacetimidate (63) can be carried out in the presence of a Lewis acid as HBF.

Reaction Scheme 105 Process for preparing a stereoisomerically pure compound of fraps- (1 S 2 S) -aminocyclohexyl ether of formula (79) (meso) (racemate) (87) (90) In another separate step, the tosylate group of formula (78) is displaced by an amino compound, such as 3 / -pyrrolidinol (65), with inversion of the configuration. 3R-pyrrolidinoi (65) is commercially available (eg, from Sigma-Aldrich, Yes. Louis, Missouri) or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil 1997, 130, 385 -397). The reaction can be carried out with or without solvency and at an appropriate femur scale allowing the production of the product (79) at an adequate rate. An excess of the amino compound (65) can be used to convert the compound (78) to the maximum in the production (79). The reaction can be done in the presence of a base that can facilitate production formation. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to its final termination, the desired production is recovered from the reaction mixture by means of conventional organic chemistry techniques, and purified accordingly. In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 106, which comprises perform under the appropriate conditions the steps shown in the reaction scheme 106, where all the formulas and symbols are as described above. As summarized in reaction scheme 106, the preparation of a pure stereoisomeric frans-aminocyclohexyl ether compound of formula (79) can be carried out starting with the monotosylation of c / s-1,2-cyclohexanediol (83) with TsCI in the presence of Bu2SnO and eryrylamine, under the appropriate conditions (MJ Martinelli et al., "Selective monosulfonylation of internal 1, 2-diols cayalyzed by di-n-butyltin oxide" Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxyitosylabs comprising the compounds (62) and (87), is subjected to a lipase-mediated resolution procedure under the appropriate conditions, such as the racemate (62) and (87), with vinyl acetylation. (88), in the presence of a lipase derived from Pseudomonas sp. (N. Boaz and Oros, Tetra, Asymmetry, 1994, 5, 153), to provide the compounds (89) and (62).

Reaction Scheme Method for preparing a stereoisomerically pure trans- compound. { ? S.2S) -aminoc? Clohexyl-ether of formula (79) (79) (78) In a separate step, the pure stereoisomeric compound of formula (89) obtained from the resolution process is subjected to a soft, base-calibrated meylanysis (G. Zemplen and Oros, Ber., 1936, 69, 1827) to form the compound (87). ). This is rented under the appropriate conditions by irradiation with the trichloroaceimide (63), to form the compound (78). The trichloroacetylimide (63) is easily prepared from the corresponding alcohol, 3,4-dimethioxyphenethyl alcohol, which is commercially available (eg, from Sigma-Aldrich, Yes. Louis, Missouri), by irradiation with trichloroaceyoniiril. The alkylation of compound (87) with trichloroacetylimide (63) can be carried out in the presence of a Lewis acid such as HBF4. In another separate step, the phosphide group of formula (78) is displaced by an amino compound such as 3R-pyrrolidinol (65) with inversion of the configuration. 3R-pyrrolidinol (65) is commercially available (eg, from Sigma-Aldrich, St. Louis, Missouri) or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil 1997, 130, 385 -397). The reaction can be carried out with or without solvent and at an appropriate temperaure scale which allows the production of the product (79) at an adequate rate. An excess of the amino compound (65) can be used to convert the compound (78) to the product (79) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to its substantial completion, the desired product is recovered from the reaction mixture by means of conventional organic chemistry techniques, and purified accordingly.

In another embodiment, the present invention provides a process for the preparation of a pure stereoisomeric compound of formula (79), which comprises performing under the appropriate conditions the steps shown in reaction scheme 107, wherein all the formulas and symbols are as is described above. As summarized in reaction scheme 107, the preparation of a stereoisomerically pure compound of frans-aminocyclohexyl ether of formula (79), can be carried out starting with the monotosylation of c / s-1,2-cyclohexanediol (83 ) with TsCl in the presence of Bu2SnO and eryrylamine, under the appropriate conditions (MJ Martinelli et al., "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-buylylide oxide", Tetrahedron Letters, 2000, 41, 3773). The racemic mixture resulting from hydroxyphosilates comprising the compounds (62) and (87) is subjected to a chromatographic resolution process under the appropriate conditions, as HPLC with an appropriate chiral stationary phase and simulated moving bed technology, to provide the compounds (62) and (87) in stereoisomerically pure form.

Reaction Scheme Process for preparing a stereoisomerically pure compound of f r / S - (1 S, 2 S) -aminocyclohexyl ether of formula (79) (87) (62) (79) (7S) In a separate step, the stereoisomerically pure compound of formula (87), obtained from the resolving process, is alkylated under the appropriate conditions by treatment with trichloroacetylimide (63), to form the compound (64). The trichloroacetylimide (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenephyl alcohol, which is commercially available (eg, from Sigma-Aldrich, Yes. Louis, Missouri), by irradiation with ichloroaceyoniiril. The alkylation of the compound (87) with an .alkyl aceacetimidate (63) can be carried out in the presence of a Lewis acid such as HBF4. In another separate step, the tosyloyl group of formula (78) is displaced by an aminoalcompound such as 3? -pyrrolidinol (65), with inversion of the configuration. 3R-pyrrolidinol (65) is available commercially (eg, from Sigma-Aldrich, Yes. Louis, Missouri) or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil 1997, 130, 385-397 ). The reaction can be carried out with or without solvent and at an appropriate temperature scale which allows the formation of the product (79) at a suitable speed. An excess of the amino compound (65) can be used to convert the compound (78) to the product (79) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to its substantial completion, the desired production is recovered from the reaction mixture by means of conventional organic chemistry techniques, and purified accordingly. The above-described reaction sequences (reaction schemes 105, 106 and 107) generally produce the compound of formula (79) as the free base. If desired, the free base can be converted to the monohydrochloric salt by the known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid, under the appropriate conditions. The acid addition salts can also be prepared metaphase by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt. In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 108, which comprises the steps of starting with a racemic mixture comprising formulas (53) and (84), and proceeding with a reaction sequence analogous to the applicable portion described in reaction scheme 104, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S, 2S) -aminocyclohexyl ether of formula (75) (racemate) Resolution In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 109, which comprises the steps of starting with a racemic mixture comprising formulas (62) and (87), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 105, wherein all formulas and symbols are as described above.

Reaction Scheme Process for preparing a stereoisomerically pure compound of fraps-d S.2 S) -aminocyclohexyl ether of formula (79) (racemate) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out under the appropriate conditions, by means of a procedure as summarized in reaction scheme 110, which comprises the steps of starting with a racemic mixture comprising formulas (62) and (87), and proceeding with a reaction sequence analogous to the applicable portion described in reaction scheme 106, wherein all formulas and symbols are as described above.

Reaction Scheme 110 Process for preparing a stereoisomerically pure compound of fraps-H S.2S) -aminocyclohexyl ether of formula (79) (racemate) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl-ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 111, which comprises the steps of starting with a racemic mixture comprising formulas (62) and (87), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 107, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of transA S.2 S) -aminocyclohexyl ether of formula (79) (racemate) In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 112, which comprises the steps of starting with a compound of formula (86), wherein G-? is hydrogen, and follow with a reaction sequence analogous to the applicable portion which is described in reaction scheme 104, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of fraps- (1 S, 2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a pure stereoisomeric compound of trans-aminocyclohexyl ether of formula (75) can be carried out under suitable conditions, by means of a procedure as summarized in reaction scheme 113, which comprises the steps of starting with a compound of formula (86), wherein G. is not hydrogen, and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 104, wherein all the formulas and Symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of trans-II S.2 S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 114, which comprises the steps of starting with a compound of formula (87), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 105, wherein all the formulas and symbols are as described above.

Reaction Scheme 114 Method for preparing a stereoisomerically pure compound of frans- (1S, 2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 115, which comprises the steps of starting with a compound of formula (89), and proceeding with a reaction sequence analogous to the applicable portion that is described in reaction scheme 106, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1 S.2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a stereoisomerically pure compound of formula (74) can be carried out under suitable conditions, by means of a process as summarized in reaction scheme 116, which comprises the steps of starting with The compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 104, where all the formulas and symbols are as described above.

Reaction Scheme 116 Method for preparing a stereoisomerically pure compound of formula (74) Resolution (G. -H) In another embodiment, the preparation of a pure stereoisomeric compound of formula (74) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 117, which comprises the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 104, wherein all formulas and symbols are as described above.

Reaction Scheme 117 Method for preparing a stereoisomerically pure compound of formula (74) In another embodiment, the preparation of a pure stereoisomeric compound of formula (78) can be carried out under suitable conditions, by means of a procedure as summarized in reaction scheme 118, comprising the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 105, wherein all formulas and symbols are as described above.

Reaction Scheme 118 Process for preparing a stereoisomerically pure compound of formula (78) (racemate) In another embodiment, the preparation of a pure stereoisomeric compound of formula (78) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 119, which comprises the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 106, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (78) (racemate) In another embodiment, the preparation of a stereoisomerically pure compound of formula (78) can be carried out under the appropriate conditions, by means of a process as summarized in reaction scheme 120, which comprises the steps of starting with the compound of formula (83), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 107, wherein all the formulas and symbols are as described above.

Reaction Scheme 120 Process for preparing a stereoisomerically pure compound of formula (78) .OH ot_k OTs In another embodiment, the present invention provides a compound of formula (85), or a solvate or pharmaceutically acceptable salt thereof., where all the formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (86), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (54), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that R3, R4 and s can not be all hydroIn another embodiment, the present invention provides a compound of formula (55), or a pharmaceutically acceptable salt or solvate thereof, wherein all formulas and symbols are as described above, with the proviso that when R3, R and R5 they are hydromud, then J is not a methanesulfonyl group. In another embodiment, the present invention provides a compound of formula (87), or a pharmaceutically acceptable salt or solvate thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (62), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (89), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (90), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (64), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (74), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that when R3, R4 and R5 they are all hydro so J is not a melanosulfonyl group. In another embodiment, the present invention provides a compound of formula (78), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In one embodiment, the present invention provides a process for the preparation of a stereoisomerically pure compound of formula (57): (57) wherein R1 and R2, when taken together with the nitrogen atom to which they are directly attached in the formula (57), form a ring denoted by the formula (II): and R3, R4 and R are independently selected from hydrogen, hydroxy and C-? - C6 alkoxy, with the proviso that R3, R4 and Rs can not be hydrogen ions; comprising the steps of starting with a monohalobenzene (49), wherein X can be F, Cl, Br or I; and continue with a reaction sequence as summarized in reaction scheme 121, under the appropriate conditions, where Pro represents the appropriate protection group of the hydroxy function, with retention of the stereochemistry; -O-Q represented a good leaving group by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound; and -O-J represents a good leaving group by reaction with a nucleophilic reagent, with inversion of the stereochemical configuration, as illustrated in reaction scheme 121, and all formulas and symbols are as described above.

Reaction Scheme 121 Process for preparing a stereoisomerically pure compound of frans- (1R2"?) - aminocyclohexyl ether of formula (57) H (56) R2 In another embodiment, the present invention provides a method for the preparation of a pure stereoisomerically pure compound of formula (66), which comprises performing under the appropriate conditions the steps shown in reaction scheme 122, wherein all the formulas and symbols are as is described above. As summarized in reaction scheme 122, the preparation of a pure transferaminocyclohexyl ether compound of formula (66) can be carried out starting with a bio-transformation of chlorobenzene (58) to compound (59) by means of a microorganism such as Pseudomonas putida 39 / D. The experimental conditions of biotransformation are well established (Organic Synthesis, Vol. 76, 77 and T. Hudiicky et al., Aldrichimica Acta, 1999, 32, 35, and references cited therein). In a separate step, the less hindered hydroxy function of the compound (59) is selectively monosilylated as the compound (95) by reaction with a silylating reaction, such as f-butyldiphenylsilyl chloride (TBDPSCI), under the appropriate conditions (e.g. , imaidazole in CH2Cl2) (T. Hudiicky and Oíros, Aldrichimica Acta, 1999, 32, 35, SM Brown and T. Hudiicky, in "Organic Syn- thesis: Theory and Applications", T. Hudiicky, Ed .; JAI Press: Greenwich, Connecticuf, 1993; Vol 2, page 113, and references cited therein). In another separate step, the compound (95) is converted to the compound (96) by reduction, such as hydrogenation and hydrogenolysis, in the presence of a calychator and under the appropriate conditions. Palladium on activated carbon is an example of the catalysts. The reduction of the compound (95) can be done under basic conditions, for example in the presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetyl or calcium carbonate. The base can be added in a portion or incrementally during the reaction. In a separate step, the free hydroxy group of the compound (96) is alkylated under the appropriate conditions to form the compound (97). The trichloroacetimidate (63) is easily prepared from the corresponding alcohol, 3,4-dimethioxy-phenethylalcohol, which is commercially available (for example, from Aldrich), by treatment with iochloroacefonifril. The alkylation of the compound (96) with iochloroacefimidafo (63) can be carried out in the presence of a Lewis acid such as HBF4. In another separate step, the l-butyldiphenylsilyl protecting group (TBDPS) of the compound (97) can be removed by a standard procedure (e.g., tetrabutylammonium fluoride in teirahydrofuran (THF), or as described in Greene, "Proieclive Groups in. Organic Chemistry ", John Wiley &Sons, New York NY (1991)), to produce the hydroxyether compound (98). In a separate step, the hydroxyl group of the compound (98) is converted, under the appropriate conditions, into an acivated form such as the tosylate of formula (64). In another separate step, the tosylate group of formula (64) is displaced by an aminoal compound such as 3f? -pyrrolidinol (65), with inversion of the configuration. 3R-pyrrolidinol (65) is commercially available (eg, from Aldrich), or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil, 1997, 130, 385-397). The reaction can be carried out with or without solvency and at a scale of appropriate temperature that allows the formation of the product (66) at an adequate rate. An excess of the amino compound (65) can be used to maximize the compound (64) in the production (66). The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally, the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to its substantial completion, the desired product is recovered from the reaction mixture by means of conventional organic chemistry techniques, and purified accordingly.

Reaction Scheme 122 Process for preparing a stereoisomerically pure compound of frans- (1R2 / γ) - aminociclohexyl ether of formula (66) H__ Pd / C The above-described reaction sequence (reaction scheme 122) generally produces the compound of formula (66) as the free base. If desired, the free base can be converted to the monohydrochloric salt by the known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid under the appropriate conditions. The acid addition salts can also be prepared metaphaseically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt. In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (69) can be carried out by means of a process as summarized in reaction scheme 123, which comprises the steps of starting with chlorobenzene (58), and follow with a reaction sequence analogous to the applicable portion described in reaction scheme 122 above, under the appropriate conditions, yielding the compound of formula (64). This is reacted with an amino compound of formula (68). The compound (68), 3S-pyrrolidinol, is commercially available (for example, from Aldrich) or can be prepared according to a published procedure (for example, Chem. Ber./Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperature scale which allows the formation of the product (69) at a suitable speed. An excess of the amino compound (68) can be used to convert the compound (64) to the product (69) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. The product is a stereoisomerically pure fraps-aminocyclohexyl ether compound of formula (69), and is formed as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid, under the appropriate conditions. Acid addition salts can also be prepared metastasically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme 123 Process for preparing a stereoisomerically pure compound of fraws- (1R2R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out by means of a process as summarized in reaction scheme 124, which comprises the steps of starting with the compound of formula (50), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 124 Process for preparing a stereoisomerically pure compound of trans- [R2f?) - aminocyclohexyl ether of formula (57) R? Hi 2 In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by means of a process as summarized in reaction scheme 125, which comprises the steps of starting with the compound of formula (59), and follow with a reaction sequence analogous to the applicable portion described in reaction scheme 122, under the appropriate conditions, wherein all formulas and symbols are as described above. The 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of formula (59) is a commercially available product (for example, from Aldrich) or is synthesized according to a published procedure ( example, Organic Synthesis, Vol. 76, 77 and T. Hudiicky et al., Aldríchimica Acta, 1999, 32, 35, and references cited therein).

Reaction Scheme 125 Process for preparing a stereoisomerically pure compound of frans- (1R2R) -aminocyclohexyl ether of formula (66) Hz, Pd / C In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (69) can be carried out by means of a process as summarized in reaction scheme 126, which comprises the steps of starting with the compound of formula (59), and continuing with a reaction sequence analogous to the applicable portion that is described in reaction scheme 123, under the appropriate conditions, wherein all the formulas and symbols are as describes above.

Reaction Scheme 126 Process for preparing a stereoisomerically pure compound of frans-d R2R) -aminocyclohexyl ether of formula (69) H2, Pd / C ? 0THBDPS In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out by means of a process as summarized in reaction scheme 127, which comprises the steps of starting with The compound of formula (91), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of trans-M R2R-aminocyclohexyl ether of formula (57) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by means of a process as summarized in reaction scheme 128, comprising the steps of starting with the compound of formula (95), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 122, under the appropriate conditions, wherein all the formulas and symbols are as described above.

REACTION SCHEME 128 Process for preparing a stereoisomerically pure compound of fra /? S- (1R2R) -aminocyclohexyl ether of formula (66) AyOTI!%!%! / '? TBDPS H¿, P < J7C In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out by means of a process as summarized in reaction scheme 129, which comprises the steps of starting with the compound of formula (95), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 123, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 129 Process for preparing a stereoisomerically pure compound of fra /? S- (1R2ffl-aminocyclohexyl ether of formula (69) H, Pd / C In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out by means of a process as summarized in reaction scheme 130, comprising the steps of starting with The compound of formula (92), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 130 Process for preparing a stereoisomerically pure compound of fraps-H R2f?) - aminocichelohexyl ether of formula (57) HN In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by means of a process as summarized in reaction scheme 131, which comprises the steps of starting with the compound of formula (96), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 122, under the appropriate conditions, wherein all the formulas and symbols are as described above.

REACTION SCHEME 131 Process for preparing a stereoisomerically pure compound of trans-C 2ff) -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out by means of a process as summarized in reaction scheme 132, comprising the steps of starting with the compound of formula (96), and follow with a reaction sequence analogous to the applicable portion which is described in reaction scheme 123, under the appropriate conditions, wherein all the formulas and symbols are as described above.

REACTION SCHEME 132 Process for preparing a stereoisomerically pure compound of frans- (1R2R aminociclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out by means of a process as summarized in reaction scheme 133, comprising the steps of starting with The compound of formula (93), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method to prepare a stereoisomerically pure compound of frans- (1R2R> -aminocyclohexyI-ether of formula (57) R, HN R? In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (66) can be carried out by means of a procedure as summarized in reaction scheme 134, comprising the steps of starting with the compound of formula (97), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 122, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Process for preparing a stereoisomerically pure compound of fraps- (1R2Ri-aminociclohexyl ether of formula (66) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out by means of a process as summarized in reaction scheme 135, which comprises the steps of starting with The compound of formula (97), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 123, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of trans-C R2R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out by means of a process as summarized in reaction scheme 136, which comprises the steps of starting with the compound of formula (94), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1-R2-phenyl-aminocyclohexyl ether of formula (57) HNs In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by means of a process as summarized in reaction scheme 137, which comprises the steps of starting with the compound of formula (98), and continuing with a reaction sequence analogous to the applicable portion described in reaction scheme 122, under the appropriate conditions, wherein all formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans-H R2R) -aminocyclohexyl ether of formula (66) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out by means of a process as summarized in reaction scheme 138, which comprises the steps of starting with the compound of formula (98), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 123, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure trans- compound. { R2_R) -aminocyclohexyl ether of formula (69) In another embodiment, the preparation of a stereoisomerically pure compound of formula (55) can be carried out by means of a process as summarized in reaction scheme 139, which comprises the steps of starting with the compound of formula ( 49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 139 Process for preparing a stereoisomerically pure compound of formula (55) In another embodiment, the preparation of a stereoisomerically pure compound of formula (64) can be carried out by means of a process such as that summarized in reaction scheme 140, which comprises the steps of starting with the compound of formula ( 58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 122, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (64) H2. Pd / C In another embodiment, the preparation of a stereoisomerically pure compound of formula (94) can be carried out by means of a process as summarized in reaction scheme 141, which comprises the steps of starting with the compound of formula ( 49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 141 Process for preparing a stereoisomerically pure compound of formula (94) In another embodiment, the preparation of a stereoisomerically pure compound of formula (98) can be carried out by means of a process such as that summarized in reaction scheme 142, comprising the steps of starting with the compound of formula ( 58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 122, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 142 Process for preparing a stereoisomerically pure compound of formula (98) Hz, Pd / C In another embodiment, the preparation of a stereoisomerically pure compound of formula (93) can be carried out by means of a process as summarized in reaction scheme 143, which comprises the steps of starting with the compound of formula ( 49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (93) In another embodiment, the preparation of a stereoisomerically pure compound of formula (97) can be carried out by means of a process as summarized in reaction scheme 144, comprising the steps of starting with the compound of formula ( 58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 122, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (97) Ha. Pd / C In another embodiment, the preparation of a pure stereoisomeric compound of formula (92) can be carried out by means of a process as summarized in reaction scheme 145, which comprises the steps of starting with the compound of formula ( 49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 121, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (92) In another embodiment, the preparation of a stereoisomerically pure compound of formula (96) can be carried out by means of a process as summarized in reaction scheme 146, which comprises the steps of starting with the compound of formula ( 58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 122, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 146 Process for preparing a stereoisomerically pure compound of formula (96) H ,, Pd / C In another embodiment, the present invention provides a compound of formula (92), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (54), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that R3, R4 and Rs are not they can all be hydrogen. In another embodiment, the present invention provides a compound of formula (93), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that R3, R4 and Rs are not They can be all hydrogen. In another embodiment, the present invention provides a compound of formula (94), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that R3, R4 and R5 do not they can all be hydrogen. In another embodiment, the present invention provides a compound of formula (55), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that when R3, R4 and R5 they are all hydrogen, then J is not a methanesulfonyl group. In another embodiment, the present invention provides a compound of formula (96), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (63), or a pharmaceutically acceptable salt or solvate thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (97), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (98), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (64), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. The present invention provides sinílic procedures with which the compounds of formula (75) can be prepared in a stereoisomerically pure manner, with a frans- (1S, 2S) configuration for the ether and amino functional groups. The compounds of the formulas (79) and (81) are some of the examples represented by the formula (75). The present invention also provides synthetic methods with which the compounds of the formulas can be prepared (92), (99), (84) and (74) in a stereoisomerically pure form. The compounds (96), (100), (62) and (78) are examples of the formulas (92), (99), (84) and (74), respectively. As summarized in Reaction Scheme 147, the preparation of a pure stereoisomeric frans-aminocyclohexyl ether compound of formula (75) can be carried out following a process starting with a monohalobenzene (49), wherein X can be F , Cl, Br or I.

Reaction Scheme Method for preparing a stereoisomerically pure compound of fra /? S- (1S.2S) -aminocyclohexyl ether of formula (75) (49) (50) (91) In a first step, the compound (49) is transformed by means of a well established microbial oxidation in the c / 's-cyclohexanedienol (50) in a stereoisomerically pure form (T. Hudiicky et al., Aldrichimica Acta, 1999, 32, 35 and references therein). In a separate step, the least hindered hydroxy function of the compound (50) can be selectively monoprotered as the compound (91), where Pro represents the appropriate protecting group of the hydroxy function, with retention of the stereochemistry (T. Hudiicky et al. , Aldrichimica Acta, 1999, 32, 35, SM Brown and T. Hudiicky, in "Organic Synthesis: Theory and Applications", T. Hudiicky, Ed .; JAI Press, Greenwich, Connecticut, 1993; Vol. 2, p, 113 and references cited there). Some of the possible examples of Pro are the trialkylsilyl groups, such as ioisopropylsilyl (TIPS) and ε-butyldimethylsilyl (TBDMS), and alkyl-diarylsilyl groups such as ε-buildyldiphenylsilyl (TBDPS). Suitable reaction conditions are described, for example, in Greene, "Proactive Groups in Organic Chemistry," John Wiley & Sons, New York, NY (1991). In a separate step, the conversion of compound (91) to compound (92) can be effected by hydrogenation and hydrogenolysis in the presence of a catalyst and under the appropriate conditions. Palladium on activated carbon is an example of the catalysts. The hydrogenolysis of alkyl or alkenyl halide such as (91) can be done under basic conditions. In some examples the presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetate or calcium carbonate is possible. The base can be added in one portion or incrementally during the reaction. In a separate step, the hydroxy group of the compound (92) is converted under suitable conditions into a derivative form, represented by the formula (99). A "acylated form" as used herein means that the hydroxy group is converted into a good leaving group (-O-J). The leaving group can be a mesylate group (MsO-), tosylate (TsO-) or nosylate (NsO-). The hydroxy group can also be converted into other suitable leaving groups according to well-known procedures. In a typical reaction for the formation of a tosylate, the compound (92) was brought with a hydroxy activation reagent such as tosyl chloride (TsCl) in the presence of a base, such as pyridine or ithylamine. In general, the reaction is performed satisfactorily at about 0 ° C, but can be adjusted as necessary to maximize the yield of the desired product. An excess of the hydroxy activating reagent (for example, tosyl chloride) can be used with respect to the compound (92) to convert the hydroxy group to the activated form as much as possible. In a separate step, the compound (84) is produced by removing the protecting group (Pro) from the compound (99) by standard procedures (for example, tetrabuylammonium fluoride in the hydrofuran, or as described in Greene, "Proiecive Groups! n Organic Chemistry, John Wiley &Sons, New York, NY (1991) In a separate step, the free hydroxy group of the compound (84) is alkylated under the appropriate conditions with the compound (54) to form the compound ( 74), where -OQ represented a good leaving group, by reaction with a hydroxy function, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound.Trichloroacetimidate is an example of the -OQ function. some compounds (54), it may be necessary to introduce suitable protecting groups before carrying out this step.The suitable protecting groups are described for example in Greene, "Protective Groups in Organic Chemistry", John Wi Law &Sons, New York NY (1991).

In a separate step, the resulting compound (74) is treated under suitable conditions with an amino compound of formula (56) to form the compound (75) as a product. The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (75) at a suitable speed. An excess of the amino compound (56) can be used to convert the compound (74) to the product (75) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to substantial completion, the product is recovered from the reaction mixture by means of conventional organic chemistry techniques and purified accordingly. The protecting groups can be removed at the appropriate stage of the reaction sequence. Suitable methods are described for example in Greene, "Proteclive Groups in Organic Chemistry", John Wiley & amp;; Sons, New York NY (1991). The above-described reaction sequence (reaction scheme 147) generates the compound of formula (75) as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatively in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metasystically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

All publications and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication or patent application was specifically and individually incorporated as a reference. In one embodiment, the present invention provides a process for the preparation of a stereoisomerically pure compound of formula (75): (75) wherein R-i and R2, when taken together with the nitrogen atom to which they are directly attached in the formula (75), form a ring denoted by the formula (II): (H) and R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-? -C6 alkoxy, with the proviso that R3, R4 and R5 can not all be hydrogen; comprising the steps of starting with a monohalobenzene (49), wherein X can be F, Cl, Br or I; and following with a reaction sequence as summarized in the reaction scheme 147 under the appropriate conditions, wherein: Pro represents a suitable protective group of the hydroxy function with retention of the stereochemistry; -O-Q represents a good leaving group, by reaction with a hydroxy function under the appropriate conditions, with retention of the stereochemical configuration of the hydroxy function in the formation of an ether compound; and -O-J represents a good leaving group by reaction with a nucleophilic reagent under the appropriate conditions, with inversion of the stereochemical configuration as shown in reaction scheme 147, and all formulas and symbols are as described above. In another embodiment, the present invention provides a process for the preparation of a pure stereoisomeric compound of formula (79), comprising the steps outlined in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as is described above. As summarized in reaction scheme 148, the preparation of a pure stereoisomeric fraps-aminociclohexyl ether compound (79) can be carried out starting with a biofransformation of chlorobenzene (49) to the compound (59), with a micro-organism such as Pseudomonas putida 39 / D. The experimental conditions for biofransformation are well established (Organic Synthesis, Vol. 76, 77, and T. Hudiicky and Oíros, Aldrichimica Acta, 1999, 32, 35, and references cited therein). In a separate step, the less hindered hydroxy function of the compound (59) is selectively monosilylated as the compound (95) by reaction with a silylating reagent such as t-butyldiphenylsilyl chloride (TBDPSCI), under the appropriate conditions (e.g. imaidazole in CH2Cl2) (T. Hudiicky et al., Aldrichimica Acta, 1999, 32, 35, SM Brown and T. Hudiicky, in "Organic Synthesis: Theory and Applications", T. Hudiicky, Ed .; JAI Press: Greenwich, Connecticut , 1993; Vol 2, p 113, and references cited therein). In another separate step, the compound (95) is converted to the compound (96) by reduction, eg as hydrogenation and hydrogenolysis, in the presence of a catalyst and under the appropriate conditions. Palladium on activated carbon is an example of the catalysts. The reduction of the compound (95) can be done under basic conditions, for example in the presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetate or calcium carbonate. The base can be added in one portion or incrementally during the reaction. In a separate step, the hydroxy group of the compound (96) is converted under the appropriate conditions into an activated form, such as the tosylate of formula (100), by treatment with osyl chloride (TsCl) in the presence of pyridine. In another separate step, the t-butyldiphenylsilyl protecting group (TBDPS) of the compound (100) can be removed by a standard procedure (eg, telrabutylammonium fluoride in tetrahydrofuran, or as described in Greene, "Protecfive Groups in Organic Chemistry"). , John Wiley &Sons, New York NY (1991)), to produce the hydroxyphosphorylated compound (62). In a separate step, the free hydroxy group of the compound (62) is alkylated under the appropriate conditions to form the compound (78). The trichloroacetylimide (63) is easily prepared from the corresponding alcohol, 3,4-dimethoxyphenellyl alcohol, which is available commercially (for example, from Aldrich), by trichloroaceyoniiril trailing. The alkylation of the compound (60) with 1-chloroacetylamide (63) can be done in the presence of a Lewis acid such as HBF4. In a separate step, the losylate group of formula (78) is displaced by an amino compound such as 3R-pyrrolidinol (65), with inversion of the configuration. 3R-pyrrolidinol (65) is commercially available (eg, from Aldrich), or can be prepared according to a published procedure (eg, Chem. Ber. / Recueil, 1997, 130, 385-397). The reaction can be carried out with or without a solvent and at a scale of appropriate temperature which allows the formation of the product (79) at a suitable speed. An excess of the amino compound (65) can be used to convert the compound (78) to the product (79) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation and isolation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. When the reaction has proceeded to its substantial completion, the desired product is recovered from the reaction mixture by means of conventional organic chemistry techniques, and purified accordingly.

