RU2330017C2 - Compounds of simple amino-cyclohexyle ether and methods of their use - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (IE) or of its pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer,

including its chosen enantiomeric, diastereomeric and geometric isomers and their mixtures, where R₄ and R₅ are independently selected from C₁-C₆ alkoxy.

EFFECT: it makes it possible to use them in the pharmaceutical compositions and the methods of blocking Na channels in warm-blooded animals.

18 cl, 5 tbl, 18 ex

Description

The present invention relates to aminocyclohexyl ether compounds, pharmaceutical compositions and methods for preparing aminocyclohexyl ether compounds and methods for their therapeutic use.

Ion channels are common membrane proteins in the cells of warm-blooded animals such as mammals. Their main physiological role is to regulate the electrical potential on both sides of the membrane, mediate ionic and fluid balance, promote neuromuscular and neural transmission, rapid transmembrane signal transmission and regulate secretion and contractility.

For example, cardiac ion channels are proteins that are located in the cell membrane and regulate the electrical activity of cardiac tissue. In response to external stimuli, such as changes on both sides of the cell membrane, these ion channels can form a pore through the cell membrane and allow specific ions to move into and out of the cell. The integrated behavior of thousands of ion channels in one cell leads to ion current, and the integrated behavior of many of these ion currents makes up the characteristic cardiac action potential.

Arrhythmia is a deviation from the normal heart rate and generally represents the end product of the abnormal structure, quantity or function of ion channels. Atrial arrhythmias and ventricular arrhythmias are known. The main cause of deaths due to cardiac arrhythmias is a subtype of ventricular arrhythmias, known as ventricular fibrillation (VF). Conservative estimates indicate that in the United States alone, one million Americans each year will have a new or recurrent coronary attack (defined as myocardial infarction or fatal coronary heart disease). Approximately 650,000 of these will be the first heart attacks and 450,000 will be relapses. About one third of people who have had these attacks die from them. At least 250,000 people a year die from coronary heart disease within 1 hour after the onset of symptoms and before they are hospitalized. These are cases of sudden death caused by cardiac arrest, usually resulting from ventricular fibrillation.

Atrial fibrillation (the term “ciliary arrhythmia” is accepted in medicine) (AF), is the most common arrhythmia observed in clinical practice, and it causes the incidence of many individuals (Pritchett EL, N. Engl. J. Med. 327 (14) : 1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123 (l): 264-7 Jan. 1992). Its prevalence is likely to increase as the population ages, and it is estimated that 3-5% of patients over the age of 60 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 the leading cause of stroke (Hinton RC, Kistler JP, Fallon JT, Friedlich AL, Fisher S.M., American Journal of Cardiology 40 (4): 509-13, 1977; Wolf PA, Abbot RD, Kannel WB, Archives of Internal 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).

WO95 / 08544 discloses a class of aminocyclohexyl ester compounds as compounds that can be used in the treatment of arrhythmias.

WO93 / 19056 discloses a class of aminocyclohexylamides as compounds that can be used in the treatment of arrhythmias and in the induction of local anesthesia.

WO99 / 50225 discloses a class of aminocyclohexyl ether compounds as compounds that can be used in the treatment of arrhythmias.

Antiarrhythmic drugs have been developed to prevent or alleviate cardiac arrhythmias. For example, class I antiarrhythmic compounds were used to treat supraventricular arrhythmias and ventricular arrhythmias. The treatment of ventricular arrhythmias is very important, since such an arrhythmia can be fatal. Severe ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) most often occur in the presence of ischemia and / or myocardial infarction. Ventricular fibrillation often occurs in acute myocardial ischemia before a heart attack develops. Currently, there is no satisfactory pharmacotherapy for the treatment and / or prevention of ventricular fibrillation during acute ischemia. In fact, class I antiarrhythmic compounds can actually increase mortality in patients who have previously had myocardial infarction.

Class Ia, Ic, and III antiarrhythmic drugs have been used to convert newly-onset AF to sinus rhythm and prevent recurrence of arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs 48 (3): 345-71, 1994). However, drug therapy is often limited by side effects, including the possibility of increased mortality and inadequate efficacy (Feld GK, Circulation. 83 (6): 2248-50, 1990; Coplen SE, Antman EM, 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 frequencies for class I antiarrhythmic drugs range from 50 to 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): S 104-8, 1998). Class III antiarrhythmic drugs appear to be more effective in stopping atrial flutter than for AF, and are generally considered less effective than class I drugs in stopping AF (Nattel S., T. Hadjis, Talajic M., Drugs. 48 (3): 345-71, 1994; Capucci A., Aschieri D., Villani GQ, Drugs & Aging 13 (1): 51 - 70, 1998). Examples of such preparations include ibutilide, dofetilide and sotalol. The conversion rates for these drugs range from 30 to 50% of the recent onset of AF (Capucci A., Aschieri D., Villani GQ, Drugs & Aging 13 (1): 51-70, 1998), and they are also associated with risk induction of ventricular tachyarrhythmias such as flutter-ventricular fibrillation. For ibutilide, the risk of ventricular proarrhythmia is estimated to be 4% with 7% of patients requiring defibrillation for persistent ventricular arrhythmias (Kowey PR, VanderLugt JT, Luderer JR, American Journal of Cardiology 78 (8A): 46-52, 1996). Such events are especially tragic in the case of AF, since this arrhythmia in itself is rarely fatal.

In this area, there remains a need to identify methods of antiarrhythmic treatment for ventricular arrhythmias, as well as for atrial arrhythmias. The present invention satisfies these needs and, in addition, provides other related problems.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, provided that all R ₃ , R ₄ and R _{5 are} not may be hydrogen.

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, provided that all R ₃ , R ₄ and R _{5 are} not may be hydrogen.

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, provided that all R ₃ , R ₄ and R _{5 are} not may be hydrogen.

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, provided that all R ₃ , R ₄ and R _{5 are} not may be hydrogen.

In one embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, provided that all R ₄ and R ₅ cannot be hydrogen.

In one embodiment, the present invention provides a compound, or any salt thereof, or any solvate thereof, or a mixture comprising one or more of these compounds, or any salt thereof, or any solvate thereof, selected from the group consisting of

Structure Chemical name

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

In another embodiment, the present invention provides a composition that includes one or more of the compounds listed in the above table, or includes a solvate or pharmaceutically acceptable salt of one or more of the compounds listed in the above table. The composition may or may not include additional components, as described in detail later in this patent.

In one embodiment, the present invention provides a compound or mixture comprising compounds, or any solvate thereof, selected from the group consisting of

Compound No. Structure Chemical name one

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 2

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 3

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride four

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 5

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 6

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 7

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

In another embodiment, the present invention provides a composition that includes one or more of the compounds listed in the above table, or comprises a solvate of one or more of the compounds listed in the above table. The composition may or may not include additional components, as described in detail later in this patent.

In one embodiment, the present invention provides a compound which is the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound that is a free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound that is a free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof.

In one embodiment, the present invention provides a compound that is a free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane 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-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof.

In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3S) -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 - [(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 trained variants of all the compounds described in this patent. That is, for each compound described in this patent, the invention also includes the form of a quaternary trained amine of the compound. These forms of the quaternary trained amine of the compounds may be present in the solid phase, for example in crystalline or amorphous form, and may be present in solution. These forms of the quaternary trained amine of the compounds can be associated with pharmaceutically acceptable anionic counterions, including, but not limited to, counterions 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 thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomes Temperature and mixtures thereof in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for preparing such a composition or medicament.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof in the complex tion with a pharmaceutically acceptable carrier, diluent or excipient, and, in addition, provides a method for the manufacture of such a composition or drug.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, a stereoisomer, a stereoisomeric mixture, a geometric isomer, a crystalline or amorphous form, or a metabolite thereof, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof in combination with a pharmaceutically acceptable carrier, diluent or excipient, and furthermore provides a method for the manufacture of such a composition or drug.

In another embodiment, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof in combination with a pharmaceutically acceptable carrier, diluent or excipient, and furthermore provides a method for the manufacture of such a composition or drug.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or drug comprising compounds as described above for use in methods of modulating ion channel activity in a warm-blooded animal or for modulating ion channel activity in vitro. In one embodiment of this embodiment, the warm-blooded animal in which the ion channel activity is modulated is a mammal; in one embodiment, the warm-blooded animal is a human; in one embodiment, the warm-blooded animal is an agricultural animal.

As disclosed in the framework of the present invention, a variety of cardiac pathological conditions can be treated and / or prevented by the use of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE ), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomer s, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above. Without being bound by theory, the applicants believe that the compounds of the present invention are compounds that modulate ion channels, which, either separately or together with one or more additional compounds, are capable of selectively modulating certain ion currents. The ionic currents indicated herein are generally cardiac currents, and more specifically, are sodium currents and early repolarizing currents.

In this patent, applicants describe various means by which, in their opinion, the compounds described in this patent can act. Such descriptions are not intended to be limiting, but represent an understanding by applicants of how these compounds may act.

Pathological conditions that can be treated and / or prevented by the present invention may include, but are not limited to, various cardiovascular diseases.

Cardiac pathological conditions that can be treated and / or prevented by the present invention may include, but are not limited to, arrhythmias, such as various types of atrial and ventricular arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter.

In another embodiment, the present invention provides ion modulating channel compounds that can be used to selectively inhibit cardiac early repolarizing currents and cardiac sodium currents under conditions where an "arrhythmogenic substrate" is present in the heart. An "arrhythmogenic substrate" is characterized by a decrease in the duration of the cardiac action potential and / or changes the morphology of the action potential, premature action potentials, high heart rate and may also include an increased variability in the time interval between action potentials and an increase in the acidity of the heart due to ischemia or inflammation. Changes such as these are observed during conditions of ischemia or inflammation of the myocardium and those conditions that precede the onset of arrhythmias, such as atrial fibrillation.

In other embodiments, the present invention provides a method for modulating ion channel activity in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC) , (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous oh form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating the activity of ion channels in vitro, comprising administering in vitro an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), ( ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor nicknames or prodrugs, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound, or a mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for blocking / inhibiting ion channel activity / conductivity in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB) , (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating potassium ion channel activity in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC ), (ID) or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline and whether an amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating the activity of cardiac sodium ion channels in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), ( IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crista a batch or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating the activity of ion channels of early repolarizing currents and cardiac sodium currents in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture and, a geometric isomer, crystalline or amorphous, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), ( IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous a form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a medicament that contains one or more compounds of the present invention, such as compounds according to formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric and isomers thereof, and mixtures thereof, as described above, in an amount effective to treat a disease or condition in a warm-blooded animal suffering from or having this disease or condition, and / or to prevent a disease or condition in a warm-blooded animal that would otherwise occur, and, in addition to Moreover, it contains a pharmaceutically acceptable carrier, diluent or excipient.

The invention further provides methods of treating a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and / or preventing the occurrence of the disease and condition in a warm-blooded animal, in which a therapeutically effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereo isomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, or a composition or drug, which includes the compound or mixture comprising the compounds as described above , administered to a warm-blooded animal in need. By way of illustration, and not limitation, examples of some of the diseases, disorders, and conditions in which the compounds, compositions, drugs, and methods of the present invention are used are: arrhythmia, atrial arrhythmia; ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, central nervous system diseases, cramps, epileptic cramps, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, allergies intestinal disorders, urinary incontinence, irritable bowel syndrome, cardiovascular disease, cerebral and myocardial ischemia, hypertension, long QT interval syndrome, stroke, migraine, eye disease I, diabetes mellitus, myopathy, Becker myotonia, generalized myasthenia gravis, congenital paramiotonia, malignant hyperthermia, periodic hyperkalemia paralysis, Thomsen myotonia, autoimmune disorders, organ transplant rejection or bone marrow transplantation, heart failure, hypotension, other psychosis, Alzheimer's disease or other and baldness.

In one embodiment, the compounds of the present invention can be used to treat and / or prevent arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, atrial flutter, or ventricular flutter; in another embodiment, the compounds can be used to treat arrhythmia, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, atrial flutter, or ventricular flutter; in another embodiment, the compounds can be used to prevent arrhythmias, atrial arrhythmias, ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, atrial flutter, or ventricular flutter.

In other embodiments, the present invention provides a composition or medicament containing one or more compounds of the present invention, such as compounds according to formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof , a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and g ometricheskie isomers and mixtures thereof as described above in an amount effective to create analgesia or local anesthesia in need thereof a warm-blooded animal, and a pharmaceutically acceptable carrier, diluent or excipient.

The invention also provides a method of creating analgesia or local anesthesia 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 compounds in accordance with formula (IA), (IB), (IC ), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolically the precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, or a composition or drug, which includes the compound or mixture comprising the compounds as described above. These compositions, drugs 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 one or more compounds of the present invention, such as compounds according to formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof , a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and g ometricheskie isomers and mixtures thereof as described above, in an amount effective to enhance the libido in need thereof a warm-blooded animal, and a pharmaceutically acceptable carrier, diluent or excipient.

The invention also provides a method for enhancing libido 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 compounds in accordance with formula (IA), (IB), (IC), ( ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prol quality, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, or a composition or drug, which includes the compound or mixture comprising the compounds as described above. These compositions and methods can be used, for example, to treat sexual dysfunction, such as impotence in males, and / or to enhance the sexual desire of a patient without sexual dysfunction. As an example, a therapeutically effective amount can be administered to a bull (or other farm animal) to facilitate increased ejaculation of the seed when the seed is collected and stored for use as necessary for insemination of cows with the assistance of a livestock breeding program.

The compounds of the present invention are effective antiarrhythmic agents. It was found that the compounds in accordance with the present invention exhibit predominantly low toxicity to the central nervous system (CNS), while maintaining high antiarrhythmic activity.

In another embodiment, the present invention provides methods for the synthesis of compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), and, in particular, methods for the synthesis of compounds:

the free base and the corresponding (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride;

the free base and the corresponding (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride;

the free base and the corresponding (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride;

the free base and the corresponding (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride;

the free base and the corresponding (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride;

free base and the corresponding monohydrochloride of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

the free base and the corresponding (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride;

some general methods for the synthesis of aminocyclohexyl ethers have been described in WO 99/50225 and the references cited therein.

These and other embodiments of the present invention will become apparent with reference to the following description, drawings and examples.

Brief Description of the Drawings

Figure 1 illustrates the reaction sequence by which the following aminocyclohexyl ether compounds of the present invention can be synthesized:

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (Compound 1);

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (Compound 2);

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (Compound 3);

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (Compound 4);

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (Compound 5);

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (Compound 6);

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane;

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (Compound 7).

Figure 2 illustrates a synthesis method that can be used to prepare the trans-aminocyclohexyl ether compound of the present invention.

FIG. 3 illustrates a synthesis method for producing the amine 1e required for the formation of amino alcohol 2e (as shown in FIG. 2).

4 illustrates a synthesis sequence that can be used to prepare the cis-aminocyclohexyl ether compound of the present invention, such as compound 25.

Figure 5 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

6 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1R, 2R) -aminocyclohexyl ester of formula (66).

FIG. 7 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 8 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

FIG. 9 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

Figure 10 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

11 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1R, 2R) -aminocyclohexyl ester of formula (66).

12 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of the formula (66).

FIG. 13 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

Fig. 14 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (69).

FIG. 15 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (57).

FIG. 16 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 17 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 18 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

FIG. 19 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

FIG. 20 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (57).

FIG. 21 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 22 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

23 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

24 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of the formula (69).

25 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (57).

FIG. 26 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 27 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 28 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

Fig. 29 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

FIG. 30 illustrates a general reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (57).

FIG. 31 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

Fig. 32 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

Fig. 33 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (69).

Fig. 34 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (69).

Fig. 35 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

Fig. 36 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (69).

Fig. 37 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (55).

Fig. 38 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (64).

Fig. 39 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (67).

FIG. 40 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (71).

Fig. 41 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (53).

Fig. 42 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (62).

Fig. 43 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (52).

Fig. 44 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (61).

Fig. 45 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

Fig. 46 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 47 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

48 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 49 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 50 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

Fig. 51 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 52 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 53 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 54 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 55 illustrates a general reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

Fig. 56 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 57 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 58 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 59 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 60 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

Fig. 61 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ester of formula (79).

Fig. 62 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

63 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 64 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 65 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

Fig. 66 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) -aminocyclohexyl ether compound of formula (79).

Fig. 67 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 68 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ester of formula (81).

69 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

70 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

Fig. 71 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 72 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

FIG. 73 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1S, 2S) -aminocyclohexyl ether compound of formula (81).

Fig. 74 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (81).

Fig. 75 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ester of formula (79).

Fig. 76 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ester of formula (81).

Fig.77 illustrates a reaction scheme that can be used as a method of obtaining stereoisomerically essentially pure compounds of formula (74).

78 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (78).

Fig. 79 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (80).

Fig. 80 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (82).

Fig. 81 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (73).

Fig. 82 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (77).

Fig. 83 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (72).

84 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (76).

Fig. 85 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

Fig. 86 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

Fig. 87 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

Fig. 88 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

Fig. 89 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

Fig. 90 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

Fig. 91 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

Fig. 92 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

Fig. 93 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

Fig. 94 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

Fig. 95 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (55).

Fig. 96 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (55).

Fig. 97 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (64).

Fig. 98 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (64).

99 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (64).

100 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (85) and a stereoisomerically substantially pure compound of formula (86).

101 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (62) and a stereoisomerically substantially pure compound of formula (89).

102 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (87) and a stereoisomerically substantially pure compound of formula (90).

103 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (62) and a stereoisomerically substantially pure compound of formula (87).

Fig. 104 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

FIG. 105 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) -aminocyclohexyl ether compound of formula (79).

106 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ester of formula (79).

107 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 108 illustrates a general reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

109 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ester of formula (79).

110 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

FIG. 111 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig. 112 illustrates a general reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

FIG. 113 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

FIG. 114 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1S, 2S) -aminocyclohexyl ether compound of the formula (79).

FIG. 115 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1S, 2S) -aminocyclohexyl ether compound of the formula (79).

FIG. 116 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (74).

FIG. 117 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (74).

FIG. 118 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (78).

FIG. 191 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (78).

Fig. 120 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (78).

Fig. 121 illustrates a general reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

FIG. 122 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 123 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

Fig. 124 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

125 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (66).

FIG. 126 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

Fig. 127 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

FIG. 128 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 129 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

130 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

FIG. 131 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 132 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

FIG. 131 illustrates a general reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

FIG. 134 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

FIG. 135 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (69).

Fig. 136 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (57).

FIG. 137 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1R, 2R) -aminocyclohexyl ether compound of formula (66).

Fig. 138 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1R, 2R) aminocyclohexyl ether compound of formula (69).

FIG. 139 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (55).

Fig. 140 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (64).

FIG. 141 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (94).

FIG. 142 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (98).

Fig illustrates a reaction scheme that can be used as a method of obtaining stereoisomerically essentially pure compounds of formula (93).

FIG. 144 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (97).

FIG. 145 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (92).

146 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (96).

147 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

FIG. 144 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1S, 2S) -aminocyclohexyl ether compound of the formula (79).

Fig illustrates a reaction scheme that can be used as a method for producing a stereoisomerically essentially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ether of the formula (81).

Fig. 150 illustrates a general reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

FIG. 151 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ether of formula (79).

FIG. 152 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1S, 2S) -aminocyclohexyl ether compound of formula (81).

153 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

154 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

Fig illustrates a reaction scheme that can be used as a method for producing a stereoisomerically essentially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ether of the formula (81).

FIG. 156 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans- (1S, 2S) -aminocyclohexyl ether compound of formula (75).

157 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (79).

158 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) -aminocyclohexyl ether compound of formula (81).

159 illustrates a general reaction scheme that can be used as a method for producing a stereoisomerically substantially pure trans (1S, 2S) aminocyclohexyl ether compound of formula (75).

FIG. 160 illustrates a reaction scheme that can be used as a method for preparing a stereoisomerically substantially pure trans (1S, 2S) -aminocyclohexyl ether compound of formula (79).

FIG. 161 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of a simple trans- (1S, 2S) -aminocyclohexyl ether of formula (81).

FIG. 162 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (74).

163 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (78).

164 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (84).

Fig illustrates a reaction scheme that can be used as a method of obtaining stereoisomerically essentially pure compounds of formula (62).

FIG. 166 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (99).

FIG. 167 illustrates a reaction scheme that can be used as a method for producing a stereoisomerically substantially pure compound of formula (100).

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention relates to aminocyclohexyl ether compounds of the formula such as (IA), (IB), (IC), (ID) or (IE), methods for their preparation, pharmaceutical compositions containing aminocyclohexyl ether compounds and various uses for compounds and compositions. Such uses include treatment of arrhythmias, modulation of ion channels, and other uses as described herein.

Understanding the present invention can help reference to the following definitions and explanation of the transformations used in the present description.

The aminocyclohexyl ether compounds of the invention have an ether oxygen atom at position 1 of the cyclohexane ring and an amine nitrogen atom at position 2 of the cyclohexane ring at other positions numbered in the corresponding order, as shown below in structure (A):

The bonds from the cyclohexane ring to the oxygen atoms in position 1 and nitrogen in position 2 in the above formula can be relatively located in either the cis or trans ratio. In a preferred embodiment of the present invention, the stereochemistry of the substituents of the cyclohexane ring in the form of an amine or an ether is either an (R, R) trans or an (S, S) trans. In another preferred embodiment, the stereochemistry is either (R, S) -cis or (S, R) -cis.

A wavy bond from the substituent to the central cyclohexane ring indicates that this group can be located on either side of the plane of the central ring. When a wavy bond is shown intersecting the ring, this indicates that said substituent group can be attached to any position on the ring that can bind to the substituent group, and that the substituent group may lie above or below the plane of the ring system to which it is attached.

Following the standard practice of description in the chemical literature and in accordance with the use in this patent, a solid wedge bond means above the plane of the ring, and a dotted wedge bond means below the plane of the ring; one solid bond and one dashed bond (i.e., ----) means trans configuration, while 2 solid bonds or 2 dotted bonds mean cis configuration.

In the formulas depicted herein, a bond with a substituent and / or a bond that connects the molecular moiety to the rest of the compound can be shown as intersecting one or more bonds in a ring structure. This indicates that the bond can be attached to any of the atoms that make up the ring structure, while a hydrogen atom could otherwise be present at that atom. When certain substituent (s) are not identified for a specific position in the structure, then hydrogen (s) is present in that position. For example, compounds of the invention containing compounds having a group (B):

where group (B) is intended to encompass groups where any ring atom that might otherwise be substituted with hydrogen may instead be substituted with any of R ₃ , R ₄ or R ₅ , provided that each of R ₃ , R ₄ or R ₅ appears once or only once in the ring. Ring atoms that are not substituted by any of R ₃ , R ₄ or R ₅ are substituted by hydrogen. In cases where the invention determines that the non-aromatic ring is substituted by one or more functional groups, and these functional groups are shown by bonds linked to the non-aromatic ring that bind the ring bonds in half, the functional groups may be present on different ring atoms or on the same ring atom, while this atom could otherwise be replaced by a hydrogen atom.

The compounds of the present invention contain at least 2 asymmetric carbon atoms and thus exist as enantiomers and diastereomers. Unless otherwise indicated, the present invention includes all enantiomeric and diastereomeric forms of the aminocyclohexyl ether compounds of the invention. Pure stereoisomers, mixtures of enantiomers and / or diastereomers and mixtures of various compounds of the invention are included in the scope of the present invention. Thus, the compounds of the present invention can occur as racemates, racemic mixtures and as separate diastereomers or enantiomers until a particular stereoisomer, enantiomer or diastereomer is identified, all of the isomeric forms included in the present invention. A racemate or racemic mixture does not imply a mixture of 50:50 stereoisomers. Unless otherwise indicated, the phrase “stereoisomerically substantially pure” generally refers to those asymmetric carbon atoms that are described and illustrated in the structural formulas for this compound.

By way of example, and in no way limiting the general nature of the foregoing, the compound indicated by the formula

includes at least 3 chiral centers (cyclohexyl carbon bonded to oxygen, cyclohexyl carbon bonded to nitrogen and pyrrolidinyl carbon bonded to oxygen) and therefore has at least 8 separate stereoisomers, which are (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; and (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (phenethoxy substituted with R ₃ , R ₄ and R ₅ ) cyclohexane; and, unless the context otherwise clarifies, the compound of the formula used in the present patent

means a composition that includes a component that is either one of 8 pure enantiomeric forms of the compound, or a mixture of any two or more pure enantiomeric forms, where the mixture may include any number of enantiomeric forms in any ratio.

As an example, and in no way limiting the general nature of the foregoing, until the context clarifies otherwise, the compound used in this patent, denoted by the chemical formula (1R, 2R) / (1S, 2S) -2 - [(3R) - hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane means a composition that includes a component that is either one of two pure enantiomeric forms of the specified compound (i.e. (1R, 2R) -2 - [(3R) - hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy ) cyclohexane), or a racemic mixture of two pure enantiomeric forms, wherein the racemic mixture may include any relative amount of two enantiomers.

The phrase “independently at each occurrence” is intended to mean (i) when any variable appears more than once in the compound of the invention, the definition of this variable at each occurrence, regardless of its definition at each other occurrence; and (ii) the identity of any of two different variables (for example, R ₁ within the set of R ₁ and R ₂ ) is chosen without regard to the identity of the other member of the set. However, combinations of substituents and / or variables are permissible only if such combinations result in compounds that do not violate standard chemical valency rules.

In accordance with the present invention, in the absence of specially indicated other designations, the following terms used in the present description are defined as having the following meanings:

“Acid addition salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar to them, or with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, para-toluenesulfonic acid, salicylic acid and the like, and include, but are not limited to the acids described, for example, 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.

“Alkoxy” refers to an (O) oxygen atom substituted with an alkyl group, for example, alkoxy may include, but is not limited to, methoxy, which may also be referred to as —OCH ₃ , —OME or C ₁ alkoxy.

"Modulation" in connection with the activity of the ion channel means that the activity of the ion channel can either be increased or decreased in response to the administration of the compound or composition or the method of the present invention. Thus, the ion channel can be activated in order to transport more ions, or it can be blocked (inhibited) so that fewer ions are transported by the channel or the ion transport stops altogether.

"Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985). For example, you can use a sterile saline and saline solution with phosphate buffer at physiological pH. Preservatives, stabilizers, colorants and even flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid, and para-hydroxybenzoic acid esters can be added as preservatives (ibid., P. 1449). In addition, antioxidants and suspending agents can be used (ibid.).

"Pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, obtained from a combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts). Examples of pharmaceutically acceptable salts include, but are not limited to, 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. The compounds of the present invention can be used either in the form of a free base or in the form of a salt, both forms being considered to be within the scope of the present invention.

A “therapeutically effective amount” of a compound of the present invention will depend on the route of administration, the type of warm-blooded animal being treated, and the physical characteristics of the particular warm-blooded animal in question. These factors and their relationship with the determination of this amount are well known to an experienced specialist in the field of medicine. This amount and route of administration can be selected to achieve optimal effectiveness, but they will depend on factors such as body weight, diet, concomitant medication and other factors that are known to specialists in the field of medicine.

Described in the present description of the composition as "containing a compound, for example, formula (IA)" encompasses compositions that contain more than one compound of formula (IA).

Compounds of the present invention

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, provided that all R ₃ , R ₄ and R _{5 are} not may be hydrogen.

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, 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 thereof, a pharmaceutically acceptable salt, wherein R ₄ and R ₅ are selected from hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, where R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy.

In one embodiment, the present invention provides a compound of formula (IA) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy .

In another embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, wherein R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof .

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy.

In one embodiment, the present invention provides a compound of formula (IB) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy .

In another embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, wherein R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof .

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy.

In one embodiment, the present invention provides a compound of formula (IC) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy .

In another embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, wherein R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof .

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy.

In one embodiment, the present invention provides a compound of formula (ID) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₃ is hydrogen, R ₄ and R ₅ are C ₁ alkoxy .

In another embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug:

where R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

In one embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, 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 thereof, a pharmaceutically acceptable salt, wherein R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₆ alkoxy, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof .

In one embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₄ and R _{5 are} independently selected from hydroxy and C ₁ -C ₃ alkoxy .

In one embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy.

In one embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₄ and R _{5 are} independently selected from C ₁ -C ₃ alkoxy.

In one embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₄ and R ₅ are C ₁ alkoxy.

In one embodiment, the present invention provides a compound of formula (IE) or a solvate thereof, a pharmaceutically acceptable salt, including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, wherein R ₄ and R ₅ are C ₁ alkoxy.

In one embodiment, the present invention provides a compound or any salt thereof or any solvate or mixture thereof comprising one or more of these compounds or any salt thereof or any solvate thereof selected from the group consisting of

Structure Chemical name

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

In another embodiment, the present invention provides a composition that includes one or more of the compounds listed in the above table, or includes a solvate or pharmaceutically acceptable salt of one or more of the compounds listed in the above table. The composition may or may not include additional components, as described in detail later in this patent.

In another embodiment, the present invention provides a compound or mixture comprising compounds or any solvate thereof selected from the group consisting of:

Compound No. Structure Chemical name one

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 2

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 3

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride four

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 5

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 6

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 7

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

In another embodiment, the present invention provides a composition that includes one or more of the compounds listed in the above table, or comprises a solvate of one or more of the compounds listed in the above table. The composition may or may not include additional components, as described in detail later in this patent.

In one embodiment, the present invention provides a compound which is the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound that is a free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound that is a free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof.

In one embodiment, the present invention provides a compound that is a free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane 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-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof.

In one embodiment, the present invention provides a compound that is (1R, 2R) -2 - [(3S) -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 - [(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 trained variants of all the compounds described in this patent. That is, for each compound described in this patent, the invention also includes the form of a quaternary trained amine of the compound. These forms of the quaternary trained amine of the compounds may be present in the solid phase, for example in crystalline or amorphous form, and may be present in solution. These forms of the quaternary trained amine of the compounds can be associated with pharmaceutically acceptable anionic counterions, including, but not limited to, counterions 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.

Description of the method for producing compounds of the invention

The aminocyclohexyl ether compounds of the present invention contain amino functional groups and ether functional groups located at position 1,2 on the cyclohexane ring. As shown, amino functional groups and ether functional groups can be located either in the cis or trans position relative to each other and to the plane of the cyclohexane ring.

The present invention provides a synthesis method for the preparation of aminocyclohexyl ether compounds in accordance with the present invention, as described herein. The aminocyclohexyl ether compounds described herein can be prepared from amino alcohols and alcohols, following the general methods described below, and as illustrated in the examples. Some general synthetic methods for aminocyclohexyl ethers have been described in WO 99/50225 and the references cited therein. Other methods that can be used to obtain the compounds of the present invention are described in the following provisional patent applications: US 60/476083, US 60/476447, US 60/475884, US 60/475912 and US 60/489659 and in the references cited therein.

Trans compounds of the present invention can be obtained by analogy with a known synthesis method. In one method, shown in FIG. 1, compounds are prepared by the synthesis of Williamson ethers (Feuer, H .; Hooz, J. Methods of Formation of the Ether Linkage. In Patai, Wiley: New York, 1967; pp 445-492) between an activated form of the 4R amino alcohol with 3,4-dimethoxyphenylethyl alcohol alkoxide in a polar solvent such as dimethoxyethane (ethylene glycol dimethyl ether) (DME) (FIG. 1), which gives the corresponding 5R amino ether in high yield. Subsequently, diastereomers are separated, for example, by chromatographic separation (for example, HPLC) to obtain 5RRR and 5SSR followed by hydrogenolysis, which gives respectively compound 1 and compound 2.

