Barrett G. M. (London, GB)
Choi, Lewis Siu Leung (Burnaby, CA)
Chou, Dough Ta Hung (Vancouver, CA)
Jung, Grace (New Westminster, CA)
Plouvier, Bertrand M. C. (Vancouver, CA)
Liu, Yuzhong (Vancouver, CA)
Zhu, Jeff Jiqun (Greensboro, NC, US)
Sheng, Tao (Westwood, MA, US)

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10/555364

05/03/2007

10/31/2003

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Cardiome Pharma Corp. (6190 Agronomy Road, 6th FL.,, Vancouver, CA)

548/541

514/424

A61K31/4015; C07D207/02

SEED INTELLECTUAL PROPERTY LAW GROUP PLLC (701 FIFTH AVE, SUITE 5400, SEATTLE, WA, 98104, US)

1. 1-100. (canceled)

101. A method of stereoselectively making an aminocyclohexyl ether comprising: reacting a compound of formula (55), or a compound of formula (74), with a compound of formula (56), to form a compound of formula (57), or a compound of formula (75), respectively, wherein R₁ and R₂, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): and wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; and wherein O-J is a leaving group.

102. A method of making a compound of formula (55) or formula (74): wherein the method comprises: alkylating a compound of formula (53), or a compound of formula (84), with a compound of formula (54), to form the compound of formula (55) or the compound of formula (74); respectively; and optionally protecting a compound of formula (53), or a compound of formula (84), before said alkylating step; wherein O-Q is a leaving group that reacts with —OH in formula (53) or formula (84) to form the compound of formula (55) or the compound of formula (74), such that the stereochemical configuration of the compound of formula (53) or the compound of formula (84) is retained in the compound of formula (55) or the compound of formula (74), respectively; wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; and wherein O-J is a leaving group.

103. A method of making a compound of formula (74) or formula (55): wherein the method comprises: activating a compound of formula (73), or a compound of formula (94), with a hydroxy activating reagent to form the compound of formula (74) or the compound of formula (55), respectively; wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; and wherein O-J is a leaving group.

104. A method of making a compound of formula (73): wherein the method comprises: hydrogenating and hydrogenolyzing a compound of formula (72), to form the compound of formula (73); wherein X is a halide; and wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen.

105. A method of making a compound of formula (72): wherein the method comprises: alkylating a compound of formula (51), with a compound of formula (54), to form the compound of formula (72); wherein X is a halide wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; and wherein O-Q is a leaving group that reacts with —OH in the compound of formula (51) to form the compound of formula (72), such that the stereochemical configuration of the compound of formula (51) is retained in the compound of formula (72).

106. A method of making a compound of formula (93): wherein the method comprises: alkylating a compound of formula (92), with a compound of formula (54), to form the compound of formula (93); wherein Pro is a protecting group; wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy, and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; and wherein O-Q is a leaving group that reacts with —OH in the compound of formula (92) to form the compound of formula (93), such that the stereochemical configuration of the compound of formula (92) is retained in the compound of formula (93).

107. A method of making a compound of formula (92): wherein the method comprises: hydrogenating and hydrogenolyzing a compound of formula (91), to form the compound of formula (92); wherein Pro is a protecting group; and wherein X is a halide.

108. A method of making a compound of formula (53): wherein the method comprises: hydrogenating and hydrogenolyzing a compound of formula (52), to form the compound of formula (53); wherein X is a halide; and wherein O-J is a leaving group.

109. A method of making a compound of formula (52): wherein the method comprises: activating a compound of formula (51), with a hydroxy activating reagent to form the compound of formula (52); wherein X is a halide; and wherein O-J is a leaving group.

110. A method of making a compound of formula (99): wherein the method comprises: activating a compound of formula (92), with a hydroxy activating reagent to form the compound of formula (99); wherein Pro is a protecting group; and wherein O-J is a leaving group.