Reaction Scheme 148 Process for preparing a stereoisomerically pure trans- compound. { ? S, 2S) -aminocyclohexyl ether of formula (79) m (79) The above-described reaction sequence (reaction scheme 148) generates the compound of formula (79) as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods or, if desired, alternatively in other acid addition salts by reaction with an inorganic or organic acid under the appropriate conditions. Acid addition salts can also be prepared metastasically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out by means of a process as summarized in reaction scheme 149, which comprises the steps of starting with chlorobenzene (58), and follow with a reaction sequence analogous to the applicable portion described in reaction scheme 148 above, under the appropriate conditions, yielding the compound of formula (78). This is reacted with an amino compound of formula (68). The compound (68), 3S-pyrrolidinol, is commercially available (for example, from Aldrich) or can be prepared according to a published procedure (for example, Chem. Ber. / Recueil 1997, 130, 385-397). The reaction can be carried out with or without solvent and at an appropriate temperature scale that allows the formation of the product (81) at a suitable rate. An excess of the amino compound (68) can be used to convert the compound (78) to the product (81) as much as possible. The reaction can be done in the presence of a base that can facilitate the formation of the product. Generally the additional base is not nucleophilic in its chemical reactivity. The product is a stereoisomerically pure rans-aminocyclohexyl ether compound of formula (81) and is formed as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods, or alternatively in other acid addition salts by reaction with an organic or inorganic acid, under the appropriate conditions. Acid addition salts can also be prepared metasystically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt.

Reaction Scheme Process for preparing a stereoisomerically pure compound of frapS "(1S, 2S) -aminocyclohexyl ether of formula (81) (58) (59) (95) ^ - \ OTs A-OTS TsCI AAN? H - A OTTBDPS (87) (100) CC OTBDPS (96) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out by means of a process as summarized in reaction scheme 150, which comprises the steps of starting with the compound of formula (50), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 147, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 150 Process for preparing a stereoisomerically pure compound of trans-11 S, 2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out by means of a process as summarized in reaction scheme 151, which comprises the steps of starting with The compound of formula (59), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as described above. The 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of formula (59) is a commercially available product (for example, from Aldrich) or is synthesized according to a published procedure (by example, Organic Synthesis, Vol. 76, 77, and T. Hudiicky et al., Aldrichimica Acta, 1999, 32, 35, and references cited therein).

Reaction Scheme Method for preparing a stereoisomerically pure compound of fraps-d S.2 S) -aminocyclohexyl ether of formula (79) ce? TBDPS In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out by means of a process as summarized in reaction scheme 152, which comprises the steps of starting with the compound of formula (59), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 149, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of frans- (1S.2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (75) can be carried out by means of a process as summarized in reaction scheme 153, which comprises the steps of starting with the compound of formula (91), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 147, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure trans- compound. { S.2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out by means of a procedure as summarized in reaction scheme 154, comprising the steps of starting with the compound of formula (95), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of fraps- (1S, 2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (81) can be carried out by means of a process as summarized in reaction scheme 155, which comprises the steps of starting with the compound of formula (95), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 149, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 155 Process for preparing a stereoisomerically pure compound of fraps-f1S.2S) -aminocyclohexyl ether of formula (81) ce OTBDPS In another embodiment, the preparation of a pure stereoisomeric trans-aminocyclohexyl ether compound of formula (75) can be carried out by means of a process as summarized in reaction scheme 156, comprising the steps of starting with the compound of formula (92), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 147, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 156 Process for preparing a stereoisomerically pure compound of •? Ra? S- (1S.2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out by means of a process as summarized in reaction scheme 157, comprising the steps of starting with the compound of formula (96), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of fra /? S- (1S.2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out by means of a process as summarized in reaction scheme 158, comprising the steps of starting with the compound of formula (96), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 149, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of fraps- (1S, 2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (75) can be carried out by means of a process as summarized in reaction scheme 159, which comprises the steps of starting with the compound of formula (99), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 147, under the appropriate conditions, wherein all formulas and symbols are as described above.

Reaction Scheme 159 Method for preparing a stereoisomerically pure compound of trans-j? S.2S) -aminocyclohexyl ether of formula (75) In another embodiment, the preparation of a pure stereoisomeric trans-aminociclohexyl ether compound of formula (79) can be carried out by means of a process as summarized in reaction scheme 160, which comprises the steps of starting with The compound of formula (100), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 160 Process for preparing a stereoisomerically pure compound of frans- (1S.2S) -aminocyclohexyl ether of formula (79) In another embodiment, the preparation of a esphereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out by means of a process as summarized in reaction scheme 161, comprising the steps of starting with the compound of formula (100), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 149, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 161 Process for preparing a stereoisomerically pure compound of frans- (1 S, 2S) -aminocyclohexyl ether of formula (81) In another embodiment, the preparation of a pure stereoisomeric compound of formula (74) can be carried out by means of a process such as that summarized in reaction scheme 162, which comprises the steps of starting with the compound of formula ( 49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 147, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 162 Process for preparing a stereoisomerically pure compound of formula (74) In another embodiment, the preparation of a pure stereoisomeric compound of formula (78) can be carried out by means of a process such as that summarized in reaction scheme 163, which comprises the steps of starting with the compound of formula ( 58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 163 Process for preparing a stereoisomerically pure compound of formula (78) In another embodiment, the preparation of a pure stereoisomeric compound of formula (84) can be carried out by means of a process as summarized in reaction scheme 164, which comprises the steps of starting with the compound of formula ( 49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 147, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 184 Process for preparing a stereoisomerically pure compound of formula (84) In another embodiment, the preparation of a pure stereoisomerically pure compound of formula (62) can be carried out by means of a process as summarized in reaction scheme 165, which comprises the steps of starting with the compound of formula ( 58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme 165 Process for preparing a stereoisomerically pure compound of formula (62) In another embodiment, the preparation of a pure stereoisomeric compound of formula (99) can be carried out by means of a process such as that summarized in reaction scheme 166, which comprises the steps of starting with the compound of formula ( 49), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 147, under the appropriate conditions, where all the formulas and symbols are as described above.

Reaction Scheme 166 Process for preparing a stereoisomerically pure compound of formula (99) In another embodiment, the preparation of a pure stereoisomeric compound of formula (100) can be carried out by means of a process such as that summarized in reaction scheme 167, which comprises the steps of starting with the compound of formula ( 58), and follow with a reaction sequence analogous to the applicable portion that is described in reaction scheme 148, under the appropriate conditions, wherein all the formulas and symbols are as described above.

Reaction Scheme Method for preparing a stereoisomerically pure compound of formula (100) A? ^ .O? TisS TsCl .OH ~ V 'OvTroBDmP »If OTBDPS In another embodiment, the present invention provides a compound of formula (92), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (99), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (84), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (54), or a pharmaceutically acceptable solvate or salt thereof, wherein all formulas and symbols are as described above, with the proviso that R3, R4 and Rs are not they can all be hydrogen.

In another embodiment, the present invention provides a compound of formula (74), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above, with the proviso that when R3, R4 and R5 they are all hydrogen, then J is not a methanesulfonyl group. In another embodiment, the present invention provides a compound of formula (96), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (100), or a solvate or pharmaceutically acceptable salt thereof., where all the formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (62), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (63), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. In another embodiment, the present invention provides a compound of formula (78), or a solvate or pharmaceutically acceptable salt thereof, wherein all formulas and symbols are as described above. The above-described reaction sequences (reaction schemes 1 and 2) generate the aminocyclohexyl ether compounds of the present invention initially as the free base. If desired, the free base can be converted to the monohydrochloride salt by the known methods, or alternatively in other acid addition salts by reaction with the appropriate organic or inorganic acid. The acid addition salts can also be prepared melasically by reacting an acid addition salt with an acid that is stronger than the acid that originates the initial salt. It is recognized that there may be one or more chiral centers in the compounds used within the scope of the present invention, and therefore such compounds will exist as various stereoisomeric forms. Applicants intend to include all stereoisomers within the scope of the invention. Although the compounds can be prepared as racemates and can conveniently be used as such, the individual enantiomers can also be isolated or, if desired, preferably synthesized by known techniques. Such individual racemates and enantiomers and their mixtures are considered to be included in the scope of the present invention. If pure enantiomeric forms are produced, they can be isolated by preparative chiral HPLC. If desired, the free base can be converted to the monohydrochloride salt by means of known techniques, or alternatively in other acid addition salts by reaction with other organic or inorganic acids. Acid addition salts can also be prepared metasystically by reaction of an acid addition salt with an acid that is stronger than the acid that originates the initial salt. The present invention also encompasses pharmaceutically acceptable salts, esters, amides, complexes, chelates, solvates, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs of the compounds of the present invention. Acceptable pharmaceutically acceptable esters and amides can be prepared by reacting a hydroxy or amino functional group, respectively, with a pharmaceutically acceptable organic acid, as identified below. A prodrug is a drug that has been chemically modified and may be biologically inactive at its site of action, but is degraded or modified by one or more enzymatic processes or other processes in vivo, forming the original bioactive form. In general, a prodrug has a pharmacokinetic profile different from the original drug, such that for example it is more easily absorbed through the mucosal epithelium, it has a better solubility or salt formation, or it has a better seismic stability (for example longer life). average in the plasma). Those skilled in the art will recognize that chemical modifications of an original drug to produce a prodrug include: (1) terminal ester or amide derivatives that are susceptible to being cut by esterases or lipases; (2) terminal peptides that can be recognized by specific or nonspecific proteases; or (3) a derivative that causes the prodrug to accumulate at a site of action by means of membrane selection, and combinations of the above techniques. Conventional procedures for the selection and preparation of prodrug derivatives are described in H. Bundgaard, "Design of Prodrugs", (1985). The experts in maíeria are very familiar with the preparation of the prodrugs and their meaning. The present invention also encompasses pharmaceutically acceptable complexes, chelates, metabolites or meiabolic precursors of the compounds of the present invention. Information on the meaning of these terms and references on their preparation can be obtained by searching several databases, for example on the Chemical Abstracts website and the Food and Drug Administration (FDA). . From the FDA are available documents such as: "Guidance for Indusfry: In Vivo Drug Metabolism / Drug Interaction Study-Study Design, Data Analysis, and Recommendations for Dosing and Labeling", US Department of Health and Human Services [Department of Health and Services US Human], Food and Drug Administration, Cener for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) [Center for Evaluation and Research of Biological Products], Nov. 1999. "Guidance for Industry: In Vivo Drug Metabolism / Drug Interacion Diseases in the Drug Development Process: Studies in Vitro", US Department of Health and Human Services, Food and Drug Administration, Cenière for Drug Evaluation and Research (CDER) , Center for Biologics Evaluation and Research (CBER), April 1997. Synthetic procedures described in the present, especially when taken according to the knowledge In this field, they provide sufficient guidance for people with average knowledge in the field to perform the synthesis, isolation and purification of the compounds of the present invention.

Compositions and modes of administration In other embodiments, the present invention provides a composition or medicament that includes one or more compounds, selected from any of the compounds, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, mixture esphereoisomeric, geometrical isomer, chylaaline or amorphous form, mebolite, mephabolic precursor or prodrug thereof, including its enaniomeric, diasphereomeric and geometric isolated isomers, and mixtures thereof, previously described; in combination with a pharmaceutically acceptable carrier, diluent or excipient; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically salt acceptable, ester, amide, complex, chelate, stereoisomer, sphereoisomeric mixture, geomethyric isomer, chylaaline or amorphous form, mebolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, in combination with a pharmaceutically acceptable vehicle, diluent or excipient; and also provides a method of manufacturing said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically salt acceptable, stereoisomer, stereoisomeric mixture, geomethyric isomer, chylaaline or amorphous form, or mebolite thereof, including its enantiomeric, diastereomeric, and isolated geometrical isomers, and mixtures thereof, in combination with a pharmaceutically acceptable vehicle, diluent, or excipient; and also provides a method of manufacturing said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cciohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphene-oxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxy? -rolidolidinyl] -1- (3,4-dimethoxyphenexy) -cydohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; in combination with a pharmaceutically acceptable vehicle, diluent or excipient; and also provides a method of manufacturing said composition or medication. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of: (1R, 2R) -2 - [(3R) -hydroxy-pyrrolidinyl] -1- ( 3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 S, 2 S) -2 - [(3 S) -hydroxypyrrolidinyl] -1- (3,4-dι-methoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2- [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; in combination with a pharmaceutically acceptable vehicle, diluent or excipient; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxy-pyrrolidinyl] -1- (3,4-dimethoxyphenexy) monohydrochloride. -cyclohexane, or any solvate thereof; in combination with a pharmaceutically acceptable carrier, diluent or excipient; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds of the present invention according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate , pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or metabolite thereof, in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of: (1R, 2R) -2 - [(3R) -hydroxypyridinyl] -1- ( 3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenefoxy) -cyclohexane monohydrochloride, or any solvate thereof; in combination with appropriate amounts of USP sodium chloride, USP cyclic acid, NF sodium hydroxide and water for USP injection; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds of the present invention according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or metabolite thereof, in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce an intravenous isotonic solution of said compound at a concentration of about 0.1 mg / ml to 100 mg / ml, in sodium curing of about 1 to 400 mM , at a pH of approximately 7. 5 a 4. 0; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of: (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-pheneioxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce an intravenous isotonic solution of said compound at a concentration of about 0.1 mg / ml to 100 mg / ml, in sodium cyrate from about 1 to 400 mM, at a pH of about 7.5 to 4.0; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane monohydrochloride, or any solvate thereof; in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce an intravenous isotonic solution of said compound at a concentration of about 0.1 mg / ml to 100 mg / ml, in sodium citrate of about 1 to 400 mM, at a pH of about 7.5 to 4.0; and also provides a method for manufacturing said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds of the present invention according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or metabolite thereof, in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce an intravenous isotonic solution of said compound at a concentration of about 5 mg / ml to 80 mg / ml, in sodium citraium of about 10 to 80 mM, at a pH of about 6.5 to 4.5; and also provides a method of manufacturing said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of: (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3t4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce an intravenous isotonic solution of said compound at a concentration of about 5 mg / ml to 80 mg / ml, in sodium citrate of about 10 to 80 mM, at a pH of about 6.5 to 4.5; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) monohydrochloride. cyclohexane, or any solvate thereof; in combination with appropriate amounts of sodium chloride USP, USP-cyclic acid, sodium hydroxide NF and water for injection USP, which produce an intravenous isoonic solution of said compound at a concentration of about 5 mg / ml to 80 mg / ml, sodium citrate of about 10 to 80 mM, at a pH of about 6.5 to 4.5; and also provides a method of making said composition or medicament. In other modalities, the present invention provides a composition or medicament that includes one or more compounds of the present invention according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, salt pharmaceutically acceptable, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or metabolite thereof, in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce a solution intravenous isotonic of said compound at a concentration of about 10 mg / ml to 40 mg / ml, in sodium citrate of about 20 to 60 mM, at a pH of about 6 to 5; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of: (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxypheneyoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce an intravenous isotonic solution of said compound at a concentration of about 10 mg / ml to 40 mg / ml, in sodium citrate of about 20 to 60 mM, at a pH of about 6 to 5; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cciohexane monohydrochloride, or any solvation thereof; in combination with appropriate amounts of sodium chloride USP, USP-cyclic acid, sodium hydroxide NF and water for injection USP, which produce an intravenous isoonic solution of said compound at a concentration of about 10 mg / ml to 40 mg / ml, sodium concentration of about 20 to 60 mM, at a pH of about 6 to 5; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds of the present invention according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or metabolite thereof, in combination with appropriate amounts of sodium chloride USP, citric acid USP, sodium hydroxide NF and water for injection USP, which produce an intravenous isotonic solution of said compound at a concentration of about 20 mg / ml, in about 40 mM sodium citrate, at a pH of about 5.5; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of: (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; in combination with appropriate amounts of USP sodium chloride, USP-cyclic acid, sodium hydroxide NF and water for injection USP, which produce an in-venous iso-ionic solution of said compound at a concentration of about 20 mg / ml, in about 40% sodium citrate. mM, at a pH of about 5.5; and also provides a method of making said composition or medicament. In other embodiments, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxy-pyrrolidinyl] -1- (3,4-dimethoxyphenexy) cyclohexane monohydrochloride, or any solvate thereof; in combination with appropriate amounts of sodium chloride USP, USP-cyclic acid, sodium hydroxide NF and water for injection USP, which produce an intraveniso-ionic solution of said compound at a concentration of about 20 mg / ml, in sodium curing approximately 40 mg / ml. mM, at a pH of about 5.5; and also provides a method of making said composition or medicament. In another embodiment, the present invention provides compositions that include a compound of the present invention in admixture or association of another type with one or more inert carriers, excipients and diluents, as well as optional ingredients if desired. These compositions are useful, for example as test standards, convenient means of preparing bulk dispensing, or pharmaceutical compositions. An assayable amount of a compound of the invention is an amount that is easily measurable by standard testing procedures and techniques well known and appreciated by those skilled in the art. The assayable amounts of a compound of the invention will generally vary from about 0.001% by weight to about 75% by weight of the entire weight of the composition. Inert carriers include any material that does not degrade or otherwise react covalently with a compound of the invention. Examples of suitable inert carriers are water, aquebuffers, such as those which are generally useful in the analysis of high performance liquid chromatography (HPLC); organic solvents such as acetonitrile, ethyl acetate, hexane and the like (which are suitable for use in diagnosis or in vitro tests, but are usually not suitable for administration to a warm-blooded animal), and pharmaceutically acceptable carriers, such as saline physiological Thus, the present invention provides a pharmaceutical or veterinary composition (hereinafter simply referred to as a pharmaceutical composition) containing a compound of the present invention, in admixture with a pharmaceutically acceptable carrier, excipient or diluent. The invention further provides a pharmaceutical composition containing an effective amount of compound of the present invention, in association with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention can be in any form that allows the composition to be administered to the patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal and intranasal. The term "parenteral," as used herein, includes subcutane intraven intramuscular, epidural, intrasternal injection or infusion techniques. The pharmaceutical composition of the invention is formulated in order to allow the active ingredients contained therein to be bioavailable after administration of the composition to a patient. The compositions that will be administered to a patient are prepared in one or more unit doses, wherein for example a tablet, capsule or wafer can be a single unit dose, and a container of the aerosolized compound can retain a plurality of unit doses. . The materials used to prepare the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. The compositions of the invention may include one or more known compounds (active ingredients) which have a particularly desirable effect. It will be apparent to the maize expert that the optimum dosage of the active ingredient in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the mode of administration and the composition employed. In general, the pharmaceutical composition includes a compound of the present invention described in the present, in mixture with one or more vehicles. The vehicles can be in particles, such that the compositions are, for example, in the form of a tablet or powder. The vehicles can be liquids, the compositions being, for example, an oral syrup or an injectable liquid. In addition, the carriers can be gaseous in order to provide an aerosol composition, useful for example in administration by inhalation. For oral administration, the composition is preferably in solid or liquid form, wherein the semi-solid, semi-liquid, suspension or gel forms are included within the forms considered herein as solid or liquid. As a solid composition for oral administration, the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, pouch, chewing gum, wafer, lozenge, or the like. Said solid composition will normally contain one or more inert diluents or edible carriers. In addition, one or more of the following auxiliaries may be present: binders, such as syrups, acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth or gelatin, and mixtures thereof; excipients, such as starch, lactose or dextrins; disinfectant agents, such as alginic acid, sodium alginate, primogel, corn starch and the like; lubricants, such as magnesium stearate or Steroíex; fillers, such as lactose, mannitol, starch, calcium phosphate, sorbitol, methycellulose and mixtures thereof; lubricants, such as magnesium alloy, polymers of molecular weight such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica; Wetting agents, such as sodium lauryl sulfafo; free radicals, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; flavoring agents, such as peppermint, meilylic salicylate or orange flavor, and a coloring agent. When the composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as polyethylene glycol or a fatty acid. The composition may be in the form of a liquid, for example an elixir, syrup, solution, emulsion or aqueous or oily suspension, or even dry powders which can be reconstituted with water or other liquid medium before use. The liquids can be for oral administration or for injection, as two examples. When intended for oral administration, preferred compositions contain, in addition to the present compounds, one or more of: a sweetening agent, thickening agent, preservative (for example alkyl p-hydroxybenzoal), dye / coloring and flavor enhancer ( flavoring). In a composition intended to be administered by injection, one or more of: a surfactant, conservative agent (for example alkyl p-hydroxybenzoane), wetting agent, dispersing agent, suspending agent (for example sorbitol, glucose or another sugar syrup), buffer, stabilizer and isotonic oil. The emulsifying agent may be selected from lecithin or sorbitol monooleate. The liquid pharmaceutical compositions of the invention, whether solutions, suspensions or other similar form, may include one or more of the following auxiliaries: sterile diluents such as water for injection, saline, preferably physiological saline, Ringer's solution, isotonic sodium, fixed oils such as synthetic mono- or diglycerides, which may serve as solvents or suspending media, polyethylene glycols, glycerin, propylene glycol or other solvents; amphibole agents, such as benzyl alcohol or meilparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminephefracetic acid; buffers, such as acetates, cyrates or phosphates; and agents for tonicity adjustment, such as sodium chloride or dexory. Parenteral preparation can be packaged in ampoules, disposable syringes or multiple-dose vials made of glass or plastic. Physiological saline is a preferred auxiliary. An injectable pharmaceutical composition is preferably sterile. Liquid compositions intended for parenteral or oral administration may contain such an amount of the compound of the invention that a suitable dosage is obtained. Normally this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may vary between 0.1 and about 70% of the weight of the composition. Preferred oral compositions contain between about 4% and about 50% of the amino-cyclohexyl-acid acyl compound. Preferred compositions and preparations according to the present invention are prepared in such a way that a parental unit dose contains between 0.01 and 10% by weight of the active compound. The pharmaceutical composition can be used for topical administration, in which case the vehicle can suitably comprise a solution, emulsion, ointment, cream or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as alcohol and water, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If they are intended for transdermal administration, the composition may include a transdermal patch or an iontophoresis device. Topical formulations may contain a concentration of the active compound from about 0.1 to about 25% w / v (weight per unit volume). The composition can be used for rectal administration, in the form for example of a suppository that is fused in the rectum and releases the drug. The composition for rectal administration may contain an oily substance as a suitable non-irritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. For the preparation of a suppository, low melting point waxes are preferred, wherein mixtures of fatty acid glycerides or cocoa butter are suitable waxes. The waxes can be melted and the aminocyclohexyl ether compound dispersed homogeneously with stirring. The molten homogeneous mixture is then emptied into molds of suitable size and allowed to cool, whereby it solidifies. The composition may include various materials that modify the physical form of a solid or liquid unit dose. For example, the composition may include materials that form a cover coating around the active ingredients. The materials forming the coating cover are normally inert and may be selected, for example, from sugar, shellac and other enteric coating agents. Alternatively, the active ingredients can be enclosed in a gelatin capsule or sachet. The composition in solid or liquid form can include an agent that binds to the aminocyclohexyl ether compound and thus aid in the supply of the active components. Suitable agents that can acfue in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome. The pharmaceutical composition of the present invention may consist of gaseous unit doses, for example they may be in the form of an aerosol. The term aerosol is used to denote a variety of systems that vary from those of colloidal nature to systems consisting of pressure vessels. The supply can be by means of a liquefied or compressed gas or by means of a suitable pump system that dispenses the active ingredients. The aerosols of the compounds of the invention can be supplied in single-phase, two-phase or three-phase systems for supplying the active ingredient. The supply of the aerosol includes a necessary container, activators, valves, secondary vessels and the like, which together form a device. Preferred aerosols can be determined by the maize expert without further experimentation. Either in solid, liquid or gaseous form, the pharmaceutical composition of the present invention may contain one or more known pharmacological agents used in methods to modulate the activity of ion channels in a warm-blooded animal, or to modulate activity of in vitro ion channels, or that can be used in the treatment or prevention of arrhythmia, including atrial / supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, central nervous system diseases, seizures, cardiovascular diseases (for example, diseases caused by elevation of cholesterol or triglycerides in the blood), cerebral or myocardial ischemia, hypertension, prolonged QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, myotonia of Becker, myasthenia gravis, congenital paramyotonia, malignant hyperthermia, hyperpotassium periodic paralysis, Thomsen's myonymology, autoimmune disorders, graft rejection in organ transplants or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, dementia and others mental disorders, alopecia, sexual dysfunction, impotence, demyelinating diseases, multiple sclerosis, amyotrophic lateral sclerosis, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, ios, inflammation, arthritis, allergies, incontinence urinary tract, irritable bowel syndrome and gastrointestinal disorders such as gastrointestinal inflammation and ulcer or other diseases. The compounds of the present invention can be combined with other known agents that cause increased libido, analgesia or local anesthesia. The compositions can be prepared with the known methodology in pharmaceutical practice. The aminocyclohexyl ether compounds of the present invention may be in the form of a solvate in a pharmaceutically acceptable solvent, such as water or physiological saline. Alternatively, the compounds may be in the form of the free base or in the form of a pharmaceutically acceptable salt, such as the hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate salt. and other known salts. The appropriate salt would be chosen to increase the bioavailability or stability of the compound for the appropriate mode of use (for example, for oral or parenteral administration routes). A composition intended to be administered by injection can be prepared by combining the aminocyclohexyl ether compound of the present invention with water, and preferably buffering agents, in order to form a solution. Preferably, the water is sterile, pyrogen-free water. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension. The surfactants are compounds that interact non-covalently with the aminocyclohexyl ether compound in order to facilitate the homogeneous dissolution or suspension of the aminocyclohexyl ether compound in the aqueous supply system. Suitably, surfactant agents in the aqueous compositions of the invention will be present because the aminocyclohexyl ether compounds according to the present invention can be hydrophobic. Other vehicles for injection include, without limitation, peroxide-free sterile ethyl oleate, dehydrated alcohols, propylene glycol, as well as mixtures thereof. Suitable pharmaceutical adjuvants for injectable solutions include stabilizing agents, solubilizing agents, buffers and viscosity regulators. Examples of such adjuvants include ethylene, ethylenediamine-acetic acid (EDTA), buffers, buffers and viscosity regulators of high molecular polyethylene oxide. These pharmaceutical formulations can be injected intramuscularly, epidurally, iniraperioneally or iniravenously. As used herein, "arrhythmia irradiation" refers to arrhythmia therapy. An effective amount of a composition of the present invention is used to treat arrhythmia in a warm-blooded animal, such as a human. The methods of administering effective amounts of antiarrhythmic agents are well known and include the administration of an oral or parenteral dosage form. Said dosage forms include, without limitation, the parenteral dosage form. Said dosage forms include, without limitation, parenteral solutions, tablets, capsules, sustained release implants and fransdermal delivery systems. Generally, oral or in-venous administration is preferred for some treatments. The dose and frequency are selected to create an effective concentration of the agent without harmful effects. Generally it will vary from a dosage of approximately 0.01 to approximately 100 mg / kg / day, and usually from about 0.1 to 10 mg / kg, where it is administered orally or intravenously for antiarrhythmic effect or other therapeutic application. The administration of the compositions of the present invention can be carried out in combination with the administration of other agents. For example, if a compound exhibits opioid activity, it may be convenient to administer an opioid antagonism such as naloxone when said activity is undesirable. Naloxone can aniagonize the opioid activity of the administered compound without adversely affecting the ampiarrhythmic activity. As another example, an aminocyclohexyl ether compound of the invention can be coadministered with epinephrine to induce local anesthesia. You will hear compositions. The present invention also provides kits containing a pharmaceutical composition that includes one or more compounds of the above formulas. The kit also includes instructions for using the pharmaceutical composition to modulate the activity of the ion channels, for the treatment of the arrhythmia or for the production of analgesia or local anesthesia, and for other utilities described herein. Preferably, a commercial package will contain one or more unit doses of the pharmaceutical composition. For example, said unit dose may be in an amount sufficient for the preparation of an intravenous injection. It will be apparent to the person skilled in the art that compounds that are sensitive to light or air may require packaging or special formulation. For example, a light-opaque package can be used, or it can be sealed from contact with ambient air, or formulated with suitable coatings or excipients.