The free base and the corresponding monohydrochloride (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane (compound 6) and the free base and the corresponding monohydrochloride (1S, 2S) -2- [ (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane (compound 7) is obtained using the same synthesis sequence, but starting with 3- (S) -hydroxypyrrolidine.

Hydrogenolysis of (1R, 2R) / (1S, 2S) -2 - [(3R) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane (5R) gives the free base and the corresponding monohydrochloride (1R, 2R) / (1S , 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane (compound 4). Similarly, starting from 3- (S) -hydroxypyrrolidinyl instead of 3- (R) -hydroxypyrrolidinyl and following the same synthesis sequence, (1R, 2R) / (1S, 2S) -2 - [(3S) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane. The latter after hydrogenolysis will give the free base and the corresponding monohydrochloride (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane (compound 5). The free base and the corresponding (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (compound 3) can also be synthesized in a similar manner starting with racemic 3-hydroxypyrrolidine.

Figure 2 shows a second general method by which the compounds of the present invention can be obtained. Compounds of formula (IA), (IB), (IC), (ID) or (IE) can be prepared by reduction of the corresponding NaBH ₄ ketopyrrolidinylcyclohexyl ether compound in 2-propanol. The preparation of the starting amino alcohol 2e requires the preparation of an amine 1e, for which a suitable preparation method is shown in FIG. 3-hydroxypyrrolidine 1a is N-protected by carbamoylation with benzyl chloroformate to give 1b; oxidation of Swern (Mansuco, AJ; Swern, D. Activated Dimethyl Sulfoxide: Useful Reagents for Synthesis. Synthesis 1981, 165-185) in 1c followed by ketalization with ethylene glycol gives 1d, which is then hydrogenated to give 1e.

The present invention provides synthesis methods by which it is possible to obtain compounds of formula (57) with a trans (1R, 2R) configuration for an ether functional group and an amino functional group in substantially stereoisomerically pure form. The compounds of formulas (66), (67), (69) and (71) are some examples represented by formula (57). The present invention also provides synthesis methods by which it is possible to synthesize compounds of formulas (52), (53) and (55) in substantially stereoisomeric pure form. Compounds (61), (62) and (64) are examples of compounds of formulas (52), (53) and (55), respectively.

As shown in FIG. 5, the preparation of a substantially stereoisomerically pure form of a trans-aminocyclohexyl ether compound of formula (57) can be carried out as follows, starting from monohalogenbenzene (49), where X may be F, Cl, Br or I.

In the first step, compound (49) is transformed by well-established microbial oxidation to cis-cyclohexanedienediol (50) in a substantially stereoisomerically pure form (T. Hudlicky 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 compound (51) (e.g., H ₂ -Rh / Al ₂ O ₃ ; 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 less blocked hydroxy group of formula (51) selectively transforms under suitable conditions into an activated form, as represented by formula (52). Used in the present description, the term "activated form" means that the hydroxy group is converted into an appropriate leaving group (-OJ), which after interaction with the corresponding nucleophile will lead to the replacement product with an inversion of the stereochemical configuration. The leaving group may be a mesylate group (MsO-), a tosylate group (TsO-) or a nosylate group (NsO-), or other equivalent appropriate leaving group. The hydroxy group may also be converted to another suitable leaving group in accordance with procedures well known in the art. In a typical tosylate reaction, compound (52) is treated with a hydroxyactivating agent such as tosyl chloride (TsCl) in the presence of a base such as pyridine or triethylamine. The reaction is generally satisfactorily carried out at about 0 ° C, but the temperature can be adjusted if necessary to maximize the yields of the target product. Excess hydroxyactivating reagent (e.g., tosyl chloride) relative to compound (52) can be used to maximize the conversion of the hydroxy group to the activated form. In a separate step, the transformation of compound (52) to compound (53) can be carried out by hydrogenation and hydrogenolysis in the presence of a catalyst under appropriate conditions. Activated carbon palladium is one example of a catalyst. Hydrogenolysis of an alkyl halide or alkenyl halide such as (52) can be carried out under basic conditions. The presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetate or calcium carbonate are some possible examples. The base can be added in one portion or fractionally during the reaction. In a separate step, the alkylation of the free hydroxy group in compound (53) to form (55) is carried out under appropriate conditions with compound (54), where —OQ represents the appropriate leaving group after reacting with hydroxy-function while maintaining the stereochemical configuration of hydroxy-function during formation of the ether compound. Trichloroacetimidate is one example of a -OQ function. For some compounds (54), it may be necessary to introduce appropriate protecting groups before performing this step. Suitable protecting groups are presented, 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 compound (57) as a product. The reaction can be carried out with or without a solvent and at an appropriate temperature range, which allows the formation of the product (57) with a suitable rate. Excess amino compound (56) can be used to maximize the conversion of compound (55) to product (57). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified. 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 (FIG. 5) generates a compound of formula (57) as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

All publications and patent applications referred to in the description are incorporated by reference to the same extent as if each individual publication or patent application were specifically and separately incorporated by reference.

In one embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (57):

where R ₁ and R ₂ taken together with the nitrogen atom with which they are directly connected in the formula (57), form a ring indicated by the formula (II):

and R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, provided that all R ₃ , R ₄ and R ₅ cannot be hydrogen;

comprising the start stages of monohalogenbenzene (49), where X may be F, Cl, Br or I, and performing the sequence of interaction, as shown in figure 5, under suitable conditions, and

—O — Q represents an appropriate leaving group after reaction with hydroxy function while maintaining the stereochemical configuration of hydroxy function in the formation of an ether compound; and

-O-J represents an appropriate leaving group after reaction with a nucleophilic reagent with an inverse stereochemical configuration, as shown in FIG. 5 and in all formulas and symbols as described above.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (66), comprising the steps under suitable conditions, as shown in FIG. 6, where all formulas and symbols are as described above. As shown in FIG. 6, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out starting from the biotransformation of chlorobenzene (58) to compound (59) by a microorganism such as Pseudomonas putida 39 / D. The 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 compound (60) (e.g., H ₂ -Rh / Al ₂ O ₃ ; 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 less blocked hydroxy group of formula (60) is selectively converted under suitable conditions into an activated form, such as tosylate (TsO-) of formula (61) (e.g., TsCl in the presence of pyridine). In a separate step, compound (61) is converted to compound (62) by reduction, such as hydrogenation and hydrogenolysis, in the presence of a catalyst under appropriate conditions. Activated carbon palladium is one example of a catalyst. The reduction of compound (61) can be carried out 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 fractionally during the course of the reaction. In another separate step, the free hydroxy group in compound (62) is alkylated under appropriate conditions to form compound (64). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g. Aldrich), by treatment with trichloroacetonitrile. Alkylation of compound (62) with trichloroacetimidate (63) can be carried out in the presence of Bronsted acid or Lewis acid, such as HBF ₄ . In a separate step, the tosylate group of formula (64) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Aldrich), or it 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 a solvent and in the appropriate temperature range, which allows the formation of the product (66) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (64) to product (66). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

The above reaction sequence (FIG. 6) generally generates a compound of formula (66) as a free base. The free base can, if desired, be converted into the monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 7, including the starting steps from chlorobenzene (58) and observing a reaction sequence similar to the applicable part ( i.e., from compound (58) to compound (64)), which is described above in FIG. 6, and leads to the formation of a compound of formula (64). The latter is reacted under suitable conditions with the amino compound of formula (65A), where Bn represents a benzyl protecting group of the hydroxy function 3R-pyrrolidinol to form compound (67). Compound (65A) is commercially available (e.g., 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 a solvent and in the appropriate temperature range, which allows the formation of the product (67) with a suitable rate. Excess amino compound (65A) can be used to maximize the conversion of compound (64) to product (67). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The benzyl protecting group (Bn) of compound (67) can be removed by a standard procedure (for example, by hydrogenation in the presence of a catalyst under appropriate conditions). Activated carbon palladium is one example of a catalyst. Other suitable conditions are as described in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991). The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (66) and generally forms as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with inorganic or organic acids under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. 8, including the starting steps from chlorobenzene (58), and observing a reaction sequence similar to the applicable part, which is described above in FIG. 6, and leads to the formation of a compound of formula (64). The latter interacts with the amino compound of formula (68). Compound (68), 3S-pyrrolidinol, is commercially available (e.g., 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 a solvent and in the appropriate temperature range, which allows the formation of the product (69) with a suitable rate. Excess amino compound (68) can be used to maximize the conversion of compound (64) to product (69). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) and is formed as the free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. 9, including the starting steps from chlorobenzene (58) and observing a reaction sequence similar to the applicable portion, which described above in FIG. 7, and leads to the formation of a compound of formula (64). The latter interacts with the amino compound of formula (70), where Bn represents a benzyl protecting group of the hydroxy function of 3R-pyrrolidinol to form compound (71). Compound (70) is commercially available (e.g., 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 a solvent and in the appropriate temperature range, which allows the formation of the product (71) with a suitable rate. Excess amino compound (70) can be used to maximize the conversion of compound (64) to product (71). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The benzyl protecting group (Bn) of compound (71) can be removed by a standard procedure (e.g., hydrogenation in the presence of a catalyst under appropriate conditions). Activated carbon palladium is one example of a catalyst. Other suitable conditions are as described in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991)). The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) and generally forms as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with inorganic or organic acids under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (57) can be carried out under suitable conditions by the method shown in FIG. 10, comprising the start steps of the compound of the formula (50) and observing a reaction sequence similar to the applicable part, which is described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 11, comprising the start steps of the compound of formula (59), and observing a reaction sequence similar to the applicable part, which is described in FIG. 6, where all formulas and symbols are as described above. 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of the formula (59) is a commercially available product (e.g., Aldrich), or synthesized according to a published procedure (e.g., Organic Synthesis Vol. 76, 77 and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; and references cited therein).

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (66) can be carried out under suitable conditions by the method shown in FIG. 12, comprising the start steps of the compound of the formula (59) and observing a reaction sequence similar to the applicable part, which is described in Fig.7, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 13, comprising the start steps of the compound of the formula (59) and observing a reaction sequence similar to the applicable part, which is described in FIG. 8, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. 14, comprising the start steps of the compound of formula (59) and observing a reaction sequence similar to the applicable part, which is described in FIG. 9, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (57) can be carried out under suitable conditions by the method shown in FIG. 15, comprising the start steps of the compound of the formula (51) and observing a reaction sequence similar to the applicable part, which is described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 16, comprising the start up steps of the compound of formula (60), and observing a reaction sequence similar to the applicable part, which is described in Fig.6, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 17, comprising the start steps of the compound of formula (60) and observing a reaction sequence similar to the applicable part, which is described in FIG. 7, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 18, comprising the start steps of the compound of the formula (60) and observing a reaction sequence similar to the applicable part, which is described in FIG. 8, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 19, comprising the start steps of the compound of the formula (60) and observing a reaction sequence similar to the applicable part, which is described in FIG. 9, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (57) can be carried out under suitable conditions by the method shown in FIG. 20, comprising the start steps of the compound of the formula (52) and observing a reaction sequence similar to the applicable part, which is described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (66) can be carried out under suitable conditions by the method shown in FIG. 21, comprising the start steps of the compound of the formula (61) and observing a reaction sequence similar to the applicable part, which is described in FIG. 6, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 22, comprising the start steps of the compound of formula (61) and observing a reaction sequence similar to the applicable part, which is described in FIG. 7, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 23, comprising the start steps of the compound of the formula (61) and observing a reaction sequence similar to the applicable part, which is described in FIG. 8, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 24, comprising the start steps of the compound of the formula (61) and observing a reaction sequence similar to the applicable part, which is described in FIG. 9, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (57) can be carried out under suitable conditions by the method shown in FIG. 25, comprising the start steps of the compound of the formula (53) and observing a reaction sequence similar to the applicable part, which is described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 26, comprising the steps of starting with a compound of formula (62) and observing a reaction sequence similar to the applicable part, which is described in FIG. 6, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 27, comprising the steps of starting with a compound of formula (62), and observing a reaction sequence similar to the applicable part, which is described in FIG. 7, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 28, comprising the start steps of the compound of the formula (62) and observing a reaction sequence similar to the applicable part, which is described in FIG. 8, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 29, comprising the start steps of the compound of the formula (62) and observing a reaction sequence similar to the applicable part, which is described in FIG. 9, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (57) can be carried out under suitable conditions by the method shown in FIG. 30, comprising the start steps of the compound of the formula (55) and observing a reaction sequence similar to the applicable part, which is described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (66) can be carried out under suitable conditions by the method shown in FIG. 31, comprising the start steps of the compound of the formula (64) and observing a reaction sequence similar to the applicable part, which is described in FIG. 6, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 32, comprising the start steps of the compound of formula (64), and observing a reaction sequence similar to the applicable part, which is described in FIG. 7, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. 33, comprising the steps of starting with a compound of formula (64) and observing a reaction sequence similar to the applicable part, which is described in FIG. 8, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 34, comprising the start steps of the compound of the formula (64) and observing a reaction sequence similar to the applicable part, which is described in FIG. 9, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 35, comprising the steps of starting with a compound of formula (67) and observing a reaction sequence similar to the applicable part, which is described in FIG. 7, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 36, comprising the start steps of the compound of the formula (71) and observing a reaction sequence similar to the applicable part, which is described in FIG. 9, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (55) can be carried out under suitable conditions by the method shown in FIG. 37, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence similar to that applicable to that described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (64) can be carried out under suitable conditions by the method shown in FIG. 38, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence similar to that applicable to that described in FIG. 6, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (67) can be carried out under suitable conditions by the method shown in FIG. 39, comprising the start steps of the compound of the formula (58) and observing a reaction sequence similar to the applicable part, which is described in FIG. 7, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (71) can be carried out under suitable conditions by the method shown in FIG. 40, comprising the start steps of the compound of the formula (58) and observing a reaction sequence similar to the applicable part, which is described in FIG. 9, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (53) can be carried out under suitable conditions by the method shown in FIG. 41, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence similar to that applicable to that described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (62) can be carried out under suitable conditions by the method shown in FIG. 42, comprising the steps of starting with a compound of formula (58), and following a reaction sequence similar to that applicable to that described in FIG. 6, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (52) can be carried out under suitable conditions by the method shown in FIG. 43, comprising the steps of starting with a compound of formula (49) and following a reaction sequence similar to that applicable to that described in FIG. 5, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (61) can be carried out under suitable conditions by the method shown in FIG. 44, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence similar to the applicable part as described in FIG. 6, where all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (52), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (53), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (54), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that all R ₃ , R ₄ and R ₅ cannot represent hydrogen itself.

In another embodiment, the present invention provides a compound of formula (55), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that when R ₃ , R ₄ and R ₅ are hydrogen , then J does not represent a methanesulfonyl group.

In another embodiment, the present invention provides a compound of formula (61), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (62), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (64), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (67), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides synthesis methods whereby compounds of formula (75) with a trans (1S, 2S) configuration for an ether functional group and an amino functional group can be prepared in substantially stereoisomerically pure form. The compounds of formulas (79), (80), (81) and (82) are some examples represented by formula (75). The present invention also provides synthesis methods by which the compounds of formulas (72), (73) and (74) can be synthesized in stereoisomerically substantially pure forms. Compounds (76), (77) and (78) are examples of formulas (72), (73) and (74), respectively.

As shown in FIG. 45, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out following a process starting with monohalogenbenzene (49), where X may be F, Cl, Br or I.

In the first step, compound (49) is transformed by well-established microbial oxidation to cis-cyclohexanedienediol (50) in a substantially stereoisomerically pure form (T. Huldicky 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 compound (51) (e.g., H ₂ -Rh / Al ₂ O ₃ ; 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, compound (51) is converted to compound (72) by reaction with compound (54) under appropriate conditions, where —OQ represents an appropriate leaving group after reaction with hydroxy-function while maintaining the stereochemical configuration of hydroxy-function in the formation of the ether compound. Trichloroacetimidate is one example of a -OQ function. For some compounds (72), it may be necessary to introduce appropriate protecting groups before performing this step. Suitable protecting groups are presented, for example, in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991).

In a separate step, the transformation of compound (72) into compound (73) can be carried out by hydrogenation and hydrogenolysis in the presence of a catalyst under appropriate conditions. Activated carbon palladium is one example of a catalyst. Hydrogenolysis of an alkyl halide or alkenyl halide such as (72) can be carried out under basic conditions. The presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetate or calcium carbonate are some possible examples. The base can be added in one portion or fractionally during the reaction. In another separate step, the hydroxy group of compound (73) is selectively converted under suitable conditions into an activated form, as represented by compound (74). As used herein, the term “activated form” means that the hydroxy group is converted to an appropriate leaving group (—O — J), which, after reaction with the corresponding nucleophile, will result in a substitution product with an inversion of the stereochemical configuration. The leaving group may be a mesylate group (MsO-), a tosylate group (TsO-) or a nosylate group (NsO-). The hydroxy group may also be converted to another suitable leaving group in accordance with procedures well known in the art. In a typical tosylate reaction, compound (73) is treated with a hydroxyactivating agent such as tosyl chloride (TsCl) in the presence of a base (e.g., pyridine or triethylamine). The reaction is generally satisfactorily carried out at about 0 ° C, but the temperature can be adjusted if necessary to maximize the yields of the target product. An excess of a hydroxyactivating reagent (e.g., tosyl chloride) with respect to compound (73) can be used to maximize the conversion of the hydroxy group to the activated form.

In a separate step, the resulting compound (74) is treated under suitable conditions with an amino compound of formula (56) to form compound (75) as a product. The reaction can be carried out with or without a solvent and with an appropriate temperature range, which allows the formation of the product (75) with a suitable rate. Excess amino compound (56) can be used to maximize the conversion of compound (74) to product (75). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the product is recovered from the reaction mixture by conventional methods of organic chemistry and, accordingly, purified. Protecting groups can be removed at the appropriate stage in 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 (FIG. 45) generates a compound of formula (75) as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

All publications and patent applications referred to in this description are incorporated by reference to the same extent as if each individual publication or patent application was specifically and separately incorporated by reference.

In one embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (75):

where R ₁ and R ₂ taken together with the nitrogen atom with which they are directly connected in the formula (75), form a ring indicated by the formula (II):

and R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, provided that all R ₃ , R ₄ and R ₅ cannot be hydrogen;

comprising steps starting from monohalogenbenzene (49), wherein X may be F, Cl, Br or I, and a subsequent reaction sequence as shown in FIG. 45, under suitable conditions, wherein

—O — Q represents an appropriate leaving group after reaction with hydroxy function while maintaining the stereochemical configuration of hydroxy function in the formation of an ether compound; and

-O-J represents an appropriate leaving group after reaction with a nucleophilic reagent with an inversion of the stereochemical configuration, as shown in Fig. 45 and in all formulas and symbols as described above.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (79) comprising the steps under suitable conditions, as shown in FIG. 46, where all formulas and symbols are as described above. As shown in FIG. 46, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out starting from the biotransformation of chlorobenzene (58) to compound (59) by a microorganism such as Pseudomonas putida 39 / D. The 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 compound (60) (e.g., H ₂ -Rh / Al ₂ O ₃ ; 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, compound (60) is converted to compound (76) by reaction with compound (63) under appropriate conditions. Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g. Aldrich), by treatment with trichloroacetonitrile. Alkylation of compound (60) with trichloroacetimidate (63) can be carried out in the presence of Bronsted acid or Lewis acid, such as HBF ₄ . The reaction temperature can be adjusted if necessary to maximize the yields of the target product. In a separate step, compound (76) is converted to compound (77) by reduction, such as hydrogenation and hydrogenolysis in the presence of a catalyst under appropriate conditions. Activated carbon palladium is one example of a catalyst. The reduction of compound (76) can be carried out 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 fractionally during the course of the reaction. In another separate step, the hydroxy group of compound (77) is converted, under appropriate conditions, into an activated form, such as tosylate (TsO-) of formula (78) (e.g., TsCl in the presence of pyridine). In a separate step, the tosylate group of formula (78) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., 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 a solvent and in the appropriate temperature range, which allows the formation of the product (79) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (78) to product (79). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

The reaction sequence described above (FIG. 46) generally generates a compound of formula (79) as a free base. The free base can, if desired, be converted into the monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 47, including the starting steps from chlorobenzene (58), and observing a reaction sequence similar to the applicable part ( i.e., from compound (58) to compound (78)), which is described above in FIG. 46, and leads to the formation of a compound of formula (78). The latter is reacted under suitable conditions with the amino compound of formula (65A), where Bn represents a benzyl protecting group of the hydroxy function of 3S-pyrrolidinol to form compound (80). Compound (65A) is commercially available (e.g., 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 a solvent and in the appropriate temperature range, which allows the formation of the product (80) with a suitable rate. Excess amino compound (65A) can be used to maximize the conversion of compound (78) to product (80). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The benzyl protecting group (Bn) of compound (80) can be removed by standard procedures (for example, by hydrogenation in the presence of a catalyst under appropriate conditions). Activated carbon palladium is one example of a catalyst. Other suitable conditions are as described in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991). The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) and generally forms as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with inorganic or organic acids under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 48, including the starting steps from chlorobenzene (58), and observing a reaction sequence similar to the applicable part, which is described above in FIG. 46, and leads to the formation of a compound of formula (78). The latter interacts with the amino compound of formula (68). Compound (68), 3S-pyrrolidinol, is commercially available (e.g., 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 a solvent and in the corresponding temperature range, which allows the formation of the product (81) with a suitable rate. Excess amino compound (68) can be used to maximize the conversion of compound (78) to product (81). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (81) and is formed as the free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 49, including the starting steps from chlorobenzene (58), and observing a reaction sequence similar to the applicable part, which is described above in FIG. 47, and leads to the formation of a compound of formula (78). The latter interacts with the amino compound of formula (70), where Bn represents a benzyl protecting group of the hydroxy function 3S0-pyrrolidinol to form compound (82). Compound (70) is commercially available (e.g., 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 a solvent and in the appropriate temperature range, which allows the formation of the product (82) with a suitable rate. Excess amino compound (70) can be used to maximize the conversion of compound (78) to product (82). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The benzyl protecting group (Bn) of compound (82) can be removed by a standard procedure (for example, hydrogenation in the presence of a catalyst under appropriate conditions. Activated carbon palladium is one example of a catalyst. Other suitable conditions are as described in Greene, "Protective Groups in Organic Chemistry ", John Wiley & Sons, New York NY (1991)). The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) and generally forms as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with inorganic or organic acids under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (75) can be carried out under suitable conditions by the method shown in FIG. 50, comprising the steps of starting with the compound of the formula (50) and observing a reaction sequence similar to the applicable part, which is described in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 51, comprising the start steps of the compound of the formula (59) and observing a reaction sequence similar to the applicable part, which is described in FIG. 46, where all formulas and symbols are as described above. 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of the formula (59) is a commercially available product (e.g., Aldrich), or synthesized according to a published procedure (e.g., Organic Synthesis Vol. 76, 77 and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; and references cited therein).

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 52, comprising the start steps of the compound of the formula (59) and observing a reaction sequence similar to the applicable part, which is described in FIG. 47, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 53, comprising the steps of starting with a compound of formula (59) and observing a reaction sequence similar to the applicable part, which is described in FIG. 48, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (81) can be carried out under suitable conditions by the method shown in FIG. 54, comprising the start steps of the compound of the formula (59) and observing a reaction sequence similar to the applicable part, which is described in FIG. 49, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (75) can be carried out under suitable conditions by the method shown in FIG. 55, comprising the start steps of the compound of the formula (51) and observing a reaction sequence similar to the applicable part, which is described in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 56, comprising the start steps of the compound of the formula (60) and observing a reaction sequence similar to the applicable part, which is described in FIG. 46, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 57, comprising the start steps of the compound of the formula (60) and observing a reaction sequence similar to the applicable part, which is described in FIG. 47, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (81) can be carried out under suitable conditions by the method shown in FIG. 58, comprising the start steps of the compound of the formula (60) and observing a reaction sequence similar to the applicable part, which is described in FIG. 48, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 59, comprising the steps of starting with a compound of formula (60) and observing a reaction sequence similar to the applicable part, which is described in FIG. 49, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (75) can be carried out under suitable conditions by the method shown in FIG. 60, comprising the steps of starting with a compound of formula (72) and observing a reaction sequence similar to the applicable part, which is described in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 61, comprising the start steps of the compound of formula (76) and observing a reaction sequence similar to the applicable part, which is described in FIG. 46, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 62, comprising the start steps of the compound of formula (76) and observing a reaction sequence similar to the applicable part, which is described in FIG. 47, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 63, comprising the start steps of the compound of formula (76) and observing a reaction sequence similar to the applicable part, which is described in FIG. 48, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 64, comprising the steps of starting with a compound of formula (76) and observing a reaction sequence similar to the applicable part, which is described in FIG. 49, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (75) can be carried out under suitable conditions by the method shown in FIG. 65, comprising the start steps of the compound of the formula (73) and observing a reaction sequence similar to the applicable part, which is described in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 66, comprising the start steps of the compound of the formula (77) and observing a reaction sequence similar to the applicable part, which is described in FIG. 46, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. which is described in FIG. 47, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 68, comprising the steps of starting with a compound of formula (77) and observing a reaction sequence similar to the applicable part, which is described in FIG. 48, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (81) can be carried out under suitable conditions by the method shown in FIG. 69, comprising the start steps of the compound of the formula (77) and observing a reaction sequence similar to the applicable part, which is described in FIG. 49, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (75) can be carried out under suitable conditions by the method shown in FIG. 70, comprising the start steps of the compound of the formula (74) and observing a reaction sequence similar to the applicable part, which is described in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 71, comprising the steps of starting with the compound of the formula (78) and observing a reaction sequence similar to the applicable part, which is described in FIG. 46, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 72, comprising the start steps of the compound of the formula (78) and observing a reaction sequence similar to the applicable part, which is described in FIG. 47, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (81) can be carried out under suitable conditions by the method shown in FIG. 73, comprising the start steps of the compound of the formula (78) and observing a reaction sequence similar to the applicable part, which is described in FIG. 48, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 74, comprising the steps of starting with a compound of formula (78) and observing a reaction sequence similar to the applicable part, which is described in FIG. 49, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 75, comprising the steps of starting with the compound of the formula (80) and observing a reaction sequence similar to the applicable part, which is described in FIG. 47, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 76, comprising the steps of starting with a compound of formula (82) and observing a reaction sequence similar to the applicable part, which is described in FIG. 49, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (74) can be carried out under suitable conditions by the method shown in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (78) can be carried out under suitable conditions by the method shown in FIG. 78, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence similar to that applicable to that described in FIG. 46, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (80) can be carried out under suitable conditions by the method shown in FIG. 79, comprising the start steps of the compound of the formula (58) and observing a reaction sequence similar to the applicable part, which is described in FIG. 47, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (82) can be carried out under suitable conditions by the method shown in FIG. 80, comprising the start steps of the compound of the formula (58) and observing a reaction sequence similar to the applicable part, which is described in FIG. 49, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (73) can be carried out under suitable conditions by the method shown in FIG. 81, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence similar to that applicable to that described in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (77) can be carried out under suitable conditions by the method shown in FIG. 82, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence similar to that applicable to that described in FIG. 46, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (72) can be carried out under suitable conditions by the method shown in FIG. 83, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence similar to that applicable to that described in FIG. 45, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (76) can be carried out under suitable conditions by the method shown in FIG. 84, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence similar to that applicable to that described in FIG. 46, where all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (72), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (73), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (73), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that all R ₃ , R ₄ and R ₅ cannot represent hydrogen itself.

In another embodiment, the present invention provides a compound of formula (74), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above, provided that when R ₃ , R ₄ and R ₅ are hydrogen , then J does not represent a methanesulfonyl group.

In another embodiment, the present invention provides a compound of formula (76), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (77), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (78), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (80), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

The present invention provides synthesis processes whereby compounds of formula (57) with a trans (1R, 2R) configuration for ether and amino functional groups can be obtained in stereoisomerically pure form. The compound of formula (66) is an example represented by formula (57). The present invention also provides synthesis methods by which it is possible to obtain compounds of formula (75) with a trans (1S, 2S) configuration for ether and amino functional groups in stereoisomerically pure form. The compound of formula (79) is an example represented by formula (75). The present invention further provides synthesis methods by which it is possible to synthesize compounds of formulas (85), (86), (55) and (74) in substantially stereoisomerically pure form. Compounds of formulas (62) and (90) are examples of compounds of formula (85). Compounds of formulas (87) and (89) are examples of compounds of formula (86). Compound (64) is an example of a compound of formula (55). Compound (78) is an example of a compound of formula (74). The aminocyclohexyl ether compounds of the present invention can be used for medical applications, including, for example, cardiac arrhythmia, such as atrial arrhythmia or ventricular arrhythmia.

As shown in FIG. 85, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out as follows, starting with a racemic mixture of meso-cis-1,2-cyclohexanediol (83). Compound (83) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), or it can be easily synthesized by published methods (e.g., JETaylor et al., Org. Process Res. & Dev., 1998, 2, 147; Organic Synthesis, CV6, 342).

In the first stage, one of the hydroxy groups of compound (83) is converted, under suitable conditions, into the activated form, as represented by a racemic mixture consisting of compounds of formulas (53) and (84). Used in the present description, the term "activated form" means that the hydroxy group is converted into an appropriate leaving group (-OJ), which after interaction with the corresponding nucleophile will result in a substitution product with an inversion of the stereochemical configuration. The leaving group may be any suitable leaving group after reaction with a nucleophilic reagent with an inversion of the stereochemical configuration known in the art, including, but not limited to, compounds disclosed in MBSmith 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—), a tosylate group (TsO—), a 2-bromophenyl sulfonate group, a 4-bromophenyl sulfonate group or a nosylate group (NsO—). The hydroxy group may also be converted to another suitable leaving group according to procedures well known in the art using any suitable activating substance, including, but not limited to, those disclosed in MBSmith and J. March in "March's Advanced Organic Chemistry" , Fifth edition, Chapter 10, John Wiley & Sons, Inc., New York, NY. (2001). In a typical tosylate reaction, compound (83) is treated with a controlled amount of a hydroxyactivating reagent such as tosyl chloride (TsCl) in the presence of a base such as pyridine or triethylamine. The reaction can be controlled and generally satisfactorily carried out at about 0 ° C, but the conditions can be adjusted if necessary to maximize the yields of the target product. Addition of other reagents can advantageously be used to promote the formation of monotosylates (e.g., MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" Tetrahedron Letters, 2000, 41, 3773). The racemic mixture comprises compounds of formulas (53) and (84), then undergoes a separation process, whereby 2 optically active isomers are separated into products that are presented in substantially stereoisomerically pure form, such as (85) and (86), where G and G _{1 are} independently selected from hydrogen, C ₁ -C ₈ acyl, or any other suitable functional groups that are introduced as part of the separation process necessary to separate the two isomers. In some situations, it may be appropriate for the separation process to give compounds (85) and (86) with sufficient enrichment of their optical purity for use in subsequent steps of the synthesis process. Methods for resolving racemic mixtures are well known in the art (e.g., ELEliel and SH Wilen, in Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; Chapter 7, and references therein). Suitable methods, such as enzymatic separation (e.g., lipase-mediated) and chromatographic separation (e.g., HPLC by chiral stationary phase and / or simulated moving layer), are some of the examples that can be applied.