111. A method of making a compound of formula (53) or a compound of formula (84): wherein the method comprises: removing a functional group G or G₁ from a compound of formula (85), or a compound of formula (86), respectively, to form the compound of formula (53) or the compound of formula (84), respectively; wherein O-J is a leaving group.

112. A method comprising separating a racemic mixture of a compound of formula (53), and a compound of formula (84),

113. A method of forming a racemic mixture of a compound of formula (53) and a compound of formula (84): wherein the method comprises: activating a compound of formula (83), with a hydroxy activating reagent to form the racemic mixture of the compound of formula (53) and the compound of formula (84); wherein O-J is a leaving group.

114. A method for stereoselectively making an aminocyclohexyl ether of formula (57): wherein R₁ and R₂, when taken together with the nitrogen atom to which they are directly attached in formula (57), form a ring denoted by formula (II): and wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; wherein the method comprises: (a) reacting a compound of formula (53), wherein O-J is a leaving group, with a compound of formula (54), wherein R₃, R₄ and R₅ are as defined above and O-Q is a leaving group that reacts with the hydroxy group (—OH) in formula (53) to form a compound of formula (55), such that the stereochemical configuration of the compound of formula (53) is retained in the compound of formula (55); (b) optionally protecting the compound of formula (53) before the first reaction; and (c) reacting the compound of formula (55) with a compound of formula (56), wherein R₁ and R₂ are as defined above, to form the aminocyclohexyl ether of formula (57).

115. A method for stereoselectively making an aminocyclohexyl ether of formula (75): wherein R₁ and R₂, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): and wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; wherein the method comprises: (a) reacting a compound of formula (84), wherein O-J is a leaving group, with a compound of formula (54), wherein R₃, R₄ and R₅ are as defined above and O-Q is a leaving group that reacts with the hydroxy group (—OH) in the compound of formula (84) to form a compound of formula (74), such that the stereochemical configuration of the compound of formula (84) is retained in the compound of formula (74); (b) optionally protecting the compound of formula (84) before the first reaction step (a); and (c) reacting the compound of formula (74) with a compound of formula (56), wherein R₁ and R₂ are as defined above, to form the aminocyclohexyl ether of formula (75).

116. A method for stereoselectively making an aminocyclohexyl ether of formula (75): wherein R₁ and R₂, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): and wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; wherein the method comprises: (a) reacting a compound of formula (73), with a hydroxy activating reagent to form a compound of formula (74), wherein O-J is a leaving group, and R₃, R₄ and R₅ are as defined above; and (b) reacting the product of the first reaction, compound of formula (74) with a compound of formula (56), wherein R₁ and R₂ are as defined above, to form the aminocyclohexyl ether of formula (75).

117. A method for stereoselectively making an aminocyclohexyl ether of formula (57): wherein R₁ and R₂, when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): and wherein R₃, R₄ and R₅ are independently selected from hydrogen, hydroxy and C₁-C₆alkoxy, with the proviso that R₃, R₄ and R₅ cannot all be hydrogen; wherein the method comprises: (a) hydrogenating and hydrogenolyzing a compound of formula (91), to form a compound of formula (92), wherein Pro is a protecting group and X is a halide; (b) alkylating the compound of formula (92) with a compound of formula (54), wherein R₃, R₄ and R₅ are as defined above and O-Q is a leaving group that reacts with the hydroxy group in formula (92) to form a compound of formula (93), such that the stereochemical configuration of the compound of formula (92) is retained in the compound of formula (93); (c) deprotecting the compound of formula (93) to form a compound of formula (94), (d) activating the compound of formula (94) to form a compound of formula (55), wherein O-J is a leaving group; and (e) reacting the compound of formula (55) with a compound of formula (56), wherein R₁ and R₂ are as defined above, to form the amino cyclohexyl ether of formula (57).