Pharmacological Modalities In other embodiments, the present invention provides one or more compounds of the present invention, corresponding to formula (IA), (IB), (IC), (ID) or (IE), or a solvate, pharmaceutically salt acceptable, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including enantiomeric, diastereomeric and geometric isomers isolated from them, and mixture thereof; or a composition or medicament including said compound; or a mixture comprising the above-described compounds, for use in methods for modulating the activity of an ion channel in a warm-blooded animal, or for modulating the activity of an ion channel in vitro. In a version of this mode, the warm-blooded animal in which the activity of the ion channel is modulated is a mammal; in one version, the warm-blooded animal is a human; In one version, the warm-blooded animal is a farm animal. In other embodiments, the present invention provides one or more compounds selected from the group consisting of: (1R / 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3, 4- dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimiroxifenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenenoxy) -cciohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimiroxifenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvation thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above, for use in methods for modulating the activity of the ion channel in a warm-blooded animal, or for modulating the activity of the ion channel in vitro. In a version of this embodiment, the warm-blooded animal in which the activity of the ion channel is modulated is a mammal; in one version, the warm-blooded animal is a human being; In one version, the warm-blooded animal is a farm animal. As described in the present invention, a variety of cardiac pathological conditions can be treated or prevented using one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and isolated geometries, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. These compounds of the present invention are ion channel modulator compounds which, individually or june with one or more additional compounds, are capable of selectively modulating some ionic currents. The ionic currents referred to herein are generally cardiac currents and, more specifically, are sodium currents and early repolarization currents. The early repolarization currents correspond to cardiac ion currents that are activated rapidly after depolarization of the membrane voltage and repolarize the cell. Many of these currents are potassium currents and may include, without limitation, the transient external current lt0 .. such as Kv4.2 and Kv4.3, and the ultrafast delayed rectifier current (l «ur). such as Kv1.5 and Kv1.4 and Kv2.1. The ultra-fast delayed rectifier current (l? Ur) has also been described as us. A second calcium-dependent transient external current (lt02>) has also been described - Pathological conditions that can be treated or prevented by the present invention may include, without limitation, various cardiac diseases.Cardiac pathological conditions that can be treated or prevented by the present invention may include without limitation arrhythmias, such as the various types of atrial and ventricular arrhythmias, for example atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter.In one embodiment, the present invention provides ion channel modulating compounds. which can be used to selectively inhibit cardiac currents of early repolarization and cardiac sodium currents In another embodiment, the present invention provides ion channel modulator compounds that can be used to selectively inhibit early repolarization cardiac currents. a and cardiac sodium currents, under conditions where an "arrhythmogenic substrate" is present in the heart. An "arrhythmogenic substrate" is characterized by a reduction in the duration of the cardiac action potential or changes in the morphology of the action potential, premature action potentials, high cardiac frequencies, and may also include greater variability in time between the potentials of action and an increase in heart acidity due to ischemia or inflammation. Changes such as these are observed during conditions of ischemia or inflammation of the myocardium and the conditions that precede the appearance of arrhythmias such as atrial fibrillation. In other embodiments, the present invention provides a method for modulating the activity of the ion channel in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof, an effective amount of one or more compounds of the present invention. such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for modulating ion channel activity in an in vitro environment, comprising administering in vitro an effective amount of one or more compounds of the present invention such as those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for blocking / inhibiting the activity / conductance of the ion channel in a warm-blooded animal, comprising administering to the warm-blooded animal in need thereof, an effective amount of one or more compounds of the present invention as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture , geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for blocking / inhibiting the activity / conductance: of the ion channel in an in vitro environment, which comprises administering in vitro an effective amount of one or more compounds of the present invention such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form , metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for modulating the activity of the potassium ion channel in a warm-blooded animal, comprising administering to the warm-blooded animal in need thereof, an effective amount of one or more compounds of the present invention as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, isomer geometric, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the above-described compounds. In other embodiments, the present invention provides a method for modulating the activity of the void-regulated poisonous ion channel in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, as formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture leaves them , geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for modulating the activity of cardiac sodium currents in a warm-blooded animal, which comprises administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for modulating the ion channel activity of early repolarization cardiac currents and cardiac sodium currents in a warm-blooded animal, which comprises administering the warm-blooded animal in need thereof. an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide , complex, chelate, stereoisomer, stereoisomeric mixture, geometiric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diaisteromeric and geometiric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for blocking / inhibiting ion channel activity of early repolarization cardiac currents and cardiac sodium currents in a warm-blooded animal, which comprises administering the warm-blooded animal in need. thereof an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (lE), or a solvate, pharmaceutically acceptable salt, ester , amide, complex, chelate, stereoisomer, sphereoisomeric mixture, geomethyric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for blocking / inhibiting cardiac ion channels, responsible for the ion channel activity of early repolarization cardiac currents and cardiac sodium currents in a warm-blooded animal, comprising administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geomeric isomers, and mixtures of the same; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for blocking / inhibiting ion channel activity of early repolarization cardiac currents and cardiac sodium currents in a warm-blooded animal, under conditions where an arrhythmogenic substrate is present in the heart of said warm-blooded animal, comprising administering to the warm-blooded animal in need thereof, an effective amount of one or more compounds of the present invention such as those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, meiabolic precursor or prodrug thereof, including its isomers enantiomeric, diastereomeric and geometiric isolates, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for blocking / inhibiting cardiac ion channels, responsible for the ion channel activity of the early repolarization cardiac currents and the cardiac currents of sodium in a warm-blooded animal, under conditions where an arrymogenic subsystem is present in the heart of said warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof, an effective canine of one or more compounds of the present invention such as those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof same; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the early repolarization cardiac currents referred to in the present invention comprise ionic currents that are rapidly activated after depolarization of membrane volya, and which repolarize the cell. In other embodiments, the early repolarization cardiac currents referred to in the present invention comprise the transient external potassium current (l.0) or the ultrafast delayed rectifier current (l? Ur). In other embodiments, the transient external potassium current (lt0) or the ultrafast delayed rectifier current (l? Ur) referred to in the present invention comprise at least one of the currents Kv4.2, Kv4.3, Kv2.1, Kv1.4 and Kv1.5. In other embodiments, the present invention provides a method for irradiating or preventing arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, spherical mixture, geomeric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof or a composition or medicament including said compound or a mixture comprising the above-described compounds. In other embodiments, the present invention provides a method for trailing or preventing atrial arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention. , like those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer , crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for trailing or preventing ventricular arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention. , such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer , crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for the eradication or prevention of atrial fibrillation in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention. , like those of formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer , crystalline or amorphous form, meiabolium, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other modalities, the present invention provides a method for the delivery or prevention of ventricular fibrillation in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline form or amorphous, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above.

In other embodiments, the present invention provides a method for the framing or prevention of atrial flutter in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, spherical mixture, isomeric, crystalline or amorphous form, metabolite, meiabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and isolated geometrical isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for the irradiation or prevention of ventricular flutter in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those of the formula (IA), (IB), (IC), (m), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and isolated geometrical isomers, and mixtures thereof; or a composition or medicament including said compound or a mixture comprising the above-described compounds. In other embodiments, the present invention provides a method for treating or preventing arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, as selected from the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1 - (3,4-dimethoxyphenetoxy) -cyclohexane , free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimeloxifene-oxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphene-oxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvaío of the same; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for the diagnosis or prevention of atrial arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention. , as selected from! group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphene-oxy) -cyclohexane, free base or any salt thereof , or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any soivafole thereof; (1R, 2R) -2 - [(3R) -hydroxypyridinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethyloxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphene-oxy) -cciohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxy-pyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenenoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for the delivery or prevention of ventricular arrhythmia in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof, an effective amount of one or more compounds of the present invention. invention, such as those selected from the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, base free or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt of! same, or any solvate thereof; (1 R, 2R) -2 - [(3S) -hydroxypyrrolyl-dinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (394-dimethoxyphenetoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxypheneloxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxypheneloxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyridinidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate of the same; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other modalities, the present invention provides a method for the delivery or prevention of atrial fibrillation in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as selected from the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dmemexypheneloxy) -cyclohexane , free base or any salt thereof, or any solvation thereof; (1 R, 2 R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphene-oxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-d, -methio-pheneneoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) -2 - [(3R) -h -droxypyrrolidinyl] -1- (3,4-dimethoxyphenefoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenenoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate of the same; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for the treatment or prevention of ventricular fibrillation in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention. , as selected from the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cydohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetox'-cyclohexane, free base or any salt thereof, or any solvate thereof, or a composition or medicament including said compound or a mixture comprising the compounds described above., the present invention provides a method for the treatment or prevention of atrial flutter in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as those selected of the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2 R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate of the same; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxy-pyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cydohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3I4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate of the same; or a composition or medicament including said compound or a mixture comprising the compounds described above. In other embodiments, the present invention provides a method for the treatment or prevention of ventricular flutter in a warm-blooded animal, which comprises administering to the warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, as selected from the group consisting of: (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1 - (3,4-dimethoxyphenetoxy) -cyclohexane , free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphene-oxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1 - (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1 R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy-phenetoxy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethioxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethyloxyphenexy) -cycothexane, free base or any salt thereof, or any solvate thereof; (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenexy) -cyclohexane, free base or any salt thereof, or any solvate thereof; or a composition or medicament including said compound or a mixture comprising the compounds described above. As indicated above, the present invention provides for the use of the compounds described above in in vitro and in vivo methods. In one embodiment, ion channels, such as cardiac potassium channels, are blocked in vitro or in vivo. Ion channels are ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Its critical functions include the control of the electrical potential through the membrane, the mediation of the ionic and fluid balance, the facilitation of neuromuscular and neuronal transmission, the rapid transduction of the fransmembrane signal, and the regulation of secretion and coniractility. Accordingly, compounds that are capable of modulating the activity or function of the appropriate ion channels will be useful in the treatment or prevention of a variety of diseases or disorders caused by defective or inadequate function of the ion channels. The compounds of the invention have a significant activity of modulating the activity of several ion channels, both in vivo and in vitro. In one embodiment, the present invention provides a compound of the present invention or a composition comprising said compound, for use in methods to modulate the activity of the ion channel in a warm-blooded animal, or to modulate the activity of the ion channel. in vitro Some of the ion channels over which the compounds, compositions and methods of the present invention have a modulating effect, are several potassium and sodium channels. These potassium and sodium channels can be voltage activated (also known as voltage regulated) or ligand activated (also known as ligand regulated), and can be present in cardiac or neuronal systems. In one embodiment, the invention provides a compound of the present invention as those of formula (IA), (IB), (IC), (ID) or (IE), or a composition containing said compound, for use in methods to modulate the activity of ion channels in a warm-blooded animal, or to modulate the activity of ion channels in vitro, wherein said ion channels correspond to some of the cardiac or neuronal ion channels that are responsible for one or more early repolarization currents, which include those that are activated rapidly after depolarization of the membrane and that repolarize the cells. In another embodiment of the present invention, the aforementioned early repolarization currents comprise the transient external potassium current (lt0 for the cardiac or neuronal), or the ultrafast delayed rectifier current (lKur); and include at least one of the streams Kv4.2, Kv4.3, Kv2.1, Kv1.3, Kv1.4 and Kv1.5. In another embodiment, the present invention provides a compound of the present invention, such as those of formula (IA), (IB), (IC), (ID) or (IE), or a composition containing said compound, for use in methods for modulating the activity of ion channels in a warm-blooded animal, or for modulating the activity of ion channels in vitro, wherein said ion channels correspond to the cardiac or neuronal ion channels that are responsible for the current Kv1.5. In another embodiment, the present invention provides a compound of the present invention, such as those of formula (IA), (IB), (IC), (ID) or (IE), or a composition containing said compound, for use in methods for modulating the activity of the ion channels in a warm-blooded animal, or for modulating the activity of the ion channels in vitro, wherein said ion channels correspond to the poiasium channel responsible for the Kv4.2 current. In addition, voltage-activated sodium ion channels comprise the Nav1, Nav2 or Nav3 series and may be present in cardiac, neuronal, skeletal muscle, central nervous or peripheral nervous systems (eg, hH1 a). For cardiac sodium channels, studies on ion channels in human atrial myocytes have shown that the compounds of the present invention block cardiac sodium channels in a frequency-dependent manner. In these studies, an increase in the blockade of cardiac sodium channels was observed at higher stimulation speeds, with sodium blockade increasing several times during high stimulation rates. These protocols are designed to mimic short recovery intervals during fibrillation. As indicated above, the modulation of the activity of an ion channel, as used above, may involve blocking or inhibiting the conductance of the current through the ion channel, but is not limited thereto. Thus, the present invention provides methods of treating a disease or condition in a warm-blooded animal suffering from the disease or condition, or preventing a disease or condition in a warm-blooded animal, where it is administered to the animal. of hot blood a therapeutically effective amount of a compound of the present invention, or a composition containing a compound of the present invention. Some diseases and conditions in which the compounds, compositions and methods of the present invention can be applied are the following: arrhythmia, which includes atrial / supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, diseases of the central nervous system, convulsion, cardiovascular diseases (for example, diseases caused by elevated cholesterol or triglycerides in the blood), cerebral or myocardial ischemia, hypertension, prolonged QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, congenital paramyotonia, malignant hyperthermia, hyperkalemic periodic paralysis, myotonia of Thomsen, autoimmune disorders, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, dementia and others t mental disorders, alopecia, sexual dysfunction, impotence, demyelinating diseases, multiple sclerosis, amyotrophic lateral sclerosis, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory diseases, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, incontinence urinary tract, irritable bowel syndrome and gastrointestinal disorders such as gastrointestinal inflammation and ulcer. In addition, the present invention provides a method for producing analgesia or local anesthesia in a warm-blooded animal, which includes administering to the warm-blooded animal in need thereof, an effective amount of a compound of the present invention, or a pharmaceutical composition containing said compound. These methods can be used to alleviate or prevent the sensation of pain in a warm-blooded animal. The invention also provides a method for increasing libido in a warm-blooded animal, which includes administering to the warm-blooded animal in need thereof an effective amount of a compound of the present invention, or a pharmaceutical composition containing said compound. These compositions and methods can be used, for example, to treat sexual dysfunction, for example, impotence in males, or to increase the sexual desire of a patient without sexual dysfunction. As another example, the therapeutically effective amount may be administered to a bull (or other breeding stock), to promote an increase in semen ejaculation, where the ejaculated semen is collected and stored for use as required to inseminate the semen. females in a breeding program. In addition, the present invention provides a method in an in vitro environment, wherein a preparation containing ion channels is contacted with an effective amount of an aminocyclohexyl ether compound of the invention. Suitable preparations containing cardiac channels of sodium or potassium include cells isolated from cardiac tissue and also cultured cell lines. The step of contacting includes for example the incubation of the ion channels with a compound, under conditions and time sufficient to allow the modulation of the activity of the channels by the compound. The administration of the compositions of the present invention can be done in combination with other agents. For example, if a compound exhibits opioid activity it may be desirable to administer an opioid antagonist such as naloxone. Naloxone can antagonize the opioid activity of the administered compound without adversely affecting the antiarrhythmic activity. As another example, an aminocyclohexyl ether compound of the invention can be coadministered with epinephrine to induce local anesthesia. To determine if a compound has a desired pharmacological activity it can be subjected to a series of tests. The precise test to be used depends on the physiological response of interest. The published literature contains many protocols for testing the efficacy of a potential therapeutic agent, and these protocols can be employed with the present compounds and compositions. For example, with respect to the treatment or prevention of arrhythmia, a series of four tests can be performed. In the first of these, a compound of the present invention is given to a conscious rat as an increasing intravenous infusion (doubling it with each dose) every 5 minutes. The effects of the compound on blood pressure, heart rate and ECG are continuously measured. Increasing doses are given until a severe adverse event occurs. The adverse event related to the drug is identified as of respiratory origin, central nervous system or cardiovascular system. This test gives an indication of whether the compound modulates the activity of sodium channels or potassium channels, and also gives information on acute toxicity. Sodium channel blockade rates are an increasing P-R interval and QRS enlargement of the ECG. Blocking the potassium channel causes prolongation of the Q-T interval of the ECG. A second test includes the administration of a compound as an infusion in anesthetized rats, in which the left ventricle is subjected to a square electrical wave stimulation performed in accordance with a pre-established protocol that is described below in greater detail. This protocol includes the determination of thresholds for inducing extrasystoles and ventricular fibrillation. further, the effects on electric refractoriness are determined by an extra simple heartbeat technique. In addition, the effects on blood pressure, heart rate and ECG are recorded. In this test, the sodium channel blockers produce the ECG changes expected from the first test. In addition, sodium channel blockers also raise thresholds for inducing premature beats and ventricular fibrillation. Blocking of the potassium channel is revealed by increasing refractoriness and widening of the Q-T intervals of the ECG. A third test includes exposing isolated rat hearts to increasing concentrations of a compound. The ventricular pressure, heart rate, conduction velocity and ECG of the isolated heart are recorded in the presence of variable concentrations of the compound. The test gives evidence of direct toxic effects on the myocardium. Additionally, the selectivity, potency and efficacy of a compound can be determined under conditions that simulate ischemia. It is expected that the effective concentrations found in this test will be effective in electrophysiological studies. A fourth test is the estimation of the antiarrhythmic activity of a compound compared to arrhythmias induced by coronary artery occlusion in anesthetized rats. It is expected that a good antiarrhythmic compound has antiarrhythmic activity at doses that have minimal effects on the ECG, blood pressure or heart rate under normal conditions. All the above tests are performed using rat tissue. To ensure that a compound is not having effects that are only specific to rat tissue, more experiments are conducted on dogs and primates. To determine in vivo a possible blocking action of the sodium channel and the potassium channel, the effects of a compound on the ECG, the ventricular epicardial conduction velocity and the responses to electrical stimulation are tested in dogs. An anesthetized dog undergoes an open thoracic procedure to expose the left ventricular epicardium. After removing the pericardium from the heart, a recording / stimulation electrode is drawn on the epicardial surface of the left ventricle. Using this arrangement and appropriate stimulation protocols, the conduction velocity through the epicardium and also the sensitivity to electrical stimulation can be determined. This information together with the ECG measurements allow to determine if blockade of the sodium or potassium channel occurs. As in the first test in the rats, a compound is administered as a series of increasing bolus doses. At the same time, the possible toxic effects of a compound on the cardiovascular system of the dog are determined. The effects of a compound on the ECG and the responses to electrical stimulation are also determined in intact anaesthetized monkeys (Macaca fascicularis). In this preparation, a blood pressure cannula and ECG electrodes are suitably placed in an anesthetized monkey.

In addition, a stimulation electrode is placed in the right atrium or ventricle, along with a monophasic-acting potential electrode. As in the test described above, the ECG and the electrical stimulation response to a compound reveal the possible presence of sodium or potassium channel blockade. The monophasic action potential also reveals whether a compound amplifies the action potential, an expected action of a potassium channel blocker. As another example, with respect to the mitigation or prevention of pain sensation, the following test can be performed. To determine the effects of a compound of the present invention on the response of an animal to a sensation of acute pain, the effects of a slight puncture are determined with a syringe of 7.5 g of weight conditioned with a 23G needle, on the shaved back of a guinea pig (Cavia porcellus), after subcutaneous administration of sufficient solution in saline vehicle (50 μl, 10 mg / ml) to raise a visible blister on the skin. Each test is performed on the central area of the ampule and also on its periphery, to verify the diffusion of the test solution from the point of administration. If the test animal recoils in response to the stimulus, this demonstrates the absence of blockage of the sensation of pain. The test can be done at intervals of up to 8 hours or more after administration. The blister formation sites are examined after 24 hours to verify skin abnormalities consistent with the local administration of the test substances or the vehicle used for the preparation of the test solutions. The following examples are offered by way of illustration and not limitation. In the examples, unless otherwise specified, the starting materials were obtained from well-known suppliers, for example, Aldrich Chemical Company (Milwaukee, Wisconsin), and were of standard grade and purity. "Ether and" ethyl ether "refer to diethyl ether," h "refers to hours," min "refers to minutes," GC "refers to gas chromatography," v / v "refers to volume per volume and the ratios are by weight, unless otherwise indicated.

Example 1 (1R, 2R) -2-r (3R) -hydroxiplrroidinyl] -1- (3,4-dimethoxifenetoxOichohexane) monochlorohydrate (Compound 1) The procedure for the preparation of compound 1 described herein is illustrated in reaction scheme 1.

Preparation of the intermediates? / - tert-Butoxycarbonyl-3-pyrrolidinol (1 R) To a cold solution (0 ° C) in an agitation of (R) -3-pyrrolidinol (20.6 g, 236 mmol; Omega ca. # HP- 2113) in anhydrous THF (800 mL), a solution of di-tert-butyl dicarbonate (56.7 g, 260 mmol, Aldrich cat. # 20.524-9) in THF (200 mL) was added to the beads, and the solution The resulting mixture was stirred at room temperature for 18 h. By concentration in vacuo of the reaction mixture, and short-time distillation in vacuo of the light yellow residue, 1R (42g, 95% yield) was obtained as a colorless and clear oil, which crystallized upon standing. Characterization: Rf 0.58 (CHCl3-MeOH, 4: 1, v / v), 1H NMR (200 MHz, CDCl 3) d 4.4 (br s, 1 H), 3.5-3.2 (m, 4 H), 2.5 (br s, 1 H), 2.0-1.9 (m, 2 H), 1.4 (s, 9 H); 13 C NMR (75 MHz, CDCl 3) d 154.7, 79.3, 70.6, 69.8, 54.1, 53.9, 43.9, 43.4, 33.8, 33.3, 28.4; IR (film) 3411, 1678 cm -1; EIMS m / z (relative intensity) 187 (M +, 8), 169 (M-H2O, 0.5), 132 (25), 114 (39), 87 (13), 57 (100); HRMS m / z cale, for C9H17NO3 (M +) 187.12081, found 187.12084. ? / - tert-Butoxycarbonyl-3R-benzyloxypyrrolidine (2R) A suspension of sodium hydride (8.08 g, 269 mmol, 80%, Aldrich cat. # 25,399-5) in anhydrous THF (100 mL), was stirred, left settle, and the supernatant was discarded. The gray residue was washed with THF (2 x 50 mL) and then resuspended in THF (700 mL). To the stirred, cold (0 ° C) sodium hydride suspension, a solution of 1R (41.7 g) was added dropwise., 223 mmol) in THF (200 mL), and the resulting mixture was refluxed for 1 h. After the reaction mixture was cooled to room temperature, benzyl bromide (26.5 mL, 223 mmol) and tetrabufilamonium iodide (8.20 g, 22.3 mmol, Aldrich cat. # 14.077-5) were successively added. The mixture was stirred 18 h at room temperature and then concentrated under reduced pressure. To the residue was added brine (300 mL) and water (50 mL), and the pH of the resulting mixture was adjusted to neutral with 1M aqueous HCl. This mixture was extracted with hexane (100 mL) and the hexane extract was dried (anhydrous gSO4) and concentrated under reduced pressure, to give 64.3 g (>98% yield) of a yellow oil that, according to a GC analysis, consists almost exclusively of the desired product. A small amount of the oil was subjected to flash column chromatography on silica gel, eluting with hexane-ethyl acetate (3: 1), to give 2R as a colorless oil, which crystallized upon standing. Characterization of 2R: Rf 0.58 (CHCl3-MeOH, 4: 1, v / v), 1H NMR (400 MHz, CDCI3) d 7.35-7.25 (m, 5H), 4.58-4.47 (m, 2H), 4.12 (br s, 1 H), 3.55-3.40 (m, 4H), 2.10-2.00 (m, 1 H), 2.00-1.90 (m, 1H), 1.48 (s, 9H); 13 C NMR (75 MHz, CDCl 3) d 154.5, 138.0, 128.3, 127.6, 79.1, 77.7, 76.8, 70.8, 51.4, 50.7, 44.0, 43.6, 31.4, 30.4, 28.4; IR (film) 2975, 1691, 1410 cm "1; HRMS m / z cale for C .6H23NO3 (M +) 277.16779, found 277.16790 3R-Benciloxipirrolidina (3R) A mixture of trifluoroacetic acid (50 mL, Aldrich cat. T6, 220-0) and 2R (20 g, 72 mmol) was stirred 1 h at room temperature and then concentrated under reduced pressure.The residue was taken up in water (250 mL) and the resulting aqueous acid solution was extracted with Et2O ( 2 x 150 mL). the acidic aqueous layer was carefully added in solid portions NaHCO3 until saturation. the basic aqueous solution was then extracted with CH2CI2 (2 x 150 mL) and the combined organic extract was dried (anhydrous Na2SO4). the evaporation of the solvent in vacuo gave 8.0 g of 3R (62% yield) Characterization of 3R: Rf 0.24 (CHCl3-MeOH, 9: 1, v / v), 1 H NMR (400 MHz, CDCl 3) d 7.40-7.17 ( m, 5H), 4.43 (s, 2H), 4.09-4.03 (m, 1H), 3.10- 2.98 (m, 2H), 2.85-2.70 (m, 2H), 2.46 (s, 1H), 1.90-1.78 ( m, 2H); IR (film) 3400, 1452, 1100, 1068 cm-1. (1 R. 2R) / (1 S.2S) -1-f (3R) -Benzyloxypyrrolidinincyclohexan-2-ol (4R) A mixture of cyclohexene oxide (12.5 mL, 120.9 mmol, Aldrich cat. # C10, 250-4), 3R (14.3 g, 80.6 mmol) and water (6 mL), was heated at 80 ° C for 9.5 h, after which a GC analysis revealed complete consumption of 3R. The reaction mixture was allowed to cool to room temperature and diluted with water (140 mL). The pH was adjusted to 4.6 by adding ac HCl. 1M (55 mL), and the mixture was extracted with Et2O (2 x 200 mL). Then, the aqueous layer was adjusted to pH 12.5 by adding aq NaOH. 40% (NaCl can be added to separate in 2 transparent layers), and extracted with Et2O (1 x 400 mL, 1 x 200 mL). The combined Et2O extract (from the basic aqueous layer) was dried (anhydrous Na2SO4), and concentrated under reduced pressure and then under vacuum at 55 ° C, with stirring, to give 4R as an orange oil (15.9 g, 72% ) with 96% purity (GC). Characterization of 4R: Rf 0.24 (EtOAc-iPrNH2, 98: 2, v / v); 1 H NMR (200 MHz, CDCl 3) d 7.4-7.2 (m, 5H), 4.5 (s, 2H), 4.2-4.0 (m, 1 H), 3.9 (br s, 1H), 3.4-3.2 (m, 1 H), 3.0-2.5 (m, 4H), 2.4 (l, J 10 Hz, 1H), 2.2-1.9 (m, 2H), 1. 9-1.6 (m, 4H), 1.3-1.1 (m, 4H); 13 C NMR (75 MHz, CDCl 3) d 138.30, 128.35, 127. 61, 127.55, 77.98, 77.71, 71.07, 71.01, 70.52, 70.45, 64.96, 64.89, 54.16, 52.74, 46.83, 45.43, 33.24, 31.53, 31.34, 25.20, 24.13, 21.40, 21.33; IR (film) 3450 (broad) cm-1. (1R.2R) / (1S.2S) -2-r (3R) -Benzyloxypyrrolidinin-1- (3,4-dimethoxy-phenetoxy) -cyclohexane (5R) (a) To a cold solution (0 ° C) and with stirring of 4R (32.7 g, 88% purity according to GC analysis, 104 mmol) and EtβN (13.8 g, 135 mmol, Aldrich cat. # 13,206-3) in CH 2 Cl 2 (210 mL), was added dropwise. methanesulfonyl chloride (15.8 g, 135 mmol, Aldrich cat. # M880-0). The reaction mixture was stirred at 0 ° C for 30 min and then at room temperature for 2 h 15 min. The reaction mixture was then washed with a 1: 1 mixture of H2O-NaHC 3 aq. saturated (200 mL). The aqueous layer was extracted with CH2Cl2 (1 x 200 mL, 2 x 150 mL) and the organic extracts were combined and the product was dried over sodium sulfate. Concentration of the organic layer under vacuum produced the crude mesylate as a viscous oil, which was stirred at high vacuum for 3 h to remove residual traces of volatile material, and then used in the next step without further purification. (b) To a suspension of NaH (3.75 g, 80% dispersion in mineral oil, 125 mmol, Aldrich cat. # 25,399-5) in anhydrous ethylene glycol dimethyl ether (350 mL), an alcohol solution of 3% was added. , 4-dimethoxyphenethyl ether (23.2 g, 125 mmol, Aldrich cat. # 19,765-3) in ethylene glycol dimethyl ether (100 mL). The resulting mixture was then stirred at room temperature for 2 h to complete the formation of sodium alkoxide.