For a compound of formula (85), when G is hydrogen, (85) is the same compound as compound (53), and in a separate reaction step, the alkylation of the free hydroxy group in compound (85) to form (55) is carried out under appropriate conditions with compound (54), wherein —OQ represents an appropriate leaving group after reacting with a hydroxy function while maintaining the stereochemical configuration of the hydroxy function in the formation of an ether compound. A leaving group may be any suitable leaving group known in the art, including, but not limited to, the compounds disclosed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991). Specific examples of —OQ groups include trichloroacetimidate. For some compounds (54), it may be necessary to introduce appropriate protecting groups before performing this step. Suitable protecting groups are set forth, for example, in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991). For a compound of formula (85), when G is not hydrogen, suitable methods are used to convert (85) to compound (53). For example, when G is a C ₂ acyl function, methanolysis catalyzed by a weak base (G. Zemplen et al., Ber., 1936, 69, 1827) can be used to transform (85) in (53). The latter can then undergo the same reaction with (54) to obtain (55) as described above.

In a separate step, the resulting compound (55) is treated under suitable conditions with an amino compound of formula (56) to form compound (57) as a product. The reaction can be carried out with or without a solvent and at an appropriate temperature range, which allows the formation of the product (57) with a suitable rate. Excess amino compound (56) can be used to maximize the conversion of compound (55) to product (57). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the product is recovered from the reaction mixture by conventional methods of organic chemistry and, accordingly, purified. Protecting groups may be removed at an appropriate stage in 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 (FIG. 85) generates a compound of formula (57) as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In one embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (57):

where R ₁ and R ₂ taken together with the nitrogen atom with which they are directly connected in the formula (57), form a ring indicated by the formula (II):

and R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, provided that all R ₃ , R ₄ and R ₅ cannot be hydrogen;

comprising the start stages of monohalogenbenzene (49), where X may be F, Cl, Br or I, and performing the sequence of interaction, as shown in Fig. 45, under suitable conditions, and

—O — Q represents an appropriate leaving group after reaction with hydroxy function while maintaining the stereochemical configuration of hydroxy function in the formation of an ether compound; and

-OJ represents an appropriate leaving group after reaction with a nucleophilic reagent with an inverse stereochemical configuration, as shown in FIG. 45 and in all formulas and symbols as described above, including the steps of starting a compound of formula (83) and performing an interaction sequence as described in FIG. .85, under suitable conditions, where

G and G _{1 are} independently selected from hydrogen, C ₁ -C ₈ acyl, or any other suitable functional groups that are introduced as part of the separation process necessary to separate the two isomers;

-OQ represents an appropriate leaving group after reacting with a hydroxy function while maintaining the stereochemical configuration of the hydroxy function to form an ether compound, including, but not limited to, the compounds disclosed in "Protective Groups in Organic Chemistry" by John Wiley & Sons, New York NY (1991 ); and

-OJ represents an appropriate leaving group after reaction with a nucleophilic reagent with an inversion of the stereochemical configuration, including, but not limited to, the groups disclosed in the "Protective Groups in Organic Chemistry" publication by John Wiley & Sons, New York NY (1991), as shown in 85, and all formulas and symbols are as described above.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (66) comprising the steps under suitable conditions, as shown in FIG. 86, where all formulas and symbols are as described above. As shown in FIG. 86, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by monotosylation of cis-1,2-cyclohexanediol (83) with TsCl in the presence of Bu ₂ SnO and triethylamine under suitable conditions ( MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" (Tetrahedron Letters, 2000, 41, 3773). The initial non-optimized outputs of 80-90% were achieved, and further optimization was carried out. The resulting racemic mixture of hydroxytosylates, including compounds (62) and (87), undergoes a lipase-mediated separation method under suitable conditions, such as treating the racemates (62) and (87) with vinyl acetate (88) in the presence of a lipase derived from Pseudomonas (N. Boaz et al., Tetra. Asymmetry, 1994, 5, 153) for providing compounds (62) and (89). In a separate step, the substantially stereoisomerically pure compound of formula (62) resulting from the separation process is alkylated under appropriate conditions by treatment with trichloroacetimidate (63) to form compound (64). Initial unoptimized yields of 60-70% have been achieved, and further optimization is underway. Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), by treatment with trichloroacetonitrile. Alkylation of compound (62) with trichloroacetimidate (63) can be carried out in the presence of Lewis acid, such as HBF ₄ .

In a separate step, the tosylate group of formula (64) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missour), or it may 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 a solvent and in the corresponding temperature range, which allows the formation of the product (66) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (64) to product (66). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified. Initial, unoptimized outputs of 40% have been achieved, and further optimization is underway.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by the method as shown in FIG. 87, comprising steps under suitable conditions, as shown in FIG. 87, where all formulas and symbols are as described above. As shown in FIG. 87, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by monotosylation of cis-1,2-cyclohexanediol (83) with TsCl in the presence of Bu ₂ SnO and triethylamine under suitable conditions ( MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" (Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxytosylates includes compounds (62) and (87) and undergoes a lipase-mediated separation method under suitable conditions, such as treating the racemates (62) and (87) with vinyl acetate (88) in the presence of a lipase derived from Pseudomonas species (N. Boaz et al., Tetra. Asymmetry, 1994, 5, 153) to provide compounds (90) and (87).

In a separate step, the substantially stereoisomerically pure compound of formula (90) obtained by the separation process is subjected to weak base catalyzed methanolysis (G. Zemplen et al., Ber., 1936, 69, 1827) to form compound (62). The latter is alkylated under appropriate conditions by treatment with trichloroacetimidate (63) to form compound (64). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), by treatment with trichloroacetonitrile. Alkylation of compound (88) with trichloroacetimidate (63) can be carried out in the presence of Lewis acid, such as HBF ₄ .

In a separate step, the tosylate group of formula (64) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missour), or it may 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 a solvent and in the corresponding temperature range, which allows the formation of the product (66) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (64) to product (66). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (66), comprising the steps of under appropriate conditions, as shown in FIG. 88, where all the formulas and symbols are as described above. As indicated in FIG. 88, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out by monotosylation of cis-1,2-cyclohexanediol (83) with TsCl in the presence of Bu ₂ SnO and triethylamine under suitable conditions ( MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" (Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxytosylates, including compounds (62) and (87), is subjected to chromatographic separation under suitable conditions, such as HPLC with the corresponding chiral stationary phase and simulated moving bed technology to obtain compounds (62) and (87) essentially in stereo clean form.

In a separate step, the substantially stereoisomerically pure compound of formula (62) resulting from the separation process is alkylated under appropriate conditions by treatment with trichloroacetimidate (63) to form compound (64). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), by treatment with trichloroacetonitrile. Alkylation of compound (62) with trichloroacetimidate (63) can be carried out in the presence of Lewis acid, such as HBF ₄ .

In another separate step, the tosylate group of formula (64) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), or it 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 a solvent and in the corresponding temperature range, which allows the formation of the product (66) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (64) to product (66). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

The reaction sequences described above (FIG. 86, FIG. 87 and FIG. 88) generally generate a compound of formula (66) as a free base. The free base can, if desired, be converted into the monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions by the method shown in FIG. 89, comprising the steps of starting from the compound of formulas (53) and (84), and the following sequence a reaction similar to the applicable part, which is described in FIG. 85, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 90, comprising the steps starting from the compound of formulas (62) and (87), and the following sequence a reaction similar to the applicable part, which is described in FIG. 86, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 91, comprising the steps from the compound of formulas (62) and (87), and the following sequence a reaction similar to that applicable to that described in FIG. 87, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 92, comprising the steps of starting with a compound of formulas (62) and (87), and following the reaction sequence, similar to the applicable part, which is described in FIG. 88, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions by the method shown in FIG. 93, comprising the steps of starting with a compound of formula (85), where G is not hydrogen, and following the sequence reactions similar to the applicable part, which is described in FIG. 85, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 94, comprising the steps of starting with a compound of formula (90) and observing a reaction sequence similar to the applicable part, which is described in FIG. 87, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (55) can be carried out under suitable conditions by the method shown in FIG. 95, comprising the steps of starting with a compound of formula (83), and following a reaction sequence similar to that applicable to that described in FIG. 85, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (55) can be carried out under suitable conditions by the method shown in FIG. 96, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to that applicable to that described in FIG. 85, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (64) can be carried out under suitable conditions by the method shown in FIG. 86, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (64) can be carried out under suitable conditions by the method shown in FIG. 98, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to that applicable to that described in FIG. 87, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (64) can be carried out under suitable conditions by the method shown in FIG. 99, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to the applicable part as described in FIG. 88, where all formulas and symbols are as described above.

In another embodiment, the preparation of substantially stereoisomerically pure compounds of formulas (85) and (86) can be carried out under suitable conditions by the method shown in FIG. 100, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to the applicable portion, which described in FIG. 85, where all formulas and symbols are as described above.

In another embodiment, the preparation of substantially stereoisomerically pure compounds of formulas (62) and (89) can be carried out under suitable conditions by the method shown in FIG. 101, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to the applicable part, which described in FIG. 86, where all formulas and symbols are as described above.

In another embodiment, the preparation of substantially stereoisomerically pure compounds of formulas (90) and (87) can be carried out under suitable conditions by the method shown in FIG. 102, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to the applicable portion, which described in FIG. 87, where all formulas and symbols are as described above.

In another embodiment, the preparation of substantially stereoisomerically pure compounds of formulas (62) and (87) can be carried out under suitable conditions by the method shown in FIG. 103, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to the applicable portion, which described in FIG. 88, where all formulas and symbols are as described above.

In another embodiment, the present invention further provides a synthesis method by which compounds of formula (75) with the trans (1S, 2S) configuration for ether and amino functional groups can be prepared in substantially stereoisomerically pure form. As shown in FIG. 104, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out in the following manner, starting with a racemic mixture of meso-cis-1,2-cyclohexanediol (83). Compound (83) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), or it can be easily synthesized by published methods (e.g., JE Taylor et al., Org. Process Res. & Dev., 1998, 2, 147; Organic Synthesis, CV6, 342).

In the first stage, one of the hydroxy groups of compound (83) is converted, under suitable conditions, into the activated form, as represented by a racemic mixture consisting of compounds of formulas (53) and (84). Used in the present description, the term "activated form" means that the hydroxy group is converted into an appropriate leaving group (-OJ), which after interaction with the corresponding nucleophile will result in a substitution product with an inversion of the stereochemical configuration. The leaving group may be any suitable leaving group after reaction with a nucleophilic reagent with an inverse stereochemical configuration known in the art, including, but not limited to, the compounds disclosed in MB 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—), a tosylate group (TsO—), a 2-bromophenyl sulfonate group, a 4-bromophenyl sulfonate group or a nosylate group (NsO—). The hydroxy group can also be converted to another suitable leaving group according to procedures well known in the art using any suitable activating substance, including, but not limited to, the substances disclosed in MB 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 tosylate reaction, compound (83) is treated with a controlled amount of a hydroxyactivating reagent, such as tosyl chloride (TsCl), in the presence of a base such as pyridine or triethylamine. The reaction can be controlled and generally satisfactorily carried out at about 0 ° C, but the conditions can be adjusted if necessary to maximize the yields of the target product. Addition of other reagents can advantageously be used to promote the formation of monotosylates (e.g., MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" Tetrahedron Letters, 2000, 41, 3773). The racemic mixture, including the compounds of formulas (53) and (84), is then subjected to a separation process, whereby 2 optically active isomers are separated into products that are present in stereoisomerically substantially pure form, such as (85) and (86), where G and G _{1 are} independently selected from hydrogen, C ₁ -C ₈ acyl, or any other suitable functional groups that are introduced as part of the separation process necessary to separate the two isomers. In some situations, it may be appropriate for the separation process to give compounds (85) and (86) with sufficient enrichment of their optical purity for use in subsequent steps of the synthesis process. Methods for resolving racemic mixtures are well known in the art (e.g., EL Eliel and SH Wilen, in Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; Chapter 7, and references therein). Suitable methods, such as enzymatic separation (e.g., lipase-mediated) and chromatographic separation (e.g., HPLC by chiral stationary phase technology and / or simulated moving bed), are some of the methods that can be used.

For the compound of formula (86), when G ₁ is hydrogen, (86) is the same compound as compound (84), and in a separate reaction step, the alkylation of the free hydroxy group in compound (86) to form (74) is carried out in the corresponding conditions with compound (54), wherein —OQ represents an appropriate leaving group after reacting with a hydroxy function while maintaining the stereochemical configuration of the hydroxy function in the formation of the ether compound. A leaving group may be any suitable leaving group known in the art, including, but not limited to, the compounds disclosed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991). Trichloroacetimidate is one example of a -OQ function. For some compounds (54), it may be necessary to introduce appropriate protecting groups before performing this step. Suitable protecting groups are set forth, for example, in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991). For the compound of formula (86), when G _{1 is} not hydrogen, suitable methods are used to convert (86) to compound (84). For example, when G ₁ is a C ₂ acyl function, methanolysis catalyzed by a weak base (G. Zemplen et al., Ber., 1936, 69, 1827) can be used to transform (86) in (84). The latter can then undergo the same reaction with (54) to obtain (74) as described above.

In a separate step, the resulting compound (74) is treated under suitable conditions with an amino compound of formula (56) to form compound (75) as a product. The reaction can be carried out with or without a solvent and at an appropriate temperature range, which allows the formation of the product (75) with a suitable rate. Excess amino compound (56) can be used to maximize the conversion of compound (74) to product (75). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the product is recovered from the reaction mixture by conventional methods of organic chemistry and, accordingly, purified. Protecting groups may be removed at an appropriate stage in 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 (FIG. 104) generates a compound of formula (75) as a free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In one embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (75):

where R ₁ and R ₂ taken together with the nitrogen atom with which they are directly connected in the formula (75), form a ring indicated by the formula (II):

and R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, provided that all R ₃ , R ₄ and R ₅ cannot be hydrogen;

comprising the start stages of the compound of formula (83) and following the sequence of interaction, as shown in Fig, under suitable conditions, and

G and G _{1 are} independently selected from hydrogen, C ₁ -C ₈ acyl, or any other suitable functional groups that are introduced as part of the separation process necessary to separate the two isomers;

-OQ represents an appropriate leaving group after reacting with a hydroxy function while maintaining the stereochemical configuration of the hydroxy function to form an ether compound, including, but not limited to, the groups disclosed in "Protective Groups in Organic Chemistry" by John Wiley & Sons, New York NY (1991 ); and

-OJ represents an appropriate leaving group after reaction with a nucleophilic reagent with an inversion of the stereochemical configuration, including, but not limited to, the groups disclosed in the "Protective Groups in Organic Chemistry" publication by John Wiley & Sons, New York NY (1991), as shown in 85, and all formulas and symbols are as described above.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (79), comprising the steps under suitable conditions, as shown in FIG. 105, where all formulas and symbols are as described above. As shown in FIG. 105, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out by monotosylation of cis-1,2-cyclohexanediol (83) with TsCl in the presence of Bu ₂ SnO and triethylamine under suitable conditions ( MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" (Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxytosylates, including compounds (62) and (87), undergoes a lipase-mediated separation method under suitable conditions, such as treating the racemates (62) and (87) with vinyl acetate (88) in the presence of a lipase derived from Pseudomonas (N. Boaz et al., Tetra. Asymmetry, 1994, 5, 153) for providing compounds (87) and (90). In a separate step, the substantially stereoisomerically pure compound of formula (87) obtained by the separation process is alkylated under appropriate conditions by treatment with trichloroacetimidate (63) to form compound (78). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), by treatment with trichloroacetonitrile. Alkylation of compound (87) with trichloroacetimidate (63) can be carried out in the presence of Lewis acid, such as HBF ₄ .

In another separate step, the tosylate group of formula (78) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), or it 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 a solvent and in the appropriate temperature range, which allows the formation of the product (79) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (78) to product (79). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out by the method as shown in FIG. 106, comprising steps under suitable conditions, as shown in FIG. 106, where all formulas and symbols as described above. As shown in FIG. 106, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out by monotosylation of cis-1,2-cyclohexanediol (83) with TsCl in the presence of Bu ₂ SnO and triethylamine under suitable conditions ( MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" (Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxytosylates includes compounds (62) and (87) and undergoes a lipase-mediated separation method under suitable conditions, such as treating the racemates (62) and (87) with vinyl acetate (88) in the presence of a lipase derived from Pseudomonas species (N. Boaz et al., Tetra. Asymmetry, 1994, 5, 153) to provide compounds (89) and (62).

In a separate step, the substantially stereoisomerically pure compound of formula (89) obtained by the separation process is subjected to weak base catalysis (G. Zemplen et al., Ber., 1936, 69, 1827) to form compound (87). The latter is alkylated under appropriate conditions by treatment with trichloroacetimidate (63) to form compound (78). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), by treatment with trichloroacetonitrile. Alkylation of compound (87) with trichloroacetimidate (63) can be carried out in the presence of Lewis acid, such as HBF ₄ .

In a separate step, the tosylate group of formula (78) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missour) 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 a solvent and in the appropriate temperature range, which allows the formation of the product (79) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (78) to product (79). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (79), comprising the steps under suitable conditions, as shown in FIG. 107, where all formulas and symbols are as described above. As shown in FIG. 107, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out by monotosylation of cis-1,2-cyclohexanediol (83) with TsCl in the presence of Bu ₂ SnO and triethylamine under suitable conditions ( MJ Martinelli, et al. "Selective monosulfonylation of internal 1,2-diols catalyzed by di-n-butylin oxide" (Tetrahedron Letters, 2000, 41, 3773). The resulting racemic mixture of hydroxytosylates, including compounds (62) and (87), is subjected to chromatographic separation under suitable conditions, such as HPLC with the corresponding chiral stationary phase and simulated moving bed technology to obtain compounds (62) and (87) essentially stereometrically clean form.

In a separate step, the substantially stereoisomerically pure compound of formula (87) obtained by the separation process is alkylated under appropriate conditions by treatment with trichloroacetimidate (63) to form compound (64). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri), by treatment with trichloroacetonitrile. Alkylation of compound (87) with trichloroacetimidate (63) can be carried out in the presence of Lewis acid, such as HBF ₄ .

In another separate step, the tosylate group of formula (78) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Sigma-Aldrich, St. Louis, Missouri) 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 a solvent and in the appropriate temperature range, which allows the formation of the product (79) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (78) to product (79). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

The reaction sequences described above (FIG. 105, FIG. 106 and FIG. 107) generally generate a compound of formula (79) as a free base. The free base can, if desired, be converted into the monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment of the present invention, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions by the method shown in FIG. 108, comprising the start steps of the compound of formulas (53) and (84), and following the sequence reactions similar to the applicable part, which is described in FIG. 104, where all formulas and symbols are as described above.

In another embodiment of the present invention, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 109, comprising the start steps of the compound of formula (62) and (87), and following the sequence reactions similar to the applicable part, which is described in FIG. 105, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 110, comprising the steps of starting with a compound of formulas (62) and (87), and following the reaction sequence, similar to the applicable part, which is described in FIG. 106, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 111, comprising the steps of starting with a compound of formulas (62) and (87), and following the reaction sequence, similar to the applicable part, which is described in FIG. 107, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions by the method shown in FIG. 112, comprising the start steps of a compound of formula (86), where G ₁ is hydrogen and following the sequence reactions similar to the applicable part, which is described in FIG. 104, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions by the method shown in FIG. 113, comprising the start steps of a compound of formula (86), where G _{1 is} not hydrogen, and observing a reaction sequence similar to the applicable part, which is described in FIG. 104, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (79) can be carried out under suitable conditions by the method shown in FIG. 114, comprising the start steps of the compound of the formula (87) and observing a reaction sequence similar to the applicable part, which is described in FIG. 105, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 115, comprising the start steps of the compound of formula (89) and observing a reaction sequence similar to the applicable part which is described in FIG. 106, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (74) can be carried out under suitable conditions by the method shown in FIG. 116, comprising the steps of starting with a compound of formula (83), and following a reaction sequence similar to that applicable to that described in FIG. 104, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (74) can be carried out under suitable conditions by the method shown in FIG. 117, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to that applicable to that described in FIG. 104, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (78) can be carried out under suitable conditions by the method shown in FIG. 118, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to that applicable to that described in FIG. 105, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (78) can be carried out under suitable conditions by the method shown in FIG. 191, comprising the steps of starting with a compound of formula (83) and observing a reaction sequence similar to that applicable to that described in FIG. 106, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (78) can be carried out under suitable conditions by the method shown in FIG. 120, comprising the steps of starting with a compound of formula (83), and following a reaction sequence similar to the applicable part as described in FIG. 107, where all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (85), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (86), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (54), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that all R ₃ , R ₄ and R ₅ cannot represent hydrogen itself.

In another embodiment, the present invention provides a compound of formula (55), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that when R ₃ , R ₄ and R ₅ are hydrogen , then J does not represent a methanesulfonyl group.

In another embodiment, the present invention provides a compound of formula (87), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (62), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (89), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (90), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (64), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (74), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above, provided that when R ₃ , R ₄ and R ₅ are hydrogen , then J does not represent a methanesulfonyl group.

In another embodiment, the present invention provides a compound of formula (78), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In one embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (57):

where R ₁ and R ₂ taken together with the nitrogen atom with which they are directly connected in the formula (57), form a ring indicated by the formula (II):

and R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, provided that all R ₃ , R ₄ and R ₅ cannot be hydrogen;

comprising the start stages of monohalogenbenzene (49), where X may be F, Cl, Br or I, and performing the sequence of interaction, as shown in Fig, in suitable conditions, and

Pro represents an appropriate hydroxy-functional protecting group while maintaining stereochemistry;

—O — Q represents an appropriate leaving group after reaction with hydroxy function while maintaining the stereochemical configuration of hydroxy function in the formation of an ether compound; and

-O-J represents an appropriate leaving group after reaction with a nucleophilic reagent with an inverse stereochemical configuration, as shown in FIG. 5 and in all formulas and symbols as described above.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (66), comprising the steps under suitable conditions, as shown in FIG. 122, where all formulas and symbols are as described above. As shown in FIG. 122, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be accomplished by biotransformation of chlorobenzene (58) into compound (59) by a microorganism such as Pseudomonas putida 39 / D. The 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 another separate step, the less blocked hydroxy function in compound (59) selectively monosilifies as compound (59) with a silylating reagent such as tert-butyldiphenylsilyl chloride (TBDPSCl) under suitable conditions (e.g. imidazole in CH ₂ Cl ₂ ) (Hudlicky et al. , Aldrichimica Acta, 1999, 32, 35; SM Brown and T. Hudlisky, In Organic Synthesis: Theory and Applications; T. Hudlicky, Ed .; JAI Press: Greenwich, CT, 1993; Vol.2, p 113; and cited in them links). In another separate step, compound (95) is converted to compound (96) by reduction, such as hydrogenation and hydrogenolysis, in the presence of a catalyst under appropriate conditions. Activated carbon palladium is one example of a catalyst. The reduction of compound (95) can be carried out 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 fractionally during the course of the reaction. In another separate step, the free hydroxy group in compound (96) is alkylated under appropriate conditions to form compound (97). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g. Aldrich), by treatment with trichloroacetonitrile. Alkylation of compound (96) with trichloroacetimidate (63) can be carried out in the presence of a Lewis acid such as HBF ₄ . In another separate step, the tert-butyl diphenylsilyl protecting group (TBDPS) in compound (97) can be removed by standard procedures (e.g. tetrabutylammonium fluoride in tetrahydrofuran (THF) or as described in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991)) to prepare a hydroxy ester compound (98). In a separate step, the hydroxy group of compound (98) is converted, under appropriate conditions, into an activated form, such as a tosylate of formula (64). In another separate step, the tosylate group of formula (64) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Aldrich), or it 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 a solvent and in the appropriate temperature range, which allows the formation of the product (66) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (64) to product (66). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

The reaction sequence described above (FIG. 122) generally generates a compound of formula (66) as a free base. The free base can, if desired, be converted into the monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. 123, including the starting steps from chlorobenzene (58), and following the reaction sequence under suitable conditions similar to the applicable part, which is described above in FIG. 122, and leads to the formation of a compound of formula (64). The latter interacts with the amino compound of formula (68). Compound (68), 3S-pyrrolidinol, is commercially available (e.g., 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 a solvent and in the appropriate temperature range, which allows the formation of the product (69) with a suitable rate. Excess amino compound (68) can be used to maximize the conversion of compound (64) to product (69). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) and is formed as the free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with inorganic or organic acids under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment of the present invention, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions by the method shown in FIG. 124, comprising the start up steps of the compound of formula (50), and observing the reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 121, where all formulas and symbols are as described above.

In another embodiment of the present invention, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 125, comprising the start steps of the compound of formula (59), and observing the reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 122, where all the formulas and symbols are as described above. 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of the formula (59) is a commercially available product (e.g., Aldrich) or synthesized in accordance with a published procedure (e.g., Organic Synthesis, Vol. 76, 77 and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; and references cited therein).

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out by the method shown in FIG. 126, comprising the start steps of the compound of the formula (59) and observing the reaction sequence under suitable conditions, similar to the applicable part, which is described in FIG. 123, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out by the method as shown in FIG. 127, comprising the steps of starting with the compound of formula (91) and observing the reaction sequence under suitable conditions similar to the applicable portion , which is described in FIG. 121, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (66) can be carried out by the method shown in FIG. 128, comprising the steps of starting with a compound of formula (95) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 122, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (69) can be carried out under suitable conditions by the method shown in FIG. 129, comprising the start steps of the compound of the formula (95) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 123, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions by the method shown in FIG. 130, comprising the start steps of the compound of formula (92), and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 121, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 131, comprising the start steps of the compound of formula (96), and following a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 122, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. 132, comprising the steps of starting with a compound of formula (96) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 123, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions by the method shown in FIG. 13, comprising the steps of starting with a compound of formula (93) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 121, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (66) can be carried out under suitable conditions by the method shown in FIG. 134, comprising the start steps of the compound of formula (97), and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 122, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. 135, comprising the steps of starting with a compound of formula (97) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 123, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (57) can be carried out under suitable conditions by the method shown in FIG. 136, comprising the steps of starting with a compound of formula (94) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 121, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (66) can be carried out under suitable conditions by the method shown in FIG. the applicable part, which is described in FIG. 122, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (69) can be carried out under suitable conditions by the method shown in FIG. the applicable part, which is described in FIG. 123, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (55) can be carried out under suitable conditions by the method shown in FIG. 139, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (64) can be carried out under suitable conditions by the method shown in FIG. 140, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (94) can be carried out under suitable conditions by the method shown in FIG. 141, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (98) can be carried out under suitable conditions by the method shown in FIG. 142, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (93) can be carried out under suitable conditions by the method shown in FIG. 144, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence under suitable conditions similar to the applicable portion that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (97) can be carried out under suitable conditions by the method shown in FIG. 144, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (92) can be carried out under suitable conditions by the method shown in FIG. 145, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (96) can be carried out under suitable conditions by the method shown in FIG. 146, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence under suitable conditions similar to the applicable portion that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (92), or a solvate thereof, or a pharmaceutically acceptable salt; where all the formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (54), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that all R ₃ , R ₄ and R ₅ cannot represent hydrogen itself.

In another embodiment, the present invention provides a compound of formula (93) or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein all the formulas and symbols are as described above, provided that all R _3, R ₄ and R ₅ can not represent hydrogen itself.

In another embodiment, the present invention provides a compound of formula (94), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that all R ₃ , R ₄ and R ₅ cannot represent hydrogen itself.

In another embodiment, the present invention provides a compound of formula (55), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that when R ₃ , R ₄ and R ₅ are hydrogen , then J does not represent a methanesulfonyl group.

In another embodiment, the present invention provides a compound of formula (96), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (63), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (97), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (98), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (64), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

The present invention provides synthesis methods whereby compounds of formula (75) with a trans (1S, 2S) configuration for an ether functional group and an amino functional group can be prepared in substantially stereoisomerically pure form. The compounds of formulas (79) and (81) are some of the examples represented by formula (75). The present invention also provides synthetic methods by which the compounds of formulas (92), (99), (84) and (74) can be synthesized in stereoisomerically substantially pure forms. Compounds (96), (100), (62) and (78) are examples of formulas (92), (99), (84) and (74), respectively.

As shown in FIG. 147, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out following a process starting with monohalogenbenzene (49), where X may be F, Cl, Br or I.

In the first step, compound (49) is transformed by well-established microbial oxidation to cis-cyclohexanedienediol (50) in a substantially stereoisomerically pure form (T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; and references cited therein). In a separate step, the less blocked hydroxy function in compound (50) can be selectively mono-protected as compound (91), where Pro represents the corresponding hydroxy function protecting group while maintaining stereochemistry (T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; SMBrown and T. Hudlisky, In Organic Synthesis: Theory and Applications; T. Hudlicky, Ed .; JAI Press: Greenwich, CT, 1993; Vol.2, p 113; and references cited therein). Trialkylsilyl groups such as triisopropylsilyl (TIPS) and tert-butyldimethylsilyl (TBDMS), and alkyl diarylsilyl groups such as tert-butyldiphenylsilyl (TBDPS) are some of the possible examples for Pro. Suitable interaction conditions are set forth, for example, in Greene, "Protective 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 carried out by hydrogenation and hydrogenolysis in the presence of a catalyst under appropriate conditions. Activated carbon palladium is an example of a catalyst. The hydrogenolysis of an alkyl or alkenyl halide such as compound (91) can be carried out under basic conditions. The presence of a base such as sodium ethoxide, sodium bicarbonate, sodium acetate or calcium carbonate are some possible examples. The base can be added in one portion or fractionally during the course of the interaction. In a separate step, the free hydroxy group of compound (92) is converted to the activated form as represented by formula (99) under suitable conditions. As used herein, the term “activated form” means that the hydroxy group is converted to the appropriate leaving group (—O — J). The leaving group may be a mesylate group (MsO-), a tosylate group (TsO-) or a nosylate group (NsO-). The hydroxy group may also be converted into other suitable leaving groups in accordance with procedures well known in the art. In a typical tosylate reaction, compound (92) is treated with a hydroxyactivating agent such as tosyl chloride (TsCl) in the presence of a base such as pyridine or triethylamine. The reaction is generally satisfactorily carried out at about 0 ° C, but the temperature can be adjusted if necessary to maximize the yields of the target product. Excess hydroxyactivating reagent (e.g., tosyl chloride) relative to compound (92) can be used to maximize the conversion of the hydroxy group to the activated form. In a separate step, the removal of the protective group (Pro) in compound (99) by standard procedures (for example, tetrabutylammonium fluoride in tetrahydrofuran, or as described in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991) ) gives the compound (84). In a separate step, the alkylation of the free hydroxy group in compound (84) to form (74) is carried out under appropriate conditions with compound (54), where —O — Q represents an appropriate leaving group after reacting with a hydroxy function while maintaining the stereochemical configuration of the hydroxy function to form an ether compound. Trichloroacetimidate is one example of the function of —O — Q. For some compounds (54), it may be necessary to introduce appropriate protecting groups before performing this step. Suitable protecting groups are presented, for example, in Greene, "Protective Groups in Organic Chemistry", John Wiley & 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 compound (75) as a product. The reaction can be carried out with or without a solvent and at an appropriate temperature range, which allows the formation of the product (75) with a suitable rate. Excess amino compound (56) can be used to maximize the conversion of compound (74) to product (75). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the product is recovered from the reaction mixture by conventional methods of organic chemistry and, accordingly, purified. Protecting groups can be removed at the appropriate stage in 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 reaction sequence (FIG. 147) generates a compound of formula (75) as a free base. The free base can, if desired, be converted into the monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

All publications and patent applications referenced herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and separately incorporated by reference.