118. A method of making compound (1) or compound (2): wherein the method comprises: a) reacting with (Boc)₂O under suitable conditions to form compound (1R): b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R): c) hydrolyzing compound (2R) under suitable conditions to form compound (3R): d) reacting compound (3R) with under suitable conditions to form compound (4R): e) reacting compound (4R) with under suitable conditions to form compound (5R); f) resolving compound (5R) under suitable conditions to form compound (5RRR) and compound (5SSR): and g) hydrogenolyzing compound (5RRR) under suitable conditions to form compound (1), as described above, and hydrogenolyzing compound (5SSR) under suitable conditions to form compound (2), as described above.

119. A method of making compound (5RRR) or compound (5SSR): wherein the method comprises: a) reacting with (Boc)₂O under suitable conditions to form compound (1R): b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R): c) hydrolyzing compound (2R) under suitable conditions to form compound (3R): d) reacting compound (3R) with under suitable conditions to form compound (4R): e) reacting compound (4R) with under suitable conditions to form compound (5R); and f) resolving compound (5R) under suitable conditions to form compound (5RRR) and compound (5SSR), as described above.

120. The method of claim 119 further comprising: reacting compound (5RRR) under suitable conditions to form compound (17):

121. A method of making compound (5R): wherein the method comprises: a) reacting with (Boc)₂O under suitable conditions to form compound (1R): b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R): c) hydrolyzing compound (2R) under suitable conditions to form compound (3R): d) reacting compound (3R) with under suitable conditions to form compound (4R): and e) reacting compound (4R) with under suitable conditions to form compound (5R), as described above.

122. The method of claim 121 further comprising: reducing compound (5R) under suitable conditions to form compound (4):

123. The method of claim 121 further comprising: reacting compound (5R) under suitable conditions to form compound (12):

124. A method of making compound (4R): wherein the method comprises: a) reacting with (Boc)₂O under suitable conditions to form compound (1R): b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R): c) hydrolyzing compound (2R) under suitable conditions to form compound (3R): and d) reacting compound (3R) with under suitable conditions to form compound (4R), as described above.

125. A method of making compound (3R): wherein the method comprises: a) reacting with (Boc)₂O under suitable conditions to form compound (1R): b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R): and c) hydrolyzing compound (2R) under suitable conditions to form compound (3R), as described above.

126. A method of making compound (1): wherein the method comprises hydrogenolyzing compound (5RRR): under suitable conditions to form compound (1), as described above.

127. The method of claim 126 further comprising, prior to the hydrogenolyzing step, resolving compound (5R): under suitable conditions to form compound (5RRR), as described above.

128. The method of claim 127 further comprising, prior to the resolving step, reacting compound (4R): with under suitable conditions to form compound (5R), as described above.

129. The method of claim 128 further comprising, prior to the reacting step, reacting compound (3R): with under suitable conditions to form compound (4R), as described above.

130. The method of claim 129 further comprising, prior to the reaction of compound (3R) with hydrolyzing compound (2R): under suitable conditions to form compound (3R), as described above.

131. A method of making compound (2): wherein the method comprises hydrogenolyzing compound (5SSR): under suitable conditions to form compound (2), as described above.

132. The method of claim 131 further comprising, prior to the hydrogenolyzing step, resolving compound (5R): under suitable conditions to form compound (5SSR), as described above.

133. The method of claim 132 further comprising, prior to the resolving step, reacting compound (4R): with under suitable conditions to form compound (5R), as described above.

134. The method of claim 133 further comprising, prior to the reacting step, reacting compound (3R): with under suitable conditions to form compound (4R), as described above.

135. The method of claim 134 further comprising, prior to the reaction of compound (3R) with hydrolyzing compound (2R): under suitable conditions to form compound (3R), as described above.

136. A method of making compound (6) or compound (7): wherein the method comprises: a) reacting with (Boc)₂O under suitable conditions to form the following compound: b) reacting the compound formed in step a) with benzyl bromide under suitable conditions to form the following compound: c) hydrolyzing the compound formed in step b) under suitable conditions to form the following compound: d) reacting the compound formed in step c) with under suitable conditions to form the following compound: e) reacting the compound formed in step d) with under suitable conditions to form the following compound: f) resolving the compound formed in step e) under suitable conditions to form the following compounds: and g) hydrogenolyzing the following compound formed in step f): under suitable conditions to form compound (6), as described above; and hydrogenolyzing the following compound formed in step f): under suitable conditions to form compound (7), as described above.