A mesylation solution (see part (a) above) in anhydrous ethylene glycol dimethyl ether (100 mL) was added rapidly to the alkoxide mixture (see part (b) above), and the resulting mixture was refluxed under Argon for 17 h. The reaction mixture was allowed to cool to ambient temperature and then quenched with water (200 mL), followed by concentration under reduced pressure. The resulting aqueous solution was diluted with water (400 mL) and its pH adjusted to 0.5 by adding ac HCl. to 10%. To remove unreacted 3,4-dimethoxyphenethyl alcohol, the aqueous acid layer was extracted with Et 2 O (2 x 600 mL). The pH of the aqueous solution was then adjusted to 6.3 by adding aq. NaOH. 5M and the resulting aqueous layer was extracted with E2O (600 mL). Et2O (600 mL) was added to the aqueous layer, the pH was adjusted to 6.4 and the layers were separated. This operation was repeated for pH adjustments to 6.5 and 6.7. The ether extracts after pH adjustment at 6.3-6.7 were combined, and the combined product was concentrated under reduced pressure to a volume of ~ 800 mL and dried (anhydrous Na2S? 4). Solvent removal under vacuum produced 34.4 g of the title compound as a brown oil (95% purity by GC analysis). Purification of this material by chromatography in a vaporous column on silica gel, eluting with a gradient solvent system of hexane-EtOAc (6.6: 1 -> 2: 1) containing 0.5% v / v / PrNH2. gave the 5R diastereomeric mixture as a yellow oil (70% yield) in two fractions: 7.9 g (97% purity by GC analysis) and 25.5 g (95% purity by GC analysis). Characterization: R. 0.14 (hexane-EtOAc, 2: 1 containing / - 0.5% PrNH2); 13C NMR (100 MHz, CDCI3) d 148.94, 147.59, 138.77, 132.30, 128.30, 127.62, 127.42, 120.90, 112.77, 111.55, 79. 18, 78.07, 70.93, 69.82, 63.93, 57.46, 56.02, 55.90, 49.22, 36.59 , 31.37, 28.70, 26.97, 23.08, 22.82; EIMS m / z (relative intensity) 440 (M +, 2) 333 (15) 274 (67) 165 (40) 91 (100). Resolution of (1S.2S) - v (1 R.2R) -2-r.3R) -benzyloxy-pyrrolidinyl-1- (3,4-dimethoxypheneioxO-cyclohexanes (5RRR v 5SSR) The diasferomeric mixture 5R was separated using a Prochrom 110 HPLC equipped with a column body of 110 mm internal diameter, a bed length of 850 mm, and a maximum bed length of 400 mm (packed column) .The column was packed with Kromasil silica (10 microns), 100 angstrom, normal phase). The 5RRR was isolated with a diasteroselectivity of 99.5% and a chemical purity of 97%. Preparation of the compound (1), monohydrochloride of (1 R, 2R) -2-r (3R) -hydroxypyrrolidinin-1- (3,4-dimethoxyphenetoxy) cyclohexane To a malenry 500 mL Erlenmeyer equipped with a union 24/40, at 22 ° C and charged with an agitated solution of 5RRR (12.7 mmol) in isopropyl alcohol (70 mL, HPLC grade of EM science, file No. PX1838-1), a solution of hydrochloric acid (5 mL, 37%, Aldrich # 25,814-8). After stirring the solution for 10 min, Pd-C calibrator (1.5 g, 10%, Aldrich # 20.569-9) was added, and the reaction vessel was equipped with a gas-stripping adapter (24/40 junction, Konies, dropped no .. KT185030-2440) connected to a water aspirator. The reaction mafraz was evacuated by water aspiration 1 min and then charged with H2 by means of a balloon attached to the gas gill. After vigorously stirring the reaction mixture for 1 h at 22 ° C under a positive pressure of H2, a TLC and GC analysis indicated the total substrate consumption and a clean conversion to the desired product. The reaction mixture was filtered through a column packed with Celite 545® (Fisher) (45 mm in diameter and 35 mm in height, pre-wetted with methanol under suction to remove air pockets and ensure efficient entrapment of carbon during the filtration), and the Pd-C catalyst was rinsed well with methanol (3 x 40 mL). The acid methanol solution was concentrated azeotropically under reduced pressure with benzene or toluene to give a residue which was stirred vigorously in ethyl acetate for 1-2 days, to facilitate the formation of a solid or crystals. Characterization: p.f. 144-150 ° C; Rf 0.37 (AcOEt / isoPrNH2, 95: 5); IR 1514, 1263, 1111 crt? 1; MS (ES) m / z 350.5; 13 C NMR (75 MHz, CDCl 3) d 148.84, 147.57, 131.10, 120.54, 112.14, 111.26, 69.41, 68.81, 67.51, 66.32, 59.48, 55.88, 52.35, 35.80, 32.32, 30.06, 28.05, 24.23, 22.95; Cale, for C20H31NO4.HCI: C 62.24%; H 8.36%; N 3.63%; found C 62.00%; H 8.42%; N 3.57%; [α] D-46.7 ° (c 1.52, CH 3 OH); [afo -39.6 ° (c 1.00, CHCI3). Preparation of simple crystals of compound 1 for X-ray crystallography. Compound 1 (200 mg) was dissolved in hot EtOH (3 mL) and then the solution was allowed to slowly evaporate at room temperature for 3 days. Crystals were formed and by additional evaporation of the remaining solvent (~ 1mL) during another 2 days, suitable chrysolics were obfuscated for X-ray diffraction measurements: The sample was stored under argon. Determination of the structure of compound 1 by means of X-rays Experimental part Data collection: A transparent plate crystal of C2oH32NO4CI having approximate dimensions of 0.25 x 0.20 x 0.04 mm, was mounted on a fiberglass. All measurements were made in an ADSC CCD area detector coupled with a Rigaku AFC7 diffractometer with Mo-Ka monochrome graphite radiation. The cell constants and an orientation matrix for data collection corresponded with a monoclinic cell with the dimensions: a = 8.4333 (7) A b = 9.4675 (9) A ß = 93.125 (7) ° c = 12.581 (1) AV = 1003.0 (1) A3 For Z = 2 and FW = 385.93, the calculated density is 1.28 g / cm3. Based on the systematic absences of: OkO: k ± 2n a statistical analysis of intensity distribution, and the correct solution and refinement of the structure, it was determined that the space group was: P2? (# 4) Damages were collected at a femperairy of -100 ± 1 ° C to a maximum 2T value of 50.2 °. Damages were collected in oscillations of 0.50 ° with exposures of 60.0 seconds. Was a damage sweep made using oscillations? from -18.0 to 23.0 ° a? = - 90.0 °. A second sweep was made using oscillations f from 0.0 to 190.0 ° a? = - 90.0 °. The crystal distance to detector was 39.68 mm. The scan angle of the detector was -5.50 °. Data reduction Of the 7703 reflections that were collected, 3390 were unique (R¡nt = 0.053, Friedels not combined); the equivalent reflections were combined. Damages were collected and processed using d * TREK1. Nefas intensities and sigmas were derived in the following way: F2 = [S (Pi - mBave)]. Lp where P. is the value in the accounts of the i-th pixel M is the number of pixels in the integration area Bave is the average of the background Lp is the Lorentz factor and polarization Bave =? (Bj) / n in where n is the number of pixels in the background area Bj is the value of the jth pixel in the s2CF accounts) - [(£ Pi) Lp - crrmuí - C erradd '? where erradd = 0.05 errmul = 1.40 The linear absorption coefficient, μ, for Mo-Ka radiation is 2.1 cm-1. An empirical absorption correction was applied, which caused transmission factors from 0.73 to 1.00. The data was corrected for Lorentz and polarization effects. Solution and refinement of the structure The structure was solved by direct methods2 and expanded using Fourier3 techniques. The non-hydrogen atoms were anisotropically refined. This configuration was chosen based on the results of a parallel refinement of the two possible configurations and was further confirmed by the refined Flack parameter. The hydrogen atoms involved in hydrogen bonding were refined isotropically, the rest were included in the fixed positions. The final cycle of least-squares refinement of complete matrix4 on F2 was based on 3390 observed reflections and 242 variable parameters, and converged (the largest parameter deviation was 0.00 times its esd) with weighted and unweighted agreement factors of : Rl = S jjFoi - | Fc | [S | Fo. { - 0.057 wR2 = [t (w (Fo2 - Fc2) 2) / S w (Fo2) 2jl / 2 ^ 0 > 0S2 The standard deviation of a unit weight observation5 was 0.97. The weighting scheme was based on statistical statistics. The graphs of S w (| Fo | - | Fc |) 2 coníra | Fo |, the order of reflection in the data collection, sen? /? and several kinds of indexes, did not show unusual trends. The maximum and minimum peaks on the Fourier final difference map correspond to 0.30 and -0.32 eVA3, respectively. The neutral atom dispersion factors of Cromer and Waber6 were taken. Abnormal dispersion effects were included in Fcalc7; the values for? f and? f were those of Creagh and McAuley8. The values of the mass attenuation coefficients are those of Creagh and Hubbell9. All calculations were made using the teXsan10 crystallographic software package from Molecular Síructure Corporation. References (1) d * TREK: Software Detector Area. Version 4.13. Molecular Structure Corporation (1996-1998). (2) SIR97: Altomare, A., Burla, M. C, Cammalli, G. Cascarano, M., Giacovazzo, C, Guagliardi, A, Moliiemi, AGG, Polidori, G., Spagna, A., "SIR97: a new tool for crystal structure determination and refinement "(1990) J. Appl. Cryst, 32, 115-119. (3) DIRDIF94: Beurskens, P. T., Admiraal, G., Beurskens, G., Bosman, W. P., de Gelder, R., Israel, R. and Smits, J. M. M. (1994), "The DIRDIF-94 program system", Technical report of the crystallography laboratory, University of Nijmegen, The Netherlands. (4) Minimized least squares function:? W (F02-Fc2) 2 (5) Standard deviation of a unit weight observation: [Sw (F02-Fc2) 2 / (No-Nv)] 1 2 where: N0 = number of observations Nv = number of variables (6) Cromer, DT and Waber, JT; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, table 2.2 A (1974). (7) ibers, J. A. and Hamilton, W. C; Acta Crystallogr., 17, 781 (1964). (8) Creagh, D.C. and McAuley, W. J; "International Tables for Crystallography ", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2. 6.8, p. 219-222 (1992). (9) Creagh, D. C. and Hubbell, J. H; "International Tables for Crystallography ", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2. 4.3, p. 200-206 (1992). (10) teXsan for Windows, version 1.06: Crystal Structure Analysis Package, Molecular Structure Corporation (1997-9).

Experimental details A. Crystal data Empirical formula C20H32NO4CI Weight of the formula 385.93 Glass color, transparent habit, plate glass Dimensions 0.25 X 0.20 X 0.04 mm Monoclinic crystal system Network type Primitive Network parameters a = 8.4333 (7) A b = 9.4675 (9) A c = 12.581 (1) A ß = 93.125 (7) ° V = 1003.0 (1) A3 Space group P2? (# 4) Value Z 2 Dcalc 1.278 g / cm3 Fooo 416.00 μ (MoKa) 2.15 crt? 1 B. Intensity measurements ADSC Quantum 1 CCD detector Rigaku goniometer AFC7 MoKa radiation (? = 0.71069 A) monochrome graphite Detector aperture 94 mm x 94 mm Data images 462 exposures @ 60.0 s Scale of oscillation? (? = - 90.0> -18.0-23.0 ° Oscillation scale f (? = - 90.0) 0.0-190.0 ° Detector position 39.68 mm Detector rotation angle -5.50 ° ümax 50.2 ° No. of measured reflections Total: 7703 Unique: 3390 (R¡nt = 0.053, Friedels not combined) Corrections Lorentz-polarization Absorption / fall / escalation (trans factors: 0.7295-1.0000) C. Solution and refinement of structure Structure solution Direct methods (SIR97) Refining Least squares of full matrix in F2 Minimized function S w (Fo2-Fc2) 2 Weights of least squares 1 / s2 (Fo2) = 4Fo2 / s2 (Fo2) Abnormal dispersion All non-hydrogen atoms No. of observations (l> 0.00s ( l)) 3390 No. of variables 242 Reflection ratio / parameter 14.01 Residuals (refined in F2, all data): R1; wR2 0.057; 0.082 Goodness of adjustment indicator 0.97 Deviation / Error Max in the final cycle 0.00 No. of Observations (l> 3.00s (l)) 2624 Residuals (refined in F> 3.00s (l)): R 1; wR2 0.033; 0.038 Maximum peak in map of dif. final 0.30 e "/ A3 Minimum peak on final map of final -0.32 e" / Á3 X-ray structure of compound 1 The results of the determination of the X-ray structure for compound 1 confirmed the absolute configuration and the structural assignment as (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxy) monohydrochloride Phenetoxy) -cyclohexane. By inference and spectroscopic analysis, the absolute configuration and structural assignment for compound 2, compound 3, compound 4, compound 5, compound 6 and compound 7 were consequently confirmed.

Example 2 (1S, 2S) -2-r (3R) -hydroxypyrrolidinin-1 - (3,4-dimethoxyphenetoxOichohexane) monochlorohydrate (Compound 2) The 5SSR, (1S, 2S) -2 - [(3R) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane was prepared and resolved according to the example 1. Compound 2 was then obtained from 5SSR using the procedure described above in Example 1 with respect to the preparation of compound 1. Characterization: Cale, for C20H3? NO4.HCI: C 62.24, H 8.36, N 3.63, found: C 62.20, H 8.46, N 3.55; [a] D + 26.69 ° (c 13.04 g / L, CHCI3) Example 3 (1R.2R) / (1S, 2S) -2-r (3R) / (3S) -hydroxypyrrolidol1-1 - (3,4-dimethoxyphenetoxO-cyclohexane) monochlorohydrate (Compound 3) Preparation of intermediates N-Benzyloxycarbonyl-3-pyrrolidinol (Ib): To a cold solution (-60 ° C) of (20.0 g, 225 mmol) and Et3N (79 mL, 560 mmol) in CH2Cl2 (200 mL), he added dropwise a solution of benzyl chloroformate (34 mL, 225 mmol) in CH2Cl2 (80 mL). After the addition was complete in 45 min, the reaction mixture (a yellow suspension) was allowed to warm to room temperature and was stirred under argon at room temperature overnight. The reaction mixture was then quenched with ac HCl. 1M (350 mL) and the organic layer was collected. The aqueous acid layer was extracted with CH2Cl2 (2 x 150 mL) and the combined organic layer was dried. Evaporation under vacuum of the solvent gave 59.6 g of a pale yellow oil, which was further pumped into the high vacuum for 15 min to yield 58.2 g (17% of theory) of Ib, suitable for the next step without further purification. Rf 0.42 (EtOAc- / PrNH2, 98: 2, v / v); 1 H NMR (200 MHz, CDCl 3) d 7.40-7.30 (m, 5H), 5.10 (s, 2H), 4.40 (br s, 1H), 3.60-3.40 (m, 4H), 2.80 (d, J 15 Hz, 1 H), 2.00-1.90 (m, 2H); 13 C NMR (50 MHz, APT, CDCl 3) d 137.0 (+), 128. 5 (-), 127.5 (-), 71.0 (-), 70.0 (-), 66.5 (+), 55.0 (+), 54.5 ( +), 44.0 (+), 43.5 (+), 34.0 (+), 33.5 (+); IR (film) 3415 (wide), 1678 cm-1. N-Benzyloxycarbonyl-3-pyrrolidinone (le): To a cold solution (-60 ° C) of oxalyl chloride (23 mL, 258.6 mmol) in CH2Cl2 (400 mL), a solution of DMSO (36.7) was added dropwise. mL, 517.3 mmol) in CH2Cl2 (20 mL), at a suitable rate to maintain the temperature below -40 ° C. The reaction mixture was then stirred at -60 ° C for 15 min. Then a solution of Ib (58.2 g) was added dropwise, not more than 225 mmol) in CH2Cl2 (80 mL), keeping the temperature of the reaction mixture below -50 ° C. The reaction mixture was then stirred at -60 ° C for 30 min before adding Et3N (158.3 mL, 1125 mol). The resulting mixture was allowed to warm to room temperature and then washed with water (600 mL), aq. 1M (580 mL) and water (400 mL). The organic layer was dried and concentrated in vacuo to leave 54.5 g of an amber oil, which was pumped additionally to the empty ally, with stirring and at room temperature for 25 min, to give 52 g of 1c (5.6% over the theoretical yield). , suitable for the next step without further purification. Rf 0.81 (EtOAc- / PrNH2, 98: 2, v / v); 1 H NMR (200 MHz, CDCl 3) d 7.40-7.30 (m, 5H), 5.20 (s, 2H), 3.90-3.80 (m, 4H), 2.60 (t, J 7Hz, 2H); 13 C NMR (50 MHz, APT, CDCl 3) d 136.0 (+), 128.5 (-), 128.0 (-), 67.0 (+), 52.5 (+), 42.5 (+), 36.5 (+); IR (film) 1759, 1708 cm-1. 7-Benzyloxycarbonyl-1,4-dioxa-7-azaspiro [4.4] nonane (Id): A mixture of le (52 g, not more than 225 mmol) and ethylene glycol (18.8 mL, 337.4 mmol) in íoluene (180 mL) , with a catalytic amount of p-TsOH.H20 (1.0 g, 5.4 mmol), was refluxed in a Dean-Stark apparatus for 16 h. The reaction mixture was then diluted with more toluene (250 mL) and washed with a saturated aqueous solution of NaHC 3 (150 mL) and brine (2 x 150 mL). The combined aqueous layer was back extracted with toluene (100 mL). The combined organic layer was dried and concentrated in vacuo to leave 79.6 g of a dark oil. The crude product was dissolved in EtOH (500 mL) and passed through a bed of activated carbon (80 g), discoloring the resulting solution. The carbon was washed with more EtOH (1000 mL) and toluene (500 mL). The filtrate was concentrated in vacuo and further pumped into the high vacuum for 1 h, to yield 63.25 g of Id (6.8% over theoretical yield), suitable for the next step without further purification. Rf 0.78 (EtOAc- / PrNH2, 98: 2, v / v); 1 H NMR (200 MHz, CDCl 3) d 7.40-7.20 (m, 5H), 5.20 (s, 2H), 4.00 (s, 4H), 3.60-3.50 (m, 2H), 3.50-3.40 (m, 2H), 2.10-2.00 (m, 2H); 13 C NMR (50 MHz, APT, CDCl 3) d 137.0 (+), 128.5 (-), 128 (-), 67.0 (+), 65.0 (+), 5.5 (+), 45.0 (+), 34.5 (+); IR (film) 1703 crn-1. 1, 4-Dioxa-7-azaspiro [4.4] nonane (le): A mixture of Id (34.8 g, not more than 124 mmol) and Pd 10% -C (14 g) in EtOH (90 mL), was hydrogenated (4.2 kg / cm2) in a Parr shaker at room temperature for 1.5 h. The catalyst was removed by filtration, the solvent was evaporated in vacuo and the residue was pumped under high vacuum for 20 min to produce it (15.9 g, quantitative yield). Rf 0.14 (EOAc- / PrNH2, 95: 5, v / v); 1 H NMR (200 MHz, CDCl 3) d 4.00 (s, 4 H), 3.10 (,, J7 Hz, 2 H), 2.90 (s, 2 H), 2.00 (,, J7 Hz, 2 H); 13 C NMR (50 MHz, APT, CDCl 3) d 64.5 (+), 55.0 (+), 45.5 (+), 37.0 (+); IR (film) 3292 cm "1. (1 R, 2R) / (1 S, 2 S) -1 - (1,4-Dioxa-7-azaspiro [4.4] non-7-yl) -cyclohexan-2-ol (2e): A mixture of le (23.5 g, not more than 182 mmol), cyclohexene oxide (23 mL, 220 mmol) and water (8 mL), was heated at 80 ° C for 2 h. it was then partitioned between 40% aq NaOH (60 mL) and Et2O (120 mL) The basic aqueous layer was extracted twice more with E2O2 (2 x 120 mL) The combined organic extract was dried and concentrated in vacuo. The residue was then heated to the vacuum at 50 ° C for 1 h with stirring (to remove excess cyclohexene oxide), to yield 32.8 g of 2e (79% yield) Rf 0.33 (EtOAc - / 'PrNH2 , 98: 2, v / v); 13C NMR (50 MHz, APT, CDCI3) d 115.5 (+), 70.0 (-), 65.0 (-), 64.5 (+), 57.0 (+), 46.5 (+) , 36.0 (+), 33.5 (+), 25.0 (+), 24.0 (+), 21.5 (+); IR (film) 3457 cm "1. It was brought (1R, 2R) / (1S, 2S) -1- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -2- (3,4-dimethoxyphenoxy) cyclohexane in E2O (80 mL) with ethereal HCl. Solvent was evaporated in vacuo and the residue was taken up with E2O2 and trifurized. The monohydrochloride of (1R, 2R) / (1S, 2S) -1- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -2- (3,4-dimethoxyphenoxy) cyclohexane was precipitated of a mixture of CH2Cl2-EI2O. A solution of (1R, 2R) / (1S, 2S) -1- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -2- (3,4-dimethoxyphenoxy) cyclohexane with ac HCl . 6 M (50 mL) in 2-butanone (200 mL) was refluxed for 12 h. The butanone was evaporated in vacuo and the solution was diluted to 250 mL with water. The aqueous solution was extracted with Ef2O (2 x 200 mL) and then with CH2CI2 (2 x 200 mL). The combined CH2Cl2 extract was dried and the solvent was evaporated in vacuo. The residual oil was azeotropically dried with toluene. The resulting sticky product was triturated in Et2O (500 mL) and the resulting solid was collected and solubilized in a small amount of CH2Cl2 (~10 mL); then, the addition of a large amount of E2O2 (~ 400 mL) enabled recrystallization. The solid was collected and dried under high vacuum for 3 h to yield monohydrochloride of (1R, 2R) / (1S, 2S) -1- (3,4-dimethoxyphenetoxy) -2- (3-cetopyrrolidinyl) Cyclohexane (compound 18) (1.9 g, 56% yield). 1 H NMR (400 MHz, free base, CDCl 3) d 6.70 (m, 3 H, Ar), 3.85 (2 s, 6 H, 2 x CH 3 O), 3.80-1.10 (m, 20 H, aliphatic); 13 C NMR (75 MHz, APT, free base, CDCl 3) d 215.21 (+), 148.57 (+), 147.27 (+), 131.64 (+), 120.61 (-), 112.11 (-), 111.03 (-), 79.40 (-), 69.43 (+), 63.64 (-), 58.90 (+), 55.76 (-), 55.70 (-), 48.00 (+), 37.63 (+), 36.31 (+), 29.00 (+), 27.07 (+), 23.54 (+), 23.01 (+); HRMS (El) hot mass for C20H29O4N: 347.20966, found 347.21046 (21.1%); Anal. (C20H30O4NCI) H, N; C: cale. 62.57, enconfrado, C 60.32. Preparation of monohydrochloride of (1R, 2R) / (1S, 2S, -1- (3,4-dimethoxyphenetoxy) -2- (3- (R / S) -hydroxypyrrolidinyl) cyclohexane (Compound 3). To a cold suspension ( 0 ° C) of sodium borohydride (1.53 g, 40 mmol) in isopropanol (60 mL), a solution of compound 18 (6.14 g, 16 mmol) in isopropanol (40 mL) was slowly added. stirred at 0 ° C for another 30 min and then allowed to warm to ambient temperature for 1 h The reaction mixture was cooled to 0 ° C again and slowly hydrolyzed with 1 M aq HCl (80 mL). It was left to warm to ambient temperature and was stirred overnight, the organic solvent was evaporated in vacuo, the residual aqueous layer was diluted with water to 150 mL, and extracted with diethyl ether (1 x 150 mL) and dichloromethane (3 x 150). mL) The combined dichloromethane extract was concentrated to 120 mL and treated with an aqueous solution of 0.25 M sodium hydroxide (100 mL). Stopped and extracted twice more with dichloromethane (2 x 150 mL). The combined dichloromethane extract was dried over sodium sulfate and evaporated in vacuo. Purification by dry column chromatography (ethyl acetate-hexane, 4: 1, + 0.5% isopropylamine v / v) gave 2.0 g of the compound as a free base (36% yield). The free base, 1.9 g, was partitioned between dichloromethane (24 mL) and aq. 0.5 M (24 mL). The aqueous layer was separated and extracted three more times with dichloromethane (3 x 24 mL). The combined dichloromethane extract was dried over sodium sulfate and the solveny evaporated in vacuo. By azeopyric desilylation with benzene (2 x 25 mL) and drying under high vacuum, the title compound was obtained as a whitish hygroscopic solid (1.58 g). 1 H NMR (400 MHz, free base, CDCl 3) d 6.80-6.70 (m, 3 H, Ar), 4.20-1.10 (m, 22 H, aliphatic), 3.80 (2 x s, 6 H, 2 x CH 3 O); 13 C NMR (75 MHz, APT, free base, CDCl 3) d 148.56 (+), 147.25 (+), 131.83 (+), 120.66 (-), 112.25 (-), 111.00 (-), 79.30 (-), 79.11 (-), 70.96 (-), 70.73 (-), 69.62 (+), 69.50 (+), 63.28 (-), 59.67 (+), 59.35 (+), 55.80 (-), 55.71 (-), 48.70 (+), 48.44 (+), 36.35 (+), 34.33 (+), 34.17 (+), 28.81 (+), 29.76 (+), 27.09 (+), 27.03 (+), 23.30 (+), 23.22 (+), 22.92 (+), 22.86 (+); HRMS (El) hot mass for C2oH3? N2O: 349.22531, found 349.22578 (100%); HPLC (Zorbax Extend C18, 150 x 4.6 mmm, 5 μ; 20-70% acetonitrile: 10 mM phosphate buffer (pH 2.5)) 95.8%; CE 99.8%.