In one embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (75):

where R ₁ and R ₂ taken together with the nitrogen atom with which they are directly connected in the formula (75), form a ring indicated by the formula (II):

and R ₃ , R ₄ and R _{5 are} independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, provided that all R ₃ , R ₄ and R ₅ cannot be hydrogen;

comprising the onset stages of monohalogenbenzene (49), where X may be F, Cl, Br or I, and performing an interaction sequence, as shown in FIG. 147, under suitable conditions, wherein

Pro represents an appropriate hydroxy-functional protecting group while maintaining stereochemistry;

—O — Q represents an appropriate leaving group after reaction with hydroxy function under appropriate conditions while maintaining the stereochemical configuration of hydroxy function in the formation of an ether compound; and

-O-J represents an appropriate leaving group after reaction with a nucleophilic reagent under suitable conditions with an inverse stereochemical configuration, as shown in FIG. 147 and in all formulas and symbols as described above.

In another embodiment, the present invention provides a method for producing a substantially stereoisomerically pure compound of formula (79), comprising the steps under suitable conditions, as shown in FIG. 148, where all formulas and symbols are as described above. As shown in FIG. 144, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be accomplished by biotransformation of chlorobenzene (49) into compound (59) by a microorganism such as Pseudomonas putida 39 / D. The 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, the less blocked hydroxy function in compound (59) selectively monosilifies as compound (95) by reacting with a silylating reagent such as tert-butyldiphenylsilyl chloride (TBDPSCl) under suitable conditions (e.g. imidazole in CH ₂ Cl ₂ ) (T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; SM Brown and T. Hudlisky, In Organic Synthesis: Theory and Applications; T. Hudlicky, Ed .; JAI Press: Greenwich, CT, 1993; Vol.2, p 113; and references cited therein). In another separate step, compound (95) is converted to compound (96) by reduction, such as hydrogenation and hydrogenolysis, in the presence of a catalyst under appropriate conditions. Activated carbon palladium is one example of a catalyst. The reduction of compound (95) can be carried out 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 fractionally during the course of the reaction. In a separate step, the free hydroxy group of compound (96) is converted, under appropriate conditions, into an activated form, such as a tosylate of formula (100), by treatment with tosyl chloride (TsCl) in the presence of pyridine. In another separate step, the tert-butyl diphenylsilyl protecting group (TBDPS) in compound (100) can be removed by standard procedures (for example, tetrabutylammonium fluoride in tetrahydrofuran or, as described in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York NY (1991)) to prepare the hydroxytosylate compound (62). In a separate step, the free hydroxy group in compound (62) is alkylated under appropriate conditions to form compound (78). Trichloroacetimidate (63) is readily prepared from the corresponding alcohol, 3,4-dimethoxyphenethyl alcohol, which is commercially available (e.g. Aldrich), by treatment with trichloroacetonitrile. Alkylation of compound (62) with trichloroacetimidate (63) can be carried out in the presence of Lewis acid, such as HBF ₄ . In a separate step, the tosylate group of formula (78) is replaced by an amino compound such as 3R-pyrrolidinol (65) with an inverse configuration. 3R-pyrrolidinol (65) is commercially available (e.g., Aldrich), or it 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 a solvent and in the appropriate temperature range, which allows the formation of the product (79) with a suitable rate. Excess amino compound (65) can be used to maximize the conversion of compound (78) to product (79). The reaction can be carried out in the presence of a base, which can promote the formation and isolation of the product. In general, the base is non-nucleophilic in chemical interactions. When the reaction is substantially complete, the desired product is recovered from the reaction mixture by conventional organic chemistry techniques and, accordingly, purified.

The reaction sequence described above (FIG. 144) generally generates a compound of formula (79) as a free base. The free base can, if desired, be converted into the monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. the applicable part, which is described above in FIG. 144, and leads to the formation of a compound of formula (78). The latter interacts with the amino compound of formula (68). Compound (68), 3S-pyrrolidinol, is commercially available (e.g., 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 a solvent and in the corresponding temperature range, which allows the formation of the product (81) with a suitable rate. Excess amino compound (68) can be used to maximize the conversion of compound (78) to product (81). The reaction can be carried out in the presence of a base, which can promote product formation. In general, the additional base is non-nucleophilic in chemical interactions. The product is a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of the formula (81) and is formed as the free base. The free base can, if desired, be converted into monohydrochloride by known methods, or alternatively, into other acid addition salts by reaction with inorganic or organic acids under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent salt.

In another embodiment of the present invention, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions by the method shown in FIG. 150, comprising the start steps of the compound of formula (50) and observing the reaction sequence under suitable conditions, similar to the applicable part, which is described in FIG. 147, where all formulas and symbols are as described above.

In another embodiment of the present invention, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. similar to the applicable part, which is described in Fig.148, where all the formulas and symbols are as described above. 3-chloro- (1S, 2S) -3,5-cyclohexadiene-1,2-diol of the formula (59) is a commercially available product (e.g., Aldrich) or synthesized in accordance with a published procedure (e.g., Organic Synthesis, Vol. 76, 77 and T. Hudlicky et al., Aldrichimica Acta, 1999, 32, 35; and references cited therein).

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out by the method shown in FIG. 152, comprising the steps of starting with a compound of formula (59) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 149, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out by the method as shown in FIG. 153, comprising the steps of starting with the compound of formula (91) and observing a reaction sequence under suitable conditions similar to the applicable portion which is described in FIG. 147, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out by the method shown in FIG. 154, comprising the steps of starting with a compound of formula (95) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 144, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. 155, comprising the steps of starting with a compound of formula (95) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 149, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions by the method shown in FIG. 156, comprising the steps of starting with a compound of formula (92) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 147, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. 157, comprising the steps of starting with a compound of formula (96) and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 148, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. the applicable part, which is described in FIG. 149, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ether compound of formula (75) can be carried out under suitable conditions by the method shown in FIG. 159, comprising the steps of starting with a compound of formula (99), and observing a reaction sequence under suitable conditions similar to the applicable part, which is described in FIG. 147, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (79) can be carried out under suitable conditions by the method shown in FIG. the applicable part, which is described in FIG. 144, where all formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure trans-aminocyclohexyl ester compound of formula (81) can be carried out under suitable conditions by the method shown in FIG. the applicable part, which is described in FIG. 149, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (74) can be carried out under appropriate conditions by the method shown in FIG. on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (78) can be carried out under suitable conditions by the method shown in FIG. 163, comprising the steps of starting with a compound of formula (58), and by observing a reaction sequence under suitable conditions similar to the applicable portion that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (84) can be carried out under suitable conditions by the method shown in FIG. 164, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (62) can be carried out under suitable conditions by the method shown in FIG. 165, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence under suitable conditions similar to the applicable part that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (99) can be carried out under suitable conditions by the method shown in FIG. 166, comprising the steps of starting with a compound of formula (49) and observing a reaction sequence under suitable conditions similar to the applicable portion that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the preparation of a substantially stereoisomerically pure compound of formula (100) can be carried out under suitable conditions by the method shown in FIG. 167, comprising the steps of starting with a compound of formula (58) and observing a reaction sequence under suitable conditions similar to the applicable portion that is described on Fig, where all the formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (92), or a solvate thereof, or a pharmaceutically acceptable salt; where all the formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (99), or a solvate thereof, or a pharmaceutically acceptable salt; where all the formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (84), or a solvate thereof, or a pharmaceutically acceptable salt; where all the formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (54), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that all R ₃ , R ₄ and R ₅ cannot represent hydrogen itself.

In another embodiment, the present invention provides a compound of formula (74), or a solvate thereof, or a pharmaceutically acceptable salt, where all formulas and symbols are as described above, provided that when all R ₃ , R ₄ and R ₅ are hydrogen, then J does not represent a methanesulfonic group.

In another embodiment, the present invention provides a compound of formula (96), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (100), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (62), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (63), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

In another embodiment, the present invention provides a compound of formula (78), or a solvate thereof, or a pharmaceutically acceptable salt, wherein all formulas and symbols are as described above.

The reaction sequences described above (FIG. 1 and FIG. 2) generate aminocyclohexyl ether compounds initially as the free base. If desired, the free base can be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with the corresponding inorganic or organic acids. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent 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 thus, such compounds will exist in the form of various stereoisomeric forms. Applicants intend to include all of the various stereoisomers within the scope of the invention. Although the compounds can be obtained in the form of racemates and their use in this form is possible, if desired, it is also possible to isolate or preferably synthesize individual enantiomers by known methods. Such racemates and individual enantiomers and mixtures thereof are intended to be included within the scope of the present invention. Pure enantiomeric forms upon their preparation can be isolated by preparative chiral HPLC. If desired, the free base can be converted into monohydrochloride by known methods, or alternatively, if desired, into other acid addition salts by reaction with an inorganic or organic acid under appropriate conditions. Acid addition salts can also be obtained by an exchange reaction by reacting one acid addition salt with an acid that is stronger than the parent 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. Pharmaceutically acceptable esters and amides can be prepared by reacting, respectively, a hydroxy or amino functional group with a pharmaceutically acceptable organic acid, such as that identified above. A prodrug is a drug that has been chemically modified, and may be biologically inactive at the site of its action, but which is destroyed or modified by one or more enzymatic or other processes in vivo into the maternal biologically active form. In general, the prodrug has a pharmacokinetic profile different from the parent drug, so that, for example, it is more easily absorbed through the epithelium of the mucous membrane, it has better salt formation or solubility, and / or it has better systemic resistance (e.g., increased plasma half-life) .

Those skilled in the art will recognize that chemical modifications of the parent drug for the prodrug include: (1) terminal ester or amide derivatives that are susceptible to cleavage by esterases or lipases; (2) terminal peptides that can be recognized by specific or non-specific proteases; or (3) a derivative that causes prodrug accumulation in the site of action by selecting a membrane and a combination of the above techniques. Conventional procedures for the selection and preparation of prodrug derivatives are described in H. Bundgaard, Design of Prodrugs (1985). Specialists in this field have extensive experience in obtaining prodrugs, and they are well aware of its significance.

The present invention also encompasses pharmaceutically acceptable complexes, chelates, metabolites, or metabolic precursors of the compounds of the present invention. Information on the meaning of these terms and references to their receipt can be obtained by searching various databases, for example, Chemical Abstracts and the Food and Drug Administration's Internet site (FDA). Documents like the following are available from the FDA: Guidance for Industry, "In Vivo Drug Metabolism / Drug Interaction Studies - Study Design, Data Analysis, and Recommendations for Dosing and Labeling", U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologies Evaluation and Research (CBER), November 1999. Guidance for Industry, "In Vivo Drug Metabolism / Drug Interaction Studies in the DRUG DEVELOPMENT PROCESS: STUDIES IN VITRO ", US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologies Evaluation and Research (CBER), April 1997.

The synthesis procedures described herein, especially those taken with a general understanding of the art, provide sufficient guidance to those skilled in the art to carry out the synthesis, isolation, and purification of the compounds of the present invention.

Compositions and methods 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 described in this patent, or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomes Temperature and mixtures thereof in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method of making such a composition or medicament.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof in the complex tion with a pharmaceutically acceptable carrier, diluent or excipient, and, in addition, provides a method for the manufacture of such a composition or drug.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, a stereoisomer, a stereoisomeric mixture, a geometric isomer, a crystalline or amorphous form or a metabolite thereof, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof in combination with a pharmaceutically acceptable carrier, diluent or excipient, and, further provides a method for the manufacture of such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or any salt thereof or any solvate thereof;

in combination with a pharmaceutically acceptable carrier, diluent or excipient, and furthermore provides a method for the manufacture of such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that comprises a compound that is a free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any a salt thereof, or any solvate thereof in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of such a composition or drug.

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 monohydrochloride, or any thereof a salt, or any solvate thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds of the present invention in accordance with formula (IA), (IB), (IC), (ID) or (IE) or a solvate thereof, a pharmaceutically acceptable salt , stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or its metabolite in combination with appropriate amounts of sodium chloride in accordance with the requirements of USP (US Pharmacopoeia), citric acid according to USP, sodium hydroxide ia in accordance with the requirements of NF (National Pharmaceutical Formulary) and water for injection according to USP; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof in combination with the corresponding amounts of sodium chloride according to USP, citric acid by USP, sodium hydroxide by NF and water for injection by USP; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or drug that comprises a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof ; in combination with appropriate amounts of sodium chloride according to USP, citric acid according to USP, sodium hydroxide according to NF and water for injection according to USP; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or drug that comprises one or more compounds of the present invention in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or a metabolite thereof, in combination with appropriate amounts of sodium chloride according to USP, citric acid according to USP, sodium hydroxide according to NF and water for injection according to USP, which drive t to obtain an isotonic solution for intravenous administration of said compound in a concentration from about 0.1 mg / ml to 100 mg / ml in sodium citrate of about 1 to 400 mM at a pH from about 7.5 to 4.0; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound in concentration from about 0.1 mg / ml to 100 mg / ml in sodium citrate from about 1 to 400 mm at a pH of from about 7.5 to 4.0; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or drug that comprises a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof ; in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound in concentration from about 0.1 mg / ml to 100 mg / ml in sodium citrate from about 1 to 400 mm at a pH of from about 7.5 to 4.0; and, furthermore, provides a method of manufacturing such a composition or drug.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds of the present invention in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or a metabolite thereof, in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance and with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound at a concentration of from about 5 mg / ml to 80 mg / ml in sodium citrate from about 10 to 80 mM at a pH of about 6.5 to 4.5; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound in concentrations from about 5 mg / ml to 80 mg / ml in sodium citrate from about 10 to 80 mM at a pH from about 6.5 to 4.5; and, furthermore, provides a method of manufacturing such a composition or drug.

In another embodiment, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof , in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, resulting in an isotonic solution for intravenous conducting said compound in a concentration from about 5 mg / ml to 80 mg / ml in sodium citrate of about 10 to 80 mM at a pH from about 6.5 to 4.5; and, furthermore, provides a method of manufacturing such a composition or drug.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds of the present invention in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or a metabolite thereof, in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance and with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound at a concentration of from about 10 mg / ml to 40 mg / ml in sodium citrate from about 20 to 60 mM at a pH of about 6 to 5; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound in concentrations from about 10 mg / ml to 40 mg / ml in sodium citrate from about 20 to 60 mM at a pH from about 6 to 5; and, furthermore, provides a method of manufacturing such a composition or drug.

In another embodiment, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof , in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, resulting in an isotonic solution for intravenous conducting said compound in a concentration from 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, furthermore, provides a method of manufacturing such a composition or drug.

In another embodiment, the present invention provides a composition or drug that comprises one or more compounds of the present invention in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or a metabolite thereof, in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance and with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound at a concentration of about 20 mg / ml in sodium citrate about 40 mm at a pH of about 5.5; and, furthermore, provides a method of manufacturing such a composition or drug.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds selected from the group consisting of

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, which results in an isotonic solution for intravenous administration of the compound in a concentration of about 20 mg / ml in sodium citrate about 40 mm at a pH of about 5.5; and, furthermore, provides a method of manufacturing such a composition or drug.

In another embodiment, the present invention provides a composition or medicament that includes a compound that is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride or any solvate thereof , in combination with appropriate amounts of sodium chloride, in accordance with USP, citric acid, in accordance with USP, sodium hydroxide, in accordance with NF and water for injection, in accordance with USP, resulting in an isotonic solution for intravenous conducting said compound at a concentration of about 20 mg / ml in sodium citrate of about 40 mM at a pH of about 5.5; and, furthermore, provides a method of manufacturing such a composition or drug.

In another embodiment, the present invention provides compositions that comprise combining the present invention in a mixture or in other association with one or more inert carriers, excipients and diluents, and optionally with optional ingredients. These compositions can be used, for example, as analytical standards, convenient bulk transport agents, or pharmaceutical compositions. An assay amount of a compound of the invention is an amount that is readily measured by standard analytical procedures and techniques that are well known and understood by those skilled in the art. The analyzed amounts of the compounds of the invention will generally vary from about 0.001 wt.% To about 75 wt.% Of the total weight of the composition. Inert carriers include any material that does not break down or otherwise covalently react with a compound of the invention. Examples of suitable inert carriers are water, aqueous buffers, such as those generally used in high performance liquid chromatography (HPLC) analysis, organic solvents, such as acetonitrile, ethyl acetate, hexane and the like (which are suitable for use in diagnostics or analyzes in vitro, but are usually not suitable for administration to a warm-blooded animal), and pharmaceutically acceptable carriers such as physiological saline.

Thus, the present invention provides a pharmaceutical or veterinary composition (hereinafter simply referred to as a pharmaceutical composition) comprising a compound of the present invention in admixture with a pharmaceutically acceptable carrier, excipient or diluent. The invention further provides a pharmaceutical composition comprising an effective amount of a compound of the present invention in association with a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may be in any form that enables administration of the composition to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Typical routes of administration include, but are not limited to, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. As used herein, the term “parenteral” includes subcutaneous injections, intravenous, intramuscular, epidural, intrathecal injection, or infusion techniques. The pharmaceutical compositions of the invention are formulated so as to enable the ingredients contained in them to be bioavailable after administration of the composition to a patient. The compositions to be administered to the patient take the form of one or more dosage forms, where, for example, a tablet, capsule or sachet may be a single dosage form, and the container of the compound in aerosol form may contain many dosage forms.

The materials used in the preparation of the pharmaceutical compositions must be pharmaceutically pure and non-toxic in the amounts used. The compositions of the invention may include one or more compounds (active ingredients), known for their particularly desirable effect. It will be apparent to those of ordinary skill in the art that the optimal dosage of the active ingredient (s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, but are not limited to, the type of individual (eg, human), the particular form of the active ingredient, route of administration, and composition used.

In General, the pharmaceutical composition includes a compound of the present invention, as described in the present invention, in admixture with one or more carriers. The carrier (s) may be in the form of particles, so that the compositions are presented, for example, in the form of a tablet or powder. The carrier (s) may be a liquid, the composition being, for example, an oral syrup or injection liquid. In addition, the carrier (s) may be gaseous in order to provide an aerosol composition that can be used, for example, by inhalation.

When the composition is intended for oral administration, it is preferably presented in either solid or liquid form, the semi-solid, semi-liquid, suspension and gel forms being included in the range of forms contemplated herein as either a solid or liquid.

As a solid composition for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, sachet, chewing gum, wafer, lozenges or the like. Such a solid composition will typically include one or more diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders, such as syrups, acacia, sorbitol, polyvinylpyrrolidone, carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth resin or gelatin, and mixtures thereof, excipients, such as starch, lactose, or lactose or disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex (sterotex); fillers such as lactose, mannitol, starch, calcium phosphate, sorbitol, methyl cellulose and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silicon dioxide, wetting agents such as sodium lauryl sulfate, glossy agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin, a flavoring such as peppermint, methyl salicylate or orange flavoring, and coloring.

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 type indicated above, a liquid carrier such as polyethylene glycol or fatty oil.

The composition may be in the form of a liquid, for example, an elixir, syrup, solution, aqueous or oily emulsion, or suspension, or even dry powders that can be dissolved with water and / or other liquid media before use. As two examples, the liquid may be intended for oral administration or for delivery by injection. When the compositions are intended for oral administration, they preferably contain, in addition to the present compounds, one or more sweeteners, thickeners, a preservative (e.g., para-hydroxybenzoate alkyl), a colorant / tint, and a flavor and odor enhancer (flavor). One or more surfactants, preservatives (e.g., para-hydroxybenzoate alkyl), a wetting agent, dispersing agent, suspending agent (e.g. sorbitol, glucose or other sugar syrups), a buffer may be included in a composition intended for administration by injection. , stabilizer and isotonic substance. The emulsifying agent can be selected from lecithin or sorbitan monooleate.

The liquid pharmaceutical compositions of the invention, whether they are solutions, suspensions or another similar form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils, such as synthetic mono- or diglycerides, which can serve as a solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other ra diluents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and tonicity agents such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic. A preferred adjuvant is physiological saline. The injectable pharmaceutical composition is preferably sterile.

Liquid compositions intended for parenteral or oral administration should contain such an amount of a compound of the invention that a suitable dosage is obtained. Typically, this amount is at least 0.01% of the compound of the invention in the composition. When the composition is intended for oral administration, this amount may vary from 0.1 to about 70% by weight of the composition. Preferred oral compositions contain from about 4% to about 50% of the active aminocyclohexyl ether active compound. Preferred compositions and preparations in accordance with the present invention are prepared so that the parenteral dosage form contains from 0.01 to 10% by weight of the active compound.

The pharmaceutical compositions may be intended for topical use, in which case the carrier may include a base in the form of a solution, emulsion, ointment, cream or gel. A base, for example, may include one or more of the following materials: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the topical pharmaceutical composition. If the composition is intended for transdermal administration, it may include a transdermal patch or device for iontophoresis. Topical compositions may contain a concentration of a compound of the invention from about 0.1 to about 25% w / v. (mass per unit volume).

The composition may be intended for rectal administration in the form of, for example, a suppository, which will melt in the rectum to release the drug. The composition for rectal administration may contain an oily base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol. Low melting waxes are preferred for the manufacture of a suppository, with suitable waxes being mixtures of fatty acid glycerides and / or cocoa butter. Waxes can melt, and the aminocyclohexyl ether compound is uniformly dispersed in them by stirring. Then the molten homogeneous mixture is poured into molds of a suitable size, allowed to cool and therefore harden.

The composition may include various materials that modify the physical form of a solid or liquid dosage form. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are usually inert and can be selected, for example, from sugar, shellac and other enteric coated agents. Alternatively, the active ingredients may be enclosed in a gelatin capsule or sachet.

The composition in solid or liquid form may include an agent that binds to the aminocyclohexyl ether compound and thereby facilitates the delivery of the active components. Suitable agents that can act to deliver the active components include a monoclonal or polyclonal antibody, protein, or liposome.

The pharmaceutical composition of the present invention may consist of gaseous dosage forms, for example, it may be in the form of an aerosol. The term "aerosol" is used to denote a variety of systems ranging from colloidal systems to systems consisting of sealed packages. Delivery may be by liquefied or compressed gas or by a suitable pumping device that delivers the active ingredients. Aerosols of the compounds of the invention can be delivered in single-phase, two-phase or three-phase systems for delivery of the active ingredient (s). Aerosol delivery includes the necessary container, activators, valves, subcontainers, and the like, which together form the kit. Preferred aerosols can be determined by a person skilled in the art without undue experimentation.

Regardless of whether the pharmaceutical composition of the present invention is presented in solid, liquid or gaseous form, it may contain one or more known pharmacological agents used in methods or for modulating the activity of ion channels in a warm-blooded animal, or for modulating the activity of ion channels in vitro, or used in the treatment and / or prevention of arrhythmias, including atrial / supraventricular arrhythmias and ventricular arrhythmias, atrial fibrillation, ventricular fibrillation, t atrial flutter, ventricular flutter, central nervous system diseases, seizures, cardiovascular diseases (for example, diseases caused by elevated cholesterol or triglycerides in the blood), cerebral and myocardial ischemia, hypertension, long QT syndrome, stroke, migraine, ophthalmic , diabetes mellitus, myopathies, Becker myotonia, generalized myasthenia gravis, congenital paramyotonia, malignant hyperthermia, periodic hyperkalemia paralysis, myotonia T Omsen, autoimmune disorders, transplant rejection during organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, dementia and other mental disorders, baldness, sexual dysfunction, impotence, demyelinating diseases, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, epilepsy, anxiety, schizophrenia, Parkinson’s disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, urinary incontinence, syndrome ohm irritated bowel and gastrointestinal disorders such as inflammation and ulcer of the gastrointestinal tract, or other diseases. Other agents that are known to cause increased libido, analgesia, or local anesthesia can be combined with the compounds of the present invention.

Compositions can be obtained by a method well known in the pharmaceutical field. 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 a free base or in the form of a pharmaceutically acceptable salt, such as hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in this area. An appropriate salt should be selected to enhance the bioavailability or stability of the compound for the appropriate type of use (eg, oral or parenteral routes of administration).

A composition for administration by injection can be prepared by combining the aminocyclohexyl ether compound of the present invention with water, and preferably with buffering agents, to form a solution. The water is preferably sterile pyrogen-free water. A surfactant may be added to facilitate the formation of a uniform solution or suspension. Surfactants are compounds that non-covalently interact with the aminocyclohexyl ether compound in order to facilitate dissolution or uniform suspension of the aminocyclohexyl ether compound in the aqueous delivery system. Surfactants are desirably present in the aqueous compositions of the invention because the aminocyclohexyl ether compounds of the present invention can be hydrophobic. Other carriers for injection include, but are not limited to, sterile ethyl peroxide without peroxide, dehydrogenated alcohols, propylene glycol, and mixtures thereof.

Suitable pharmaceutical adjuvants for injectable solutions include stabilizing agents, solubilizing agents, buffers and viscosity regulators. Examples of these adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity regulators. These pharmaceutical compositions can be injected intramuscularly, epidurally, intraperitoneally or intravenously.

As used herein, the term “treatment of arrhythmia” refers to the treatment of arrhythmia. An effective amount of the composition of the present invention is used to treat arrhythmias in a warm-blooded animal, such as a human. Methods for administering effective amounts of antiarrhythmic agents are well known in the art and include administering an oral or parenteral dosage form. Such dosage forms include, but are not limited to, a parenteral dosage form. Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants, and transdermal delivery systems. In general, for certain treatments, oral or intravenous administration is preferred. The amount and frequency of administration are chosen to create an effective level of the drug without harmful effects. They should generally range from a dosage of from about 0.01 to about 100 mg / kg / day, and usually from about 0.1 to 10 mg / kg, when administered orally or intravenously for an antiarrhythmic effect or other therapeutic use.

The administration of the compositions of the present invention can be carried out in combination with the administration of other agents. For example, it may be desirable to administer an opioid antagonist such as naloxone if the compound exhibits opioid activity, where such activity may be undesirable. Naloxone can counteract the opioid activity of the administered compound without adverse effects on antiarrhythmic activity. As another example, the aminocyclohexyl ether compound of the invention may be co-administered with epinephrine in order to cause local anesthesia.

Other compositions

The present invention also provides kits that comprise a pharmaceutical composition that includes one or more compounds of the above formulas. The kit also includes instructions for using the pharmaceutical composition for modulating the activity of ion channels, for treating arrhythmias, or for producing analgesia and / or local anesthesia, and for other uses disclosed herein. Preferably, the packaging for sale should contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be an amount sufficient to produce an intravenous injection solution. It will be apparent to those of ordinary skill in the art that compounds that are sensitive to light and / or air may require special packaging and / or formulation. For example, a package that is opaque to light and / or sealed against contact with ambient air and / or formulated with suitable coatings or excipients may be used.

Pharmacological embodiments

In other embodiments, the present invention provides one or more compounds of the present invention, such as compounds in accordance with formulas (IA), (IB), (IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, complex ether, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or drug that comprises said compound or mixture comprising compounds as described above for use in methods of modulating ion channel activity in a warm-blooded animal or modulating ion channel activity in vitro. In one embodiment of this embodiment, the warm-blooded animal in which the ion channel activity is modulated is a mammal; in one embodiment of this embodiment, the warm-blooded animal is a human; in one embodiment of this embodiment, the warm-blooded animal is an agricultural animal.

In other preferred embodiments, the present invention provides one or more compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition or drug that comprises said compound or mixture comprising compounds as described above for use in methods of modulating ion channel activity in a warm-blooded animal or modulating ion channel activity in vitro.

In one embodiment of this embodiment, the warm-blooded animal in which the ion channel activity is modulated is a mammal; in one embodiment, the warm-blooded animal is a human; in one embodiment, the warm-blooded animal is an agricultural animal.

As disclosed in the framework of the present invention, a variety of cardiac pathological conditions can be treated and / or prevented by the use of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE ), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomer s, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above. These compounds of the present invention are compounds that modulate ion channels, which, either individually or together with one or more additional compounds, are capable of selectively modulating certain ion currents. The ionic currents indicated herein are generally cardiac currents, and more specifically, are sodium currents and early repolarizing currents.

Early repolarizing currents correspond to those cardiac ion currents that are rapidly activated after depolarization of the membrane potential difference and which affect cell repolarization. Many of these currents are potassium currents and may include, but are not limited to, transient output current I _to1 , for example, Kv4.2 and Kv4.3) and ultrafast, delayed, rectifying current (I _Kur ), for example, Kv1.5 and Kv1.4 and Kv2.1). Ultrafast, delayed, rectifying current (I _Kur ) has also been described as I _sus . A second calcium-dependent transient output current (I _to2 ) has also been described.

Pathological conditions that can be treated and / or prevented by the present invention may include, but are not limited to, various cardiovascular diseases.

Cardiac pathological conditions that can be treated and / or prevented by the present invention may include, but are not limited to, arrhythmias, such as various types of atrial and ventricular arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter.

In one embodiment, the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarizing currents and cardiac sodium currents.

In another embodiment, the present invention provides ion modulating channel compounds that can be used to selectively inhibit cardiac early repolarizing currents and cardiac sodium currents under conditions where an "arrhythmogenic substrate" is present in the heart. An "arrhythmogenic substrate" is characterized by a decrease in the duration of the cardiac action potential and / or changes the morphology of the action potential, premature action potentials, high heart rate and may also include an increased variability in the time interval between action potentials and an increase in the acidity of the heart due to ischemia or inflammation. Changes such as these are observed during conditions of ischemia or inflammation of the myocardium and those conditions that precede the onset of arrhythmias, such as atrial fibrillation.

In other embodiments, the present invention provides a method for modulating ion channel activity in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC) , (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous oh form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating the activity of ion channels in vitro, comprising administering in vitro an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), ( ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor nicknames or prodrugs, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for blocking / inhibiting ion channel activity / conductivity in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB) , (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for blocking / inhibiting the activity / conductivity of ion channels in vitro, comprising administering in vitro an effective amount of one or more compounds of the present invention, such as compounds in accordance with 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 th precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating potassium ion channel activity in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC ), (ID) or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline and whether an amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating the activity of the potential difference-controlled potassium ion channels 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 compounds in accordance with formula (IA), (IB) , (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geomet nical isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating the activity of cardiac sodium ion channels in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), ( IC), (ID) or (IE), or a solvate thereof, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crista a batch or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating the activity of ion channels of early repolarizing currents and cardiac sodium currents in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture and, a geometric isomer, crystalline or amorphous, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for blocking / inhibiting the ion channel activity of cardiac early repolarizing 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 compounds in accordance with the formula ( IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisome a, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of blocking / inhibiting the activity of ion channels responsible for cardiac early repolarizing currents and cardiac sodium currents in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as the compounds of with the formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chel that, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for blocking / inhibiting the ion channel activity of cardiac early repolarizing 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 compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or x solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for blocking / inhibiting the activity of ion channels responsible for cardiac early repolarizing 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 an effective amount to the warm-blooded animal in need thereof one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC ), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, early repolarizing currents indicated in the present invention include ionic currents that are rapidly activated after depolarization of the membrane potential difference and which affect cell repolarization.

In other embodiments, early repolarizing currents indicated in the present invention include cardiac transient output potassium current (I _to ) and / or ultrafast, delayed, rectifying current (I _Kur ).