137. The method of claim 136 further comprising: reducing the compound formed in step e) under suitable conditions to form compound (5):

138. A method of making compound (3): wherein the method comprises: a) reacting with (Boc)₂O under suitable conditions to form the following compound: b) reacting the compound formed in step a) with benzyl bromide under suitable conditions to form the following compound: c) hydrolyzing the compound formed in step b) under suitable conditions to form the following compound: d) reacting the compound formed in step c) with under suitable conditions to form the following compound: e) reacting the compound formed in step d) with under suitable conditions to form the following compound: f) hydrogenolyzing the following compound formed in step e): under suitable conditions to form compound (3), as described above.

139. The compound (5RRR):

140. The compound (5SSR):

141. The compound (5R):

142. The compound (4R):

TECHNICAL FIELD

The present invention is directed to aminocyclohexyl ether compounds, pharmaceutical compositions, and processes for the synthesis of the aminocyclohexyl ether compounds, and therapeutic uses thereof.

BACKGROUND OF THE INVENTION

Ion channels are ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Their critical physiological roles include control of the electrical potential across the membrane, mediation of ionic and fluid balance, facilitation of neuromuscular and neuronal transmission, rapid transmembrane signal transduction, and regulation of secretion and contractility.

For example, cardiac ion channels are proteins that reside in the cell membrane and control the electrical activity of cardiac tissue. In response to external stimuli, such as changes in potential across the cell membrane, these ion channels can form a pore through the cell membrane, and allow movement of specific ions into or out of the cell. The integrated behavior of thousands of ion channels in a single cell results in an ionic current, and the integrated behavior of many of these ionic currents makes up the characteristic cardiac action potential.

Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are known. The major cause of fatalities due to cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the U.S. alone, each year over one million Americans will have a new or recurrent coronary attack (defined as myocardial infarction or fatal coronary heart disease). About 650,000 of these will be first heart attacks and 450,000 will be recurrent attacks. About one-third of the people experiencing these attacks will die of them. At least 250,000 people a year die of coronary heart disease within 1 hour of the onset of symptoms and before they reach a hospital. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E. L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(1):264-7 January 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 years have AF (Kannel W. B., Abbot R. D., Savage D. D., McNamara P. M., N. Engl. J. Med. 306(17):1018-22, 1982; Wolf P. A., Abbot R. D., Kannel W. B. Stroke. 22(8):983-8, 1991). While AF is rarely fatal, it can impair cardiac function and is a major cause of stroke (Hinton R. C., Kistler J. P., Fallon J. T., Friedlich A. L., Fisher C. M., American Journal of Cardiology 40(4):509-13, 1977; Wolf P. A., Abbot R. D., Kannel W. B., Archives of Internal Medicine 147(9):1561-4, 1987; Wolf P. A., Abbot R. D., Kannel W. B. Stroke. 22(8):983-8, 1991; Cabin H. S., Clubb K. S., Hall C., Perhmutter R. A., Feinstein A. R., American Journal of Cardiology 65(16): 1112-6, 1990).

WO95/08544 discloses a class of aminocyclohexylester compounds as useful in the treatment of arrhythmias.

WO93/19056 discloses a class of aminocyclohexylamides as useful in the treatment of arrhythmia and in the inducement of local anaesthesia.

WO99/50225 discloses a class of aminocyclohexylether compounds as useful in the treatment of arrhythmias.

Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia. For example, Class I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias. Treatment of ventricular arrhythmia is very important since such an arrhythmia can be fatal. Serious ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) occur most often in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs in the setting of acute myocardial ischemia, before infarction fully develops. At present, there is no satisfactory pharmacotherapy for the treatment and/or prevention of ventricular fibrillation during acute ischemia. In fact, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction.