Example 4 Monohydrochloride of (1R, 2R) / (1S.2S) -2-r (3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxD-cyclohexane (Compound 4) (1R, 2R) / (1S, 2S) -2 - [(3R) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane was prepared according to Example 1. The title compound was formed by hydrogenolysis of (1 R, 2R) / (1S, 2S) -2 - [(3R) -benzyloxypyrrolidinyl] -1- (3,4-d¡methoxyphenetoxy) cyclohexane under the conditions describe in example 1.

Example 5 (1R, 2R) / (1S, 2S) -2-r (3S) -hydroxypyrrolidinin-1 - (3,4-dimethoxyphenethoxy) -cyclohexane monochlorohydrate (Compound 5) (1R, 2R) / (1S, 2S) -2 - [(3S) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane was prepared according to example 1. The title compound was prepared by hydrogenolysis of (1R, 2R) / (1S, 2S) -2 - [(3S) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane under the conditions described in example 1.

Example 6 Monohydrochloride of (1 R.2R) -2-R3S) -hydroxy pyrrolidinip-1 - (3,4- dimethoxyphenetoxyCyclohexane (Compound 6) Mono (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane monohydrochloride (compound 6) was prepared according to the method of example 1, but starting with 3- (S ) -hydroxypyrrolidine.

Example 7 (1S.2S) -2-r (3S) -hydroxypyrrolidinyl-3,4-dirnetoxifenetoxhexano (Compound 7) monohydrochloride (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) cyclohexane monohydrochloride (compound 7) was prepared according to the method of examples 1 and 2, but starting from with 3- (S) -hydroxypyrrolidine.

Comparative example 8 Monohydrochloride of (1 R.2R) / (1S.2S) -1 - (3,4-di methoxy-enetoxy) -2- (1,4-dioxa-7-azaspiror4.41non-7-yl) cyclohexane (Compound 9) To a cold (0 ° C) solution of 2e (4.62 g, 20 mmol) and triethylamine (2.64 g, 26 mmol) in dichloromethane (40 mL), methanesulfonyl chloride (3.0 g, 26 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 45 min and then at room temperature for 2 h. The reaction mixture was then washed with a mixture of water-saturated aqueous sodium bicarbonate solution (1: 1, v / v, 30 mL). The aqueous layer was collected and back extracted with dichloromethane (2 x 30 mL). The combined organic extract was dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude mesylate, suitable for the next step without further purification. To a dispersion of sodium hydride (0.72 g, 80% dispersion in mineral oil, 24 mmol) suspended in DME (20 mL), was added a solution of 3,4-dimethoxyphenethyl alcohol (4.46 g, 24 mmol) in DME (20 mL). The resulting mixture was then stirred at ambient temperature for 2 hours. The mesylate in DME (40 mL) was added rapidly to the alkoxide and the resulting mixture was refluxed under argon for 20 h. The cold reaction mixture was quenched with water (60 mL) and the organic solvent was evaporated in vacuo. The residual aqueous solution was acidified with aq. 10% at pH 0.3 and extracted with diethyl ether (2 x 75 mL). The aqueous layer was collected, basified to pH 7.0 with aq. NaOH. 5 M and extracted with diethyl ether (3 x 70 mL). The combined diethyl ether extract was dried over sodium sulfate and the solvent was evaporated in vacuo to yield 7.1 g (89% yield) of the title compound as a free base. The free amine (0.58 g, 1.48 mmol) was partitioned between dichloromethane (8 mL) and aq. 0.5 M (8 mL). The aqueous layer was collected and expelled twice more with dichloromethane (2 x 8 mL). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to yield 0.62 g (98% yield) of the title compound. Rf 0.13 (EOAc-hexane, 1: 4, v / v, + 0.5% v / v / PrNH2); 1 H NMR (400 MHz, free amine, CDCl 3) d 6.75 (m, 3 H, Ar), 3.86-1.16 (m, 24 H, aliphatic); 13 C NMR (75 MHz, APT, free amine, CDCl 3) d 148.59 (+), 147.2 (+), 131.95 (+), 120.74 (-), 115.24 (+), 112.26 (-), 111.04 (-), 79.10 (-), 69.78 (+), 64.22 (+), 64.00 (-), 60.48 (+), 55.84 (-), 55.74 (-), 49.92 (+), 36.48 (+), 35.84 (+), 28.60 (+), 26.92 (+), 23.01 22.74, HRMS (El) hot mass for C22H33NO5: 391.23587, found 391.23546 (100%); HPLC (Zorbax Extend C18.150 x 4.6 mm, 5 μ; 20-7-% acetoniiril: 10 mM phosphate buffer (pH 2.5)) 84.2%; CE 98.5%.

Comparative Example 9 (1R, 2R) / (1S.2S) -1- (3,4-d? Methoxlfenetoxy) -2- (pyrrolidinyl) cyclohexane monochlorohydrate (Compound 10) Pyrrolidine (10.5 g, 148 mmol), cyclohexene oxide (15 mL, 148 mmol) and water (5 mL) were refluxed under nitrogen for 7 h. The orange and cold mixture was divided between saturated aqueous sodium hydroxide solution (150 mL) and diethyl ether (150 mL). The aqueous layer was rinsed with diethyl ether (75 mL) and the combined layer of diethyl ether was dried over sodium sulfate. The diethyl ether was removed in vacuo and the residual oil was distilled in vacuo (p.b., 51 ° C under complete vacuum) to give (1R, 2R) / (1S, 2S) -2- (pyrrolidinyl) cyclohexan-1. -ol (21.9 g, 87%). 13C NMR (50 MHz, APT, CDCI3) d 70.47 (-), 64.82 (-), 47.44 (+), 33.15 (+), 25.11 (+), 24.23 (+), 24.00 (+), 21.12 (+) . To a cold (0 ° C) solution of (1R, 2R) / (1S, 2S) -2- (pyrrolidinyl) cyclohexan-1-ol (1.7 g, 10 mmol) and triethylamine (1.8 mL, 13 mmol) in dichloromethane (50 mL), pure methanesulfonyl chloride (1.0 mL, 13 mmol) was added. The resulting mixture was stirred at 0 ° C for another 45 min and then allowed to warm up to room temperature for 3 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2 x 50 mL). The combined washing was back extracted with dichloromethane (50 mL) and dried over sodium sulfate. Vacuum evaporation of the solvent produced the crude mesylate, suitable for the next step without further purification. To NaH (0.33 g, 11 mmol) in DME (15 mL) was added a solution of 3,4-dimethoxyphenethyl alcohol (2.0 g, 11 mmol) in DME (15 mL).

The resulting mixture was stirred for 2 h at room temperature under argon. The mesylate in DME (20 mL) was added to the alkoxide and the resulting reaction mixture was refluxed for 3 h. The solvent was evaporated in vacuo, the residue was taken up with water (100 mL) and the pH adjusted to 1 with ac HCl. 1 M. The aqueous acidic solution was then extracted with diethyl ether (100 mL) and the pH adjusted to 13. Extraction with diethyl ether (2 x 100 mL) gave the free base of the thioule compound. Trituration with ethereal hydrogen chloride followed by trituration in diethyl ether gave 1.0 g (27% yield) of the title compound as the hydrochloride salt. 1 H NMR (400 MHz, CDCl 3) d 11.60 (br s, 1 H, HN +), 6.70 (m, 3 H, Ar), 3.80 (2 xd, 2 x 6 H, CH 3 O), 3.70-1.05 (m, 22 H, aliphatic); 13 C NMR (75 MHz, APT, CDCl 3) d 148.72 (+), 147.41 (+), 131.32 (+), 120.69 (-), 112.04 (-), 111.07 (-), 77.82 (-), 68.83 (+) , 66.94 (-), 55.87 (-), 53.12 (+), 51.76 (+), 35.92 (+), 30.25 (+), 28.30 (+), 24.34 (+), 23.44 (+), 23.01 (+) , 22.13 (+); MS (+ LSIMS) M + + H 334 (100%); Anal. (C20H32O3NCI) H, N; C: cale, 64.94; found, 63.04.

Comparative Example 10 Monohydrochloride of (1 R.2R.-1 - (3- (R) -acetyloxypyrrolidinyl) -2- (3,4-dimethoxyphenetoxy) cyclohexane (Compound 17) Acetyl chloride (5 mL, 70.31 mmol) was added dropwise to a solution of (3R) -1-. { (1R, 2R) -2- [2- (3,4-dimethoxy-phenyl) -ethoxy] -cyclohexyl} pyrrolidin-3-ol, free base (2.12 g, 5.49 mmol) in methylene chloride (50 mL), at 1 ° C. The reaction was allowed to reach ambient ambience during the night. The reaction was moniformed by TLC and visualized with iodine. The Rf of (1 R, 2R) -1- (3- (R) -acetyloxypyrrolidinyl) -2- (3,4-dimethoxyphenetoxy) cyclohexane is 0.36 in methylene-methylene chloride (0.5: 95, v / v). ). Excess acetyl chloride and solvent were removed under reduced pressure, and DCM (30 mL) was added to the remaining mixture. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (30 mL), dried over magnesium sulfate and concentrated to yield the acetamide-free base (1.3 g, 4.35 mmol) with 61% yield.

Comparative example 11 Monohydrochloride of (1R.2S) / (1S.2R) -1- (3- (R / S) -hydroxypyrrolidinyl) -2- (1-naphthalenetoxOcyanohexane (Compound 25) Preparation of the intermediate compound (1 R, 2S) / (1S, 2R) -1- (3-ketopyrrolidinyl) -2- (1-naphthalenetoxy) cyclohexane monochloride: To a flask containing Mg (CIO4) 2 (2.14 g, 0.95 mmol), dried in a vacuum flame, cold and charged with argon, a solution of 1-naphthalene-ethanol (21.6 g, 125 mmol) in CH3CN (15 mL) was added by means of a cannula. The resulting mixture was refluxed until all the material was dissolved and then cyclohexene oxide (1.0 g, 10 mmol) was added over a period of 2.5 h. The reaction mixture was then refluxed for 16 h, cooled to room temperature and partitioned between water (150 mL), saturated aqueous solution of NaHCO3 (50 mL) and Et2O (100 mL). The aqueous layer was collected and extracted twice with E2O2 (2 x 100 mL). The combined extract of E2O2 was rinsed with brine (50 ml), dried and concentrated in vacuo to yield 25.2 g of crude material, which solidified upon standing. The excess of 1-naphthalene ethanol was recovered by successive recrystallizations from Et 2 O-hexane (1: 1, v / v). The resulting mother liquor obtained after 3 recrystallizations (7.5 g) was purified by chromatography, using a mixture of EtOAc-hexane (1: 5, v / v, + 0.5% v / v / PrNH2), to give 1.5 g (55 g). % yield) of crude (1R, 2R) / (1S, 2S) -2- (1-naphthalenetoxy) cyclohexan-1-ol, which was used in the next step without further purification. To a suspension of pyridinium chlorochromate (PCC) (4.78 g, 22.2 mmol) in CH2Cl2 (35 mL), a solution of (1R, 2R) / (1S, 2S) -2- (1) was added at once. -naphthaleneloxy) cyclohexan-1-ol (1.5 g, 5.5 mmol) in CH2Cl2 (5 mL). The resulting dark brown mixture was stirred at room temperature for 16 h and then filtered through a plug of silica gel covered with Na 2 SO 4. The plug was further rinsed with Et 2 O (3 x 40 mL) and the filtrate was concentrated in vacuo to yield 2.0 g of crude material. The crude material was applied to a dry column of silica gel and eluted with a mixture of EtOAc-hexane (1: 6, v / v, + 0.5% v / v / PrNH2) to yield 1.0 g of (2R / 2S ) -2- (1-naphthalenetoxy) cyclohexan-1-one (68% yield). 13 C NMR (50 MHz, APT, CDCl 3) d 203.0 (+), 135.0 (+), 134.0 (+), 132 (+), 129.0 (-), 127.0 (-), 125.5 (-), 125.0 (-) , 123.5 (-), 113.0 (-), 83.0 (-), 70.0 (+), 40.0 (+), 34.5 (+), 33.5 (+), 28.0 (+), 23.0 (+); IR (film) 1720 crr? 1. Reflux (2R / 2S) -2- (1-naphthalenetoxy) cyclohexan-1-one (1.0 g, 3.7 mmol), 2e (1.2 g, 9.3 mmol) and poly (4-vinylpyridine) or PVP (0.4 g) were refluxed. ) in benzene (10 mL) in a Dean-Stark apparatus for 5 h. The cold reaction mixture was then transferred rapidly to a Parr shaker apparatus; Pd was added over activated charcoal (0.2 g) and the mixture was hydrogenated for 16 h. The caíalizador was removed by filiración; the filtrate was concentrated in vacuo and the resulting crude material (cis-trans, 87:13, area% / GC) was purified by dry column chromatography with a mixture of EtOAc-hexane (1: 2, v / v, + 0.5 % v / v / PrNH2), to give 1.0 g (70% yield) of (1 R, 2S) / (1 S, 2R) -1 - (1, 4-dioxo-7-azaspiro [4.4] non- 7-yl) -2- (1-naphthalenetoxy) -cyclohexane, which was refluxed with aq. 6 M (20 mL) in 2-butanone (80 mL) for 16 h. The cold reaction mixture was concentrated in vacuo and the residue was diluted with water (90 mL). The aqueous solution was then extracted with Et 2 O (2 x 50 mL) and CH 2 Cl 2 (3 x 70 mL). The combined CH2Cl2 extract was dried and the solvent was evaporated in vacuo. Trituration in Et20 gave the monohydrochloride of (1 R, 2S) / (1 S, 2R) -1- (3-ketopyrrolidinyl) -2- (1-naphthalenetoxy) -cyclohexane (0.82 g, 84% yield); p.f. 176-178 ° C; 1 H NMR (400 MHz, CDCl 3) d 12.53 (br s, 1 H, HN +), 8.06-7.32 (m, 7 H, Ar), 4.05-1.16 (m, 20 H, alif.); 13 C NMR (75 MHz, APT, CDCl 3) d 204.19 (+), 204.02 (+), 134.99 (+), 134.90 (+), 133.65 (+), 131.94 (+), 131.85 (+), 128.71 (-) , 127.12 (-), 127.04 (-), 125.92 (-), 125.84 (-), 125.53 (-), 125.45 (-), 123.75 (-), 123.68 (-), 72.49 (-), 71.79 (-) , 68.39 (+), 68.24 (+), 65.50 (-), 64.92 (-), 54. 73 (+), 54.33 (+), 48.86 (+), 48.22 (+), 35.56 (+), 35.12 ( +), 32.91 (+), 26.81 (+), 26.77 (+), 24.00 (+), 22.53 (+), 21.97 (+), 18.3 (+); HRMS (The) Anal. Mass (C22H28NO2CI) C, H, N. Preparation of compound 25. monohydrochloride (1 R.2SV (1 S.2RV1 - (3- (R / S) -hydroxypyrrolidinyl) -2- (1-naphthalenetoxOcielohexane To a solution of monohydrochloride of (1 R, 2S / (1S, 2R) -1 - (3-Cetopyrrolidinyl) -2- (1-naphthalenetoxy) cyclohexane (0.55 g, 1.5 mmol) in isopropanol (15 mL), sodium borohydride (0.3 g, 7.9 mmol) was added portionwise. it was stirred at room temperature for 16 h.The reaction mixture was quenched with 6 M aq HCl (4 mL) for 2 h and then concentrated in vacuo.The residual solid was taken with dichloromethane (20 mL), the insoluble material it was filtered off and washed once more with dichloromethane (20 mL), the combined filtrate was treated with ethereal hydrogen chloride (20 mL), the solvent was evaporated in vacuo and the residual oil was triturated in diethyl ether (80 mL). to yield 0.32 g (57% yield) of a hygroscopic solid.1H NMR (400 MHz, CDCl3) d 10.30 (br s, 1H, HN +), 8.10-7.30 (m, 7H, Ar), 5.40-1.00 (m , 22H, aliphatic); 13C NMR (75 MHz, APT, CDCI3) d 135.15 (+), 133.59 (+), 131.92 (+), 128.53 (-), 127.05 (-), 126.85 (-), 125.80 (-), 125.40 (-), 123.87 (- ), 72.51 (-), 72.17 (-), 68.81 (-), 68.76 (-), 68.57 (+), 66.41 (-), 66.25 (-), 65.19 (-), 59.75 (+), 59.08-58.68 (+), 50.43-49.82 (+), 33.02 (+), 32.98 (+), 26.75 (+), 23.96 (+), 22.93-22.42 (+), 18.23 (+); MS (ES +) M ++ H 340.1 (100%); HPLC (Zorbax Extend C18.150 x 4.6 mm, 5 μ; 20-70% acetonitrile: 10 mM phosphate buffer (pH 2.5)) 96.7%; CE 98.7%.

Comparative Example 12 Monohydrochloride of (1 R.2R) / (1 S, 2SH2- (4-morpholinyl) -1 - (2-naphtenetoxyffl-cyclohexane (Compound 30) (i) Morpholine (5 mL, 57 mmol), cyclohexene oxide (5.8 mL, 57 mmol) and water (3 mL) were refluxed for 1.5 h. A GC analysis showed that the reaction was complete. The cold mixture was partitioned between a saturated solution of NaOH (50 mL) and ether (75 mL). The aqueous layer was rinsed with ether (30 mL) and the combined ether layer was dried over sodium sulfate. The ether was removed in vacuo to leave a yellow oil (9.83 g). The crude product, (1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) cyclohexanol, was purified by vacuum distillation (p.b. 75-80 ° C in total vacuum), to give a transparent liquid (8.7 g). Performance, 82.5%. (¡I) To a cold (0 ° C) solution of (1 R, 2R) / (1S, 2S) - [2- (4-morpholinyl)] - cyclohexanol (6.0 g, 32.4 mmol) and triethylamine (6.8 mL) , 48 mmol) in dichloromethane (100 mL), a solution of methanesulfonyl chloride (3.10 mL, 40 mmol) in dichloromethane (50 mL) was added via a cannula. The addition was completed in 10 min; the reaction mixture was stirred for another hour at 0 ° C and then at room temperature for 4 hours. The dichloromethane mixture was washed with water (2 x 50 mL) and the combined aqueous wash was rinsed with dichloromethane (50 mL). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give 8.5 g (100% yield) of the crude mesylate. (iii) To a dispersion in 80% oil of sodium hydride, previously washed with hexane (3 x 20 mL), (1.24 g, 51.6 mmol) in dry dimethylformamide (50 mL), was added by means of a cannula a solution of 2-naphthalene-ethanol (6.8 g, 40 mmol) in dry dimethylformamide (50 mL). The addition was followed by the evolution of gas and, as the reaction mixture was stirred at room temperature, it began to gel. The mesylate prepared above in (ii) was dissolved in dimethylformamide (50 mL) and the resulting solution was rapidly added to the suspension of alcohol by means of a cannula. The reaction mixture was heated to 80 ° C and then the temperature was reduced to 40 ° C. The resulting yellow solution was poured into ice-water (1500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extract was rinsed with a saturated aqueous solution of sodium chloride (500 mL) and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded 13.4 g of an amber oil, which was dissolved in water (150 mL) and the pH of the solution adjusted to 2 with 1M aqueous HCl. The aqueous acid solution was extracted with ethyl ether (2 x 100 mL) and then basified to pH 10 with a 50% aqueous sodium hydroxide solution. The basic aqueous solution was extracted with ethyl ether (2 x 100 mL); The combined organic layer was dried over sodium sulfate and concentrated in vacuo to leave 7.16 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), with a mixture of ethyl acetate-chloroform (1: 1, v / v) as eluent, to yield 4.37 g of the pure free base. The product was dissolved in ethyl ether (80 mL) and converted to the monochlorhydrate salt by adding a HCl solution in ethyl ether (80 mL). An oil was separated from the solution; the solvent was evaporated in vacuo and the residue was dissolved in the minimum amount of hot ethyl alcohol; the addition of a large volume of ethyl ether activated the crystallization. The crystals were collected to yield 3.83 g (31% yield) of the compound of the extract, p. F. 158-160 ° C.

Comparative Example 13 (1R.2R) / (1 S.2S) -r2- (4-morpholinyl) -1- (4-bromophenetoxy) -1-cyclohexane monochlorohydrate (Compound 32) (i) The initial frans-aminocyclohexanol is prepared according to comparative example 12. (i) To a cold (0 ° C) solution of (±) -írans- [2-morpholinyl)] - cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 mL, 24 mmol) in dichloromethane (25 mL), a solution of methanesulfonyl chloride (1.55 mL, 20.0 mmol) in dichloromethane (25 mL) was added via a cannula. The addition was finished in 5 min and the reaction mixture was stirred at 0 ° C for another hour and then at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromelane (50 mL) and washed with water (2 x 50 mL); The combined aqueous wash was rinsed with dichloromethane (25 mL). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give 4.7 g of the crude mesylate. (iii) To a dispersion of sodium hydride (0.62 g, 25.8 mmol) at 80% in oil, washed beforehand with hexane (3 x 10 mL), in dry dimethylformamide (25 mL), a solution of alcohol 4 was added. -bromofenethylic acid (4.0 g, 20 mmol) in dimethylformamide (50 mL) by means of a cannula. The addition was followed by evolution of gas and the reaction mixture was stirred at room temperature for 4 hours. The mesylation prepared above in (ii) was dissolved in dry dimethylformamide (50 mL) and the resulting solution was added rapidly (3 min) by means of a cannula to the suspension of the alcohol. The reaction mixture was heated at 80 ° C for 2 hours and then the temperature was reduced to 35 ° C; the reaction was stirred overnight. The reaction mixture was poured into ice-water (800 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extract was rinsed with a saturated aqueous solution of sodium chloride (150 mL) and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded 7.4 g of an oil which was dissolved in ether (80 mL) and treated with a saturated solution of HCl in ether. An oil was separated from the solution; the solvent was evaporated in vacuo and the residue was dissolved in water (100 mL). The aqueous acid solution was extracted with ethyl ether (2 x 50 mL) and then basified to pH 10 with 50% aqueous sodium hydroxide solution. The basic aqueous solution was extracted with ethyl ether (2 x 50 mL); The combined organic layer was dried over sodium sulfate and concentrated in vacuo to leave 3.67 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh) with a mixture of ethyl acetate-dichloromean (1: 1, v / v) as elue, to give the pure free base. The product was dissolved in ethyl ether (30 mL) and converted to the monohydrochloride salt by adding a saturated solution of HCl in ethyl ether (30 mL). Solvent was evaporated and the residue dissolved in the minimum amount of ethyl alcohol; the addition of a large volume of ethyl ether activated the crystallization. The crystals were collected to yield 1.31 g of the compound of the extract, p. F. 148-151 ° C.

Comparative example 14 Monohydrochloride of (1R.2R) / (1S.2S) -2- (3-ketopyrrolidinyl) -1 - (2,6- dichlorophenoxyOcicylohexane (Compound 41) (vi) To a cold solution (0 ° C) of (1R, 2R) / (1S, 2S) -2- (1, 4-dioxa-7-azaspiro [4.4] non-7-yl) cyclohexanol (2e) (27.77 g, 120 mmol) and triethylamine (22 mL, 156 mmol) in dichloromethane (240 mL), methanesulfonyl chloride (12.32 mL, 156 mmol) was added. The reaction mixture was stirred at 0 ° C for 45 min and then at ambient temperature for 3 hours. The reaction mixture was washed with water (2 x 100 mL) and the combined wash was rinsed with dichloromethane (120 mL). The combined organic extract was dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude mesylate, which was further pumped into the high vacuum for 4 hours before using in step (ix) below. (vii) 2,6-Dichlorophenylethyl alcohol: To a suspension of lithium aluminum hydride (13.75 g, 365.75 mmol) in drous diethyl ether (500 mL) was added 2,6-dichlorophenylacetic acid (50 g, 243.75 mmol) by means of a funnel of powder addition. The resulting reaction mixture was refluxed for 16 hours and then quenched by the slow addition of a saturated aqueous solution of sodium sulfate (25 mL). The resulting suspension was stirred for 3 hours and then filtered; the insoluble material was carefully washed with diethyl ether (2 x 100 mL). The combined ether filtrate was dried over sodium sulfate and the solvent was evaporated in vacuo to yield 38.6 g (85% yield) of the title compound. (viii) To sodium hydride (144 mmol, 4.32 g, 80% oil dispersion) in anhydrous ethylene glycol dimethyl ether (80 mL), a solution of 6-dichlorophenethyl alcohol (27.65 g, 144 mmol) was added to dimethyl ether of anhydrous ethylene glycol (80 mL). The resulting mixture was stirred at ambient temperature under an argon atmosphere for 4 hours. (ix) (1R, 2R) / (1S, 2S) -2- [1,4-Dioxa-7-azaspiro [4.4] non-7-yl] -1- (2,6-dichlorophenoxy) cyclohexane: The mesylation of (vi) in anhydrous ethylene glycol dimethyl ether (80 mL) was added rapidly to the alkoxide mixture (viii); the resulting mixture was rapidly refluxed for 66 hours. The cold reaction mixture was poured into water (200 mL) and the organic solvent was evaporated in vacuo. The residual aqueous solution was diluted with more water to a volume of 700 mL; it was acidified to pH 0.5 with 6M aqueous HCl solution and extracted with diethyl ether (2 x 600 mL). The pH of the aqueous layer was adjusted to 5.9 and then the aqueous solution was extracted with diethyl ether (700 mL). The organic extract was dried over sodium sulfate and the solvent was evaporated in vacuo to yield 34.0 g of the title compound (70% yield). (x) Monochlorohydrate of (1R, 2R) / (1S, 2S) -2- (3-cyclopyrrolidinyl) -1- (2,6-dichlorophenoxy) cyclohexane: A mixture of (1R, 2R) / (1S, 2S ) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (2,6-dichlorophenoxy) cyclohexane (15.85 g, 38.9 mmol, step ix) and aqueous solution of 6M HCl (100 mL) in 2-buyenone (400 mL), was refluxed for 16 hours. The already cold reaction mixture was diluted with water (100 mL) and the organic solvent was evaporated in vacuo. The organic layer was diluted with more water (400 mL), extracted with diethyl ether (500 mL) and with dichloromethane (2 x 600 mL). The combined dichloromethane extract was dried over sodium sulfate and the solvent was evaporated in vacuo. Azeotropic distillation with toluene gave the thioule compound, which was further dried at high vacuum for 15 min. The hydrochloride salt was crystallized by frying in diethyl ether; the crystals were collected and recrystallized from a mixture of ethanol-diethyl ether, to yield 11.85 g of pure product (77% yield), which had the correct elemental analysis.

Comparative Example 15 Monohydrochloride of (1R, 2R, / (1S, 2S) -2-, 3-acetoxy pyrrolidinyl, -1-Í1-naphtenetoxycyclocyclohexane (Compound 43) (i) (1 R, 2R) / (1S, 2S) -2- (3-hydroxypyrrolidinyl) -1- (1-naphtenetoxy) cyclohexane monochloride: To a cold solution (0 ° C) of sodium borohydride in isopropanol (20 mL) was added a solution of (1 R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (1-naphtenetoxy) cyclohexane monohydrochloride (1.4 g, 3.75 mmol) in isopropanol (30 mL). The resulting mixture was stirred at 0 ° C for 15 min and then at ambient temperature for 30 min. The reaction is inactivated by adding water; The reaction mixture was evaporated to dryness and the residue was washed with dichloromethane (2 x 20 mL). The dichloromethane washes were dried over sodium sulfate and the solvent was evaporated in vacuo to yield the title compound. (ii) (1R, 2R) / (1S, 2S) -2- (3-acetoxypyrrolidinyl) -1- (1-naphthenhexy) cyclohexane monohydrochloride: The intermediate alcohol (i) was then refluxed in acetic anhydride ( 15 mL) for 2 hours. The excess acetic anhydride was removed in vacuo; the residue was taken with water (100 mL) and extracted with diethyl ether (2 x 30 mL). The aqueous solution was basified to pH 8.0 and extracted with diethyl ether (3 x 50 mL). The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in a small amount of dichloromethane, and a large volume of diethyl ether was added to activate the crystallization of 1.0 g (65% yield) of the title compound.