In other embodiments, cardiac transient output potassium current (I _to ) and / or ultrafast, delayed, rectifying current (I _Kur ) referred to in the present invention include 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 of treating and / or preventing arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), ( IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous a form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing atrial arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline and and the amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing ventricular arrhythmias in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline whether an amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for treating and / or preventing atrial fibrillation in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline whether an amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing ventricular fibrillation in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline th or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for treating and / or preventing atrial flutter in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline th or amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing ventricular flutter in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or their solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or an amorphous form, metabolite, metabolic precursor or prodrug, including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing atrial arrhythmias in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing ventricular arrhythmias in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition or medicament which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for treating and / or preventing ciliary arrhythmia in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing ventricular fibrillation in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method of treating and / or preventing atrial flutter 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 compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for treating and / or preventing ventricular flutter in a warm-blooded animal, comprising administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention, such as compounds selected from the group consisting of

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof;

the free base of (1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or any salt thereof, or any solvate thereof; or a composition, or a medicament, which comprises said compound or mixture comprising compounds as described above.

As noted above, the present invention provides the use of the above compounds 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 the ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Their fundamentally significant physiological roles include regulating the electrical potential on both sides of the membrane, mediating ionic and fluid balance, promoting neuromuscular and neural transmission, rapid transmembrane signaling, and regulating secretion and contractility.

Accordingly, compounds that are capable of modulating the activity or function of the respective ion channels can be used in the treatment and / or prevention of various diseases or disorders caused by impaired or inadequate function of the ion channels. It is found that the compounds of the invention have significant activity in modulating the activity of ion channels in 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 of modulating ion channel activity in a warm-blooded animal or modulating ion channel activity in vitro. Some ion channels on which the compounds, compositions and methods of the present invention have a modulating effect are various potassium and sodium channels. These potassium and sodium ion channels can be activated by potential difference (also known as regulated by potential difference) or activated ligands (also known as regulated by ligands), and they can be present in cardiac and / or neural systems.

In one embodiment, the invention provides a compound of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a composition comprising said compound for use in methods or modulation the activity of the ion channel (s) in a warm-blooded animal, or modulating the activity of the ion channel (s) in vitro, wherein said ion channel (s) corresponds to some of the cardiac and / or neural ion channels that are responsible for one or more early repolarizing currents, including currents that are rapidly activated after membrane depolarization and which affect cell repolarization.

In another embodiment of the present invention, the above early repolarizing currents include transient output potassium current (I _to for cardiac or I _A for neural) and / or ultrafast, delayed, rectifying current (I _Kur ); and include at least one of the currents 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 compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a composition containing said compound for use in methods or for modulating the activity of the ion channel (s) in a warm-blooded animal, or for modulating the activity of the ion channel (s) in vitro, wherein said ion channel (s) correspond to either the cardiac or neural ion channel (s), which are responsible for the current Kv1.5 .

In yet another embodiment, the present invention provides a compound of the present invention, such as compounds in accordance with formula (IA), (IB), (IC), (ID) or (IE), or a composition comprising said compound for use in methods or to modulate the activity of the ion channel (s) in a warm-blooded animal, or to modulate the activity of the ion channel (s) in vitro, said ion channel (s) corresponding to the potassium channels that are responsible for the Kv4.2 current.

In addition, potential difference channels activated by sodium ions include a series of Na _v 1, Na _v 2 or Na _v 3 and may be present in the cardiac, neural, musculoskeletal, central nervous and / or peripheral nervous systems (e.g., hH1Na).

For cardiac sodium channels in studies on ion channels in isolated human atrial myocytes, it has been shown that the compounds of the present invention cause a frequency-dependent blockade of cardiac sodium channels. In these studies, enhanced blockade of cardiac sodium channels was observed at faster stimulation frequencies with a several-fold increase in the sodium block during fast stimulation frequencies. These protocols were created to simulate short recovery periods during fibrillation.

As noted previously, the term “modulating the activity of the ion channel” as used above may include, but is not limited to, blocking or inhibiting the conductivity of the current through the ion channel.

Thus, the present invention provides methods of treating a disease or condition in a warm-blooded animal suffering from or having a disease or condition, and / or preventing the occurrence of a disease or condition in a warm-blooded animal in which a therapeutically effective amount of a compound of the present invention is administered to a warm-blooded animal in need thereof . Some of the diseases and conditions in which the compounds, compositions and methods of the present invention are used can be used for the following pathologies: arrhythmia, including atrial / supraventricular arrhythmia and ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, central nervous system disease, , convulsions, cardiovascular diseases (e.g., diseases caused by high cholesterol or triglycerides in the blood), cerebral or myocardial Ischemia, hypertension, long QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus, myopathy, Becker myotonia, generalized myasthenia gravis, congenital paramiotonia, malignant hyperthermia, hyperkalemia recurrent paralysis, Thomsen myotonia, autoimmune transplant organ disorders, autoimmune organ transplant disorders, bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, dementia and other mental disorders, baldness, sexual dysfunction impotence, demyelinating diseases, multiple sclerosis, amyotrophic lateral sclerosis, epileptic cramps, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, urinary incontinence, and irritable bowel syndrome intestinal disorders such as inflammation and a gastrointestinal ulcer.

In addition, the present invention provides a method for creating analgesia or local anesthesia in a warm-blooded animal, which comprises administering to a 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 enhancing libido in a warm-blooded animal, which comprises administering to a 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, such as impotence in men, and / or to enhance the sexual desire of a patient without sexual dysfunction. As another example, a therapeutically effective amount can be administered to a bull (or other farm animal) to facilitate increased ejaculation of the seed, the ejaculated seed being collected and stored for use as needed for insemination of cows with the assistance of a livestock breeding program.

In addition, the present invention provides a method for in vitro use, wherein the preparation containing ion channels is contacted with an effective amount of an aminocyclohexyl ether compound of the invention. Suitable preparations containing cardiac sodium channels and / or cardiac potassium channels include cells isolated from cardiac tissue as well as cultured cell lines. The contacting step includes, for example, incubating the ion channels with the compound under conditions and for a period of time sufficient to allow modulation of the activity of the channels by the compound.

The administration of the compositions of the present invention can be carried out in combination with the administration of other agents. For example, it may be desirable to administer an opioid antagonist such as naloxone if the compound exhibits an opioid activity, where such activity may be undesirable. Naloxone can counteract the opioid activity of the administered compound without adverse effects on antiarrhythmic activity. As another example, the aminocyclohexyl ether compound of the invention may be co-administered with epinephrine in order to cause local anesthesia.

To evaluate whether the compound of the present invention has the desired pharmacological activity, it can be subjected to a series of tests. The particular test to be used will depend on the physiological response of interest. Published literature contains numerous protocols for testing the efficacy of a potential therapeutic agent, and these protocols can be used with the present compounds and compositions.

For example, in connection with the treatment or prevention of arrhythmia, a series of 4 tests can be performed. In the first of these tests, the compound of the present invention is administered as an increasing (doubling with each dose) intravenous infusion every 5 minutes in a conscious rat. The effects of the compound on blood pressure, heart rate and ECG are continuously monitored. Increasing doses are administered until a severe side effect occurs. A drug-related adverse event is identified as originating from the respiratory, central nervous system or cardiovascular system. This test indicates whether the compound modulates the activity of sodium channels and / or potassium channels and, in addition, provides information on acute toxicity. Indicators of sodium channel blockade are the increasing P-R interval and the expansion of QRS on the ECG. Blockade of potassium channels leads to an extension of the Q-T interval on the ECG.

The second test involves administering the compound as an anesthetic pentobarbital infusion to rats in which the left ventricle undergoes electrical stimulation with square pulses, performed in accordance with a pre-established protocol described below with further details. This protocol includes the determination of thresholds for the induction of extrasystoles and ventricular fibrillation. In addition, assess the effects on electrical refractoriness using a single extrasystole technique. In addition to the effects on blood pressure, heart rate and ECG are recorded. In this test, sodium channel blockers cause ECG changes expected from the first test. In addition, sodium channel blockers also raise the thresholds for the induction of extrasystoles and ventricular fibrillation. Blockade of potassium channels is detected by increasing refractoriness and expanding Q-T intervals on the ECG.

The third test involves exposure of isolated rat hearts to increasing concentrations of the compound. Values of intraventricular pressure, heart rate, speed and ECG are recorded in an isolated heart in the presence of varying concentrations of the compound. The test provides evidence of direct toxic effects on the myocardium. Additionally, the selectivity, power and effectiveness of the compounds can be determined under conditions that mimic ischemia. The concentrations that are found to be effective in this test are expected to be effective in electrophysiological studies.

The fourth test is an assessment of the antiarrhythmic activity of the compound against arrhythmias caused by coronary artery occlusion in anesthetized rats. A suitable antiarrhythmic compound is expected to exhibit antiarrhythmic activity in doses that have minimal effects on either the ECG, blood pressure, or heart rate under normal conditions.

All of the tests described above are performed using rat tissue. In order to make sure that the compound has no effects that are specific only to rat tissue, additional experiments on dogs and primates are performed. In order to evaluate the possible blocking effect on sodium channels and potassium channels in vivo in dogs, the compound is tested to determine the effects on the ECG, the rate of ventricular epicardium, and reactions to electrical stimulation. An anesthetized dog is subjected to an open chest procedure to expose the left ventricular epicardium. After removing the pericardium from the heart, a recording / stimulating electrode is sutured onto the surface of the left ventricular epicardium. Using this antenna and appropriate stimulation protocols, it is possible to evaluate the epicardial conduction velocity as well as the reactivity to electrical stimulation. This information, combined with ECG measurements, allows you to evaluate whether blockade of sodium and / or potassium channels occurs. As in the first test in rats, the compound is administered as a series of increasing bolus doses. At the same time, the potential toxic effects of the compound on the dog's cardiovascular system are evaluated.

The effects of ECG compounds and reactions to electrical stimulation are also evaluated in intact, anesthetized monkeys (Macaca fascicularis). On this preparation, a cannula is installed in an anesthetized monkey to measure blood pressure ECG electrodes. In addition, the stimulating electrode is placed on the right atrium and / or ventricle together with the electrode of a single-phase action potential. As in the tests described above, the ECG and electrical stimulation reactions to the compound reveal the possible presence of blockade of sodium and / or potassium channels. The single-phase action potential also reveals whether the compound expands the action potential, which is the action expected from potassium channel blockers.

As another example, in connection with alleviating or preventing a sensation of pain, the following test can be performed. To determine the effects of the compound of the present invention on the response of the animal to a sharp pain sensation, the effects of a small injection of a 7.5 g syringe equipped with a 23G needle in the shaved back of a guinea pig (Cavia porcellus) after subcutaneous injection of a sufficient amount (50 μl, 10 mg / ml) solution in saline for the appearance of a visible bladder on the skin. Each test is performed on the central region of the bubble, as well as on its periphery, to test the diffusion of the test solution from the injection point. If the test animal begins to shudder in response to irritation, this demonstrates the absence of blockade of pain. Testing can be carried out at intervals of up to 8 hours or more after administration. Bladder sites are examined after 24 hours to check for skin abnormalities due to topical administration of the test substances or vehicle used to prepare the test solutions.

The following examples are provided by way of illustration and not limitation. In the examples and in the absence of other refinements, starting materials were obtained from well-known commercial supply houses, for example Aldrich Chemical Company (Milwaukee, WI), and they were of standard grade and purity. Each of the terms “ether” and “ethyl ether” refers to diethyl ether; “h” refers to a watch; “min” refers to minutes; "GC" refers to gas chromatography; “v / v” refers to volume by volume; and in the absence of other indications, the ratios are mass ratios.

Example 1

(1R, 2R) MONOHYDROCHLORIDE - 2- [(3R) -HYDROXYPYROROLIDINYL] -1- (3,4-DIMETHOXYPHENETOXY) CYCLOHEXANE (COMPOUND 1)

The reaction scheme for preparing compound 1 described herein is shown in FIG. 1.

Preparation of Intermediates

N-tert-butoxycarbonyl-3R-pyrrolidinol (1R)

To a cold (0 ° C) stirred solution of 3R-pyrrolidinol (20.6 g, 236 mmol; Omega catalog no. HP-2113) in anhydrous THF (800 ml) was added dropwise a solution of di-tert-butyl dicarbonate (56.7 g, 260 mmol, Aldrich catalog No. 20.524-9) in THF (200 ml) and the resulting solution was stirred at room temperature for 18 hours. Concentration in vacuo of the reaction mixture and molecular distillation in vacuo of a clear yellow residue gave 1R (42 g, 95% yield) ) in the form of a clear and colorless oil, which crystallizes after aging.

4,4 (ушир.с, 1H), 3,5-3,2 (м, 4H), 2,5 (ушир.с, 1H), 2,0-1,9 (м, 2H), 1,4 (с, 9H); ¹³C-ЯМР (75 МГц, CDCl₃)

154,7, 79,3, 70,6, 69,8, 54,1, 53,9, 43,9, 43,4, 33,8, 33,3, 28,4; IR (пленка) 3411, 1678 см^-1; EIMS m/z (относительная интенсивность) 187 (M⁺, 8), 169 (M-H₂О, 0,5), 132 (25), 114 (39), 87 (13), 57 (100); HRMS m/z в расчете на C₉H₁₇NO₃ (M⁺) 187,12081, обнаружено 187,12084.Characterization: R _f 0.58 (CHCl ₃ -MeOH, 4: 1, v / v), ¹ H-NMR (200 MHz, CDCl ₃ )

4.4 (br s, 1H), 3.5-3.2 (m, 4H), 2.5 (br s, 1H), 2.0-1.9 (m, 2H), 1, 4 (s, 9H); ¹³ C-NMR (75 MHz, CDCl ₃ )

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 (MH ₂ O, 0.5), 132 (25), 114 (39), 87 (13), 57 (100); HRMS m / z calculated for C ₉ H ₁₇ NO ₃ (M ⁺ ) 187.12081, found 187.12084.

N-tert-butoxycarbonyl-3R-benzyloxypyrrolidine (2R)

A suspension of sodium hydride (8.08 g, 269 mmol, 80%, Aldrich catalog No. 25,399-5) in anhydrous THF (100 ml) was stirred, allowed to settle and the supernatant was removed. The gray precipitate was washed with THF (2 × 50 ml) and then resuspended in THF (700 ml). To a cold (0 ° C) stirred suspension of sodium hydride was added dropwise a solution of 1R (41.7 g, 223 mmol) in THF (200 ml) and the resulting mixture was refluxed for 1 h. After cooling the reaction mixture to At room temperature, benzyl bromide (26.5 ml, 223 mmol) and tetrabutylammonium iodide (8.20 g, 22.3 mmol, Aldrich catalog No. 14.077-5) were successively added. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. Brine (300 ml) and water (50 ml) were added to the residue, and the pH of the resulting mixture was adjusted to neutrality with 1M aqueous HCl. The mixture was extracted with hexane (100 ml) and the hexane extract was dried (anhydrous MgSO ₄ ) and concentrated under reduced pressure to obtain 64.3 g (yield> 98%) of a yellow oil, which, as shown by GC analysis, consists almost exclusively of the desired product. A small amount of the oil was flash column chromatographed on silica gel, eluted with hexane-ethyl acetate (3: 1) to give 2R as a colorless oil, which crystallized after aging.

7,35-7,25 (м, 5H), 4,58-4,47 (м, 2H), 4,12 (ушир.с, 1H), 3,55-3,40 (м, 4H), 2,10-2,00 (м, 1H), 2,00-1,90 (м, 1H), 1,48 (с, 9H); ¹³C-ЯМР (75 МГц, CDCl₃)

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 (пленка) 2975, 1691, 1410 см^-1; HRMS m/z в расчете на С₁₆H₂₃NO₃ (М⁺) 277,16779, обнаружено 277,16790.Characterization 2R: R _f 0.58 (CHCl ₃ -MeOH, 4: 1 v / v), ¹ H-NMR (400 MHz, CDCl ₃ )

7.35-7.25 (m, 5H), 4.58-4.47 (m, 2H), 4.12 (br s, 1H), 3.55-3.40 (m, 4H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.48 (s, 9H); ¹³ C-NMR (75 MHz, CDCl ₃ )

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 calculated as C ₁₆ H ₂₃ NO ₃ (M ⁺ ) 277.16779, found 277.16790.

3R-benzyloxypyrrolidine (3R)

A mixture of trifluoroacetic acid (50 ml, Aldrich catalog No. T6,220-0) and 2R (20 g, 72 mmol) was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was then collected in water (250 ml) and the resulting acidic aqueous solution was extracted with Et ₂ O (2 × 150 ml). Solid NaHCO _{3 was} carefully added in portions to the acidic aqueous layer until saturated. The basic aqueous solution was then extracted with CH ₂ Cl ₂ (2 × 150 ml) and the combined organic extracts were dried (anhydrous Na ₂ SO ₄ ). Evaporation of the solvent in vacuo afforded 8.0 g of 3R (yield 62%).

7,40-7,17 (м, 5H), 4,43 (с, 2H), 4,09-4,03 (м, 1H), 3,10-2,98 (м, 2H), 2,85-2,70 (м, 2H), 2,46 (с, 1H), 1,90-1,78 (м, 2H); IR (пленка) 3400, 1452, 1100, 1068 см^-1.Characterization 3R: R _f 0.24 (CHCl ₃ -MeOH, 9: 1 v / v), ¹ H-NMR (400 MHz, CDCl ₃ )

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 .

(1R, 2R) / (1S, 2S) -1 - [(3R) -benzyloxypyrrolidinyl] cyclohexan-2-ol (4R)

A mixture of cyclohexane oxide (12.5 ml, 120.9 mmol, Aldrich catalog No. C10,250-4), 3R (14.3 g, 80.6 mmol) and water (6 ml) is heated to 80 ° C for 9 , 5 h, after which the GC analysis reveals the total consumption of 3R. The reaction mixture was allowed to cool to room temperature and diluted with water (140 ml). By adding 1M aqueous HCl (55 ml), the pH was adjusted to 4.6 and the mixture was extracted with Et ₂ O (2 × 200 ml). After adjusting the pH to 15.5 of the aqueous layer by adding 40% aqueous NaOH (NaCl can be added to separate into 2 transparent layers), it is extracted with Et ₂ O (1 × 400 ml, 1 × 200 ml). The combined Et ₂ O extracts (from the main aqueous layer) were dried (anhydrous Na ₂ SO ₄ ) 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 a purity of 96% (GC).

7,4-7,2 (м, 5H), 4,5 (с, 2H), 4,2-4,0 (м, 1H), 3,9 (ушир.с, 1H), 3,4-3,2 (м, 1H), 3,0-2,5 (м, 4H), 2,4 (т, J=10 Гц, 1H), 2,2-1,9 (м, 2H), 1,9-1,6 (м, 4H), 1,3-1,1 (м, 4H); ¹³C-ЯМР (75 МГц, CDCl₃)

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 (пленка) 3450 (широкая) см^-1.Characterization 4R: R _f 0.24 (EtOAc- iso- PrNH ₂ , 98: 2 v / v); ¹ H-NMR (200 MHz, CDCl ₃ )

7.4-7.2 (m, 5H), 4.5 (s, 2H), 4.2-4.0 (m, 1H), 3.9 (br s, 1H), 3.4- 3.2 (m, 1H), 3.0-2.5 (m, 4H), 2.4 (t, 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 )

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 (wide) cm ^-1 .

(1R, 2R) / (1S, 2S) -2 - [(3R) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane (5R)

(a) To a cold (0 ° C) stirred solution of 4R (32.7 g, 88% pure by GC analysis, 104 mmol) and Et ₃ N (13.8 g, 135 mmol, Aldrich catalog No. 13,206-3) in CH ₂ Cl ₂ (210 ml) methanesulfonyl chloride (15.8 g, 135 mmol, Aldrich catalog No. M880-0) was added dropwise. The reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 2 hours and 15 minutes. The reaction mixture was then washed with a 1: 1 H ₂ O-saturated aqueous NaHCO ₃ mixture (200 ml). The aqueous layer was extracted with CH ₂ Cl ₂ (1 × 200 ml, 2 × 150 ml) and the organic extracts were combined and dried over sodium sulfate. Concentration of the organic layer in vacuo afforded the crude mesylate as a viscous oil, which was stirred under high vacuum for 3 hours to remove residual traces of volatile material, and then used in the next step without further purification.

(b) A solution of 3,4-dimethoxyphenethyl alcohol (23, 2 g, 125 mmol, Aldrich catalog No. 19,765-3) in ethylene glycol dimethyl ether (100 ml). The resulting mixture was then stirred at room temperature for 2 hours to complete the formation of sodium alkoxide.

2:1), содержащей 0,5% об./об. изо-PrNH₂ дает диастереомерную смесь 5R в виде желтого масла (выход 70%) в двух фракциях: 7,9 г (чистота 97% ГХ анализом) и 25,5 г (чистота 95% ГХ анализом).A solution of the mesylate (see part (a) above) in anhydrous ethylene glycol dimethyl ether (100 ml) was quickly added to the alkoxide mixture (see part (b) above) and the resulting mixture was refluxed in an argon atmosphere for 17 hours. The reaction mixture was successively cooled to room temperature and then the reaction was quenched with water (200 ml), followed by concentration under reduced pressure. The resulting aqueous solution was diluted with water (400 ml) and its pH was adjusted to pH 0.5 by the addition of 10% aqueous HCl. To remove unreacted 3,4-dimethoxyphenethyl alcohol, the acidic aqueous layer was extracted with Et ₂ O (2 × 600 ml). The pH of the aqueous solution was then adjusted to pH 6.3 by the addition of 5M aqueous NaOH and the resulting aqueous layer was extracted with Et ₂ O (600 ml). Et ₂ O (600 ml) was added to the aqueous layer, the pH was adjusted to pH 6.4 and the layers were separated. This operation is repeated to bring the pH to 6.5 and 6.7. The ether extracts after adjusting the pH to 6.3-6.7 are combined, concentrated under reduced pressure to a volume of ml and dried (anhydrous Na ₂ SO ₄ ). Removal of the solvent in vacuo afforded 34.4 g (95% purity by GC analysis) of the title compound as a brown oil. Purification of this material by flash column chromatography on silica gel with elution with a gradient of hexane-EtOAc solvent system (6.6: 1

2: 1) containing 0.5% v / v iso-PrNH ₂ gives a 5R diastereomeric mixture as a yellow oil (70% yield) in two fractions: 7.9 g (purity 97% GC analysis) and 25.5 g (purity 95% GC analysis).

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 (относительная интенсивность) 440 (M⁺, 2) 333 (15) 274 (67) 165 (40) 91 (100).Characterization: R _f 0.14 (hexanes-EtOAc, 2: 1, containing 0.5% iso-PrNH ₂ ); ¹³ C-NMR (100 MHz, CDCl ₃ )

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).

Separation of (1S, 2S) - and (1R, 2R) -2 - [(3R) -benzyloxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexanes (5RRR and 5SSR)

The 5R diastereomeric mixture was separated using a Prochrom 110 HPLC equipped with a column body with an inner diameter of 110 mm, a layer length of 850 mm, and a maximum layer length of 400 mm (filled column). The column is filled with Kromasil silica (10 μm, 100 angstroms, normal phase). SRRR is isolated with a diastereoselectivity of 99.5% and a chemical purity of 97%.

Preparation of COMPOUND (1), MONOHYDROCHLORIDE (1R, 2R) -2 - [(3R) -HYDROXYPYROROLIDINYL] -1- (3,4-DIMETHOXYPHENETOXY) CYCLOHEXANE)

A 500 ml Erlenmeyer flask equipped with 24/40 compound at 22 ° C. and loaded with a stirred solution of 5RRR (12.7 mmol) in isopropyl alcohol (70 ml, HPLC grade from EM Science, catalog No. PX1838-1) was added dropwise. hydrochloric acid solution (5 ml, 37%, Aldrich # 25.814-8). After stirring the solution for 10 min, Pd-C catalyst (1.5 g, 10%, Aldrich # 20.569-9) was added and the reaction vessel was equipped with a gas inlet adapter (compound 24/40, Kontes catalog no. CT185030-2440), connected to a water aspirator. The contents of the reaction flask are removed by aspiration of water for 1 min and then H _{2 is} charged via a cylinder attached to the gas inlet. After vigorously stirring the reaction mixture for 1 h at 22 ° C under positive pressure of H ₂ , TLC analysis (thin layer chromatography) and GC indicated complete substrate consumption and pure conversion to the desired product. The reaction mixture was filtered through a column filled with Celite 545® (Fisher) (45 mm diameter and 35 mm long, pre-wetted with methanol under suction conditions to remove air pockets and ensure effective capture by activated carbon during filtration), and the Pd-C catalyst was washed extensively methanol (3 × 40 ml). The acid methanol solution was concentrated azeotropically under reduced pressure with benzene or toluene to give a residue, which was vigorously stirred in ethyl acetate for 1-2 days to promote the formation of solids or crystals.

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; В расчете на C₂₀H₃₁NO₄,HCl: С 62,24%; H 8,36%; N 3,63%, Обнаружено: С 62,00%; H 8,42%; N 3,57%; [α]_D-46,7° (с 1,52, СН₃ОН); [α]_D-39,6° (с 1,00, CHCl₃)Characteristic: melting point 144-150 ° С; R _f 0.37 (AcOEt / ISO-PrNH2, 95: 5); IR 1514, 1263, 1111 cm ^-1 ; MS (ES) m / z 350.5; ¹³ C-NMR (75 MHz, CDCl ₃ )

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; Based on C ₂₀ H ₃₁ NO ₄ , HCl: 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); [α] _D -39.6 ° (c 1.00, CHCl ₃ )

Obtaining single crystals of compound 1 for x-ray crystallography

Compound 1 (200 mg) was dissolved in warm EtOH (3 ml) and then the solution was allowed to slowly evaporate at room temperature for 3 days. Crystals were formed, and further evaporation of the remaining solvent (ml) for another 2 days gave suitable crystals for X-ray diffraction measurements. The sample is stored in argon atmosphere.

X-ray determination of the structure of compound 1

Experiment

Data collection

A clear plate crystal of C ₂₀ H ₃₂ NO ₄ Cl having approximate dimensions of 0.25 × 0.20 × 0.04 mm is mounted on fiberglass. All measurements are carried out on an ADSC CCD area detector connected to a Rigaku AFC7 diffractometer with graphite monochromatic radiation Mo-Kα.

The cell constants and the orientation matrix for data collection correspond to a monoclinic cell with dimensions:

a = 8.4333 (7) b = 9.4675 (9)

=93,125(7)°

= 93.125 (7) ° c = 12.581 (1) V = 1,003.0 (1) ³

For Z = 2 and total weight = 385.93, the calculated density is 1.28 g / cm ³ . Based on a systematic absence:

0k0: k ± 2n

statistical analysis of the distribution of intensity and successful dissolution and refinement of the structure, and the following spatial group was determined:

P2 ₁ (# 4)

Data is collected at a temperature of from -100 ± 1 ° C to a maximum value of 2Θ 50.2 °. Data is collected at 0.50 ° fluctuations under 60.0 s. Data coverage is carried out using fluctuations from -18.0 to 23.0 ° at χ = -90.0 °. The second coverage is performed using vibrations ⌀ from 0.0 to 190.0 ° at χ = -90.0 °. The distance from the crystal to the detector is 39.68 mm. The detector deflection angle is -5.50 °.

Data reduction

Of the 7703 reflections that were collected, 3390 were unusual (R _int = 0.053, Friedels not absorbed); equivalent reflections are absorbed. Data is collected and processed using d * TREK ¹ . The exact intensities and sigma are obtained as follows.

]

F ² = [

]

where P _i represents the value in pulses of the i- ^th pixel,

m represents the number of pixels in the integration area,

B _ave is the background average,

Lp is a factor of Lorentz and polarization,

B _ave = (B _j ) / n

where n is the number of pixels in the background,

B _j is the value in counts j ^th pixel,

where erradd = 0.05,

errmul = 1.40.

The linear absorption coefficient μ for Mo-Kα radiation is 2.1 cm ⁻¹ . Empirical absorption correction is applied, which leads to transmission factors in the range of 0.73 to 1.00. The data are corrected for Lorentz and polarization effects.

Definition and refinement of the structure

The structure is determined by direct methods ² and distributed using Fourier methods ³ . Non-hydrogen atoms are specified anisotropically. This configuration was chosen based on the results of parallel refinement of both possible configurations and was additionally confirmed by the updated Flack indicator. The hydrogen atoms involved in the binding of hydrogen were specified isotropically, the rest were included in fixed positions. The final cycle of the full-matrix minimum quadratic refinement ⁴ by F ² was based on 3390 observed reflections and 242 variable parameters and converged (the largest parameter shift was 0.00 times its estimated value) for unweighted and weighted matching factors:

The standard deviation of ⁵ unit weight observation was 0.97. The weighting scheme was based on calculation statistics. The graphs of the interdependence w (| Fo | - | Fc |) ² and | Fo |, the order of reflection during data collection, the sine Θ / λ and various classes of indicators that did not show unusual trends. The maximum and minimum peaks on the Fourier map of the final difference corresponded respectively to 0.30 and -0.32 e ^- / ³ .

The scattering factors of neutral atoms were taken from Cromer and Waber ⁶ . Anomalous dispersion effects were included in Fcalc ⁷ ; Δf 'and Δf "values were Creagh and McAuley ^{8. The} effects of mass dilution coefficients were Greagh and Hubbell ^9. All calculations were performed using the teXsan ¹⁰ Molecular Structure Corporation crystallographic software package.

References

(1) d * TREK : Area Detector Software. Version 4.13. Molecular Structure Corporation. (1996-1998).

(2) SIR97 : Altomare, A., Burla, MC, Cammalli, G. Cascarano, M., Giacovazzo, C., Guagliardi, A, Moliterni, AGG, Polidori, G., Spagna, A. SIR97: a new tool for crystal structure determination andrefinement. (1990). J. Appl. Cryst. 32, 115-119.

(3) DIRDIF94 : Beurskens, PT, Admiraal, G., Beurskens, G., Bosman, WP, de Gelder, R., Israel, R. and Smits, JMM (1994). The DIRDIF-94 program system, Technical Report of the Crystallography Laboratory, University of Nijmegen, The Netherlands.

(4) Least Squares function minimized:

(5) Standard deviation of an observation of unit weight:

where: N _o = number of observations,

Ny = number of variables.

(6) Cromer, D. T. & Waber, J. T .; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974).

(7) Ibers, J. A. & Hamilton, W. C .; Acta Crystallogr., 17, 781 (1964).

(8) Creagh, D. C. & McAuley, WJ .; "International Tables for Crystallography", Vol C, (A.J. C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).