Class Ia, Ic and III antiarrhythmic drugs have been used to convert recent onset AF to sinus rhythm and prevent recurrence of the arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs 48(3):345-71, 1994). However, drug therapy is often limited by adverse effects, including the possibility of increased mortality, and inadequate efficacy (Feld G. K., Circulation. 83(6):2248-50, 1990; Coplen S. E., Antman E. M., Berlin J. A., Hewitt P., Chalners T. C., Circulation 1991; 83(2):714 and Circulation 82(4):1106-16, 1990; Flaker G. C., Blackshear J. L., McBride R., Kronmal R. A., Halperin J. L., Hart R. G., 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). Conversion rates for Class I antiarrhythmics range between 50-90% (Nattel S., Hadjis T., Talajic M., Drugs 48(3):345-71, 1994; Steinbeck G., Remp T., Hoffmann E., Journal of Cardiovascular Electrophysiology. 9(8 Suppl):S104-8, 1998). Class III antiarrhythmics appear to be more effective for terminating atrial flutter than for AF and are generally regarded as less effective than Class I drugs for terminating of AF (Nattel S., Hadjis T., Talajic M., Drugs. 48(3):345-71, 1994; Capucci A., Aschieri D., Villani G. Q., Drugs & Aging 13(1):51-70, 1998). Examples of such drugs include ibutilide, dofetilide and sotalol. Conversion rates for these drugs range between 30-50% for recent onset AF (Capucci A., Aschieri D., Villani G. Q., Drugs & Aging 13(1):51-70, 1998), and they are also associated with a risk of the induction of Torsades de Pointes ventricular tachyarrhythmias. For ibutilide, the risk of ventricular proarrhythmia is estimated at ˜4.4%, with ˜1.7% of patients requiring cardioversion for refractory ventricular arrhythmias (Kowey P. R., VanderLugt J. T., Luderer J. R., American Journal of Cardiology 78(8A):46-52, 1996). Such events are particularly tragic in the case of AF as this arrhythmia is rarely a fatal in and of itself.

There remains a need in the art to identify new antiarrhythmic treatments, for both ventricular arrhythmias as well as for atrial arrhythmias. The present invention fulfills this need, and further provides other related advantages.

SUMMARY OF THE INVENTION

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

wherein, R ₃ , R ₄ and R ₅ are independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R ₃ , R ₄ and R ₅ cannot all be hydrogen.

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

wherein, R ₃ , R ₄ and R ₅ are independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R ₃ , R ₄ and R ₅ cannot all be hydrogen.

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

wherein, R ₃ , R ₄ and R ₅ are independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R ₃ , R ₄ and R ₅ cannot all be hydrogen.

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

wherein, R ₃ , R ₄ and R ₅ are independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R ₃ , R ₄ and R ₅ cannot all be hydrogen.

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

wherein, R ₄ and R ₅ are independently selected from hydrogen, hydroxy and C ₁ -C ₆ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R ₄ and R ₅ cannot all be hydrogen.

In another embodiment, the present invention provides a compound or any salt thereof, or any solvate thereof, or mixture comprising one or more said 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 a 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 is described elsewhere in detail 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:

Cpd. #	Structure	Chemical name
1		(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
4		(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 includes a solvate of one or more of the compounds listed in the above table. The composition may or may not include additional components as is described elsewhere in detail in this patent.

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

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

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

In one embodiment, the present invention provides a compound which is (1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane free base or any salt thereof, or any solvate thereof.

In one embodiment, the present invention provides a compound which is (1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is (1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride, or any solvate thereof.

In one embodiment, the present invention provides a compound which is (1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride, or any solvate thereof.