Comparative example 16 Monohydrochloride of (1R.2R) / (1S, 2S) -2- (3-thiazolidinyl) -1- (2,6- dichlorophenoxyOcicylohexane (Compound 48) (i) (1R, 2R) / (1S, 2S) -2- (3-thiazolidinyl) cyclohexanol: To anhydrous magnesium perchlorate (12.93 g, 53.3 mmol) was added a solution of cyclohexene oxide (6.1 mL, 58.6 mmol) in anhydrous acetoniiril (25 mL), and the resulting mixture was stirred at ambient temperature for 20 min. Then a solution of thiazolidine (5.16 g, 55.0 mmol) in anhydrous acetoniiryl was added and the reaction mixture was heated at 35 ° C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (350 mL) and diethyl ether (350 mL). The aqueous layer was separated and extracted once more with diethyl ether (350 mL). The combined organic extract was dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude aminoalcohol was purified by dry column chromatography with a mixture of acetyl ether-hexane (1: 1, v / v) as the elue, to yield 4.83 g (47% yield) of the title compound. (ii) To a cold (0 ° C) solution of (1R, 2R) / (1S, 2S) -2- (3-yiazolindinyl) -cyclohexanol (3.17 g, 16.9 mmol) and isopylamine (3.08 mL, 22.0 mmol) in dichloromean (30 mL), methanesulfonyl chloride (1.74 mL, 22.0 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for one hour and then at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water (2 x 30 mL). The combined washing was back extracted with dichloromethane (25 mL) and the combined organic extract was dried over sodium sulfate. Evaporation of the solvent in vacuo produced the mesylate, suitable for the next step without further purification. (iii) To a dispersion of sodium hydride in 80% oil (608 mg, 20.28 mmol) in dimethyl ether of ethylene glycol (30 mL), a solution of 2,6-dichlorophenethyl alcohol (3.87 g, 20.28 mmol) was added. , example 4, step vii) in ethylene glycol dimellylether (15 mL). The resulting mixture was stirred at room temperature under an argon atmosphere for 2 hours. (iv) (1 R, 2R) / (1S, 2S) -3-thiazolidin) -1- (2,6-dichlorophenoxy) cyclohexane monochloride: The mesylate (ii) in ethylene glycol dimethyl ether (15 mL) was added rapidly to the alkoxide (iii), and the reaction mixture was refluxed for 40 hours. The cold reaction mixture was poured into water (100 mL) and the organic solvent was evaporated in vacuo. The residual aqueous solution was diluted with more water (100 mL) and the pH adjusted to 1.5. The aqueous acid solution was extracted with diethyl ether (3 x 100 mL)The combined organic extract was dried over sodium sulfate and the solvent was removed in vacuo to give the crude free base. The product was purified by dry column chromatography with an acetone-hexane mixture (1:10, v / v) as eluent, to yield 2.4 g of the crude free aminoether. The pure product (1.0 g) was converted to the hydrochloride salt by treatment with ethereal HCl and the resulting salt was recrystallized from a mixture of acetyl-diethyl ether to yield 0.69 g of the title compound.

Comparative Example 17 Monohydrochloride of (1R.2R) / (1 S.2S) -2- (3-Cetopyrrolidinyl) -1 - (2,2-diphenyletoxO-cyclohexane (Compound 47) (vi) To a cold (0 ° C) solution of (1 R, 2R) / (1S, 2S) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) cyclohexanol (2e) ) (2.0 g, 8.8 mmol) and triethylamine (2.1 mL, 15 mmol) in dichloromethane (30 mL), methanesulfonyl chloride (0.9 mL, 11.44 mmol) was added. The reaction mixture was stirred at 0 ° C for 45 min and then at ambient temperature for 3 hours. The reaction mixture was diluted with dichloromethane (25 mL), washed with water (2 x 25 mL) and the combined washing was back exuded with dichloromethane (25 mL). The combined organic extract was dried over sodium sulfate and the solvent was evaporated in vacuo to produce the crude mesylate, which was further pumped into the empty vessel for 30 minutes before use in step (ix) below. (vii) Alcohol (2,2-diphenyl) ethyl: To lithium aluminum hydride (2.85 g, 23.56 mmol) in anhydrous diethyl ether (150 mL) was added, as a powder, diphenylacetic acid (5.0 g, 56 mmol) . The resulting reaction mixture was refluxed gently for one hour. The reaction was quenched with saturated aqueous sodium sulfate solution and the resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo to yield 4.0 g (86% yield) of the title compound. (viii) Sodium hydride, previously washed with hexane (253 mg, 10.56 mmol), in suspension in ethylene glycol dimethyl ether (15 mL), was added with a solution of 2,2-diphenylethyl alcohol (2.09 g, 10.56 mmol, step vii) in ethylene glycol dimethyl ether (15 mL). The resulting mixture was stirred at room temperature under an argon atmosphere for 30 min. (ix) (1R, 2R) / (1S, 2S) -2- (1, 4-Dioxa-7-azaspiro [4.4] non-7-yl) -1 - (2,2-diphenylethoxy) cyclohexane: The mesylate of (vi) in ethylene glycol dimethyl ether (20 mL) was added rapidly to the alkoxide (viii), and the reaction mixture was refluxed for 5 days. The cold reaction mixture was concentrated in vacuo, the residue was taken up with water (50 mL) and the pH was adjusted to 1.0 with 6M aqueous HCl solution. The aqueous acid solution was exfoliated with diethyl ether (2 x 50 mL); The aqueous layer was collected and basified to pH 6.0. Extraction with diethyl ether (2 x 50 mL) followed by drying over sodium sulfate and evaporation of the solvent under vacuum gave 1.55 g (43% yield) of the title compound. (x) Monochlorohydrate of (1R, 2R) / (1S, 2S) -2- (3-Clyopyrrolidinyl) -1- (2,2-diphenylenoxy) cyclohexane: A mixture of (1R, 2R) / (1S, 2S ) -2- (1, 4-dioxa-7-azaspiro [4.4] non-7-yl) -1- (2,2-diphenylenoxy) cyclohexane (1.55 g, 3. 8 mmol) in 6M HCl-butanone (1 : 4, v / v, 50 mL), was refluxed for 2 hours. The butanone was evaporated in vacuo and the residue was taken up with water (50 mL). The aqueous solution was extracted with diethyl ether (2 x 50 mL); the aqueous layer was collected and extracted with dichloromethane (2 x 50 mL). The combined dichloromean extract was dried over sodium sulfate and concentrated in vacuo to yield the crude title compound. The production was crystallized by rinsing in diethyl ether and re-precipitated from a dichloromethane-diethyl ether mixture to yield 1.21 g (80% yield) of the title compound, which had the correct elemental analysis.

General experimental procedures The melting points were determined in a Fisher-Johns apparatus and are not corrected. The NMR spectra were acquired in the indicated solvent in a Brucker AC-200, Varian XL-300, Brucker AV-300 or AV-400. The mass specimens were recorded for El in a Kratos MS50; for FAB / LSIMS in a Kratos Concept IIHQ; and for ES in a Micromass (Waíers) Quafíro (1) MSMS, connected with an HP1090 Series 2 LC (Agilent), controlled by Masslynx software version 3.3. The elemental analyzes were done on a Element Analyzer 1108 from D. & H. Malhow, University of Alberta, Edmonion, Alberta. When the analyzes are indicated only with symbols of the elements, the analytical results were within ± 0.4% of the theoretical values. Whenever elemental analyzes were not available, purity was determined by HPLC and capillary electrophoresis (CE). HPLC analyzes were done using a Gilson HPLC system (Gilson, Middleton, Wisconsin) with UV detection at 200 nm. A C-iß column of 150 x 4.6 mm, particle size 5 μ was used. The mobile phase was supplied either socratically or as a gradient at a flow rate of 1 mL / min and consisted of a combination of phosphate buffer (low or high pH) and acetonitrile. Samples were prepared at ~ 100 μg / mL in mobile phase and 20 μL was injected into the HPLC. The purity was expressed as% area. The CE analyzes were done in a P / ACE MDQ system (Beckman Coulíer, Fullerton, California). Uncoated silica capillaries with a 60 cm longitude (50 to the detector) and an internal diameter of 75 μm were used. The run buffer used was 100 mM sodium phosphate (pH 2.5). The separation voltage was 23 or 25 kV (normal polarity) and the temperature of the capillary cartridge was maintained at 20 ° C. Samples (~ 0.5 mg / mL in water) were injected by pressure at 0.035 kg / cm2 for 6 seconds. The detection was by UV at 200 or 213 nm. The purity was expressed in% area. The IRs were recorded on a Perkin-Elmer 983G spectrophotometer. Optical rotations were performed by F. Hoffman-La Roche Ltd (CH, Basel). Thin layer chromatography (TLC) was done in 20 x 20 cm TLC aluminum sheets, 60 F254 silica gel from E. Merck. Flash chromatography41 was done on silica gel 60 of E.M. Science (70-230 mesh). Dry flash chromatography42 was done with Sigma H-type silica gel. The chromatography Chromatofron (Harisson Research, E.U.) was made on a 4 mm plate with silica gel 60P F254 from EM Science with gypsum or aluminum oxide 60P F254 with gypsum (type E). Preparative HPLC was done in a Waters Delta Prep 4000 with a cartridge column (porasil, 10 μm, 125 A, 40 mm X 100 mm). The GC analyzes were done in a Hewlettf Packard HP 6890 equipped with HP-35 capillary column 30 m x 0.25 mm x 0.25 μm (PH ME siloxane entaced 35%), and a flame ionization detector. High boiling point solvents (DMF, DMSO) were Sure / Seal ™ from Aldrich; teirahydrofuran (THF) and ethylene glycol dimethyl ether (DME) were paraffined from sodium ceilylbenzophenone. The organic extractions were dried with Na 2 SO 4 unless otherwise indicated. All moisture sensitive reactions were made in dry glass material under a nitrogen or argon atmosphere.

Biological Activity Data Determination of antiarrhythmic efficacy The antiarrhythmic efficacy can be determined by investigating the effect of a compound on the incidence of cardiac arrhythmias in anesthetized rats subjected to coronary artery occlusion. Raias weighing 200-300 grams undergo preparative surgery and are divided into groups in a randomized block design. In each case, the animal is anesthetized with pentobarbital during surgical preparation. The left carotid artery is channeled to measure the mean arterial blood pressure and for the extraction of blood samples. The left jugular vein is also canalized for drug injection. The thoracic cavity is opened and a polyethylene occluder is placed loosely around the left anterior descending coronary artery. Then the thoracic cavity is closed. An ECG will be recorded by inserting electrodes placed along the anatomical axis of the heart. In an aleaforia and double blind manner, a vehicle infusion of the compound to be tested is administered approximately 15 minutes after the surgery. After 5 minutes of infusion, the occluder pulls in order to produce an occlusion of the coronary artery. ECG, arrhythmias, blood pressure, heart rate and mortality are monitored for 15 minutes after occlusion. Arrhythmias are recorded as ventricular tachycardia (VT) and ventricular fibrillation (VF), and are coded according to Curtis. M. J. and Walker, M.J.A., Cardiovasc. Res. 22: 656 (1988) (see table 1).

Table 1 where: VPB = ventricular premature beats VT = ventricular tachycardia VF = ventricular fibrillation Rats are excluded from the study if they do not exhibit potassium concentrations in preocclusion serum within the range of 2.9-3.9 mM. The occlusion is associated with increases in the height of the R wave and elevation of the "ST" segment, and an occluded zone on the scale of 25% -50% of the total weight of the left ventricle (measured after death by dye perfusion cardioverde). The results of the test compounds can be expressed as values of a given infusion rate in micromol / kg / min.

(DE50AA) that will reduce the puniuation of the arriímia in the íraíados animals, in 50% with respecío to the animals treated only with the vehicle in which the compound of test is dissolved. Table 4, column 6, shows the result of DE50AA of the tests of compounds 1 to 7 according to the invention in micromole / kg / min. Table 5, column 6, shows the result of DE50AA of tests of compounds 8 to 48 of the comparative examples in micromol / kg / min.

Measurement of cardiovascular and conduction effects A preparatory surgery is performed on Sprague Dawley rats weighing 200-300 grams and anesthetized with 65 mg / kg pentobarbital (i.p.). The femoral artery and vein are canalized using polyethylene tubing 10. Prior to surgery, this PE-10 tubing had been annealed with a wider gauge tubing (PE-50) for exanalization. The pipelined PE-10 / PE-50 is passed through a trocar and June is terminated with derivations of member ECG (lead II) (see below). The irear coils under the skin on the back and out through a small incision in the middle scapular region. A ground ECG elec- trode is inserted subcutaneously using a 20 gauge needle with the lead wire threaded through it. To place the other ECG electrodes, a small incision is made in the anterior region of the chest over the heart and the ECG leads are inserted into the subcutaneous layer of muscle in the heart region using a 20 gauge needle. Other ECG leads are insert into the subcutaneous layer of muscle in the region near the base of the neck and shoulder (right side). The animal is returned to a clean recovery cage with free access to food and water. The period of travail and observation of each animal begins after a recovery period of 24 hours. An observation period of 15 minutes is recorded, followed by the iniravenous infusion regimen of the test compound at an initial dose of 2 μmol / kg / min (at 1 ml / h). This speed doubles every 5 minutes until one of the following effects is observed: a) partial or complete seizures, b) severe arrhythmias, c) bradycardia below 120 laiids / min, d) hypotension below 50 mm Hg , e) the dose exceeds 32 times the initial dose (ie 64 μmol / kg / min). Blood pressure (BP), heart rate (HR) and ECG variables are recorded continuously as long as behavior responses are also monitored; and the cumulative total drug dose and the rate of drug infusion at which the response occurs (such as seizure, piloerection, ataxia, restlessness, compulsive chewing, lip licking, wet dog shake, eic) are recorded. Blood samples Estimates of the concentration of the test compound in the plasma are made by taking a sample of 0.5 ml of blood at the end of the experiment. The blood samples are centrifuged for 5 minutes at 4,600 x g and the plasma is decanted. Brain tissue samples are also taken and kept frozen (-20 ° C) together with the plasma samples for chemical analysis. Data Analysis The parameters of electrocardiography (ECG): PR, QRS, QTi (wave peak T), QT2 (mean T-wave deflection point) and hemodynamic parameters: BP and HR, are analyzed using the automatic analysis function in LabView (National Instruments) with an adapted autoanalysis software (Nortran Pharmaceuticals) . The infused dose that produces 25% of the control (D25) of all the recorded ECG variables is determined. The results of the tests can be expressed as D2s (micromol / kg) which are the doses required to produce a 25% increase in the measured ECG parameter. The increase in the P-R interval and the QRS interval indicates the blockade of the cardiac sodium channel, while the increase in the Q-T interval indicates a blockage of the cardiac potassium channel.

Electrophysiological test (in vivo) This experiment determines the power of the test compound on the hemodynamic and electrophysiological parameters under nonischemic conditions.

Methods Surgical Preparation Male Sprague-Dawley rats weighing 250-350 g are used. They are randomly selected from a single group and are anesthetized with pentobarbifal (65 mg / kg, i.p.), with additional anesthesia if necessary. The radicle is canalized and the rala is artificially ventilated at a blow volume of 10 ml / kg, 60 strokes / minute. The right external jugular vein and the left carotid artery are channeled for intravenous injections of compounds and blood pressure record (BP), respectively.

Needle electrodes are inserted subcutaneously along the suspicious anatomical axis of the heart (right atrium to the apex) for ECG measurement. The upper electrode is placed at the level of the right clavicle approximately 0.5 cm from the midline, while the lower electrode is placed on the left side of the thorax, 0.5 cm from the midline and at the level of the ninth rib. Two Teflon-coated silver electrodes are inserted through the chest wall using 27G needles as guides, and implanted into the epicardium of the left ventricle (4-5 mm apart). Square pulse stimulation is provided by a stimulator controlled by a computer. Software programmed in the laboratory is used to determine the following: threshold current (iT) for the induction of excisystoles, maximum subsequent frequency (MFF), effective refractory period (ERP) and ventricular flutter threshold (VTt). Briefly, the iT is measured as the minimum current (in μA) of a square wave stimulus required to capture and regulate the heart at a frequency of 7.5 Hz and an impulse amplitude of 0.5 ms; ERP is the minimum delay (in ms) for a second stimulus required to cause an extrasystole, with the heart held at a frequency of 7.5 Hz (1.5 x iT and 0.2 ms of pulse amplitude); MFF is the maximum stimulation frequency (in Hz) at which the heart is unable to follow the stimulation (1.5 x iT and 0.2 ms of pulse amplitude); VTt is the minimum impulse current (in μA) to evoke a sustained episode of VT (0.2 ms of impulse amplitude and 50 Hz) (Howard, P. G. and Walker, M. J. A.

Proc. West Pharmacol. Soc. 33: 123-127 (1990)). Blood pressure (BP) and electrocardiographic parameters (ECG) are recorded and analyzed using Lab View (National Instrumenfs) with adapted autoanalysis software (Nortran Pharmaceuticals Inc.) to calculate the mean BP (mmHg, 2/3 diastolic blood pressure + 1/3 systolic), HR (Ipm, 60 / RR interval); PR (ms, the interval from the beginning of the P wave to the peak of the R wave), QRS (ms, the interval from the beginning of the R wave due to the lack of Q wave in rat ECG, up to the peak of the S wave), QT (ms, the interval from the beginning of the R wave to the peak of the T wave). Experimental protocol The initial infusion dose is chosen based on a previous toxicological study of a test compound in conscious rats. This is an infusion dose that does not produce a 10% change in pre-drug levels in the hemodynamic parameters or ECG. The animal is allowed to stabilize before treatment of the infusion according to a predetermined random and blind table. The initial infusion treatment starts at a rate of 0.5 ml / h / 300 g (ie, 0.5 μmol / kg / min.). Each dose of infusion is doubled (in speed) every 5 minutes. All the experiments end at 32 ml / h / 300 g (ie 32 μmol / kg / min). The electrical stimulation protocols are initiated during the last two minutes of each infusion level. Data analysis The responses to the test compounds are calculated as percentages of change of the preinfusion values; this normalization is used to reduce individual variation. BP mean values and ECG parameters Immediately before the electrical stimulation period (ie, 3 minutes after the infusion), they are used to construct cumulative dose-response curves. The data points are adjusted using lines of the best fit with the minimum residual sum of squares (least squares; SlideWrite program; Advanced Graphics Software, Inc.). D25's (infused dose that produces 25% change of preinfusion value) are interpolated from individual cumulative dose-response curves and are used as indicators to determine the potency of the compounds of the present invention.

Canine model of vagal AF General methods Crossed dogs of either sex weighing 15-49 kg are anesthetized with morphine (2 mg / kg im, initially, followed by 0.5 mg / kg iv every 2 h) and a-chloralose (120 mg / kg iv, followed by an infusion of 29.25 mg / kg / h, St. Georges et al., 1997). The dogs are ventilated mechanically with ambient air supplemented with oxygen by means of an endotracheal tube, at 20-25 breaths / minute, with a tidal volume obtained from a nomogram. Catheters are inserted into the femoral artery to record blood pressure and measure gas in the blood, and in the two femoral veins for drug administration and venous sampling. The catheters are kept open with 0.9% heparinized saline. The body temperature is maintained at 37-40 ° C with a heating mantilla. The heart is exposed by means of a middle thoracotomy and a pericardial cradle is created. Three Teflon-coated stainless steel bipolar electrodes are inserted into the right atrium to record and stimulate, and one is inserted into the left atrial appendage to record. A programmable stimulator (Digital Cardiovascular Instruments, Berkeley, California) is used to stimulate the right atrium with 2 ms pulses of twice the diastolic threshold. Two Teflon-coated stainless steel electrodes are inserted into the left ventricle, one for recording and the other for stimulation. A ventricular demand pacemaker (GBM 5880, Medtronics, Minneapolis, MN) is used to stimulate the ventricles at 90 beats / minute when the ventricular velocity becomes excessively slow (particularly vagal AF). A transducer P23 ID, electrophysiological amplifier (Bloom Associates, Flying Hills, Pennsylvania) and recording paper (Astromed MT-95000, Toronto, Ontario, Canada) are used to record leads II and III of ECG, atrial and ventricular electrograms, blood pressure and stimulation artifacts. The vagal nerves are isolated in the neck, double-bound and divided, and the electrodes are inserted into each nerve (see below). To block changes in β-adrenergic effects on the heart, nadolol is administered at an initial dose of 0.5 mg / kg i.v., followed by 0.25 mg / kg i.v. every two hours.

Atrial fibrillation model Drug effects are determined to end a sustained AF, maintained during continuous stimulation of the vagal nerve. Inside the axis of each nerve, and parallel to it, unipolar hook electrodes (made of Teflon-insulated stainless steel, coated except for 1-2 cm distal) are inserted by means of a 21-gauge needle. In most experiments unipolar stimuli are applied, with a stimulator (model DS-9F, Grass Instruments, Quincy, Massachusetts) set to deliver square-wave pulses of 0.1 ms at 10 Hz and a voltage of 60% of that required to produce asystal. In some experiments, bipolar stimulation is used. The voltage required to produce asistale varied between 3-20 volts. Under control conditions, a short discharge of rapid atrial regulation (10 Hz, four times the diastolic threshold) is delivered to induce AF that is ordinarily sustained for more than 20 minutes. The vagal stimulation voltage is adjusted under the control conditions and readjusted after each treatment to maintain the same bradycardic effect. AF is defined as fast irregular atrial rhythm (> 500 minutes under control conditions) with variable electrogram morphology.

Measurement of electrophysiological variables and vagal response The diastolic threshold current is determined at a basic cycle duration of 300 ms increasing the 0.1 mA current incrementally until a stable capture is obtained. For subsequent protocols the current is set to twice the diastolic threshold. Atrial and ventricular ERP is measured with the extra stimulus method, on an interval scale S1S2 at a basic cycle length of 300 ms. A premature stimulus S2 is introduced every 15 basic stimuli. The S1S2 interval is increased in increments of 5 ms until the capture occurs, with the longer S1S2 interval consistently failing to produce a propagated response that defines ERP. The diastolic threshold and ERP are determined in duplicate and are averaged to give a single value. These values are generally within 5 ms. The interval between the stimulus artifact and the peak of the local electrogram is measured as an index of the conduction velocity. The duration of the AF cycle (AFCL) is measured during AF vagal by counting the number of cycles (number of beats-1) over an interval of 2 seconds, at each of the atrial recording sites. The three measurements of AFCLs are averaged to obtain a general average AFCL for each experimental condition. The stimulus voltage - heart rate ratio for vagal nerve stimulation is determined under control conditions in most experiments. The vagal nerves are stimulated as described above with various voltages to determine the voltage caused by the asctal (defined as a sinus pause greater than 3 seconds). The response to vagal nerve stimulation is confirmed under each experimental condition, and the voltage is adjusted to maintain a constant heart rate response to vagal nerve stimulation. In cases where it is not possible to produce asystal, the vagal nerve stimulation is adjusted to a voltage that allows two episodes of 20 minutes of vagal AF to be maintained under control conditions (see below). Experimental protocols One of the experimental groups studied is summarized in Table 3. Each dog received only one drug at the doses indicated in Table 3. The first series of experiments are dose classification studies, followed by a blinded study in which 1-3 doses are given. All drugs are administered via IV by means of an infusion pump with the drug solutions in plastic containers freshly prepared on the day of the experiment. The parameters of vagal stimulation are defined under the control conditions described above and AF maintenance is verified during 20 minutes of vagal nerve stimulation, under the control conditions. After finishing the AF, the diastolic threshold and ERP of the atrium and ventricle are determined. Subsequently, these variables are determined again in the atrium under stimulation of the vagal nerve. Usually the electrophysiological examination lasted 15-20 minutes. The heart rate response to vagal nerve stimulation is confirmed and the vagal AF / electrophysiological examination protocol is repeated. A pre-drug blood sample is obtained and vagal AF is resumed. Five minutes later one of the treatments is administered at the doses shown in Table 2. The total dose is infused for 5 minutes and immediately afterwards a blood sample is obtained. There is no maintenance infusion. If the AF ends in 15 minutes, the electrophysiological measurements obtained under the conirol conditions are repeated and a blood sample is obtained. If AF does not end with the first dose (within 15 minutes), a blood sample is obtained and vagal stimulation is discontinued to allow a return to sinus rhythm. The electrophysiological measurements are repeated and a third and last blood sample is obtained. The AF is restarted and the protocol of vagal AF / drug infusion / electrophysiological examination is repeated, until AF is terminated by the drug. Statistical analysis The group data are expressed as the mean ± SEM. The statistical analysis is carried out for effective doses for AFCL and ERP using a t test with a Bonferroini correction for multiple comparisons. The effects of drug on blood pressure, heart rate, diastolic threshold and ECG intervals are determined at the average dose for AF termination. Two bilateral tests are used and a p <is taken; 0.05 to indicate statistical significance.

Table 2 Experimental groups and drug doses Each dog was administered a single drug on the specified dose scale until AF was completed. The number of dogs in which FA was terminated at each dose is shown (number of dogs -dose, in μmol / kg). The mean ± SEM is shown as well as the average dose required to complete the AF. Each dog received only one drug. The compounds of the present invention can be evaluated by this method. The effectiveness of flecainide as a control in the present study was comparable to that previously reported.

Canine model of sterile pericarditis This model has been used to characterize the mechanisms of AF and atrial flutter (AFL). Waldo et al. Have found that FA depends on reentry and that the termination site is usually a re-arched driving area. This canine model is prepared by sprinkling falco in the exposed atrium, followed by "unloading" regulation of the atrium for a period of days after recovery. AF is inducible two days after surgery; however, on the fourth day after surgical preparation, sustainable atrial flutter is the predominant inducible kidney. The induction of AF on day 2 is somewhat variable, such that only 50% of dogs can have sustained AF (usually <60 minutes) during a 30-minute requirement. However, atrial flutter that develops on the fourth day is inducible in most preparations. Atrial flutter is more easily "mapped" to determine the mechanisms of the drug. The induction of AF decreases after the fourth day of surgery, similar to the AF that frequently develops after cardiac surgery that the model of sterile pericarditis imitates. There may be an inflammatory component involved in the etiology of AF after surgery, which would provide a degree of selectivity to an ischemia or selective acid drug. Similarly, although coronary artery bypass graft (CABG) surgery is performed to relieve ventricular ischemia, such patients may also be at risk for mild atrial ischaemia due to coronary artery disease (CAD). Although atrial infarcts are rare, there has been an association between AV nodal artery stenosis and the risk of AF after CABG surgery. Surgical interruption of the autonomic innervation of the atrium may also have a role in AF after CABG. Methods The studies are carried out in a canine model of sterile pericarditis to determine the potency and efficacy of the compounds of the present invention for terminating fibrillation / flutter. Atrial fibrillation or atrial fibrillation was induced 2 to 4 days after the creation of sterile pericarditis in adult crossed dogs, with weights of 19 kg to 25 kg. In all cases, fibrillation or atrial flutter lasted no more than 10 minutes. Creation of the fibrillation / atrial flutter model of sterile pericarditis The canine model of sterile pericarditis is created as previously described. At the time of surgery, a pair of stainless steel wire electrodes coated with FEP polymer were sutured except for the puncture (O Flexon, Davis and Geck) in the right atrial appendage, Bachman's fasciculus and the left posteroinferior atrium near the proximal portion. of the coronary sinus. The distance between each electrode of each pair is approximately 5 mm. These wire electrodes are extruded through the chest wall and subsequently exteriorized in the inescapular region for subsequent use. After the surgery, antibiotics and analgesics are given to the dogs and then allowed to recover. Postoperative care includes the administration of antibiotics and analgesics. In all dogs, beginning on postoperative day 2, the induction of stable atrial fibrillation / atrial flutter is attempted in an unsuspected conscious state, to confirm the induction and stability of atrial fibrillation / flutter and to test the efficacy of the drugs. Atrial regulation is performed through the sutured electrodes during the initial surgery. On postoperative day 4, when stable atrial flutter is induced, the open chest study is performed.For the open chest study, each dog is anesthetized with pentobarbital (30 mg / kg IV) and mechanically ventilated with 100% oxygen using a Boyle Model 50 anesthesia machine (Harris-Lake, Inc.). The temperature of each dog's body is maintained within the normal physiological scale throughout the study, with a heating pad. With the anesthetized dog, but before opening the chest, radiofrequency ablation of the His bundle is performed to create complete atrioventricular (AV) block by standard electrode catheter techniques. This is done to minimize the overlap of atrial and ventricular complexes during subsequent registrations of unipolar atrial electrograms after induction of atrial flutter. After full AV block is created, an effective ventricular rate is maintained by regulating the ventricles at a frequency of 60 to 80 beats per minute with a Medtronic 5375 pulse generator (Medtronic Inc.), to deliver stimuli by sutured electrodes in the right ventricle during the initial surgery.