(9) Creagh, D. C. & Hubbell, IH ..; "International Tables for Crystallography", Vol C, (A.J. C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 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 C ₂₀ H ₃₂ NO ₄ Cl Mass of the formula 385.93 Crystal color, shape Clear plate crystal Crystal size 0.25 × 0.20 × 0.04 mm Crystal system monoclinic Type of grill primitive Lattice options a = 8.4333 (7) b = 9.4675 (9) c = 12.581 (1)

=93,125(7)°

= 93.125 (7) ° V = 1,003.0 (1) ³ Space group P2 ₁ (# 4) Z value 2 D _estimated 1.278 g / cm ³ F ₀₀₀ 416.00

(MOK

) 2.15 cm ^-1

B. Intensity measurements Detector ADSC Quantum 1 CCD Goniometer Rigaku afc7 Radiation

(

=0,71069)MOK

(

= 0.71069) monochromatic graphite Detector hole 94 mm × 94 mm Data Images 462 exposures @ 60.0 seconds

oscillation range (χ = -90.0) -18.0-23.0 °

oscillation range (χ = -90.0) 0.0-190.0 ° Detector position 39.68 mm Detector deflection angle -5.50 ° 2θ _max 50.2 ° Number of measured reflections Total: 7703 Fancy: 3390 (R _int = 0.053, not absorbed) Corrections Lorentz polarization Absorption / degradation / exfoliation
(transformation factors: 0.7295-1.0000)

C. Definition and refinement of the structure Structure definition Direct Methods (SIR97) Clarification Full matrix minimal quadratic in F ² Minimized Function

Minimum Quadratic Masses

Anomalous dispersion All non hydrogen atoms Number of observations (1> 0.00σ (I)) 3390 Number of Variables 242 Reflection / Parameter Ratio 14.01 Differences (adjusted by F ² , all data) 0,057; 0,082 Suitability indicator 0.97 The maximum shift / error in the final cycle 0.00 Number of observations (1> 3.00σ (I)) 2624 Differences (adjusted for F> 3.00σ (I)), R1; wR2) 0.033; 0,038 The maximum peak on the map of the final difference 0.30 e ^- / ³ Minimum peak on a finite difference map -0.32 e ^- / ³

X-ray structure of compound 1

The results of x-ray structural determination of compound 1 confirmed the absolute configuration and structural distribution in the form of (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride. According to the conclusion and the data of spectroscopic analyzes, the absolute configuration and structural distribution for compound 2, compound 3, compound 4, compound 5, compound 6 and compound 7 are accordingly confirmed.

Example 2

(1S, 2S) -2 - [(3R) -HYDROXYPYROROLIDINYL] -1- (3,4-DIMETHOXYPHENETOXY) CYCLOHEXANE MONOHYDROCHLORIDE (COMPOUND 2)

5SSR, (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane was prepared and dissolved in accordance with Example 1. Then, compound 2 was prepared from 5SSR using the procedure described above in Example 1 with respect to the preparation of compound 1.

Characteristic: Calculated for C ₂₀ H ₃₁ NO ₄ HCl: C 62.24, H 8.36, N 3.63; Found: C 62.20, H 8.46, N 3.55; [α] _D + 26.69 ° (c 13.04 g / l, CHCl ₃ )

Example 3

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (COMPOUND 3)

Preparation of Intermediates

7,40-7,30 (м, 5H), 5,10 (с, 2H), 4,40 (ушир.с, 1H), 3,60-3,40 (м, 4H), 2,80 (д, J=15 Гц, 1H), 2,00-1,90 (м, 2Н); ¹³C-ЯМР (50 МГц, APT, CDCl₃)

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 (пленка) 3415 (широкая), 1678 см^-1. N-benzyloxycarbonyl-3R-pyrrolidinol (1b) . To a cold (-60 ° C) solution of 1a (20.0 g, 225 mmol) and Et ₃ N (79 ml, 560 mmol) in CH ₂ Cl ₂ (200 ml) was added dropwise a solution of benzyl chloroformate (34 ml, 225 mmol) in CH ₂ Cl ₂ (80 ml). After complete addition within 45 minutes, the reaction mixture (yellow suspension) was allowed to warm to room temperature and stirred under argon atmosphere at room temperature overnight. Then the reaction mixture was quenched with 1M aqueous HCl (350 ml) and the organic layer was collected. The acidic aqueous layer was extracted with CH ₂ Cl ₂ (2 × 150 ml) and the combined organic layers were dried. Evaporation of the solvent in vacuo afforded 59.6 g of a pale yellow oil, which was then injected under high vacuum for 15 min to obtain 58.2 g (17% higher than theoretical yield) 1b, suitable for the next step without any further purification . R _f 0.42 (EtOAc- iso- PrNH ₂ , 98: 2, v / v); ¹ H-NMR (200 MHz, CDC1 ₃ )

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, 1H), 2.00-1.90 (m, 2H); ¹³ C-NMR (50 MHz, APT, CDCl ₃ )

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 .

7,40-7,30 (м, 5H), 5,20 (с, 2H), 3,90-3,80 (м, 4H), 2,60 (т, J=7 Гц, 2H); ¹³C-ЯМР (50 МГц, APT, CDCl₃)

136,0 (+), 128,5 (-), 128,0 (-), 67,0 (+), 52,5 (+), 42,5 (+), 36,5 (+); IR (пленка) 1759, 1708 см^-1 N-benzyloxycarbonyl-3-pyrrolidinone (1c). To a cooled (-60 ° C) solution of oxalyl chloride (23 ml, 258.6 mmol) in CH ₂ Cl ₂ (400 ml) was added dropwise a solution of DMSO (36.7 ml, 517.3 mmol) in CH ₂ Cl ₂ ( 20 ml) at such a rate as to maintain the temperature below -40 ° C. Then the reaction mixture was stirred at -60 ° C for 15 minutes. Then a solution of 1b (58.2 g, not more than 225 mmol) in CH ₂ Cl ₂ (80 ml) was added dropwise, keeping the temperature of the reaction mixture below -50 ° C. Then the reaction mixture was stirred at -60 ° C for 30 min before adding Et ₃ N (158.3 ml, 1, 125 mol). The resulting mixture was allowed to warm to room temperature and then washed with water (600 ml), 1M aqueous HCl (580 ml) and water (400 ml). The organic layer was dried and concentrated in vacuo to leave 54.5 g of amber oil, which was then injected under high vacuum with stirring at room temperature for 25 min to obtain 52 g (5.6% above theoretical yield) 1 s, suitable for the next step without any further cleaning. R _f 0.81 (EtOAc- iso- PrNH ₂ , 98: 2, v / v); ¹ H-NMR (200 MHz, CDCl ₃ )

7.40-7.30 (m, 5H), 5.20 (s, 2H), 3.90-3.80 (m, 4H), 2.60 (t, J = 7 Hz, 2H); ¹³ C-NMR (50 MHz, APT, CDCl ₃ )

136.0 (+), 128.5 (-), 128.0 (-), 67.0 (+), 52.5 (+), 42.5 (+), 36.5 (+); IR (film) 1759, 1708 cm ^-1

7,40-7,20 (м, 5H), 5,20 (с, 2H), 4,00 (с, 4H), 3,60-3,50 (м, 2H), 3,50-3,40 (м, 2H), 2,10-2,00 (м, 2H); ^l3C-ЯМР (50 МГц, APT, CDCl₃)

137,0 (+), 128,5 (-), 128 (-), 67,0 (+), 65,0 (+), 5,5 (+), 45,0 (+), 34,5 (+); IR (пленка) 1703 см^-1. 7-benzyloxycarbonyl-1,4-dioxa-7-azazpiro [4,4] nonane (1d). A mixture of 1c (52 g, not more than 225 mmol) and ethylene glycol (18.8 ml, 337.4 mmol) in toluene (180 ml) with a catalytic amount of para-TsOH · H ₂ O (1.0 g, 5.4 mmol) was refluxed in a Dean & Stark apparatus for 16 hours. Then, the reaction mixture was diluted with additional toluene (250 ml) and washed with saturated aqueous NaHCO ₃ (150 ml) and brine (2 × 150 ml). The combined aqueous layers were back extracted with toluene (100 ml). The combined organic layers were dried and concentrated in vacuo to leave 79.6 g of a dark oil. The crude product is dissolved in EtOH (500 ml) and, passing it through a layer of activated carbon (80 g), the resulting solution is discolored. Activated carbon is washed with additional EtOH (1000 ml) and toluene (500 ml). The filtrate was concentrated in vacuo and then pumped under high vacuum for 1 h to obtain 63.25 g (6.8% above theoretical yield) 1d suitable for the next step without any further purification. R _f 0.78 (EtOAc- iso- PrNH ₂ , 98: 2, v / v); ¹ H-NMR (200 MHz, CDCl ₃ )

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); ^l3 C-NMR (50 MHz, APT, CDCl ₃ )

137.0 (+), 128.5 (-), 128 (-), 67.0 (+), 65.0 (+), 5.5 (+), 45.0 (+), 34.5 (+); IR (film) 1703 cm ^-1 .

4,00 (с, 4H), 3,10 (т, J=7 Гц, 2H), 2,90 (с, 2H), 2,00 (т, J=7 Гц, 2H); ¹³C-ЯМР (50 МГц, APT, CDCl₃)

64,5 (+), 55,0 (+), 45,5 (+), 37,0 (+); IR (пленка) 3292 см^-1. 1,4-dioxa-7-azaspiro [4.4] nonane (1e). A mixture of 1d (34.8 g, not more than 124 mmol) and 10% Pd-C (14 g) in EtOH (90 ml) was hydrogenolized (60 psi) in a Steam shaker at room temperature for 1.5 h. The catalyst is filtered off, the solvent is evaporated off under vacuum and the residue is pumped up under high vacuum for 20 min to yield 1e (quantitative yield 15.9 g). R _f 0.14 (EtOAc- iso- PrNH ₂ , 95: 5 v / v); ¹ H-NMR (200 MHz, CDCl ₃ )

4.00 (s, 4H), 3.10 (t, J = 7 Hz, 2H), 2.90 (s, 2H), 2.00 (t, J = 7 Hz, 2H); ¹³ C-NMR (50 MHz, APT, CDCl ₃ )

64.5 (+), 55.0 (+), 45.5 (+), 37.0 (+); IR (film) 3292 cm ^-1 .

(1R, 2R) / (1S, 2S) -1- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) cyclohexan-2-ol (2e)

115,5 (+), 70,0 (-), 65,0 (-), 64,5 (+), 57,0 (+), 46,5 (+), 36,0 (+), 33,5 (+), 25,0 (+), 24,0 (+), 21,5 (+); IR (пленка) 3457 см^-1.A mixture of 1e (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 hours. Then the reaction mixture was partitioned between 40% aqueous NaOH ( 60 ml) and Et ₂ O (120 ml). The main aqueous layer was extracted twice more with Et ₂ O (2 × 120 ml). The combined organic extracts were dried and concentrated in vacuo. The residue was then heated under high vacuum at 50 ° C for 1 h with stirring (to remove excess cyclohexene oxide) to obtain 32.8 g of 2e (79% yield). R _f 0.33 (EtOAc- iso- PrNH ₂ , 98: 2 v / v); ¹³ C-NMR (50 MHz, APT, CDCl ₃ )

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 .

6,70 (м, 3H, Ar), 3,85 (2с, 6H, 2×CH₃O), 3,80-1,10 (м, 20H, алифатический); ¹³C-ЯМР (75 МГц, APT, свободное основание, CDCl₃)

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 (+); HRMC (EI) расчетная масса для C₂₀H₂₉O₄N: 347,20966, найдено: 347,21046 (21,1%); Анализ (C₂₀H₃₀O₄NCl) H, N; C: расчетная 62,57; найдено, С 60,32,(1R, 2R) / (1S, 2S) -1- [1,4-dioxa-7-azaspiro [4,4] non-7-yl] -2- (3,4-dimethoxyphenoxy) cyclohexane in Et ₂ O (80 ml) was treated with ethereal HCl. The solvent was evaporated in vacuo and the residue was collected with Et ₂ O and triturated. (1R, 2R) / (1S, 2S) -1- [1,4-dioxa-7-azaspiro [4,4] non-7-yl] -2- (3,4-dimethoxyphenoxy) cyclohexane monohydrochloride is precipitated from the mixture CH ₂ Cl ₂ -Et ₂ O. Solution (1R, 2R) / (1S, 2S) -1- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -2- (3 , 4-dimethoxyphenoxy) cyclohexane with 6M aqueous HCl (50 ml) in 2-butanone (200 ml) is refluxed for 12 hours. The butanone is evaporated in vacuo and the residual aqueous solution is diluted to 250 ml with water. The aqueous solution was extracted with Et ₂ O (2 × 200 ml) and then CH ₂ Cl ₂ (2 × 200 ml). The combined CH ₂ Cl ₂ extracts were dried and the solvent was evaporated in vacuo. The residual oil is azeotropically dried with toluene. The resulting sticky product was triturated with Et ₂ O (500 ml), the resulting solid was collected and solubilized in a small amount of CH ₂ Cl ₂ (ml), then the addition of a large amount of Et ₂ O (ml) triggered recrystallization. The solid is collected, dried in high vacuum for 3 hours to obtain (1R, 2R) / (1S, 2S) -1- (3,4-dimethoxyphenethoxy) -2- (3-ketopyrrolidinyl) cyclohexane monohydrochloride (compound 18) ( 1.9 g, 56% yield) ¹ H-NMR (400 MHz, free base, CDCl ₃ )

6.70 (m, 3H, Ar), 3.85 (2s, 6H, 2 × CH ₃ O), 3.80-1.10 (m, 20H, aliphatic); ¹³ C-NMR (75 MHz, APT, free base, CDCl ₃ )

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 (+); HRMC (EI) calculated mass for C ₂₀ H ₂₉ O ₄ N: 347.20966, found: 347.21046 (21.1%); Analysis (C ₂₀ H ₃₀ O ₄ NCl) H, N; C: estimated 62.57; Found, C 60.32,

PRODUCTION OF MONOHYDROCHLORIDE (1R, 2R) / (1S, 2S) -1- (3,4-DIMETHOXYPHENETOXY) 2- (3- (R / S) -HYDROXYpyrrolidinyl) Cyclohexane (COMPOUNDS 3)

6,80-6,70 (м, 3H, Ar), 4,20-1,10 (м, 22H, алифатический), 3,80 (2×с, 6H, 2×CH₃О); ^l3C-ЯМР (75 МГц, APT, свободное основание, CDCl₃)

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 (+), 28,76 (+), 27,09 (+), 27,03 (+), 23,30 (+), 23,22 (+), 22,92 (+), 22,86 (+); HRMC (EI) расчетная масса для C₂₀H₃₁N₂O: 349,22531, найдено: 349,22578 (100%); ВЭЖХ (Zorbax Extend С18, 150×4,6 мм 5

; 20-70% ацетонитрил: 10 мМ фосфатный буфер (ph 2,5)) 95,8%; CE 99,8%.To a cooled (0 ° C) suspension of sodium hydrochloride (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. The resulting mixture was stirred at 0 ° C for another 30 minutes and then allowed to warm to room temperature for 1 hour. The reaction mixture was again cooled to 0 ° C and slowly hydrolyzed with 1M aqueous HCl (80 ml). The reaction mixture was allowed to warm to room 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 × 150 ml) and dichloromethane (3 × 150 ml). The combined dichloromethane extracts were concentrated to 120 ml and treated with 0.25 M aqueous sodium hydroxide (100 ml). The aqueous layer was separated and extracted twice more with dichloromethane (2 × 150 ml). The combined dichloromethane extracts were dried over sodium sulfate and evaporated in vacuo. Purification by dry column chromatography (ethyl acetate -... to 4: 1 + 0.5% v / v isopropylamine) gives 2.0 g (36% yield) of the title compound as a free base. 1.9 g of the free base was partitioned between dichloromethane (24 ml) and 0.5 M aqueous HCl (24 ml). The aqueous layer was separated and extracted three more times with dichloromethane (3 × 24 ml). The combined dichloromethane extracts were dried over sodium sulfate and evaporated in vacuo. Azeotropic distillation with benzene (2 × 25 ml) and drying under high vacuum gave the title compound as an off-white hygroscopic solid (1.58 g). ¹ H-NMR (400 MHz, free base, CDCl ₃ )

6,80-6,70 (m, 3H, Ar), 4,20-1,10 (m, 22H, aliphatic), 3.80 (2 × with, 6H, 2 × CH ₃ O); ^l3 C-NMR (75 MHz, APT, free base, CDCl ₃ )

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 (+), 28.76 (+), 27.09 (+), 27.03 (+), 23.30 (+), 23.22 (+), 22.92 ( +), 22.86 (+); HRMC (EI) calculated mass for C ₂₀ H ₃₁ N ₂ O: 349.22531, found: 349.22578 (100%); HPLC (Zorbax Extend C18, 150 × 4.6 mm 5

; 20-70% acetonitrile: 10 mM phosphate buffer (ph 2.5)) 95.8%; CE 99.8%.

Example 4

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (COMPOUND 4)

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

Example 5

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (COMPOUND 5)

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

Example 6

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (COMPOUND 6)

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (compound 6) was prepared according to the method of Example 1, but starting from 3- (S) -hydroxypyrrolidine.

Example 7

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (COMPOUND 7)

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (compound 7) is prepared according to the methods of Examples 1 and 2, but starting from 3- (S) - hydroxypyrrolidine.

Reference Example 8

(1R, 2R) / (1S, 2S) -1- (3,4-dimethoxyphenethoxy) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) cyclohexane monohydrochloride (compound 9 )

To a cooled (0 ° C.) solution of 2e (4.62 g, 20 mmol) and triethylamine (2.64 g, 26 mmol) in dichloromethane (40 ml) was added dropwise methanesulfonyl chloride (3.0 g, 26 mmol). The reaction mixture was stirred at 0 ° C. for 45 minutes and then at room temperature for 2 hours. The reaction mixture was then washed with a mixture of aqueous sodium bicarbonate saturated with water (1: 1 v / v, 30 ml). The aqueous layer was collected and back extracted with dichloromethane (2 × 30 ml). The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give a crude mesylate suitable for the next step without any further purification.

To 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 room temperature for 2 hours.

The mesylate in DME (40 ml) was quickly added to the alkoxide and the resulting mixture was refluxed in an argon atmosphere for 20 hours. The cooled reaction mixture was quenched with water (60 ml) and the organic solvent was evaporated in vacuo. The residual aqueous solution was acidified with 10% aqueous HCl to a pH of 0.3 and extracted with diethyl ether (2 × 75 ml). The aqueous layer was collected, the basicity was increased to pH 7.0 with 5M aqueous NaOH and extracted with diethyl ether (3 × 70 ml). The combined diethyl ether extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give 7.1 g (89% yield) of the title compound as a free base.

6,75 (м, 3H, Ar), 3,86-1,16 (м, 24H, алифатический); ¹³C-ЯМР (75 МГц, APT, свободный амин, CDCl₃)

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 (+); HRMC (EI) расчетная масса для С₂₂Н₃₃NO₅: 391,23587, found: 391,23546 (100%); ВЭЖХ (Zorbax Extend C18, 150×4,6 мм, 5

; 20-7-% ацетонитрил:10 мМ фосфатный буфер (pH 2,5)) 84,2%; CE 98,5%.Free amine (0.58 g, 1.48 mmol) was partitioned between dichloromethane (8 ml) and 0.5 M aqueous HCl (8 ml). The aqueous layer was collected and extracted twice more with dichloromethane (2 × 8 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 0.62 g (98% yield) of the title compound. R _f 0.13 (EtOAc-hexanes, 1: 4 v / v, + 0.5% v / v PrNH ₂ ); ¹ H-NMR (400 MHz, free amine, CDCl ₃ )

6.75 (m, 3H, Ar); 3.86-1.16 (m, 24H, aliphatic); ¹³ C-NMR (75 MHz, APT, free amine, CDCl ₃ )

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 (+); HRMC (EI) Estimated Mass for C ₂₂ H ₃₃ NO ₅ : 391.23587, Found: 391.23546 (100%); HPLC (Zorbax Extend C18, 150 × 4.6 mm, 5

; 20-7-% acetonitrile: 10 mM phosphate buffer (pH 2.5)) 84.2%; CE 98.5%.

Reference Example 9

(1R, 2R) / (1S, 2S) -1- (3,4-dimethoxyphenethoxy) -2- (pyrrolidinyl) cyclohexane monohydrochloride (compound 10)

70,47 (-), 64,82 (-), 47,44 (+), 33,15 (+), 25,11 (+), 24,23 (+), 24,00 (+), 21,12 (+).Pyrrolidine (10.5 g, 148 mmol), cyclohexane oxide (15 ml, 148 mmol) and water (5 ml) are refluxed in a nitrogen atmosphere for 7 hours. The cooled orange mixture is partitioned between saturated aqueous sodium hydroxide ( 150 ml) and diethyl ether (150 ml). The aqueous solution was washed with a reverse stream of diethyl ether (75 ml) and the combined layers of diethyl ether were dried over sodium sulfate. Diethyl ether was removed in vacuo, the residual oil was distilled in vacuo (bp 51 ° C under full vacuum) to obtain (1R, 2R) / (1S, 2S) -2- (pyrrolidinyl) cyclohexan-1-ol (21.9 g, 87%). ¹³ C-NMR (50 MHz, APT, CDCl ₃ )

70.47 (-), 64.82 (-), 47.44 (+), 33.15 (+), 25.11 (+), 24.23 (+), 24.00 (+), 21 , 12 (+).

To a cooled (0 ° С) solution of (1R, 2R) / (1S, 2S) -2- (pyrrolidinyl) cyclohexan-1-ol (1.7 g, 10 mmol), triethylamine (1.9 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 minutes and then allowed to warm to room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2 × 50 ml). The combined washings were back extracted with dichloromethane (50 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded the crude mesylate suitable for the next step without any further purification.

To NaH (0.33 g, 11 mmol) in DME (20 ml) was added a solution of 3,4-dimethoxyphenethyl alcohol (2.0 g, 11 mmol) in DME (15 ml). The resulting mixture was then stirred for 2 hours at room temperature under argon.

11,60 (ушир.с, 1H, HN⁺), 6,70 (м, 3H, Ar), 3,80 (2×д, 2×6H, CH₃O), 3,70-1,05 (м, 22H, алифатический); ¹³C-ЯМР (75 МГц, APT, CDCl₃)

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 (+); МС (+LCIMC) М⁺+H 334 (100%); Анализ (C₂₀H₃₂O₃NCl) H, N; C: расчетная, 64,94; найдено, 63,04.The mesylate in DME (20 ml) was added to the alkoxide and the resulting mixture was refluxed for 3 hours. The solvent was evaporated in vacuo, the residue was taken up in water (100 ml) and the pH was adjusted to pH 1 with 1 M aqueous HCl. The acidic aqueous solution was then extracted with diethyl ether (100 ml) and the pH adjusted to pH 13. Extraction with diethyl ether (2 × 100 ml) gave the free base of the title compound. Treatment with ether hydrochloride followed by filtration in diethyl ether gave 1.0 g (27% yield) of the title compound as hydrochloride. ¹ H-NMR (400 MHz, CDCl ₃ )

11.60 (br s, 1H, HN ⁺ ), 6.70 (m, 3H, Ar), 3.80 (2 × d, 2 × 6H, CH ₃ O), 3.70-1.05 ( m, 22H, aliphatic); ¹³ C-NMR (75 MHz, APT, CDCl ₃ )

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 (+ LCIMC) M ⁺ + H 334 (100%); Analysis (C ₂₀ H ₃₂ O ₃ NCl) H, N; C: calculated, 64.94; found, 63.04.

Reference Example 10

(1R, 2R) -1- (3 (R) -acetyloxypyrrolidinyl) -2- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (compound 17)

Acetyl chloride (5 ml; 70.31 mmol) is added dropwise to the solution of the free base (3R) -1 - {(1R, 2R) -2- [2- (3,4-dimethoxyphenylethoxy) cyclohexyl} pyrrolidin-3-ol ( 2.12 g; 5.49 mmol) in methylene chloride (50 ml) at 1 ° C. The reaction mixture was allowed to reach room temperature overnight. The reaction is monitored by TLC and visualized with iodine. R _f (1R, 2R) -1- (3 (R) -acetyloxypyrrolidinyl) -2- (3,4-dimethoxyphenethoxy) cyclohexane is 0.36 in methanol-methylene chloride (0.5: 95 v / v) . Excess acetyl chloride and solvent are removed under reduced pressure, and DCM (dichloromethane) (30 ml) is added to the remaining mixture. The organic layer was washed with saturated sodium bicarbonate solution (30 ml), dried over magnesium sulfate and concentrated to give free base acetate (1.3 g, 4.35 mmol) in 61% yield.

Reference Example 11

(1R, 2R) / (1S, 2R) -1- (3 (R / S) -hydroxypyrrolidinyl) -2- (1-naphthalenethoxy) cyclohexane monohydrochloride (compound 25)

Preparation of Intermediate

(1R, 2S) / (1S, 2R) -1- (3-ketopyrrolidinyl) -2- (1-naphthalenethoxy) cyclohexane monohydrochloride

To a flask containing Mg (ClO ₄ ) ₂ (2.14 g, 0.95 mmol) after vacuum flame drying and filled with argon, a solution of 1-naphthalenethanol (21.6 g, 125 mmol) in CH ₃ CN ( 15 ml). The resulting mixture was boiled in a vessel under reflux until all the material had dissolved, and then cyclohexene oxide (1.0 g, 10 mmol) was added over a period of 2.5 hours. Then, the reaction mixture was boiled in a vessel under reflux in for 16 hours, cooled to room temperature and partitioned between water (150 ml), saturated aqueous NaHCO ₃ (50 ml) and Et ₂ O (100 ml). The aqueous layer was collected and extracted twice with Et ₂ O (2 × 100 ml). The combined Et ₂ O extracts were washed with a reverse brine (50 ml), dried and concentrated in vacuo to give 25.2 g of crude material, which solidified after standing. The excess 1-naphthalenethanol is recovered by sequential recrystallization in Et ₂ O-hexane (1: 1 v / v). The final mother liquor (7.5 g) obtained after 3 recrystallizations was purified by chromatography using a mixture of EtOAc-hexanes (1: 5 v / v, + 0.5% v / v iso-PrNH ₂ ) to provide 1.5 g (55% yield) of crude (1R, 2R) / (1S, 2S) -2- (1-naphthalenethoxy) cyclohexan-1-ol, which is used in the next step without further purification.

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 (пленка) 1720 см^-1.To a suspension of pyridinium chlorochromate (RCC) (4.78 g, 22.2 mmol) in CH ₂ Cl ₂ (35 ml), a solution of (1R, 2R) / (1S, 2S) -2- (1-naphthalenethoxy) cyclohexane is immediately added -1-ol (1.5 g, 5.5 mmol) in CH ₂ Cl ₂ (5 ml). The resulting dark brown mixture was stirred at room temperature for 16 hours and then filtered through a plug of silica gel coated with Na ₂ SO ₄ . Then, the plug was washed with Et ₂ O (3 × 40 ml) and the filtrate was concentrated in vacuo to obtain 2.0 g of crude material. The crude material was applied to a dry silica gel column and eluted with EtOAc-hexanes (1: 6 v / v, + 0.5% v / v iso-PrNH ₂ ) to obtain 1.0 g (2R / 2S) - 2- (1-naphthalenethoxy) cyclohexan-1-one (68% yield). ¹³ C-NMR (50 MHz, APT, CDCl ₃ )

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 cm ^-1 .

12,53 (ушир.с, 1H, HN⁺), 8,06-7,32 (м, 7H, AT), 4,05-1,16 (м, 20H, алифатический); ¹³C-ЯМР (75 МГц, APT, CDCl₃)

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 (+); HRMC (EI) масс-анализ, (C₂₂H₂₈NO₂Cl) С, Н, N.(2R, 2S) -2- (1-naphthalenethoxy) 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) in benzene (10 ml) was refluxed in a Dean-Stark apparatus for 5 hours. The cooled reaction mixture was then quickly transferred to a Parr shaker, Pd on activated carbon (0.2 g) was added and the mixture hydrogenated for 16 hours. The catalyst was removed by filtration, the filtrate was concentrated in vacuo, and the obtained crude material (cis-trans, 87:13, area% / GC) was purified by dry column chromatography with a mixture of EtOAc-hexanes (1: 2 v / v) vol., + 0.5% vol./about. iso-PrNH ₂ ) to provide 1.0 g (70% yield) (1R, 2S) / (1S, 2R) -1- (1,4-dioxo-7-azaspiro [4.4] non-7- il) -2- (1-naphthalenethoxy) cyclohexane, which is refluxed with 6M aqueous HCl (20 ml) in 2-butanone (80 ml) for 16 hours. The cooled reaction mixture is concentrated in vacuo and the residue diluted with water (90 ml). Then the aqueous solution was extracted with Et ₂ O (2 × 50 ml) and CH ₂ Cl ₂ (3 × 70 ml). The combined CH ₂ Cl ₂ extracts were dried and the solvent was evaporated in vacuo. Powder grinding in Et ₂ O provides (1R, 2S) / (1S, 2R) -1- (3-ketopyrrolidinyl) -2- (1-naphthalenethoxy) cyclohexane monohydrochloride (0.82 g, 84% yield), melting point 176-178 ° C; ¹ H-NMR (400 MHz, CDCl ₃ )

12.53 (br s, 1H, HN ⁺ ), 8.06-7.32 (m, 7H, AT), 4.05-1.16 (m, 20H, aliphatic); ¹³ C-NMR (75 MHz, APT, CDCl ₃ )

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 (+); HRMC (EI) mass analysis, (C ₂₂ H ₂₈ NO ₂ Cl) C, H, N.

PRODUCTION (COMPOUNDS 25) OF (1R, 2S) / (1S, 2R) MONOHYDROCHLORIDE -1- (3- (R / S) -HYDROXYPYROROLIDINYL) -2- (1-NAPHTHALINETOXY) CYCLOHEXANE

10,30 (ушир.с, 1H, HN⁺), 8,10-7,30 (м, 7H, Ar), 5,40-1,00 (м, 22H, алифатич.); ¹³C-ЯМР (75 МГц, APT, CDCl₃)

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 (+); МС (EC+) М⁺+H 340,1 (100%); ВЭЖХ (Zorbax Extend C18, 150×4,6 мм, 5

; 20-70% ацетонитрил: 10 мМ фосфатный буфер (pH 2,5)) 96,7%; CE 98,7%.To a solution of (1R, 2S) / (1S, 2R) -1- (3-ketopyrrolidinyl) -2- (1-naphthalenethoxy) cyclohexane monohydrochloride (0.55 g, 1.5 mmol) in isopropanol (15 ml) is added in portions sodium borohydride (0.3 g, 7.9 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with 6M aqueous HCl (4 ml) for 2 hours and then concentrated in vacuo. The residual solid was collected with dichloromethane (20 ml), the insoluble material was filtered off and washed again with dichloromethane (20 ml) and the combined filtrates were treated with ether hydrochloride (20 ml). The solvents were evaporated in vacuo and the residual oil was triturated with diethyl ether (80 ml) to obtain 0.32 g (57% yield) of a ¹ H-NMR absorbent solid (400 MHz, CDCl ₃ )

10.30 (br s, 1H, HN ⁺ ), 8.10-7.30 (m, 7H, Ar), 5.40-1.00 (m, 22H, aliphatic); ¹³ C-NMR (75 MHz, APT, CDCl ₃ )

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 (EC +) M ⁺ + H 340.1 (100%); HPLC (Zorbax Extend C18, 150 × 4.6 mm, 5

; 20-70% acetonitrile: 10 mM phosphate buffer (pH 2.5)) 96.7%; CE 98.7%.

Reference Example 12

(1R, 2R) / (1S, 2S) -2- (4-morpholinyl) -1- (2-naphthenethoxy) cyclohexane monohydrochloride

(Compound 30)

(i) Morpholine (5 ml, 57 mmol), cyclohexane oxide (5.8 ml, 57 mmol) and water (3 ml) are refluxed for 1.5 hours. GC analysis shows the completeness of the reaction. The cooled mixture was partitioned between saturated NaOH solution (50 ml) and ether (75 ml). The aqueous layer was washed with a reverse stream of ether (30 ml) and the combined ether layers were 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, purified by vacuum distillation (bp 75-80 ° C under full vacuum) to obtain a clear liquid (8.7 g) . Yield 82.5%.

(ii) To a cooled (0 ° C) solution of (1R, 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) is added via cannula. The addition was completed after 10 minutes, the reaction mixture was stirred for another 45 minutes at 0 ° C. and then at room temperature for 4 hours. The dichloromethane mixture was washed with water (2 × 50 ml) and the combined aqueous washings were extracted with a reverse stream of dichloromethane (50 ml) ) The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 8.5 g (100% yield) of crude mesylate.