Determination of stimulus thresholds and refractory periods during regulation For the induction of AF / AFL one of the two methods described above is used: (1) introduction of one or two premature atrial beats after a succession of 8 regulated atrial beats to one cycle length of 400 ms, 300 ms, 200 ms or 150 ms, or (2) rapid atrial regulation for periods of 1 to 10 seconds at frequencies of 10 to 50 beats per minute, substantially greater than the spontaneous sinus frequency until atrial flutter is induced or there is an atrial capture loss of 1: 1. Atrial regulation is performed from the electrodes of the right atrial appendage or from the left post-inferior atrial electrodes. All regulation is carried out using stimuli of twice the threshold for each basic sequence with a programmable, modified Medtronic 5325 battery stimulator with a pulse amplitude of 1.8 ms. After the induction of fibrillation / stable atrial flutter (lasting more than 10 minutes), the duration of the fibrillation / atrial flutter cycle is measured and the initial mapping and analysis is performed to determine the location of the atrial fibrillation / atrial resection circuit. Atrial flutter is defined as a rapid atrial rhythm (frequency> 240 beats per minute), characterized by the duration of the beating-to-beat cycle, polarity, constant morphology and amplitude of the recorded bipolar electrograms. Drug efficacy test protocol 1. Effective refractory periods (ERPs) are measured from three sites: right atrial appendage (RAA), posterior left atrium (PLA) and Bachman's fascicle (BB), at two basic cycle durations, 200 and 400 ms. 2. A-Fib or AFL induction regulation. This is attempted for one hour. If arrhythmia is not induced, no further study is done that day. 3. If induced, the AF should be maintained for 10 minutes. Then leave a waiting period for spontaneous termination, or 20 minutes, whichever comes first. 4. AF is then reinjected and 5 minutes are allowed to pass before starting the infusion of the drug. 5. The drug is then infused in a bolus for 5 minutes. 6. If the AF ends with the first dose, then a blood sample is taken and the ERP measurements are repeated. 7. Allow 5 minutes to finish the drug. If there is no termination then the second dose is given for 5 minutes. 8. After completion and measurement of ERPs, a second attempt is made to reinject AF for a period of ten minutes. 9. If it is reinjected and maintained for 10 minutes, a blood sample is taken and the study is repeated from No. 3 above. 10. If there is no reinduction, then the study ends. The compounds of the present invention can be evaluated with this method.

Determination of pain blogging CD-1 mice (20-30 g) are restricted in an appropriate cage. A tourniquet is placed at the base of the tail and a solution of the test compound (50 μl, 5 mg / ml) is injected into the lateral vein of the tail. The tourniquet is removed 10 min after the injection. The appropriate dilutions of compound solution are used to obtain an ED50 for blocking pain at various points of time after injection. Pain responses are determined by pin pricking at regular intervals up to 4 hours after injection, and the duration of pain blockage is recorded in three animals for each test compound solution. The compounds of the present invention can be evaluated according to the method described.

In vitro determination of the inhibitory activity of the ion channel modulating compounds in different cardiac ion currents Cell culture: The relevant cloned ion channels (for example hH1Na, Kvl.4, Kvl.5, Kv4.2, Kv2.1 , Cardiac HERG, etc.) are studied by transient transfection in HEK cells using the mammalian expression vector pCDNA3. The transfections for each type of channel are made separately to allow the individual study of the ion channel of interest. Cells expressing channel protein are detected by cotransfected cells with the vector pHook-1 (Invitrogen, San Diego, California, E.U.). This plasmid encodes the production of an antibody for the phOX hapten, which when expressed is displayed on the cell surface. Equal concentrations of single channel and pHook DNA are incubated with 10x concentration of lipofectAce in modified Eagle medium (MEM, Canadian Life Technologies) and incubated with progenitor HEK cells deposited in 25 mm culture plates. After 3-4 hours, the solution is replaced with a standard culture medium plus 20% fetal bovine serum and 1% antifungal. The transfected cells are maintained for 24-48 hours at 37 ° C in a 5% air / CO2 incubator in 25 mm petri dishes, deposited on glass coverslips, to allow expression of the channel. Twenty minutes before the experiments, the cells were brought with beads coated with phOX. After 15 min, the excess beads are washed with cell culture medium and the cells having the pellets adhered thereto are used for the electrophysiological tests. Solutions: For cell recording the pipette filling conirol solution contained (in mM): KCl, 130; EGTA, 5; MgCl2, 1; HEPES, 10; Na2ATP, 4; GTP, 0.1; and it is adjusted to pH 7.2 with KOH. The control bath solution contained (in mM): NaCl, 135; KCl, 5; Acetate sodium, 2.8; MgCl2 (1; HEPES, 10; CaCl2, 1; and it is adjusted to pH 7.4 with NaOH.) The test ion modulator compound is dissolved in 10 mM water supply solutions and used at concentrations between 0.5 and 100 μM. Electrophysiological procedures: The coverslips containing the cells are removed from the incubator before the experiments and placed in a superfusion chamber (volume of 250 μl) containing the conirol bath solution from 22 ° C to 23 ° C. All records are made by variations of the patch-clamp technique using an Axopatch 200A amplifier (Axon Instrumenfs, Calif.) Electrodes of patch are removed from a thin-walled borosilicate vessel (World Precision Insírumenfs; Florida) on a squeegee of horizontal micropipey, polished to fire and filled with the appropriate solutions.The electrodes have resistances of 1.0-2.5 μohm when they are filled with the control filling solution. similarity in all cell measurements. In some experiments, leakage subtraction is applied to the data. The membrane potentials have not been corrected for any binding potential that originates between the pipette and the bath solution. The data is filtered from 5 to 10 kHz before being digitized and stored in a microcomputer for further analysis using the pClamp6 software (Axon Instruments, Foster City, California). Due to the high degree of expression of channel cDNAs in HEK cells, there is no need for signal averaging. The average cell capacitance is very small and the absence of ionic current at negative membrane potentials allows faithful subtraction of leakage data. Data analysis: The concentration-response curves of the changes in peak and constant-state currents produced by the test compound are adjusted by computer for the Hill equation: f = ll / [l + (CI5o [D]) p] [1] where f is the fractional current (f = Icarboxy / lcontroi) at the drug concentration [D]; CI5o is the concentration that produces half the maximum inhibition, and n is the Hill coefficient. The compounds of the present invention can be evaluated with this method. The results show that the tested compounds of the present invention have different degrees of effectiveness in blocking various ion channels. The blockage is determined from the decrease in the peak current of hH1 Na + or in the constant state current Kv1.5 and the integrated Kv4.2 current in the presence of the drug. To register the Na + current, the cells are depolarized from the manipulation potential of -100 mV at a voltage of -30 mV for 10 ms to completely open and inactivate the channel. To register the current Kv1.5 and Kv4.2, the cells are depolarized from the maintenance potential of -80 mV at a voltage of +60 mV for 200 ms to fully open the channel. Every 4 s constant currents are recorded at a scale of drug concentrations during stimulation. The reduction in peak current (Na + channel), constant state current (Kv1.5 channel) or integrated current (Kv4.2) in the test potential of -30 mV (Na + channel) or +60 mV (Kv1 channel) .5 and Kv4.2), normalizes to the current of conírol; then plotted against the concentration of test compound. Data from 4-6 cells are averaged. The data fits to coninuous lines using a Hill equation. In the following table (table 3) the Cl50 values for some of the compounds of the present invention are summarized in several ion channels studied: Table 3 The activity of other compounds of the present invention to modulate various ion currents of interest can be studied similarly.

Determination of risk of proarri iamia (Torsade de pointes) of ion channel modulating compounds in primates Methods General surgical preparation: All studies are carried out on Macaca fascicularis males with weights between 4 and 5.5 kg. The animals are fasted overnight and premedicated with ketamine (10 mg / kg i.m.). The two saphenous veins are channeled and a saline drip is initiated to keep the ducts open. Haloan anesthesia (1.5% in oxygen) is administered by means of a mask. Lidocaine spray (10% aerosol) is used to facilitate intubation. After obtaining sufficient anesthesia, the animals are intubated with a 4 or 5 French endotracheal tube. After intubation, halothane is administered via the endotracheal tube and the concentration is reduced to 0.75-1%. Artificial respiration is not used and all animals continue to breathe spontaneously throughout the experiment. The blood gas concentration and blood pH are measured using a blood gas analyzer (AVO OPTI I). The femoral artery is canalized to record blood pressure. Blood pressure and a modified derivation ECG II are recorded using a MACLAB 4S registration system coupled with a Macintosh PowerBook (2400c / 180). A sampling rate of 1 kHz is used for both signals and all data is archived to a Jazz disk for subsequent analysis. Vagal nerve stimulation: Any of the vagal nerves is isolated by abrupt dissection and a pair of electrodes is inserted into the nerve trunk. The proximal end of the nerve is crushed using a vascular clamp and the nerve is stimulated using square wave pulses at a frequency of 20 Hz with a pulse amplitude of 1 ms, supplied from the MACLAB stimulator. The voltage (scale 2-10 V) is adjusted to give the desired bradycardial response. The objective bradycardial response is a reduction of the heart rate by half. In cases in which a sufficient bradycardic response can not be obtained, 10 μg / kg neostigmine via i.v. This dose of neostigmine also occurs after the administration of the test drug in cases where the test drug has vagolic actions. Test Compounds: A dose close to the maximum tolerated bolus of the test compound, infused (v.v.), is used for 1 minute to determine the risk of Torsade de pointes caused by each test compound. Actual doses vary slightly depending on the weight of the animals. Clofilium, 30 μmol / kg, is used as a positive comparison (control) for these studies. The expectation is that a dose alia of drug results in an alpha incidence of arrhythmias. The test compounds are dissolved in saline immediately before administration.

Experimental pro-code: Each animal receives a single dose i.v. of a given drug.

Two episodes of 30 seconds of vagal nerve stimulation will be recorded before the experiment begins. A rest period of 5 minutes is allowed to pass between the episodes and before beginning the experiment. The test solution is administered as a bolus i.v. at a rate of 5 ml / min for 1 min, using an infusion pump (5 ml total volume). The ECG and blood pressure responses are monitored continuously for 60 minutes and the occurrence of arrhythmias is noted. The vagal nerve is stimulated 30 seconds and the following times after the injection of the drug: 30 seconds, 2, 5, 10, 15, 20, 25, 30 and 60 minutes. Blood samples (1 ml of total volume) of each treated animal are taken at the following times after administration: 30 seconds, 5, 10, 20, 30 and 60 minutes, and 3, 6, 24 and 48 hours. Blood samples taken up to 60 minutes after the administration of the drug are arterial, while those taken after this time are venous. The samples are centrifuged and the plasma is decanted and frozen. The samples are kept frozen before the analysis of the concentration of the drug and potassium in the plasma. Statistics: The effect of drugs on blood pressure, heart rate and ECG intervals is described as the mean ± SEM for a group of size "n". The compounds of the present invention can be evaluated with this method.

Determination of CNS toxicity To determine the in vivo activity of the compounds in the ion channels, it is important to know the maximum tolerated dose. Here the toxicity on the CNS was determined by investigating the minimum dose of a compound that induces partial or complete seizures in conscious rats. The procedure avoids the use of lethality as an end point and unnecessary suffering, since the experiment ends if this seems likely. If the drug precipitates a life-threatening condition (eg severe hypotension or cardiac arrhythmias), the animals are sacrificed by means of an overdose of pentobarbital. Rats weighing 200-250 g were anesthetized with anesthetic pentobabarbital and subjected to preparative surgery. The femoral artery was canalized to measure blood pressure and to draw blood samples. The femoral vein was channeled for the injection of drugs. ECG leads were inserted into the subcutaneous layer of muscle in the region of the heart and in the region near the base of the neck and shoulder. All cannulas and ECG leads were exteriorized in the middle scapular region. To relieve postoperative pain, narcotics and local anesthetics were used. The animals were returned to a recovery cage for at least 24 hours before beginning the experiment. The infusion of the compound was then initiated through the cannula of the femoral vein. The initial infusion rate was set at 2.0 micromoles / kg / min at a rate of 1 ml / h. The infusion rate doubled every minute until partial or complete seizures were observed. The maximum infusion rate used was 64 micromoles / kg / min. The speeds were continuously monitored and the infusion rate of final time was noted. Table 4, column 4, describes the results of the test for the compounds described herein, as values of a given infusion rate in micromoles / kg / min (seizure dose), which is the minimum infusion rate at the that partial or complete seizures are observed. Table 4, column 5 gives the results of the test for the compounds described, as values for the cumulative dose of seizure, which is the total amount of drug infused at the point at which partial or complete seizures are observed for the first time. . Similarly, Table 5, column 4, describes the test results for the comparative example compounds described, as values of a given infusion rate in micromoles / kg / min (seizure dose), which is the minimum infusion rate at which shows partial or complete seizures. Table 5, column 5 gives the results of the test for the compounds described in the comparative example, as values for the cumulative dose of seizure, which is the total amount of drug fused at the point at which the partial or complete seizures.

Determination of the therapeutic index The therapeutic index for compounds 1 to 7 (Table 4) according to the invention, and Compounds 8 to 49 of comparative example (Table 5), were calculated using the following formula: Cumulative dose of convulsion / ( 20 x DE5o AA) Tables 4 and 5, column 7, give the calculated value of the therapeutic index of the compounds described herein.

Table 4 Table 4 (Continued) As shown in Table 4 above, the compounds according to the present invention having the dimethoxyphenylethoxy group specified in the 1-position of the cyclohexyl ring, and the hydroxypyrrolidine group in the 2-position of the cyclohexyl ring, exhibit low toxicity for the June SNC with high antiarrhythmic activity. The experimental results cited above clearly indicate the compounds of the present invention for the effective treatment of the arrhythmia. Whereas compounds 8 to 22 of the comparative examples that only contain the dimethoxyphenylethoxy group specified in position 1 of the cyclohexyl ring, and compounds 23 to 29 of the comparative examples having only the hydroxypyrrolidine group specified in the 2-position of the cyclohexyl ring, exhibit greater CNS toxicity and lower antiarrhythmic activity compared to the compounds of the present invention (compounds 1 to 7). shown in table 4). Accordingly, the therapeutic indices of the compounds of the present invention are much better. Compounds 30 to 48 of the additional comparative examples correspond to the examples described in WO 99/50225. The test results with compound samples again showed greater CNS toxicity along with less antiarrhythmic activity than the compounds of the present invention.

Table 5 Table 5 (Continued) Table 5 (Continued) Table 5 (Continued) Table 5 (Continued) Table 5 (Continued) Table 5 (Continued) All publications and patent applications mentioned in this specification are incorporated herein by reference as if each publication and individual patent application were specifically and individually incorporated by reference. From the foregoing it will be appreciated that although specific embodiments of the invention have been described for illustrative purposes, various modifications can be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited by the specific embodiments and examples contained in this patent.