(iii) To a sodium hydride, 80% oil dispersion, pre-washed with hexanes (3 × 20 ml), (1.24 g, 51.6 mmol) in dry dimethylformamide (50 ml), a solution of 2-naphthenethanol (6, 8 g, 40 mmol) in dry dimethylformamide (50 ml). The addition is followed by evolution of gas, and as the reaction mixture is stirred at room temperature, it begins to gel. The mesylate obtained in step (ii) above is dissolved in dimethylformamide (50 ml), and the resulting solution is quickly added via cannula to the alcoholate suspension. The reaction mixture is heated to 80 ° C and then the temperature is reduced to 40 ° C. The resulting yellow solution was poured into ice water (1500 ml) and extracted with ethyl acetate (3 × 300 ml). The combined organic extracts were washed back with a saturated aqueous solution of sodium chloride (500 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo provides 13.4 g of amber oil, which is dissolved in water (150 ml) and the pH of the solution is adjusted to pH 2 with aqueous 1M HCl. The acidic aqueous solution was extracted with ethyl ether (2 × 100 ml) and then the basicity was increased to pH 10 with a 50% aqueous sodium hydroxide solution. The basic aqueous solution was extracted with diethyl ether (2 × 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 7.16 g of the crude free amino ether. The crude product is purified by silica gel 60 chromatography (70-230 mesh) with ethyl acetate-chloroform (1: 1 v / v) as an eluent to yield 4.37 g of pure free base. The product was dissolved in ethyl ether (80 ml) and converted to monohydrochloride by adding a saturated solution of HCl in ethyl ether (80 ml). The oil leaves the solution, the solvent is evaporated in vacuo and the residue is dissolved in a minimum amount of warm ethyl alcohol, the addition of a large volume of ethyl ether starts crystallization. Crystals were collected to obtain 3.83 g (31% yield) of the title compound, melting point 158-160 ° C.

Reference Example 13

(1R, 2R) / (1S, 2S) -2- (4-morpholinyl) -1- (4-bromophenethoxy) cyclohexane monohydrochloride

(Compound 32)

(i) The starting trans-aminocyclohexanol was prepared according to comparative example 12.

(ii) A chilled (0 ° C) solution of (±) trans- [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) is added via cannula. The addition was completed after 5 minutes, the reaction mixture was stirred for another 1 hour at 0 ° C and then at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2 × 50 ml) and the combined washings were extracted reverse flow of dichloromethane (25 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 4.7 g of crude mesylate.

(iii) To a sodium hydride, 80% oil dispersion, pre-washed with hexanes (3 × 10 ml), (0.62 g, 25.8 mmol) in dry dimethylformamide (25 ml), a solution of 4-bromophenethyl alcohol is added via cannula (4, 0 g, 20 mmol) in dimethylformamide (50 ml). The addition is followed by evolution of gas, and the reaction mixture is stirred at room temperature for 4 hours. The mesylate obtained in step (ii) above is dissolved in dry dimethylformamide (50 ml) and the resulting solution is quickly (3 minutes) added via cannula to the alcoholate suspension . The reaction mixture was heated to 80 ° C. for 2 hours, then the temperature was reduced to 35 ° C. and the reaction mixture was stirred overnight. The reaction mixture was poured into ice water (800 ml) and extracted with ethyl acetate (3 × 200 ml). The combined organic extracts were washed back with a saturated aqueous solution of sodium chloride (150 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo provided 7.4 g of an oil which was dissolved in ether (80 ml) and treated with a saturated solution of HCl in ether. The oil leaves the solution, the solvent is evaporated off in vacuo and the residue is dissolved in water (100 ml). The acidic aqueous solution was extracted with simple ethyl ether (2 × 50 ml) and then the basicity was increased to pH 10 with a 50% aqueous sodium hydroxide solution. The basic aqueous solution was extracted with ethyl ether (2 × 50 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 3.67 g of the crude free amino ether. The crude product is purified by silica gel 60 chromatography (70-230 mesh) with ethyl acetate-dichloromethane (1: 1 v / v) as eluent to provide a clear, free base. The product was dissolved in ethyl ether (30 ml) and converted to monohydrochloride by adding a saturated solution of HCl in ethyl ether (30 ml). The solvent is evaporated and the residue is dissolved in a minimum amount of ethyl alcohol, the addition of a large volume of ethyl ether starts crystallization. Crystals were collected to obtain 1.31 g of the title compound, melting point 158-160 ° C.

Reference Example 14

(1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride (Compound 41)

(vi) To a cooled (0 ° C) solution 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) are added methanesulfonyl chloride (12.32 ml, 156 mmol). The reaction mixture was stirred at 0 ° C. for 45 minutes and then at room temperature for 3 hours. The reaction mixture was washed with water (2 × 100 ml) and the combined washings were extracted with a reverse stream of dichloromethane (120 ml). The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to yield the crude mesylate, which was then pumped under high vacuum for 4 hours before use in the step (ix) below.

(vii) 2,6-dichlorophenethyl alcohol : in a suspension of lithium aluminum hydride (13.75 g, 365.75 mmol) in anhydrous diethyl ether (500 ml), 2,6-dichlorophenylacetic acid (50) is added via a funnel to add powder g, 243.75 mmol). The resulting reaction mixture was refluxed for 16 hours and then quenched by the slow addition of an aqueous saturated sodium sulfate solution (25 ml). The resulting suspension was stirred for 3 hours and then filtered, the insoluble matter was washed carefully with diethyl ether (2 × 100 ml). The combined ether filtrates were dried over sodium sulfate and the solvent was evaporated in vacuo to give 38.6 g (85% yield) of the title compound.

(viii) To a sodium hydride (144 mmol, 4.32 g, 80% oil dispersion) in anhydrous ethylene glycol dimethyl ether (80 ml) was added a solution of 2,6-dichlorophenethyl alcohol (27.65 g, 144 mmol) in anhydrous simple ethylene glycol dimethyl ether (80 ml). The resulting mixture was stirred at room temperature under argon for 4 hours.

(ix) (1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4,4] non-7-yl] -1- (2,6-dichlorophenethoxy) cyclohexane : The mesylate from step (vi) in anhydrous ethylene glycol dimethyl ether (80 ml) was quickly added to the alkoxide mixture (viii) and the resulting mixture was immediately refluxed for 66 hours in a vessel. The cooled reaction mixture was poured into water (200 ml) and the organic solvent was evaporated in vacuo. The residual aqueous solution was diluted with additional water to a volume of 700 ml, acidified to pH 0.5 with 6M aqueous HCl and extracted with diethyl ether (2 × 600 ml). The pH of the aqueous layer was adjusted to pH 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 (yield 70%).

(x) Monohydrochloride (1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane : Mixture (1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (2,6-dichlorophenethoxy) cyclohexane (15.85 g, 38.9 mmol, step ix) and 6M aqueous solution HCl (100 ml) in 2-butanone (400 ml) was refluxed for 16 hours. The cooled reaction mixture was diluted with water (100 ml) and the organic solvent was evaporated in vacuo. The organic layer was further diluted with water (400 ml), extracted with diethyl ether (500 ml) and dichloromethane (2 × 600 ml). The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. Azeotropic distillation with toluene afforded the title compound, which was further dried under high vacuum for 15 minutes. The hydrochloride is crystallized by trituration in diethyl ether, the crystals are collected and recrystallized from a mixture of ethanol-diethyl ether to obtain 11.85 g of pure product (yield 77%) having the correct elemental analysis.

Reference Example 15

(1R, 2R) / (1S, 2S) -2- (3-acetoxypyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane monohydrochloride

(Compound 43)

(i) Monohydrochloride (1R, 2R) / (1S, 2S) -2- (3-hydroxypyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane : To a cooled (0 ° C) solution of sodium borohydride in isopropanol (20 ml) was added a solution of monohydrochloride (1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane (1.4 g, 3.75 mmol) in isopropanol (30 ml). The resulting mixture was stirred at 0 ° C for 15 minutes and then 30 minutes at room temperature. The reaction was quenched by addition of water, the reaction mixture was evaporated to dryness and the residue was washed with dichloromethane (2 × 20 ml). The dichloromethane washes were dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound.

(ii) (1R, 2R) / (1S, 2S) -2- (3-acetoxypyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane monohydrochloride :

The intermediate alcohol (i) is then refluxed in acetic anhydride (15 ml) for 2 hours. Excess acetic anhydride is removed in vacuo; the residue was collected with water (100 ml) and extracted with diethyl ether (2 × 30 ml). The basicity of the aqueous solution was raised to pH 8.0 and extracted with diethyl ether (3 × 50 ml). The combined organic extracts were 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 start crystallization of 1.0 g (65% yield) of the title compound.

Reference Example 16

MONOHYDROCHLORIDE (1R, 2R) / (1S, 2S) -2- (3-THIAZOLIDINYL) -1- (2,6-Dichlorophenethoxy) Cyclohexane (COMPOUND 48)

(i) (1R, 2R) / (1S, 2S) -2- (3-thiazolidinyl) cyclohexanol : A solution of cyclohexene oxide (6.1 ml, 58 is added to anhydrous magnesium perchlorate (12.93 g, 53.3 mmol) , 6 mmol) in anhydrous acetonitrile (25 ml) and the resulting mixture was stirred at room temperature for 20 minutes. Then, a solution of thiazolidine (5.16 g, 55.0 mmol) in anhydrous acetonitrile 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 again with diethyl ether (350 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give a crude product. The crude amino alcohol was purified by dry column chromatography with ethyl acetate-hexane (1: 1 v / v) as eluent to give 4.83 g (47% yield) of the title compound.

(ii) To a cooled (0 ° C) solution of (1R, 2R) / (1S, 2S) -2- (3-thiazolidinyl) cyclohexanol (3.17 g, 16.9 mmol) and triethylamine (3.08 ml, 22.0 mmol) in dichloromethane (30 ml), methanesulfonyl chloride (1.74 ml, 22.0 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C. for another 1 hour and then at ambient temperature for 3 hours. The reaction mixture was diluted with dichloromethane (20 ml) and washed with water (2 × 30 ml). The combined washings were extracted with a reverse stream of dichloromethane (25 ml), and the combined organic extracts were dried over sodium sulfate. Evaporation of the solvent in vacuo gives the mesylate suitable for the next step without any further purification.

(iii) To a sodium hydride, 80% oil dispersion (608 mg, 20.28 mmol) in ethylene glycol dimethyl ether (30 ml) was added a solution of 2,6-dichlorophenethyl alcohol (3.87 g, 20.28 mmol, example 4 step vii) in ethylene glycol dimethyl ether (15 ml). The resulting mixture was stirred at room temperature under argon for 2 hours.

(iv) monohydrochloride (1R, 2R) / (1S , 2S) -2- ( 3-thiazolidinyl) -1- (2,6-dihlorfenetoksi) cyclohexane: The mesylate (ii) in ethylene glycol dimethyl ether (15 mL) was added rapidly alkoxide (iii) and the reaction mixture is refluxed for 40 hours. The cooled reaction mixture is poured into water (100 ml) and the organic solvent is evaporated in vacuo. The residual aqueous solution was diluted with an additional amount of water (100 ml) and the pH was adjusted to pH 1.5. The acidic aqueous solution was extracted with diethyl ether (3 × 100 ml), the combined organic extracts were dried over sodium sulfate. The product was purified by dry column chromatography with a mixture of ethyl acetate-hexane (1:10 v / v) as eluent to obtain 2.4 g of a crude free amino ester. The pure product (1.0 g) was converted to the hydrochloride by treatment with ethereal HCl and the resulting salt was recrystallized from a mixture of acetone-diethyl ether to give 0.69 g of the title compound.

Reference Example 17

MONOHYDROCHLORIDE (1R, 2R) / (1S, 2S) -2- (3-KETOPYROLIDINYL) -1- (2,2-DIPHENYLETOXY) CYCLOGEXANE (COMPOUND 47)

(vi) To a cooled (0 ° C) solution of (1R, 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) are added methanesulfonyl chloride (0.9 ml, 11.44 mmol). The reaction mixture was stirred at 0 ° C. for 45 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (25 ml), washed with water (2 × 25 ml) and the combined washings were extracted with a reverse stream of dichloromethane (25 ml) . The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give a crude mesylate, which was then pumped under high vacuum for 30 minutes before being used in the step (ix) below.

(vii) ( 2,6-diphenyl) ethyl alcohol : in lithium aluminum hydride (2.85 g, 23.56 mmol) in anhydrous diethyl ether (150 ml), diphenylacetic acid (5.0 g, 56 mmol). The resulting reaction mixture was carefully boiled in a vessel under reflux for 1 h. The reaction was quenched with saturated aqueous sodium sulfate and the resulting precipitate was filtered off. The filtrate was concentrated in vacuo to give 4.0 g (86% yield) of the title compound.

(viii) To a sodium hydride previously washed with hexanes (253 mg, 10.56 mmol) in a suspension in ethylene glycol dimethyl ether (15 ml), 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 argon for 30 minutes.

(ix) (1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (2,2-diphenylethoxy) cyclohexane : Mesylate from stage (vi) in ethylene glycol dimethyl ether (20 ml) is quickly added to the alkoxide (viii) and the reaction mixture is boiled in a reflux vessel for 5 days. The cooled reaction mixture was concentrated in vacuo, the residue was collected with water (50 ml), and the pH was adjusted to pH 1.0 with an aqueous solution of 6 M HCl. The acidic aqueous solution was extracted with diethyl ether (2 × 50 ml), the aqueous layer was collected and the basicity was increased to pH 6.0. Extraction with diethyl ether (2 × 50 ml) followed by drying over sodium sulfate and evaporation of the solvent in vacuo afforded 1.55 g (43% yield) of the title compound.

(x) Monohydrochloride (1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,2-diphenylethoxy) cyclohexane : Mixture (1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (2,2-diphenylethoxy) cyclohexane (1.55 g, 3.8 mmol) in 6M HCl-butanone (1: 4 vol./about., 50 ml) is boiled in a vessel under reflux for 2 hours. Butanone is evaporated in vacuo and the residue is collected with water (50 ml). The aqueous solution was extracted with diethyl ether (2 × 50 ml); the aqueous layer was collected and extracted with dichloromethane (2 × 50 ml). The combined dichloromethane extracts were dried over sodium sulfate and concentrated in vacuo to give the crude title compound. The product was crystallized by trituration in diethyl ether and reprecipitated from a mixture of dichloromethane-diethyl ether to give 1.21 g (80% yield) of the title compound having the correct elemental analysis.

General experimental procedures

Melting points were determined on a Fisher-Johns instrument and are presented without correction. NMR spectra were obtained in the indicated solvent on Brucker AC-200, Varian XL-300, Brucker AV-300 or AV-400 instruments. Mass spectra were recorded for EI on a Kratos MS50 instrument, for FAB / LSIMS on a Kratos Concept IIHQ instrument and for ES on a Micromass (Waters) Quattro (I) MSMS instrument connected to an HP1090 Series 2 LC (Agilent), adjustable version 3.3 Masslynx software. Elemental analyzes were performed on an Element Analyzer 1108 D. & H. Malhow, University of Alberta, Edmonton, AB. When analyzes are indicated only by element symbols, analytical results were within ± 0.4% of theoretical values. In cases where elemental analyzes were not available, purity was determined by HPLC and capillary electrophoresis (CE). HPLC analyzes were performed using a Gilson HPLC system (Gilson, Middleton, WI) with UV detection at 200 nm. Used column C _{18 with a} size of 150 × 4.6 mm with a particle size of 5 microns. The mobile phase was delivered isocratically or in the form of a gradient at a low rate of 1 ml / min, and it consisted of a combination of phosphate buffer (low or high pH) and acetonitrile. Samples were obtained at μg / ml in the mobile phase and 20 μl were injected into HPLC. Purity was expressed as% of area. CE analyzes were performed using a P / ACE System MDQ device (Beckman Coulter, Fullerton, CA). Used uncoated capillaries of silicon dioxide with a length of 60 (50 to the detector) cm and an inner diameter of 75 μm. The working buffer used was 100 mM sodium phosphate (pH 2.5). The separation voltage was either 23 or 25 kV (normal polarity), and the temperature of the capillary cartridge was maintained at 20 ° C. Samples (5 mg / ml in water) were injected with a pressure of 0.5 psi for 6 s. Detection was performed by UV at 200 or 213 nm. The frequency was expressed in% of the area. Infrared spectra 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 performed on aluminum sheets of TLC E. Merck 20 × 20 cm, Silica gel plates 60 F ₂₅₄ . Flash chromatography ^{41 was} performed on silica gel 60 EM Science (70-230 mesh). Dry flash chromatography ⁴² was performed Sigma silica gel type H. Chromatotron chromatography (Harrison Research, USA) was performed on 4 mm plate of silica gel EM Science 60P F ₂₅₄ calcium sulfate or oxide 60P F ₂₅₄ aluminum sulfate, calcium (type E). Preparative HPLC was performed on a Waters Delta Prep 4000 cassette column (sprinkled, 10 μm, 125 U, 40 mm × 100 mm). GC analyzes were performed on a Hewlett Packard HP 6890 equipped with an HP-35 capillary column (cross-linked 35% PH IU siloxane) 30 m × 0.25 mm × 0.25 μm and a flame ionization detector. High boiling point solvents (DMF, DMSO) were Sure / Seal ^™ from Aldrich, and tetrahydrofuran (THF) and ethylene glycol dimethyl ether (DME) were distilled from sodium benzophenone ketyl. Unless otherwise indicated, the organic extracts were dried with Na ₂ SO ₄ . All moisture-sensitive reactions were carried out in dried glassware under nitrogen or argon.

Biological Activity Data

Evaluation of antiarrhythmic efficacy

Antiarrhythmic efficacy can be assessed by examining the effect of the compound on the incidence of cardiac arrhythmias in anesthetized rats subjected to coronary artery occlusion. Rats weighing 200-300 g were subjected to preparatory operations and included in the groups by random sampling. In each case, the animal is anesthetized with pentobarbital during surgical preparation. The left carotid artery is cannulated to measure mean arterial pressure and take blood samples. The left jugular vein is also cannulated for drug injection. The chest cavity is opened and a polyethylene noose is freely placed around the left anterior descending coronary artery. Then the chest cavity is sutured. ECG record the introduction of electrodes placed along the anatomical axis of the heart. By randomization and a double-blind method, infusion of the vehicle or compound to be tested is performed approximately 15 minutes after surgery. After infusion for 5 min, the stranglehold is tightened so as to cause 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 scored in accordance with Curtis, M.J. and Walker, M.J.A., Cardiovasc. Res. 22: 656 (1988) (see table 1).

Table 1 Scoring Description 0 0-49 VPB one 50-499 VPB 2 > 499 VPB and / or 1 episode of spontaneously transient VT or VF 3 > 1 episode of VT or VF, or both (total combined duration> 60 s) four VT or VF or both (total combined duration 60-119 s) 5 VT or VF or both (total combined duration> 119 s) 6 Fatal VF starting> 15 min after occlusion 7 Fatal VF starting between 4 min and 14 min 59 s after occlusion 8 Fatal VF starting between 1 min and 3 min 59 s after occlusion 9 Fatal VF starting less than 1 min after occlusion

Where:

VPB = ventricular extrasystoles

VT = ventricular tachycardia

VF = ventricular fibrillation

Rats were excluded from the study if serum potassium concentrations in the serum were not within the range of 2.9 to 3.9 mM before occlusion. Occlusion is associated with an increase in the height of the tooth R and the rise of "S-T"; and the occluded zone (measured after cardiac green dye perfusion) was not in the range of 25% to 50% of the total left ventricular mass.

The test results of the compounds can be expressed as values of a given infusion rate in µmol / kg / min. (ED ₅₀ AA), which will reduce the arrhythmia score in treated animals to 50% of the level seen in animals treated only with a vehicle in which the test compound (s) is dissolved.

In table 4, column 6 shows the result of the determination of ED ₅₀ AA tests of compounds 1-7 in accordance with the invention in μmol / kg / min Table 5, column 6, shows the result of the determination of ED ₅₀ AA tests of the compounds of comparative examples 8-48 in µmol / kg / min.

Measurement of the effects on the cardiovascular system and behavior

The preparatory operation is performed in Sprague Dawley rats weighing 200-300 g and anesthetized with pentobarbital at a dose of 65 mg / kg (intraperitoneally). The femoral artery and vein cannulated using a tube (PE) -10. Before surgery, this PE-10 tube is annealed by attaching to a tube of a wider caliber (PE-50) for outward withdrawal. The cannulation tube RE-10 / RE-50 is passed through the trocar and brought out together with three (II leads) ECG leads from the limbs (see below). The trocar is sewn under the skin of the back and brought out through a small incision in the interscapular region. An ECG ground electrode is injected subcutaneously using a 20 gauge needle with a lead wire threaded through it. To place other ECG electrodes, a small incision is made in the region of the anterior wall of the chest cavity above the heart and ECG leads are inserted into the subcutaneous muscle layer in the region of the heart using a 20 gauge needle. Other ECG leads are injected into the subcutaneous muscle layer near the base of the neck and shoulder (on the right side). The animal is returned to a clean cage for recovery with free access to food and water. The treatment and observation period for each animal began after a 24-hour recovery period.

A 15-minute observation period is recorded, followed by an intravenous infusion of the test compound at a minimum dose of 2.0 μmol / kg / min (at a rate of 1 ml / h). This speed is doubled every 5 minutes until one of the following effects is observed:

a) partial or complete convulsions

b) severe arrhythmias

c) bradycardia below 120 beats / min

d) hypotension below 50 mmHg

e) the dose is 32 times higher than the initial, initial dose (i.e. 64 μmol / kg / min).

Blood pressure (BP), heart rate (HR) and ECG parameters are continuously recorded, while also behavioral reactions and the total cumulative dose and rate of infusion of the drug are monitored, at which a reaction occurs (such as convulsions, piloerection, ataxia, anxiety, compulsive chewing movements, smacking lips, shaking, etc.).

Blood samples

The plasma concentration of the test compound is determined by taking 0.5 ml of a blood sample at the end of the experiment. Blood samples are centrifuged for 5 min at 4600 × g and the plasma is decanted. Brain tissue samples were also extracted and kept frozen (-20 ° C) along with plasma samples for chemical analysis.

Data analysis

Electrocardiographic (ECG) indicators: PR, QRS, QT ₁ (peak of the T wave), QT ₂ (midpoint of the T wave deviation) and hemodynamic parameters: blood pressure and heart rate are analyzed using the automatic analysis function in LabView (National Instruments) with adapted autoanalysis software (Nortran Pharmaceuticals). Determine the infusion dose giving 25% control (D ₂₅ ) for all recorded ECG values.

The test results can be expressed as D ₂₅ (μmol / kg), which are the doses required to cause an increase in the measured ECG by 25%. Increases in the PR interval and the QRS interval indicate blockade of the cardiac sodium channels, while an increase in the QT interval indicates blockade of the cardiac potassium channels.

ELECTROPHYSIOLOGICAL TEST (IN VIVO)

This experiment determines the activity of the test compound with respect to its effects on hemodynamic and electrophysiological parameters in the absence of ischemia.

Methods

Surgical preparation

Male Sprague-Dawley rats weighing 250-350 g are used. They are randomly selected from the same group and anesthetized with pentobarbital (65 mg / kg ip) with the addition of an additional anesthetic if necessary.

The trachea is cannulated and the rat is ventilated with a tidal volume of 10 ml / kg and a frequency of 60 cycles / min. The right external jugular vein and the left carotid artery are cannulated, respectively, for intravenous injection of compounds and registration of blood pressure (BP).

The needle electrodes are subcutaneously inserted along the implied anatomical axis (from the right atrium to the apex) of the heart to measure ECG. The upper electrode is placed at the level of the right clavicle about 0.5 cm from the midline, while the lower electrode is placed on the left side of the chest at 0.5 cm from the midline at the level of the ninth rib.

Teflon-coated two silver electrodes are inserted through the wall of the chest cavity, using 27G needles as guides and implanted into the pericardium of the left ventricle (at a distance of 4-5 mm from each other). Stimulation by square-wave pulses is provided by a computer-controlled stimulator. Own software is used to determine the following indicators: threshold current (iT) for the induction of extrasystoles, maximum subsequent frequency (MFF), effective refractory period (ERP) and ventricular flutter threshold (VTt). In short, iT is measured as the minimum current (in μA) of the square-wave stimulus required to capture pulses and set the heart rate with a frequency of 7.5 Hz and a pulse width of 0.5 ms; ERP represents the minimum delay (in ms) for the second stimulus required to induce an extrasystole when a rhythm is imposed on the heart with a frequency of 7.5 Hz (1.5 × iT and a pulse width of 0.2 ms), MFF represents the maximum frequency stimulation (in Hz), in which the heart is unable to follow stimulation (1.5 × iT and a pulse width of 0.2 ms); VTt is the minimum pulse current (in μA) for triggering a persistent VT episode (pulse width 0.2 ms and 50 Hz) (Howard, PG and Walker, MJA, Proc. West. Pharmacol. Soc. 33: 123-127 (1990 )).

Blood pressure (BP) and electrophysiological (ECG) readings are recorded and analyzed using LabView (National Instruments) with adapted autoanalysis software (Nortran Pharmaceuticals Inc.) to calculate mean blood pressure (mmHg, 2/3 diastolic + 1/3 systolic blood pressure), heart rate (contractions / min, 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 absence of the Q wave on the rat ECG, to the peak of the S wave), QT (in ms, the interval from the beginning of the R wave to the peak T wave).

Experiment Log

The initial dose of infusion is selected based on a preliminary study of the toxicology of the test compound in awake rats. This is the dose of the infusion, which did not create a change of 10% from the level of hemodynamic or ECG parameters before administration of the drug.

The animal is left to stabilize before treatment by infusion in accordance with a given random sampling and blind method. Initial infusion treatment is started at a rate of 0.5 ml / h / 300 g (i.e. 0.5 μmol / kg / min). Each dose of the infusion is doubled (in speed) every 5 minutes. All experiments were completed at 32 ml / h / 300 g (i.e. 32 μmol / kg / min). Electrical stimulation protocols are started for at least 2 minutes at each infusion level.

Data analysis

Reactions to test compounds are calculated as changes as a percentage of values before infusion; this normalization is used to reduce individual variation. The average values of blood pressure and ECG values immediately before the period of electrical stimulation (i.e., 3 minutes after infusion) are used to construct cumulative dose-response curves. Data points are selected using best fit lines with a minimum residual sum of squares (minimum squares; Slide Write program; Advanced Graphics Software, Inc.). D ₂₅ (infused dose, which caused a 25% change in value before infusion) is interpolated from individual dose-response curves used as indicators for determining the activity of the compounds of the present invention.

VAGUS AF DOG MODEL

GENERAL METHODS

Outbred dogs of both sexes with a body weight of 15-49 kg are anesthetized with morphine (initially 2 mg / kg intramuscularly followed by intravenous administration of 0.5 mg / kg every 2 hours) and α-chloralose (120 mg / kg intravenously, followed by infusion 29, 25 mg / kg / h; St. Georges et al., 1997). Dogs undergo artificial ventilation of the lungs with room air with the addition of oxygen through an endotracheal tube with a frequency of 20-25 breaths / min with a tidal volume obtained from the nomogram. Measure gases in arterial blood and maintain in the physiological range (SAO ₂ > 90%, pH 7.30-7.45). Catheters are inserted into the femoral artery to record blood pressure and measure blood gases and into both femoral veins to administer drugs and take venous blood samples. Catheter patency is supported by a heparinized 0.9% saline solution. Body temperature is maintained at 37-40 ° C with a warming blanket.

The heart is exposed with a median thoracotomy and a pericardial substrate is created. 3 bipolar stainless steel electrodes coated with Teflon ^™ are inserted into the right atrium for registration and stimulation, and one is inserted into the ear of the left atrium for registration. A programmed stimulator (Digital Cardiovascular Instruments, Berkeley, Calif.) Is used to stimulate the right atrium with 2 ms pulses twice the diastolic threshold. 2 Teflon ^™ coated stainless steel electrodes are inserted into the left ventricle, 1 for registration and 1 for stimulation. On-demand ventricular electrical stimulator (GBM 5880, Medtronics, Minneapolis, MN) is used to stimulate the ventricles at a rate of 90 contractions / min, when (especially during vagal AF), the ventricular contraction rate became too slow. An A P23 ID transducer, an electrophysiological amplifier (Bloom Associates, Flying Hills, PA) and a paper writer (Astromed MT-95000, Toronto, ON, Canada) are used to record II and III ECG leads, atrial and ventricular electrograms, blood pressure and a stimulation artifact . Vagus nerves are secreted around the neck, twice ligated and cut, and 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 intravenously, followed by intravenous administration of 0.25 mg / kg every 2 hours.

Atrial fibrillation model

Evaluate the effects of drugs in terms of stopping persistent AF, maintained during continuous vagus nerve stimulation. Unipolar hook electrodes (stainless steel, insulated Teflon ^TM , coated, except for the distal segment 1-2 cm), are inserted through a 21 gauge needle inside and parallel to the trunk of each nerve. In most experiments, unipolar stimuli are fed with a stimulator (model DS-9F, Grass Instruments, Quincy, MA) installed to deliver 0.1 ms square-wave pulses with a frequency of 10 Hz and a potential difference of 60% of the potential difference required to cause systole. Some experiments use bipolar stimulation. The potential difference required to cause asystole ranged from 3 to 20 volts. Under control conditions, a short flash of rapid atrial stimulation (10 Hz, 4 times the diastolic threshold) is given in order to induce AF, which usually lasts for more than 20 minutes. Vagal stimulation voltage was adjusted under control conditions and then reconfigured after each treatment to maintain the same bradycardic effect. AF is defined as fast (> 500 / min under control conditions), an irregular atrial rhythm with a changing morphology of the electrogram.

Measurement of electrophysiological parameters and vagal reaction

The diastolic threshold current is determined at a main cycle length of 300 ms by a progressive increase in current of 0.1 mA until a stable pulse capture is obtained. For subsequent protocols, the current is set at a level twice the diastolic threshold. Atrial and ventricular ERP is measured by the additional stimulus method in the range of S1S2 intervals with a base cycle length of 300 ms. Premature additional stimulus S2 is applied every 15 basic stimuli. The S1S2 interval is increased by increments of 5 ms until the capture of pulses occurs during the longest S1S2 interval, which is consistently unable to cause a widespread reaction determining ERP. The diastolic threshold and ERP are determined in duplicate and averaged to obtain 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 indicator of the speed of the conduction. AF cycle length (AFCL) is measured during vagal AF by counting the number of cycles (number of contractions - 1) over a 2-second interval in each of the atrial recording sites. An average of three AFCL measurements is obtained to obtain a total average AFCL for each experimental condition.

The relationship between stimulus voltage and heart rate for vagus nerve stimulation is determined under control conditions in most experiments. The vagus nerves are stimulated, as described above, at various voltage levels to determine the voltage that caused the asystole (defined as a sinus pause of more than 3 s). The response to vagus nerve stimulation is confirmed under each condition of the experiment and the voltage is corrected to maintain a constant heart rate response to vagus nerve stimulation. In cases in which it is not possible to cause asystole, vagus nerve stimulation is corrected to a voltage that provides the ability to maintain two 20-minute episodes of vagal AF under control conditions (see below).

Experiment Logs

One of the studied experimental groups is summarized in table 3. Each dog was administered only one drug at the doses indicated in table 3. The first series of experiments was experiments in which studies were carried out to determine the range of doses followed by a blind study, in which 1- 3 doses. All preparations are administered intravenously through an infusion pump in solutions of preparations in plastic containers freshly prepared on the day of the experiment. Vagal stimulation indices were determined under control conditions, as described above, and confirm the maintenance of AF for 20 minutes of vagus nerve stimulation under control conditions. After the end of AF, the diastolic threshold and atrial and ventricular ERP are determined. Subsequently, these indicators are re-evaluated in the atrium under conditions of vagus nerve stimulation. Electrophysiological testing usually took 15-20 minutes. Confirm the heart rate response to vagus nerve stimulation and repeat the vagal AF / electrophysiological testing protocol. A blood sample is obtained before drug administration and vagal AF is started again. After 5 minutes, one of the treatments is carried out in the doses shown in Table 2. The total dose is poured over 5 minutes and a blood sample is obtained immediately afterwards. Maintenance infusion is not performed. If AF ceased within 15 minutes, repeat the electrophysiological measurements obtained under control conditions and obtain a blood sample. If AF does not stop with the first dose (within 15 minutes), a blood sample is obtained and vagal stimulation is stopped to allow a return to sinus rhythm. Electrophysiological measurements are repeated, a third and final blood sample is obtained for this dose. Resume AF and vagal AF / drug infusion / electrophysiological test protocol is repeated until the drug stops AF.

Statistical analysis

Group data are expressed as mean ± SEM (standard error of the mean). Statistical analysis was performed for effective doses for AFCL and ERP using the t-test with Bonferroni correction for multiple comparisons. The effects of the drug on blood pressure, heart rate, diastolic threshold and ECG intervals at a median dose to terminate AF are evaluated. Bilateral tests are used and p <0.05 is taken as an indicator of statistical significance.

table 2
Experimental groups and doses of drugs A drug Tested dose range (μmol / kg) Effective doses for termination of AF (μmol / kg) The average dose required to terminate AF (μmol / kg) The median dose required to terminate AF (μmol / kg) Flecainide 1.25-10 4-2.5; 1-10 4 ± 2 2,5

One drug was administered to each dog in a specific dose range until AF stopped. Shows the number of dogs in which AF was discontinued at each dose (number of dogs per dose in µmol / kg). Shown is the average ± SEM, as well as the median dose required to terminate AF. Each dog received only one drug.

The compounds of the present invention can be evaluated in this way. The efficacy of flecainide as a control in this study was comparable to that reported previously.

Dog sterile pericarditis model

This model was used to characterize AF mechanisms and atrial flutter (AFL). Waldo and coworkers found that AF is dependent on arousal circulation and that the cessation site is usually a delayed area. A model for dogs is obtained by sprinkling an exposed area with talcum powder, followed by a “flash” of electrical stimulation of this area for a period of several days after recovery. AF can be triggered 2 days after surgery, but by day 4 after surgical preparation, the prevailing induced rhythm is sustained atrial flutter. The possibility of AF induction on day 2 is somewhat variable, so only 50% of dogs can have persistent AF (in general, <60 min) at the required 30 min. However, the supported atrial flutter, which occurs by the 4th day, can be caused with most drugs. Atrial flutter is easier to "map" in order to identify drug mechanisms. The possibility of inducing AF decreases after the 4th day after surgery, similar to AF, which often develops after heart surgery, which mimics a model of sterile pericarditis. There may be an inflammatory component involved in the etiology of postoperative AF, which would provide a degree of selectivity for ischemia or an acid-selective drug. Similarly, although aorto-coronary artery bypass grafting (CABG) surgery is performed to relieve ventricular ischemia, such patients may be at risk for mild atrial ischemia due to coronary heart disease (CHD). Although atrial infarction rarely occurs, there was a link between arterial stenosis of the atrioventricular node and AF risk after CABG surgery. Surgical interruption of autonomic atrial vegetation may also play a role in AF after CABG.

Methods

Studies are carried out on a model of sterile pericarditis in dogs to determine the activity and effectiveness of the compounds of the present invention in the cessation of atrial fibrillation / atrial flutter. Atrial flutter or atrial fibrillation was caused 2-4 days after the creation of sterile pericarditis in adult purebred dogs with a body weight of 19 kg to 25 kg. In all cases, atrial fibrillation or atrial flutter lasted more than 10 minutes.

Creating a model of atrial fibrillation / atrial flutter in sterile pericarditis

A model of sterile pericarditis is created as previously described. During surgery, a pair of stainless steel wire electrodes coated with FEP polymer, with the exception of the tip (O Flexon, Davis and Geck), is sutured to the ear of the right atrium, Bachman bundle and the posterior-lower surface of the left atrium near the proximal part of the coronary sinus. The distance between each electrode of each pair is approximately 5 mm. These wire electrodes are brought out through the chest wall and carried posteriorly into the interscapular region for subsequent use. At the end of the operation, the dogs are given antibiotics and analgesics and then given the opportunity to recover. Postoperative care included the administration of antibiotics and analgesics.

In all dogs, starting from the second day after surgery, an attempt is made to cause sustained atrial fibrillation / atrial flutter during wakefulness without the introduction of sedatives to confirm the possibility of induction and resistance of atrial fibrillation / atrial flutter and to test the effectiveness of the drugs. Atrial electrical stimulation is performed through electrodes sewn during the initial operation. On the 4th day after surgery, when sustained atrial flutter is caused, a study is performed with an open chest cavity.

For open chest studies, each dog is anesthetized with pentobarbital (30 mg / kg intravenously) and 100% oxygen is ventilated using the Boyle Model 50 Anesthesia Machine (Harris-Lake, Inc.). The body temperature of each dog was maintained within the normal physiological range during the study with a heating pad. In a dog in an anesthetized state, but before opening the chest cavity, radiofrequency destruction of the His bundle is performed to create a complete atrioventricular (AV) blockade using standard electrode catheter techniques. This is done to minimize the imposition of atrial and ventricular complexes during subsequent recordings of unipolar atrial electrograms after induction of atrial flutter. After creating a complete AV block, the effective ventricular contraction rate is supported by electrical stimulation of the ventricles at a frequency of 60 to 80 pulses / min with a Medtronic 5375 Pulse Generator (Medtronic Inc.) for delivering stimuli through electrodes sewn to the right ventricle during the initial operation.

Determination of stimulus thresholds and refractory periods during electrical stimulation

One of the two previously described methods is used to induce AF / AFL: (1) delivering 1 or 2 premature atrial contractions after a series of 8 electrical stimulation-induced atrial contractions with a cycle length of 400 ms, 300 ms, 200 ms or 150 ms, or (2) rapid electrical stimulation of the atria for periods of 1 to 10 s at frequencies that are accelerated by 10-50 contractions / min, compared with a spontaneous sinus rhythm until atrial flutter is caused or there is no 1: 1 loss of retrograde propagation pulse on pre Cerda. Electrical stimulation of the atria is performed either from the electrodes of the ear of the right atrium, or the posterior-lower surface of the left atrium. All electrical stimulation is performed using stimuli twice the threshold for each main sequence of stimulating pulses with a modified, programmable, battery-powered Medtronic 5325 stimulator with a pulse width of 1.8 ms.

After the induction of persistent atrial fibrillation / flutter (lasting more than 10 minutes), the duration of the cycle of atrial fibrillation / flutter is measured and initial mapping and analysis are performed to determine the localization of the circulating excitation of atrial fibrillation / flutter. Atrial flutter is defined as a fast atrial rhythm (frequency> 240 beats / min), characterized by a constant duration of the interval between contractions, polarity, morphology and amplitude of recorded bipolar electrograms.

Drug Performance Testing Protocol

1. Effective refractory periods (ERP) are measured from three sites: the right atrium (RAA), the posterior surface of the left atrium (PLA) and the Bachman bundle (BB) for two main cycle times of 200 and 400 ms.

2. Electrical stimulation for the induction of atrial fibrillation or atrial flutter. Attempts are made within 1 hour. If arrhythmia is not caused, further research is not carried out on this day.

3. If AF is triggered, then it should be maintained for 10 minutes. Then a waiting period is allowed for a spontaneous cessation or for 20 minutes, whichever comes first.

4. Then AF is called again, and before starting the infusion of the drug provide a waiting period of 5 minutes

5. Then the drug is infused as a bolus for 5 minutes.

6. If AF is stopped by the first dose, a blood sample is taken and ERP measurements are repeated.

7. The drug is given the opportunity to terminate AF within 5 minutes If cessation does not occur, then a second dose is administered within 5 minutes.

8. After termination of AF and measurement of ERP, a second attempt is made to re-invoke AF within a period of 10 min.

9. If AF is recalled and lasts for 10 minutes, a blood sample is taken and the test is repeated from the above 3.

10. If re-induction does not occur, then the study ends.

The compounds of the present invention can be evaluated in this way.

Blockade pain assessment

CD-1 mice (20-30 g) are immobilized in an appropriate holder. The turnstile is placed at the base of the tail and a test compound solution (50 μm, 5 mg / ml) is injected into the lateral tail vein. The turnstile is removed 10 minutes after the injection. Suitable dilutions of a solution of the compound are used to prepare an ED ₅₀ for blocking pain at various points in time after injection. Pain reactions are evaluated by pricking the pins at regular intervals up to 4 hours after injection and the duration of pain block is recorded for three animals for each solution of the test compound. The compounds of the present invention can be evaluated in accordance with the described method.

EVALUATION OF IN VITRO INHIBITING ACTIVITY OF COMPOUNDS MODULATING ION CHANNELS WITH RESPECT TO VARIOUS HEART ION CURRENTS

Cell culture:

Relevant cloned ion channels (e.g., cardiac hH1Na, Kv1.4, Kv1.5, Kv4.2, Kv2.1, HERG, etc.) are examined by transient transfection into HEK cells using the mammalian expression vector pCDNA3. Transfections for each type of channel are carried out separately to enable individual studies of the ion channel of interest. Cells expressing the channel protein are detected by co-transfection of cells with a pHook-1 vector (Invitrogen, San Diego, CA, USA). This plasmid encodes the production of anti-phOX hapten antibody, which, when expressed, appears on the cell surface. Equal concentrations of a single channel and pHook DNA were incubated with 10 × concentration of lipofectAce in a modified Eagle medium (MEM, Canadian Life Life Technologies) and incubated with parental HEK cells seeded on 25 mm culture plates. After 3-4 hours, the solution is replaced with standard culture medium plus 20% fetal calf serum and 1% antimycotic. Transfected cells seeded on glass coverslips were maintained at 37 ° C in an incubator filled with air / 5% CO ₂ in 25 mm Petri dishes for 24-48 hours to allow for channel expression. 20 minutes before the experiments, cells are treated with phOX coated beads. After 15 minutes, excess beads are washed off with cell culture medium and cells that have beads adhered to them are used for electrophysiological tests.

Solutions:

To register the entire cell, the control pipette-filled solution contained (in mM): KCl, 130; EGTA, 5; MgCl ₂ , 1; HEPES, 10; Na ₂ ATP, 4; GTP, 0.1; and the pH was adjusted to a pH of 7.2 KOH. The control solution of the bath contained (in mm): NaCl, 135; KCl, 5; sodium acetate, 2.8; MgCl ₂ , 1; HEPES, 10; CaCl ₂ , 1; and the pH was adjusted to pH 7.4 with NaOH. The test compound modulating the ion channels is dissolved to the mother liquor with a solution of 10 mM in water and used in concentrations from 0.5 to 100 μM.

Electrophysiological procedures :

Coverslips containing cells were removed from the incubator before experiments and placed in a superfusion chamber (250 μl volume) containing a control bath solution at 22-23 ° C. All recordings are made using a potential clamp technique using an Axopatch 200A amplifier (Axon Instruments, CA). The applied electrodes are drawn from thin-walled borosilicate glass (World Precision Instruments; FL) on a horizontal micropipette extractor, polished in a fiery flame and filled with appropriate solutions. The electrodes have a resistance of 1.0-2.5 μOhm when filled with a control fill solution. Analogue capacitive compensation is used for all whole cell measurements. In some experiments, leak subtraction is applied to the data. Membrane potentials do not correct for any potentials arising in the compounds that arise between the pipette and the solution in the bath. Data is filtered at 5-10 kHz before digital conversion and stored in a microcomputer for later analysis using pClamp6 software (Axon Instruments, Forster City, CA). Due to the high level of expression of cDNA channels in HEK cells, signal averaging is not necessary. The average capacitive resistance of the cell is quite small, and the absence of ion current at negative membrane potentials allows accurate subtraction of leakage data.

Data Analysis :

The curves of the dependence of the reaction on concentration for changes in the maximum and steady current produced by the test compound by a computer are approximated to the Hill equation:

f = 1-1 / [1+ (IC ₅₀ [D]) ⁿ ] [1]

where f is the fractional current (f = Idrug / Icontrol) at the concentration of the drug [D]; IC ₅₀ is the concentration that provides half the maximum inhibition, and n is the Hill coefficient.

The compounds of the present invention can be evaluated in this way. The results show that the tested compounds of the present invention have varying degrees of effectiveness in blocking various ion channels. The block is determined by reducing the maximum current hH1 Na ⁺ , or stationary Kv1.5 and the integrated current in the presence of the drug. To record the Na ⁺ current, the cells are depolarized from a holding potential of -100 mV to a potential difference of -30 mV for 10 ms to completely open and inactivate the channel. To detect the current Kv1.5 and Kv4.2, the cells are depolarized from a holding potential of -80 mV to a potential difference of +60 mV for 200 ms to completely open the channel. Currents are recorded in a stationary state in the range of drug concentrations during stimulation every 4 s. Decrease in maximum current (Na ⁺ channel), stationary current (channel Kv1.5) or integrated current (Kv4.2) with a test potential of -30 mV (Na ⁺ channel), or +60 mV (channel Kv1.5 and Kv4.2 ) normalize to the control current, then plotted against the concentration of the test compound. Data are averaged over 4-6 cells. Solid lines approximate data using the Hill equation. The IC ₅₀ values for some of the compounds of the present invention for the various ion channels studied are summarized in the following table (table 3):

Table 3 Compound Kv1.5 hERG Kv4.2 H1Na Kv2.1 one 3.2 7 fifty 18.6 2 6 twenty 36,4 3 5 35 30.3 6 6 twenty 25,4 8 6 35 37,2

Similarly, the activity of other compounds of the present invention can be investigated in the modeling of various ionic currents of interest.

Risk assessment of proarrhythmia (flutter-ventricular fibrillation) with the introduction of compounds modulating the channels in primates

Methods

General surgical preparation :

All studies are carried out on males Macaca fascicularis with a body weight of 4 to 5.5 kg. Animals starve overnight and are given ketamine (10 mg / kg intramuscularly) as a sedation. Both large saphenous veins of the lower extremities cannulate and establish a dropper with saline to maintain the patency of the arteries. Halotane anesthesia (1.5% in oxygen) is carried out through the facial mask. To facilitate intubation, irrigation with lidocaine (10% aerosol) is used. After reaching a sufficient depth of anesthesia, the animals are intubated with a 4 or 5 gauge endotracheal tube. After intubation, halothane is introduced through the endotracheal tube and the concentration is reduced to 0.75-1%. Artificial lung ventilation is not used and all animals continue to breathe spontaneously throughout the experiment. Blood gas concentration and blood pH are measured using a blood gas analyzer (AVO OPTI I). The femoral artery is cannulated to record blood pressure.

Blood pressure and a modified II ECG lead are recorded using a MACLAB 4S recorder paired with a Macintosh PowerBook (2400c / 180). The sampling frequency of 1 kHz is used for both signals and all data is archived on a Jazz disk for subsequent analysis.

Vagus nerve stimulation :

Each of the vagus nerves is secreted by blunt 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 with a frequency of 20 Hz with a pulse width of 1 ms, delivered from the MACLAB stimulator. The voltage (range 2-10 V) is adjusted to obtain the desired bradycardic response. The target bradycardia reaction is to reduce the heart rate by half. In cases where a sufficient bradycardial reaction cannot be obtained, 10 μg / kg of neostigmine is administered intravenously. This dose of neostigmine is also administered after administration of the test drug in cases where the test drug has vagolytic effects.

Test compounds :

The nearly maximum tolerated bolus dose of a test compound infused (intravenously) for 1 minute is used to assess the risk of ventricular flutter-fibrillation caused by each test compound. Actual doses vary slightly depending on the weight of the animal. Clofilium, 30 μmol / kg, is used as a positive comparison (control) for these studies. The expectation is that a high dose of the drug will lead to a high incidence of arrhythmias. Test compounds are dissolved in saline immediately prior to administration.

Experiment Log :

Each animal receives one dose of this drug intravenously. Before the start of the experiment, 2 30-second episodes of vagus nerve stimulation are recorded. A 5-minute rest period is allowed between episodes and before the experiment. The test solution is administered as an intravenous bolus at a rate of 5 ml / min for 1 min using an infusion pump (total volume 5 ml). ECG and blood pressure reactions are monitored continuously for 60 minutes and the incidence of arrhythmias is noted. The vagus nerve is stimulated for 30 s at the following time points after drug injection: 30 s, 2, 5, 10, 15, 20, 25, 30, and 60 minutes.

Blood samples (with a total volume of 1 ml) are taken from each treated animal at the following time points after drug administration: 30 s, 2, 5, 10, 20, 30 and 60 minutes, as well as 3, 6, 24 and 48 hours. blood samples taken up to 60 min after administration are arterial, while samples taken after this time are venous. Samples are centrifuged, the plasma is decanted and frozen. Samples are kept frozen before analysis of the plasma concentration of the drug and potassium.

Statistics :

The effects of the drugs on blood pressure, heart rate and ECG intervals are described as mean ± SEM for group size "n".

Compounds of the present invention can be evaluated by this method.

Determination of toxicity in relation to the central nervous system

To evaluate in vivo activity of compounds acting on ion channels, it is important to know the maximum tolerated dose. In the present study, CNS toxicity was evaluated by examining the minimum dose of a compound that causes partial or complete convulsions in awake rats. The procedure avoids the use of mortality as an outcome, and also avoids unnecessary suffering, as the experiment is terminated if animal suffering seems likely. If the drug causes a life-threatening condition (for example, severe hypotension or cardiac arrhythmias), animals are killed by an overdose of pentobarbital.

Rats weighing 200-250 g are anesthetized with a pentobarbital anesthetic and subjected to preparatory surgery. The femoral artery is cannulated to measure blood pressure and take blood samples. The femoral vein is cannulated for drug injection. ECG leads are introduced into the subcutaneous muscle layer in the region of the heart and the area near the base of the neck and shoulder. All cannulas and ECG leads are brought out into the interscapular region. Anesthetics and local anesthetics are used to relieve postoperative pain. Animals are returned to the cells for recovery at least 24 hours before the start of the experiment. Infusion of the compound was then started through the cannula in the femoral vein. The initial infusion rate is set to 2.0 μmol / kg / min at a speed of 1 ml / h. The infusion rate is doubled every minute until partial or complete seizures are observed. The maximum infusion rate used is 64 μmol / kg / min. Speeds are continuously monitored and the end time of the infusion is noted.

Table 4, column 4 describes the test results of the compounds described herein in terms of a given infusion rate in μmol / kg / min (convulsive dose), which is the minimum infusion rate at which partial or complete convulsions are observed. Table 4, column 5 presents the test results for the described compounds in the form of cumulative convulsive dose values, which is the total amount of the drug poured into the point in time when partial or complete convulsions are first observed.

Similarly, table 5, column 4 describes the test results for the compounds of the comparative example described here as the given infusion rate in µmol / kg / min (convulsive dose), which is the minimum infusion rate at which partial or complete convulsions are observed . Table 5, column 5 presents the test results for the compounds described in the comparative example in the form of cumulative convulsive dose values, which is the total amount of drug injected at the point in time when partial or complete convulsions are first observed.

DEFINITION OF THE THERAPEUTIC INDICATOR

The therapeutic index for compounds 1-7 (table 4) in accordance with the invention and compounds of comparative experiments 8-49 (table 5) are calculated using the following formula:

Cumulative convulsive dose / (20 × ED ₅₀ AA)

In tables 4 and 5, column 7 presents the calculated value for the therapeutic indicator of the compounds described here.

Table 4 Compound No. Structure Chemical name Convulsive dose (μmol / kg / min) Cum.
Convulsive dose (μmol / kg) ED ₅₀ AA (μmol / kg / min) Therapeutic indicator * one

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 64 507 1.4 18.1 2

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 64 500.67 1,2 20.9 3

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 64 502 1.3 19.3 four

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 64 502 0.8 31,4 5

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 64 438 0.7 31.3 6

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 64 472.24 1,6 14.8 7

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 64 451.67 0.9 25.1

As shown in Table 4 above, the compounds of the present invention having a specific dimethoxyphenyl ethoxy group at position 1 of the cyclohexyl ring and a hydroxypyrrolidine group at position 2 of the cyclohexyl ring exhibit low CNS toxicity along with high antiarrhythmic activity. The above experimental results clearly indicate the compounds of the present invention for the effective treatment of arrhythmias. Whereas compounds 8-22 of comparative examples containing only a specific dimethoxyphenyl ethoxy group at position 1 of the cyclohexyl ring and compounds 23-29 of comparative examples having only a specific hydroxypyrrolidine group at position 2 of the cyclohexyl ring also exhibit higher CNS toxicity, and together with the lower the antiarrhythmic activity when compared with the compounds of the present invention (compounds 1-7 shown in table 4). Accordingly, the therapeutic indicators of the compounds of the present invention are much better. Additional compounds 30-48 of the comparative example correspond to the examples described in WO 99/50225. Test results with these compounds again showed higher CNS toxicity along with lower antiarrhythmic activity than the compounds of the present invention.

Table 5 Compound no. an example Structure Chemical name Convulsive dose (μmol / kg / min) Cum.
Convulsive dose (μmol / kg) ED ₅₀ AA (μmol / kg / min) Therapeutic indicator 8

Hydrochloride 4 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} morpholine 16 113 1,5 3.8 9

Hydrochloride 7 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} -1,4-dioxa-7-azaspiro [4,4] nonane 16 91.33 1,6 2.9 10

Hydrochloride 1 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} pyrrolidine 21.33 118 1.33 4.4 eleven

(3S) -3-benzyloxy-1 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} pyrrolidine hydrochloride 8 38.13 0.5 3.8 12

(3R) -3-benzyloxy-1 hydrochloride - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} pyrrolidine 8 51.1 one 2.6 13

(3S) -1 hydrochloride - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} pyrrolidin-3-yl acetate 8 51.9 1.3 2 fourteen

(3R) / (3S) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} -3-fluoropyrrolidine hydrochloride 10.67 63.33 1.4 2,3 fifteen

Hydrochloride {(2R) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} pyrrolidin-2-yl} methanol 16 142.33 0.8 8.9 16

Hydrochloride 1 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} -2,5-dihydro-1H-pyrrole 8 44,4 2,4 0.9 17

(3R) -1 - {(1R, 2R) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} pyrrolidin-3-yl acetate hydrochloride 13.33 74.3 2.1 1.8 eighteen

Hydrochloride 1 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} pyrrolidin-3-one 32 235 4,5 2.6 19

Hydrochloride 4 - {(1R, 2R) / (1S, 2S) -2- [3- (3,4-dimethoxyphenyl) propoxy] cyclohexyl} mofrolin 16 109 1,5 3.6 twenty

Hydrochloride 4 - {(1R, 2R) / (1S, 2S) -2- [4- (3,4-dimethoxyphenyl) butoxy] cyclohexyl} mofrolin 10.7 66.8 1,5 2.2 21

Hydrochloride (3R) -1 - {(1R, 2R) / (1S, 2S) -2- [3- (3-chloro-4,5-dimethoxyphenyl) propoxy] cyclohexyl} pyrrolidin-3-ol 13.33 90.9 0.6 7.6 22

Hydrochloride 1 - [(3,4-dimethoxyphenyl) acetyl] -4 - {(1R, 2R) / (1S, 2S) -2- [2- (3,4-dimethoxyphenyl) ethoxy] cyclohexyl} piperazine 21.33 133 0.6 11.1 23

(3R) / (3S) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (2,6-dichlorophenyl) ethoxy] cyclohexyl} pyrrolidin-3-ol hydrochloride 8 65 0.6 5,4 24

Hydrochloride (3R) / (3S) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (2-bromophenyl) ethoxy] cyclohexyl} pyrrolidin-3-ol 13 67 0.4 8.4 25

Hydrochloride (3R) / (3S) -1 - {(1R, 2S) / (1S, 2R) -2- [2- (1-naphthyl) ethoxy] cyclohexyl} pyrrolidin-3-ol 16 70 0.4 8.8 26

Hydrochloride (3R) / (3S) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (1-naphthyl) ethoxy] cyclohexyl} pyrrolidin-3-ol 8 67.33 0.78 4.3 27

Hydrochloride (3R) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (2-trifluoromethylphenyl) ethoxy] cyclohexyl} pyrrolidin-3-ol 16 101.93 0.7 7.3 28

Hydrochloride (3R) / (3S) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (1H-indol-1-yl) ethoxy] cyclohexyl} pyrrolidin-3-ol 16 113 0.6 9,4 29th

Hydrochloride (3R) -1 - {(1R, 2R) / (1S, 2S) -2- [2- (1-benzofuran-2-yl) ethoxy] cyclohexyl} pyrrolidin-3-ol 10.67 65.67 one 3.3 thirty

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- (2-naphthenethoxy)] cyclohexane 13.3 85 0.8 5.3 31

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- (1-naphthenethoxy)] cyclohexane 16 93 one 4.7 32

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- (4-bromophenethoxy)] cyclohexane 12 91 2.1 2.2 33

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- [2- (2-naphthoxy) ethoxy]] cyclohexane 8 61.63 2 1,5 34

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- [2- (4-bromophenoxy) ethoxy]] cyclohexane 10.7 83 3 1.4 35

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- (3,4-dimethoxyphenethoxy)] cyclohexane 16 113 four 1.4 36

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- (2- (benzo [b] thiophen-3-yl)] cyclohexane 8 65 one 3.3 37

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- (2- (benzo [b] thiophen-4-yl)] cyclohexane 8 54 one 2.7 38

(1R, 2R) / (1S, 2S) - [2- (4-morpholinyl) -1- (3-bromophenethoxy)] cyclohexane 16 131 2 3.3 39

(1R, 2R) / (1S, 2S) -2- (4-morpholinyl) -1- (2- (bromophenethoxy)] cyclohexane 16 125 one 6.3 40

(1R, 2R) / (1S, 2S) -2- (4-morpholinyl) -1- (3,4-dichlorophenethoxy) cyclohexane 16 118 1,5 3.9 41

(1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride 32 190 1,1 8.6 42

(1R, 2S) / (1S, 2R) -2- (4-morpholinyl) -1 - [(2-trifluoromethyl) phenethoxy] cyclohexane monohydrochloride 16 102 1.4 3.6 43

(1R, 2R) / (1S, 2S) -2- (3-acetoxypyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane monohydrochloride 8 65 1.4 2,3 44

(1R, 2R) / (1S, 2S) -2- (4-morpholinyl) -1 - [(2,6-dichlorophenyl) methoxy] cyclohexane monohydrochloride 16 97 1.8 2.7 45

(1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1 - [(2,6-dichlorophenyl) methoxy] cyclohexane monohydrochloride 32 214 2.1 5.1 46

(1R, 2R) / (1S, 2S) -2- (3-hydroxypyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride 8 65 0.6 5,4 47

(1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,2-diphenylethoxy) cyclohexane monohydrochloride 21 155 2,5 3,1 48

(1R, 2R) / (1S, 2S) -2- (3-thiazolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride 43 331 6.5 2,5

All publications and patent applications referenced herein are incorporated by reference to the same extent as if each individual publication or patent application were expressly and separately incorporated by reference.

It should be understood from the foregoing that although certain embodiments of the invention have been described herein for purposes of illustration, any modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited to certain embodiments and examples contained in the present patent.

Claims (18)

1. The compound of formula (IE) or its pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer:

including its isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof, where R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy. 2. The compound of formula (IE) according to claim 1, where R ₄ and R _{5 are} independently selected from C ₁ -C ₃ alkoxy. 3. The compound of formula (IE) according to claim 1, where R ₄ and R _{5 are} independently selected from C ₁ -C ₆ alkoxy. 4. The compound according to claim 1, selected from the group consisting of Structure Chemical name

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1 - (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2S) / (1S, 2R) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane

(1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

(1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

(1R, 2R) / (1S, 2S) -2 - [(3R) / (3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

(1R, 2R) / (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

(1R, 2R) / (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

(1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride

(1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride 5. The compound according to claim 1, which is a (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or a pharmaceutically acceptable salt thereof; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or a pharmaceutically acceptable salt thereof; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or a pharmaceutically acceptable salt thereof; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane or a pharmaceutically acceptable salt thereof; (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride; (1R, 2R) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride; (1S, 2S) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride; (1S, 2S) -2 - [(3S) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride. 6. The compound according to claim 1, which is (1R, 2R) -2 - [(3R) -hydroxypyrrolidinyl] -1- (3,4-dimethoxyphenethoxy) cyclohexane, or a pharmaceutical salt thereof. 7. A pharmaceutical composition exhibiting antiarrhythmic activity, comprising a compound according to any one of claims 1 to 6 in combination with a pharmaceutically acceptable carrier, excipient or diluent. 8. The compound according to any one of claims 1 to 6 to obtain a medicinal product with antiarrhythmic activity. 9. The composition according to claim 7 for obtaining a medicinal product with antiarrhythmic activity. 10. A method of blocking Na channels in vitro, comprising administering an effective amount of a compound according to any one of claims 1 to 6 or a composition according to claim 7. 11. The use of compounds according to claims 1-6 for the preparation of a medicament for blocking Na-channels in warm-blooded animals. 12. The use of the composition according to claim 7 for the manufacture of a medicament for blocking Na-channels in warm-blooded animals. 13. The use according to claim 11 for blocking / inhibition of cardiac early polarizing currents and cardiac sodium currents; blocking / inhibiting the cardiac sodium channels responsible for cardiac early polarizing currents and cardiac sodium currents in a warm-blooded animal under conditions when an arrhythmogenic substrate is present in the heart of the said warm-blooded animal. 14. The application of item 13, where these cardiac early polarizing currents include ionic currents that are rapidly activated after depolarization of the membrane potential difference and which repolarize the cell. 15. The application of claim 13 or 14, wherein said early polarizing currents include an ultrafast delayed rectifying one of the currents Kv4, Rv2.1, Kv1.5. 16. The use of a compound according to any one of claims 1 to 6 for the treatment and / or prevention of arrhythmia in a warm-blooded animal or atrial arrhythmia; or ventricular arrhythmias in a warm-blooded animal; or atrial fibrillation in a warm-blooded animal; or atrial flutter in a warm-blooded animal; or ventricular fibrillation in a warm-blooded animal; or ventricular flutter in a warm-blooded animal. 17. The use according to clause 16, where the compound according to any one of claims 1 to 6 is a compound according to claims 4, 5 or 6. 18. The use of a composition according to claim 7 for the manufacture of a medicament for the treatment and / or prevention of arrhythmia in a warm-blooded animal; or atrial arrhythmias; or ventricular arrhythmias in a warm-blooded animal; or atrial fibrillation in a warm-blooded animal; or atrial flutter in a warm-blooded animal; or ventricular fibrillation in a warm-blooded animal; or ventricular flutter in a warm-blooded animal.

Images