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1. A compound of formula (IA), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, meiabolic precursor or prodrug thereof: wherein R3, R and Rs are independently selected from hydrogen, hydroxy and Ci-Cβ alkoxy, including their enanliomeric, diastereomeric and isolated geometiric isomers, and mixtures thereof, with the proviso that R3, R4 and Rs can not be iodine hydrogen.
2. 2. The compound of formula (IA) according to claim 1, or a solvate or pharmaceutically acceptable salt thereof, further characterized in that it includes its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof. 3. The compound of formula (IA) according to claim 1, or a pharmaceutically acceptable solvate or salt thereof, further characterized in that R4 and R5 are independently selected from hydroxy and C.sub.1 -Cd alkoxy, including their enanfiomeric isomers , diasteromeric and geometric isolated, and mixtures thereof. 4. The compound of formula (IA) according to claim 1, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and Rs are independently selected from hydroxy and C.sub.6 -Calkoxy. 5. The compound of formula (IA) according to claim 1, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and R5 are independently selected from C6-C6 alkoxy. 6. The compound of formula (IA) according to claim 1, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R and Rs are independently selected from Ci-Cβ alkoxy. 7 - The compound of formula (IA) according to claim 1, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R 3 is hydrogen, and R 4 and Rs are C 8 alkoxy. The compound of formula (IA) in accordance with claim 1, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R and R5 are C9-alkoxy; A compound of formula (IB), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geomeric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof: wherein R3, R4 and Rs are independently selected from hydrogen, hydroxy and Ci-Cβ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, with the proviso that R3, R and Rs can not be all hydrogen. 10. The compound of formula (IB) according to claim 9, or a solvate or pharmaceutically acceptable salt thereof, further characterized in that it includes its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof. 11. The compound of formula (IB) according to claim 9, or a solvate or pharmaceutically acceptable salt thereof, further characterized in that R and R5 are independently selected from hydroxy and C.sub.6 -alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof. 12. The compound of formula (IB) according to claim 9, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and R5 are independently selected from hydroxy and C.-Cd alkoxy. 13. The compound of formula (IB) according to claim 9, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geomeric isomer, chylaaline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometiric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R and Rs are independently selected from d-C6 alkoxy. 14. The compound of formula (IB) according to claim 9, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R and Rs are independently selected from C? -C6 alkoxy. 15. The compound of formula (IB) according to claim 9, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R and Rs are C16 alkoxy. The compound of formula (IB) in accordance with claim 9, or a pharmaceutically acceptable solvate or salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and Rs are C- | alkoxy. 17. A compound of formula (IC), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometiric isomer, crystalline or amorphous form, metabolite, melabolic precursor or prodrug thereof: wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and Ci-Cβ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, with the proviso that R3, R4 and R5 can not be all hydrogen. 18. The compound of formula (IC) according to claim 17, or a solvate or pharmaceutically acceptable salt thereof, further characterized in that it includes its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof. 19. The compound of formula (IC) according to claim 17, or a solvate or pharmaceutically acceptable salt thereof, further characterized in that R and R5 are independently selected from hydroxy and Ci-Cβ alkoxy, including their enantiomeric isomers, diasteromeric and geometric isolated, and mixtures thereof. 20. The compound of formula (IC) according to claim 17, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and R5 are independently selected from hydroxy and C-C6 alkoxy. 21. The compound of formula (IC) according to claim 17, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometiric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and Rs are independently selected from C-C6 alkoxy. 22. The compound of formula (IC) according to claim 17, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R and Rs are independently selected from Ci-Cß-23 alkoxy. The compound of formula (IC) according to claim 17, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, mixture. stereoisomeric, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized because R3 is hydrogen, and R and Rs are C-alkoxy; 24. The compound of formula (IC) according to claim 17, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometiric isomers, and mixtures thereof, further characterized because R3 is hydrogen, and R4 and R5 are C-i alkoxy. 25. A compound of formula (ID), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, spherical mixture, geometric isomer, crystalline or amorphous form, metabolite, meiabolic precursor or prodrug thereof: wherein R 3, R and R 5 are independently selected from hydrogen, hydroxy and Ci-Cβ alkoxy, including their isolated enantiomeric, diastereomeric and geometiric isomers, and mixtures thereof, with the proviso that R 3, R 4 and R 5 can not be iodine hydrogen. 26. The compound of formula (ID) according to claim 25, or a pharmaceutically acceptable solvate or salt thereof, further characterized in that it includes its isolated enantiomeric, diastereomeric and geomeric isomers, and mixtures thereof. 27. The compound of formula (ID) according to claim 25, or a pharmaceutically acceptable solvate or salt thereof, further characterized in that R4 and R5 are independently selected from hydroxy and Ci-Cd alkoxy, including their enaniomeric isomers, isolated diastereomers and geomethers, and mixtures thereof. 28. The compound of formula (ID) according to claim 25, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R and Rs are independently selected from hydroxy and alkoxy of 29. The compound of formula (ID) according to claim 25, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geomelic isomer, crystalline or amorphous form, metabolite, meiabolic precursor or prodrug thereof, including its enaniomeric, diastereomeric and isolated geomeric isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and Rs are independently selected from Ci-Cβ alkoxy. 30. The compound of formula (ID) according to claim 25, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometiric isomers, and mixtures thereof, further characterized because R3 is hydrogen, and R4 and R5 are independently selected from C6-C6 alkoxy. 31. The compound of formula (ID) according to claim 25, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and Rs are C- .. 32-alkoxy. The compound of formula (ID) of according to claim 25, or a pharmaceutically acceptable solvate or salt thereof, including its isolated enaniomeric, diastereomeric and geomelic isomers, and mixtures thereof, further characterized in that R3 is hydrogen, and R4 and Rs are C30 alkoxy. .- A compound of formula (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geo isomer metric, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof: wherein R4 and Rs are independently selected from hydrogen, hydroxy and C-C6 alkoxy, including their enantiomeric, diastereomeric and geometric isolated isomers, and mixtures thereof, with the proviso that R4 and R5 can not all be hydrogen. 34. The compound of formula (IE) according to claim 33, or a solvate or pharmaceutically acceptable salt thereof, further characterized in that it includes its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof. The compound of formula (IE) according to claim 33, or a solvate or pharmaceutically acceptable salt thereof, further characterized in that R and Rs are independently selected from hydroxy and Ci-Ce alkoxy, including their enantiomeric isomers, diasteromeric and geometric isolated, and mixtures thereof. The compound of formula (IE) according to claim 33, or a solvate or pharmaceutically acceptable salt thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R and Rs are independently selected from hydroxy and C.sub.1 -C3 alkoxy. 37.- The compound of formula (IE) according to claim 33, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R and R5 are independently selected from Ci-Cβ alkoxy. 38.- The compound of formula (IE) according to claim 33, or a pharmaceutically acceptable solvate or salt thereof, including its isolated enaniomeric, diastereomeric and geomeric isomers, and mixtures thereof, further characterized in that R4 and Rs are independently selected from C1-C3 alkoxy. 39.- The compound of formula (IE) according to claim 33or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometiric isomer, chylaaline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including its isolated enantiomeric, diastereomeric and geometric isomers, and mixtures thereof, further characterized in that R 4 and R 5 are C 40 alkoxy. The compound of formula (IE) according to claim 33, or a solvate or pharmaceutically acceptable salt thereof, including its enantiomeric, diastereomeric isomers. and geometric isolates, and mixtures thereof, further characterized in that R4 and R5 are C13 alkoxy. A compound, or a mixture comprising compounds, or a pharmaceutically acceptable salt or solvate thereof, including its enantiomeric isomers. , isolated diastereomers and geomethers, and mixtures thereof, selected from the group consisting of: 42. - A compound, or a mixture comprising compounds, or a solvate thereof, selected from the group consisting of: 43. - A compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 44.- A compound that is (1 R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, or a pharmaceutically acceptable salt thereof, or a solvate of the same. 45. A compound that is (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 46. A compound that is (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 47. A compound which is monohydrochloride of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, or a solvate thereof. 48. A compound which is (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenetoxy) -cyclohexane monohydrochloride, or a solvate thereof. 49.- A compound that is monohydrochloride of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dmemexyphenetoxy) -cyclohexane, or a solvate thereof. 50.- A compound that is monohydrochloride of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) -cyclohexane, or a solvate thereof. 51. A composition comprising a compound as claimed in any of claims 1 to 50, in combination with a pharmaceutically acceptable vehicle or excipient or diluent. 52. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, in the preparation of a medicament. 53. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for modulating the activity of an ion channel in a warm-blooded animal. 54.- A method for modulating the activity of an ion channel in an in vitro environment, comprising administering in vitro an effective amount of a compound as claimed in any of claims 1 to 50, or a composition such as which is claimed in claim 51, or a medicament prepared according to claim 52. 55.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in Claim 51, for preparing a medicament for blocking / inhibiting the activity / conductance of an ion channel in a warm-blooded animal. 56.- A method for blocking / inhibiting the activity / conductance of an ion channel in an in vitro environment, comprising administering in vitro an effective amount of a compound as claimed in any of claims 1 to 50, or A composition as claimed in claim 51, or a medicament prepared according to claim 52. The method according to claim 54 or 56, further characterized in that said ion channel is a potassium channel. 58. The method according to claim 57, further characterized in that said potassium channel is a voltage-activated potassium channel. 59. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for modulating cardiac currents of early repolarization and currents Cardiac sodium in a warm-blooded animal. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for blocking / inhibiting cardiac currents of early repolarization and Cardiac currents of sodium in a warm-blooded animal. 61.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for blocking / inhibiting the cardiac ion channels responsible for the early repolarization cardiac currents and the cardiac currents of sodium in a warm-blooded animal. 62.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for blocking / inhibiting cardiac currents of early repolarization and cardiac currents of sodium in a warm-blooded animal, under conditions where an arrhythmogenic substrate is present in the heart of said warm-blooded animal. 63.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for blocking / inhibiting cardiac ion channels responsible for cardiac currents of early repolarization and cardiac currents of sodium in a warm-blooded animal, under conditions in which an arrymogenic substratum is present in the heart of said warm-blooded animal. 64. The use claimed in claims 59 to 63, wherein said early repolarization cardiac currents comprise ionic currents that are rapidly activated after depolarization of the membrane voltage and repolarize the cell. 65. The use claimed in claims 59 to 64, wherein said early repolarization currents comprise the transient external poisonous cardiac current (l_0) or the ultrafast delayed rectifying rectilinear current (lKur). 66.- The use claimed in claim 65, wherein the transient external potassium cardiac current (l.0) or the ultrafast refractive recirculating current (l? Ur) comprises at least one of the Kv4.2 currents, Kv4.
3. 3, Kv2.1, Kv1.4 and Kv1.5. 67.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment or prevention of arrhythmia in an animal of warm blood. 68.- A pharmaceutical composition comprising an amount of a compound as claimed in claims 1 to 50, effective to treat or prevent atrial arrhythmia in a warm-blooded animal in need of trauma or prevention, and a vehicle, diluent or excipient pharmaceutically acceptable. 69.- The use of a compound as claimed in any one of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment or prevention of atrial arrhythmia in a warm-blooded animal. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment or prevention of ventricular arrhythmia in a warm-blooded animal. 71.- A pharmaceutical composition comprising an amount of a compound as claimed in claims 1 to 50, effective to treat or prevent ventricular arrhythmia in a warm-blooded animal in need of such prevention or prevention, and a vehicle , pharmaceutically acceptable diluent or excipient. 72.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the prevention or prevention of atrial fibrillation in a warm-blooded animal. 73.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment or prevention of atrial flutter in an animal of warm blood. 74.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment or prevention of ventricular fibrillation in a warm-blooded animal. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment or prevention of ventricular flutter in an animal of warm blood. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment of atrial fibrillation in an animal of hot blood. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment of atrial flutter in a blood animal hot. 78.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment of ventricular fibrillation in an animal of hot blood. 79.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the treatment of ventricular flutter in a blood animal hot. 80.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the prevention of atrial fibrillation in an animal of hot blood. 81. - The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the prevention of atrial flutter in a warm-blooded animal. 82. The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the prevention of ventricular fibrillation in an animal of hot blood. 83.- The use of a compound as claimed in any of claims 1 to 50, or a composition as claimed in claim 51, for preparing a medicament for the prevention of ventricular flutter in a blood animal hot. 84. The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the prevention or prevention of arrhythmia in a warm-blooded animal. 85.- A pharmaceutical composition comprising an amount of a compound as claimed in claims 41 to 50, effective to treat or prevent atrial arrhythmia in a warm-blooded animal in need of such trauma or prevention, and a vehicle , diluent or pharmaceutically acceptable excipient. 86.- The use of a compound as claimed in any of claims 41 to 50, for preparing a medicament for trailing or preventing atrial arrhythmia in a warm-blooded animal. 87.- The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the prevention or prevention of ventricular arrhythmia in a warm-blooded animal. 88.- A pharmaceutical composition comprising an amount of a compound as claimed in claims 41 to 50, effective to treat or prevent ventricular arrhythmia in a warm-blooded animal in need of said treatment or prevention, and a vehicle , pharmaceutically acceptable diluent or excipient. 89.- The use of a compound as claimed in any of claims 41 to 50, for preparing a medicament for the treatment or prevention of atrial fibrillation in a warm-blooded animal. 90.- The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the traisamiento or prevention of atrial flutter in a warm-blooded animal. 91. The use of a compound as claimed in any of claims 41 to 50, for preparing a medicament for the traumatization or prevention of ventricular fibrillation in a warm-blooded animal. 92. - The use of a compound as claimed in any of claims 41 to 50, for preparing a medicament for the treatment or prevention of ventricular flutter in a warm-blooded animal. 93. The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the atrial fibrillation treatment in a warm-blooded animal. 94. The use of a compound as claimed in any of claims 41 to 50, for preparing a medicament for the atrial flutter of a warm-blooded animal. 95. The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the treatment of ventricular fibrillation in a warm-blooded animal. 96.- The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the treatment of ventricular flutter in a warm-blooded animal. 97.- The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the prevention of atrial fibrillation in a warm-blooded animal. 98.- The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the prevention of atrial flutter in a warm-blooded animal. 99.- The use of a compound as claimed in any of claims 41 to 50, for preparing a medicament for the prevention of ventricular fibrillation in a warm-blooded animal. 100.- The use of a compound as claimed in any of claims 41 to 50, to prepare a medicament for the prevention of ventricular flutter in a warm-blooded animal. 101. The use claimed in claims 53 and 55, wherein said ion channel is a potassium channel. 102. The use claimed in claim 101, wherein said potassium channel is a potassium channel activated by volya. 103. A method for preparing esfereoselectivamenie an aminociclohexil-éíer, comprising: reacting a compound of formula (55), or a compound of formula (74), with a compound of formula (56), forming a compound of formula (57), or a compound of formula (75), x and R2 (75) - •, respectively, where Ri and R2, when taken June with the nitrogen atom to which they are directly attached in the formula (57) or (75), form a ring denoted by the formula (II ): I heard) and wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-I-CT alkoxy, with the proviso that R3, R4 and Rs can not all be hydrogen; and where O-J is a leaving group. 104. The method according to claim 103, further characterized in that before said reaction, the method comprises: alkylating a compound of formula (53), (53) or a compound of formula (84), (84) with a compound of formula (54), to form the compound of formula (55) or the compound of formula (74), respectively; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; and wherein OQ is a leaving group that reacts with -OH in the formula (53) or (84), to form the compound of the formula (55) or the compound of the formula (74), in such a way that the configuration is retained stereochemistry of the compound of formula (53) or the compound of formula (84) in the compound of formula (55) or the compound of formula (74), respectively; and optionally protecting the compound of formula (53) or the compound of formula (84) before said alkylation step. 105. The method according to claim 104, further characterized in that at least one of R3, R4 and Rs is C6 alkoxy. 106. The method according to claim 105, further characterized in that the compound of formula (56) is: HN I "X (65) and wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; shape: í «) C79) 107. - The method according to claim 106, further characterized because it is formed: m 108. The method according to claim 104, further characterized in that O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; and wherein at least one of R3, R4 and R5 is C-I-CT alkoxy; and wherein O-Q is trichloroacetimidate. 109.- The method according to claim 108, further characterized in that: the compound of formula (54) is: the compound of formula (53) is: (62) the compound of formula (84) is (87); the compound of formula (55) is: and the compound of formula (74) is: (78) 110.- The method according to claim 103, further characterized in that before said reaction, the method comprises: activating a compound of formula (73), or a compound of formula (94), with a hydroxy activating reagent, to form the compound of formula (74) or the compound of formula (55), respectively. 111. The method according to claim 110, further characterized in that at least one of R3, R4 and Rs is C-i-Cβ alkoxy; and the hydroxy activating reagent is tosyl chloride. 112. The method according to claim 111, further characterized in that the compound of formula (73) or the compound of formula (94) is: (77) respectively; the compound of formula (74) is: (78) and the compound of formula (55) is: 113. - The method according to claim 110, further characterized in that before said activation step the method comprises: hydrogenating and hydrogenolizing a compound of formula (72), (72) wherein X is a halide, to form the compound of formula (73). 114. The method according to claim 113, further characterized in that the compound of formula (72) is: 115. - The method according to claim 113, further characterized in that it comprises, before said step of hydrogenation and hydrogenolysis, alkylating a compound of formula (51), (51) with a compound of formula (54), to form the compound of formula (72). The method according to claim 110, further characterized in that before said activation step, the method comprises: deprotecting a compound of formula (93), wherein Pro is a protecting group, to form the compound of formula (94). 117. The method according to claim 116, further characterized in that the compound of formula (93) is: 118. - The method according to claim 116, further characterized in that before said deprotection step, the method comprises: alkylating a compound of formula (92), a oii QFre (92) with a compound of formula (54), to form the compound of formula (93). 119. The method according to claim 118, further characterized in that the compound of formula (92) is: (96) The compound of formula (54) is: and the compound of formula (93) is: OMc r? X_ > »° 120. - The method according to claim 118, further characterized in that it comprises, before said alkylation step: hydrogenating and hydrogenolizing a compound of formula (91), (91) to form the compound of formula (92). 121. The method according to claim 104, further characterized in that it comprises, before the alkylation step: hydrogenating and hydrogenolizing a compound of formula (52), (52) wherein X is a halide, to form the compound of formula (53). 122. The method according to claim 121, further characterized in that: (52 is í 123. The method according to claim 121, further characterized in that it comprises, before said step of hydrogenation and hydrogenolysis: activating a compound of formula (51), (51) with a hydroxy activating reagent, to form the compound of formula (52). 124. The method according to claim 104, further characterized in that it comprises, prior to said alkylation step: deprotecting a compound of formula (99), wherein Pro is a protecting group, to form the compound of formula (84). 125. The method according to claim 124, further characterized in that it comprises, prior to said deprotection step: activating a compound of formula (92), wherein Pro is a protecting group, with a hydroxy activating reagent, to form the compound of formula (99). 126. - The method according to claim 125, further characterized in that it comprises, before said activation step, hydrogenating and hydrogenolizing a compound of formula (91), (W5 to form the compound of formula (92) 127. The method according to claim 125, further characterized in that: the hydroxy activating reagent is tosyl halide, the compound of formula (92) is: (96) and the compound of formula (99) is: (100) 128. The method according to claim 103, further characterized in that the compound of formula (56) is: (65A) and where it is formed: 129. - The method according to claim 104, further characterized in that it comprises, before said alkylation step: removing a functional group G or Gi of a compound of formula (85), (85) or a compound of formula (86), (86) respectively, to form: Í53) OR (84) respectively. 130. The method according to claim 104, further characterized in that it comprises, before said alkylation step: separating a racemic mixture of the compound of formula (53) and the compound of formula (84). 131. The method according to claim 130, further characterized in that said separation step comprises functionalizing one or both compounds, that of formula (53) and that of formula (84), in such a way that they are capable of resolution; and make a resolution to separate the compounds; and optionally remove the. functional group of one or both functionalized compounds. 132. The method according to claim 130, further characterized in that before said separation step, it comprises: activating a compound of formula (83), (83) with a hydroxy activating reagent, to form the racemic mixture of the compound of formula (53) and the compound of formula (84). 133. The method according to claim 131, further characterized in that the compound of formula (53) is: (62) wherein the compound of formula (84) is: and is functionalized enzymatically with OR) to form: (89) and make the resolution to separate the compound of formula (62) from (89) 134. The method according to claim 131, further characterized in that the compound of formula (84) is: (87) and wherein the compound of formula (53) is: (62) and is functionalized with: (88) to form: a O? C OTS; (90) and further comprising making a resolution to separate (90) from (87); and remove the functional group of (90) to form: v? 0Ts (62) 135.- The method according to claim 130, further characterized in that it comprises, before said separation step, activating on a hydroxy activating reagent to form a racemic mixture. 136. - A method of preparing a compound of formula (55) or formula (74): which comprises alkylating a compound of formula (53), or a compound of formula (84), (84) with a compound of formula (54), to form the compound of formula (55) or the compound of formula (74), respectively; and optionally protecting a compound of formula (53), CC (53) or a compound of formula (84), (84) before said alkylation step; wherein OQ is a leaving group that reacts with -OH in the formula (53) or (84), to form the compound of the formula (55) or the compound of the formula (74), in such a way that the stereochemical configuration is retained in the compound of formula (55) or the compound of formula (74), respectively; wherein R3, R and R5 are independently selected from hydrogen, hydroxy and C-C6 alkoxy, with the proviso that R3, R and R5 can not all be hydrogen; and where O-J is a leaving group. 137.- A method of preparing a compound of formula (74) or formula (55): which comprises activating a compound of formula (73), or a compound of formula (94), with a hydroxy activating reagent, to form the compound of formula (74) or the compound of formula (55), respectively; wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-t-Cβ alkoxy, with the proviso that R3, R4 and Rs can not all be hydrogen; and where O-J is a leaving group. 138.- A method of preparing a compound of formula (73): which comprises hydrogenating and hydrogenolizing a compound of formula (72), (72) to form the compound of formula (73); where X is a halide; and wherein R 3, R 4 and R 5 are independently selected from hydrogen, hydroxy and C 1 -C 2 alkoxy, with the proviso that R 3, R and R 5 can not all be hydrogen. 139.- A method of preparing a compound of formula (72): (72) which comprises alkylating a compound of formula (51), with a compound of formula (54), to form the compound of formula (72); where X is a halide; wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-C6 alkoxy, with the proviso that R3, R4 and R5 can not all be hydrogen; and wherein OQ is a leaving group that reacts with -OH in the compound of formula (51) to form the compound of formula (72), such that the stereochemical configuration of the compound of formula (51) in the compound is retained. of formula (72). 140.- A method of preparing a compound of formula (93): which comprises alkylating a compound of formula (92), (S2_ with a compound of formula (54), to form the compound of formula (93); where Pro is a protective group; wherein R3, R and Rs are independently selected from hydrogen, hydroxy and C_-Cß alkoxy, with the proviso that R3, R4 and R5 can not all be hydrogen; and wherein OQ is a leaving group which reacts with -OH in the compound of formula (92) to form the compound of formula (93), such that the stereochemical configuration of the compound of formula (92) in the compound is retained. of formula (93). 141. A method of preparing a compound of formula (92): (92) which comprises hydrogenating and hydrogenolizing a compound of formula (91), to form the compound of formula (92); where Pro is a group protective; and where X is a halide. 142. - A method for preparing a compound of formula (53): < «); which comprises hydrogenating and hydrogenolizing a compound of formula (52), Í52 > to form the compound of formula (53); where X is a halide; and where O-J is a leaving group. 143.- A method of preparing a compound of formula (52), (52.} which comprises activating a compound of formula (51), with a hydroxy activating reagent to form the compound of formula (52); where X is a halide; and where O-J is a leaving group. 144. A method of preparing a compound of formula (99): C (? «; which comprises activating a compound of formula (92), . { 921 with a hydroxy activating reagent to form the compound of formula (99); where Pro is a protective group; and where O-J is a leaving group. 145. A method of preparing a compound of formula (53) or a compound of formula (84): («I o- CB4); which comprises removing a functional group G or G. of a compound of formula (85), (85) or a compound of formula (86), (m respectively, to form the compound of formula (53) or the compound of formula (84), respectively, wherein OJ is a leaving group 146.- A method of separating a racemic mixture of a compound of formula (53). ), (S) and a compound of formula (84), (84) 147. - The method according to claim 146, further characterized in that it comprises functionalizing one or both compounds, the compound of formula (53) and the compound of formula (84), such that the compounds are capable of resolution; make the resolution to separate the compounds; and optionally removing the functional group in one or both functionalized compounds. 148.- A method of forming a racemic mixture of a compound of formula (53) and a compound of formula (84): (53) Í 4) which comprises activating a compound of formula (83), (83) with a hydroxy activating reagent, to form the racemic mixture of the compound of formula (53) and the compound of formula (84); where O-J is a leaving group. 149. A method for stereoselectively preparing an aminocyclohexyl ether of formula (57): wherein Ri and R2, when taken together with the nitrogen atom to which they are directly attached in the formula (57), form a ring denoted by the formula (II): (OD and wherein R3, R and Rs are selected independently of hydrogen, hydroxy and alkoxy of C.-6, with the proviso that R3, R and R5 can not all be hydrogen, said method comprises: (a) reacting a compound of formula (53), (53) wherein O-J is a leaving group, with a compound of formula (54), wherein R3, R and R5 are as defined above and O-Q is a leaving group that reacts with the hydroxy group (-OH) in the formula (53), to form a compound of the formula (55), such that the stereochemical configuration of the compound of formula (53) in the compound of formula (55) is retained; (b) optionally protecting the compound of formula (53) before the first reaction; and (c) reacting the compound of formula (55) with a compound of formula (56), (56) wherein R. and R2 are as defined above, to form the aminocyclohexyl ether of formula (57). 150. The method according to claim 149, further characterized in that, before said first reaction step (a), it comprises hydrogenating and hydrogenolizing a compound of formula (52), (52) wherein X is a halide, to form a compound of formula (53), (53). 151. The method according to claim 150, further characterized in that, prior to said hydrogenation and hydrogenolysis reaction, it comprises activating a compound of formula (51), £ 51). on a hydroxy activating reagent to form a compound of formula (52), 152. - The method according to claim 149, further characterized in that, before said said first reaction step (a), it comprises separating a racemic mixture of a compound of formula (53), (53) and a compound of formula (84), (84) to obtain (53), wherein said separation step also optionally comprises functionalizing one or both of the compound of formula (53) and the compound of formula (84), such that the compounds are capable of resolution; make the resolution to separate the compounds; and optionally removing the functional group from one or both functionalized compounds. 153. The method according to claim 152, further characterized in that said separation step comprises enzymatic resolution, crystallization or chromatographic resolution. 154. The method according to claim 152, further characterized in that said resolution is mediated by lipase. 155. The method according to claim 149, further characterized in that, before the reaction step (a), it comprises removing a functional group G from a compound of formula (85), (85) to form the compound of formula (53). 156. The method according to any of claims 149, 150, 151, 152, 153 and 154, further characterized in that at least one of R3, R4 and R5 is C6-C6 alkoxy; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; and wherein, if present, X is Cl. 157. The method according to any of claims 149, 150, 151, 152, 153 and 154, further characterized in that the compound of formula (56) is: and wherein R3 is hydrogen, and R and R5 are C-? -6 alkoxy; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulphonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; and wherein, if present, X is Cl. 158. The method according to any of claims 149, 150, 151, 152, 153 and 154, further characterized in that the compound of formula (56) is: I «'« OH. (65) wherein R3 is hydrogen, R is methoxy at the C3 of the phenyl group and R5 is methoxy at the C of the phenyl group; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; and where, if present, X is Cl; such that the aminocyclohexyl ether of formula (57) is: 159. A method for stereoselectively preparing an aminocyclohexyl ether of formula (75): wherein R. and R2, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): (II) and wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C6-6 alkoxy, with the proviso that R3, R4 and R5 can not all be hydrogen; the method comprises: (a) reacting a compound of formula (84), m wherein O-J is a leaving group, with a compound of formula (54), wherein R3, R4 and R5 are as defined above and O-Q is a leaving group that reacts with the hydroxy group (-OH) in the compound of formula (84), to form a compound of formula (74), such that the stereochemical configuration of the compound of formula (84) in the compound of formula (74) is retained; (b) optionally protecting the compound of formula (84) before the first reaction step (a); and (c) reacting the compound of formula (74) with a compound of formula (56), HN (56) where R. and R2 are as defined above, to form the aminocyclohexyl ether of formula (75). 160.- The method according to claim 159, further characterized in that, before said first reaction step (a), comprises deprotecting a compound of formula (99), (99) wherein Pro is a protecting group, to form the compound of formula (84). 161. - The method according to claim 160, further characterized in that, prior to said deprotection reaction step, it comprises activating a compound of formula (92), (92) with a hydroxy activating reagent to form the compound of formula (99), and optionally also comprises, prior to said activation reaction, hydrogenating and hydrogenolizing a compound of formula (91), (91 where X is a halide, to form the compound of formula (92) 162. The method according to claim 159, further characterized in that, before said first reaction step (a), comprises separating a racemic mixture from a compound of formula (53), and the compound of formula (84), to obtain the compound of formula (84); wherein said separation step also optionally comprises functionalizing one or both of the compound of formula (53) and the compound of formula (84), in such a way that the compounds are capable of resolution; make the resolution to separate the compounds; and optionally remove the functional group from one or both functionalized compounds. 163. The method according to claim 162, further characterized in that said separation step comprises enzymatic resolution, crystallization or chromatographic resolution. 164. - The method according to claim 162, further characterized in that said resolution is mediated by lipase. The method according to claim 159, further characterized in that, before said first reaction step (a), it comprises removing a functional group Gi from a compound of formula (86), (86), to form the compound of formula (84). 166.- The method according to any of claims 159, 160, 161, 162, 163 and 164, further characterized in that at least one of R3. R4 and Rs is C6-C6 alkoxy; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; where, if present, Pro is TBDPS; and if present, X is Cl. 167. The method according to any of claims 159, 160, 161, 162, 163 and 164, further characterized in that the compound of formula (56) is: and wherein R3 is hydrogen, and R4 and R5 are C6 alkoxy; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; where, if present, Pro is TBDPS; and if present, X is Cl. 168. The method according to any of claims 159, 160, 161, 162, 163 and 164, further characterized in that the compound of formula (56) is: (65) wherein R3 is hydrogen, R4 is methoxy at the C3 of the phenyl group and R5 is methoxy at the C4 of the phenyl group; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; where, if present, Pro is TBDPS; and if it is present, X is Cl; such that the aminocyclohexyl ether of formula (75) is: (79) 169. A method for stereoselectively preparing an aminocyclohexyl ether of formula (75): wherein R. and R2, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): 01). and wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-β alkoxy, with the proviso that R3, R4 and R5 can not all be hydrogen; comprising: (a) reacting a compound of formula (73), with a hydroxy activating reagent, to form a compound of formula (74), where O-J is a leaving group, R3, R4 and R5 are as defined above; and (b) reacting the product of the first reaction, the compound of formula (74), with a compound of formula (56), (56) wherein R-i and R2 are as defined above, to form the aminocyclohexyl ether of formula (75). 170. The method according to claim 169, further characterized in that, before reaction step (a), it comprises hydrogenating and hydrogenolizing a compound of formula (72), (72) wherein X is a halide, to form the compound of formula (73). 171. The method according to claim 170, further characterized in that, before said hydrogenation and hydrogenolysis reaction, it comprises reacting a compound of formula (51), (53) with a compound of formula (54), wherein OQ is a leaving group that reacts preferentially with one of the hydroxy (-OH) groups of the compound of formula (51), to form a compound of formula (72), such that the stereochemical configuration of the compound of Formula (51) in the compound of formula (72). 172.- The method of compliance with any of the claims 169, 170 and 171, further characterized because at least one of R3, R4 and R is C.-β alkoxy; where O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; and, if present, X is Cl. 173.- The method of compliance with any of the claims 169, 170 and 171, further characterized in that the compound of formula (56) is: (65) 0 (65A). and wherein R3 is hydrogen, and R4 and R5 are C-i-β alkoxy; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; where O-Q is trichloroacetimidate; and, if present, X is Cl. 174.- The method of compliance with any of the claims 169, 170 and 171, further characterized in that the compound of formula (56) is: HN "'OH (65) wherein R3 is hydrogen, R is methoxy at the C3 of the phenyl group and R5 is methoxy at the C4 of the phenyl group; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; and, if present, X is Cl; such that the aminocyclohexyl ether of formula (75) is: ) 175. - A method for stereoselectively preparing an aminocyclohexyl ether of formula (57): wherein R. and R2, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): (U) and wherein R3, R4 and R5 are independently selected from hydrogen, hydroxy and C-6 alkoxy, with the proviso that R3, R4 and Rs can not all be hydrogen; comprising: (a) hydrogenating and hydrogenolizing a compound of formula (91), (53) to form a compound of formula (92), (32) where Pro is a protecting group, X is a halide; (b) alkylating the compound of formula (92) with a compound of formula (54), where R3, R4 and R5 are as defined above and O-Q is a leaving group which reacts with the hydroxy group (-OH) of the formula (92), to form a compound of formula (93), such that the stereochemical configuration of the compound of formula (92) is retained in the compound of formula (93); (c) check out the compound of formula (93) to form a compound of formula (94), (d) activating the compound of formula (94) to form a compound of formula (55), where O-J is a leaving group; and (e) reacting the compound of formula (55) with a compound of formula (56), (56) < wherein R. and R2 are as defined above, to form the aminocyclohexyl ether of formula (57). 176. The method according to claim 175, further characterized in that, before the reaction step (a), it comprises protecting one of the hydroxyl groups of the compound of formula (50), to form the compound of formula (91). 177. The method according to any of claims 175 and 176, further characterized in that O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; where, if present, Pro is TBDPS; and, if present, X is Cl. 178. The method according to any of claims 175 and 176, further characterized in that at least one of R3, R4 and R5 is C, ^ alkoxy; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; where, if present, Pro is TBDPS; and, if present, X is Cl. 179. The method according to any of claims 175 and 176, further characterized in that the compound of formula (56) is: (65) 0 (6'5A). and wherein R3 is hydrogen, and R4 and R5 are C6_6 alkoxy; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; where, if present, Pro is TBDPS; and, if present, X is Cl. 180.- The method according to any of claims 175 and 176, further characterized in that the compound of formula (56) is: IFT? | MUÍ • (65) wherein R3 is hydrogen, R is methoxy at the C3 of the phenyl group and R5 is methoxy at the C4 of the phenyl group; wherein O-J is a mesylate group, a tosylate group, a nosylate group, a 2-bromophenylsulfonate group or a 4-bromophenylsulfonate group; wherein O-Q is trichloroacetimidate; where, if present, Pro is TBDPS; and, if present, X is Cl; such that the aminocyclohexyl ether of formula (57) is: 181- A method of preparing the compound (1) or the compound (2): comprising: (a) reacting l f? "OH with (BOc) 2O under the appropriate conditions to form the compound (1R): 1R. (b) reacting the compound (1R) with benzyl bromide under the appropriate conditions to form the compound (2R): 2R (c) hydrolyze the compound (2R) under suitable conditions to form the compound (3R): I3 > > ».'OBzl 3 (d) reacting the compound (3R) with under the right conditions to form the compound (4R): AR (e) reacting the compound (4R) with under the right conditions to form the compound (5R): SR (f) resolving the compound (5R) under the appropriate conditions to form the compound (5RRR) and the compound (5SSR): 5RR? and 5SSR. and (g) hydrogenolizing the compound (5RRR) under suitable conditions to form the compound (1) described above, and hydrogenolizing the compound (5SSR) under suitable conditions to form the compound (2) described above. 182.- A method of preparation of the compound (5RRR) or the compound (5SSR): 5RRR and 5SSR comprising: (a) reacting W fí) > »'OH with (Boc) 2O under the appropriate conditions to form the compound (1 R): IR i (b) reacting the compound (1R) with benzyl bromide, under the appropriate conditions to form the compound (2R): 2R (c) hydrolyze the compound (2R) under the appropriate conditions to form the compound (3R): 3R (d) reacting the compound (3R) under the appropriate conditions to form the compound (4R): 4R (e) reacting the compound (4R) with under the right conditions to form the compound (5R); 5R and (f) resolving the compound (5R) under suitable conditions to form the compound (5RRR) and the compound (5SSR) described above. 183. The method according to claim 182, further characterized in that it comprises reacting the compound (5RRR) under suitable conditions to form the compound (17): (17) 184.- A method of preparation of the compound (5R): MR comprising: (a) reacting with (Boc) 2O, under the appropriate conditions to form the compound (1R): i ° ÁAk '?)' "0H 1R (b) reacting the compound (1R) with benzyl bromide, under the appropriate conditions to form the compound (2R): 2R s (c) hydrolyze the compound (2R) under the appropriate conditions to form the compound (3R) 3R (d) reacting the compound (3R) with under the right conditions to form the compound (4R): 4R and (e) reacting the compound (4R) with under suitable conditions to form the compound (5R) described above. 185. - The method according to claim 184, further characterized in that it comprises reducing the compound (5R) under suitable conditions to form the compound (4): 186. - The method according to claim 184, further characterized in that it comprises reacting the compound (5R) under suitable conditions to form the compound (12): 187. - A method of preparation of the compound (4R): 4R comprising: (a) reacting "'OH with (Boc) 2O, under the appropriate conditions to form the compound (1R): TR? (b) reacting (1R) with benzyl bromide, under the appropriate conditions to form the compound (2R): zn I (c) hydrolyzing the compound (2R) under suitable conditions to form the compound (3R): IN- R) '> "0B.-á 3R and (d) reacting the compound (3R) with under suitable conditions to form the compound (4R) described above. 188.- A method of preparation of the compound (3R): H INNA-L5 > '"' QBzt 3R comprising: (a) reacting with (Boc) 2O under the appropriate conditions to form the compound (1R): 1R (b) reacting the compound (1R) with benzyl bromide, under suitable conditions to form the compound (2R): 2R and (c) hydrolyzing the compound (2R) under suitable conditions to form the compound (3R) described above. 189.- A method of preparing the compound (1): (1) which comprises hydrogenating the compound (5RRR): under suitable conditions to form the compound (1) described above. 190. - The method according to claim 189, further characterized because, before the step of hydrogenolysis, it comprises solve the compound (5R): 5R under suitable conditions to form the compound (5RRR) described above. 191. The method according to claim 190, further characterized in that, before the resolution step, it comprises making react the compound (4R): 4R with: under the appropriate conditions to form the compound (5R) described above. 192.- The method according to claim 191, further characterized in that, before said reaction, it comprises reacting the compound (3R): HNA. ff; OBzí 3R with: under the right conditions to form the compound (4R) above described. 193. The method according to claim 102, further characterized in that, before the reaction of the compound (3R) with comprises hydrolyzing the compound (2R): 2R under suitable conditions to form the compound (3R) described above. 194.- A method of preparing the compound (2): comprising hydrogenating the compound (5SSR): 55SR under the appropriate conditions to form the compound (2) described above. 195. The method according to claim 194, further characterized in that, before the hydrogenolysis step, it comprises resolving the compound (5R): 5R under suitable conditions to form the compound (5SSR) described above. 196. The method according to claim 195, further characterized in that, before the resolution step, it comprises reacting the compound (4R): R with: under suitable conditions to form the compound (5R) described above. 197. The method according to claim 196, further characterized in that, prior to said reaction, it comprises reacting the compound (3R): H IN- 'ff A'OBzl 3R with: under the right conditions to form the compound (4R) above described. 198. The method according to claim 197, further characterized in that, before the reaction of the compound (3R) with it comprises hydrolyzing the compound (2R): 2R under suitable conditions to form the compound (3R) described above. 199.- A method of preparing a compound (6) or a compound (7): < 6 > or < 7 > comprising: (a) reacting: with (Boc) 2O, under the appropriate conditions to form the following compound: (b) reacting the compound formed in step (a) with benzyl bromide, under suitable conditions to form the following compound: (c) hydrolyzing the compound formed in step (b) under suitable conditions to form the following compound: (d) reacting the compound formed in step (c) with: under the appropriate conditions to form the following compound: (e) reacting the compound formed in step (d) with: under the right conditions to form the following compound: (f) resolving the compound formed in step (e) under the appropriate conditions to form the following compounds: and (g) hydrogenolizing the following compound formed in step (f): under suitable conditions to form the compound (6) described above; and hydrogenolizing the following compound formed in step (f): under suitable conditions to form the compound (7) described above. 200. The method according to claim 199, further characterized in that it comprises reducing the compound formed in step (e) under suitable conditions to form the compound (5): (5) 201. - A method of preparation of compound (3): (3) comprising: (a) reacting: with (Boc) 2O, under the appropriate conditions to form the following compound: (b) reacting the compound formed in step (a) with benzyl bromide, under suitable conditions to form the following compound: (c) hydrolyzing the compound formed in step (b) under suitable conditions to form the following compound: l V-OBzl (d) reacting the compound formed in step (c) with: under the right conditions to form the following compound: cr? QBzl (e) reacting the compound formed in step (d) with: under the right conditions to form the following compound: (f) hydrogenolizing the following compound formed in step (e): under suitable conditions to form the compound (3) described above. 202.- The compound (5RRR): 5RRR 203. - The compound (5SSR): 5SSR 204. - The compound (5R): 5R 205. - The compound (4R): l J? OBZ] 4R