The present invention also provides protenated versions of all of the compounds described in this patent. That is, for each compound described in this patent, the invention also includes the quaternary protenated amine form of the compound. These quaternary protenated amine form of the compounds may be present in the solid phase, for example in crystalline or amorphous form, and may be present in solution. These quaternary protenated amine form of the compounds may be associated with pharmaceutically acceptable anionic counter ions, including but not limited to those described in 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.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds, selected from any of the compounds described in this patent or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, 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 medicament.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically 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, in combination with a pharmaceutically acceptable carrier, diluent or excipient, and further provides a method for the manufacture of such a composition or medicament.

In other embodiments, the present invention provides a composition or medicament that includes one or more compounds according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, or metabolite thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, 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 medicament.

In other embodiments, the present invention provides a composition or medicament that includes a compound which is (1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride, 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 medicament.

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

As disclosed within the present invention, a variety of cardiac pathological conditions may be treated and/or prevented by the use of one or more compounds of the present invention such as those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said compound or mixture comprising compounds as described above. Without being bound by theory, the inventors believe that the compounds of the present invention are ion channel modulating compounds that either singly or together with one or more additional compounds are able to selectively modulate certain ionic currents. The ion currents referred to herein are generally cardiac currents and more specifically, are the sodium currents and early repolarising currents.

Throughout this patent the inventors describe various means by which they believe the compounds described in this patent may act. Such descriptions are not intended to be limiting but represent the inventors' belief as to how the compounds may act.

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

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

In another embodiment, the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents under conditions where an “arrhythmogenic substrate” is present in the heart. An “arrhythmogenic substrate” is characterized by a reduction in cardiac action potential duration and/or changes in action potential morphology, premature action potentials, high heart rates and may also include increased variability in the time between action potentials and an increase in cardiac milieu acidity due to ischaemia or inflammation. Changes such as these are observed during conditions of myocardial ischaemia or inflammation 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 those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said compound or mixture comprising compounds as described above.

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

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

In other embodiments, the present invention provides a method for modulating cardiac sodium currents 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 those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for modulating cardiac early repolarising currents and cardiac sodium currents 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 those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said compound or mixture comprising compounds as described above.

In other embodiments, the present invention provides a method for 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 those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said compound or mixture comprising compounds as described above.

In another embodiments, the present invention provides a method for 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 those selected from the group consisting of:

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

(1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimet hoxyphenethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimet hoxyphenethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1R,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

(1S,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof;

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

In other embodiments, the present invention provides a composition or medicament that contain one or more compounds of the present invention such as those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric 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 the disease or condition, and/or prevent a disease or condition in a warm-blooded animal that would otherwise occur, and further contains a pharmaceutically acceptable carrier, diluent or excipient.

The invention further provides for methods of treating a disease or condition in a warm-blooded animal suffering from or having the disease or condition, and/or preventing a disease or condition from arising in a warm-blooded animal, wherein a therapeutically effective amount of one or more compounds of the present invention such as those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said compound or mixture comprising compounds as described above, is administered to a warm-blooded animal in need thereof. By way of illustration and not by way of limitation, examples of some of the diseases, disorders and conditions to which the compounds, compositions, medicaments and methods of the present invention have applicability are as follows: arrhythmia, atrial arrhythmia; ventricular arrhymia, atrial fibrillation, ventricular fibrillation, atrial flutter, ventricular flutter, diseases of the central nervous system, convulsion, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, irritable bowel syndrome, cardiovascular diseases, cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthamic diseases, diabetes mellitus, myopathies, Becker's myotonia, myasthenia gravis, paramyotonia congentia, malignant hyperthermia, hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune disorders, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease or other mental disorder, and alopecia.

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

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

The invention further provides a method for producing, analgesia or local anesthesia in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention such as those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, or a composition or medicament that includes said compound or mixture comprising compounds as described above. These compositions, medicaments and methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal.

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

The invention further provides a method for enhancing libido in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of one or more compounds of the present invention such as those according to formula (IA), (IB), (IC), (ID), or (IE), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, or a composition or medicament that includes said compound or mixture comprising compounds as described above. These compositions and methods may be used, for example, to treat a sexual dysfunction, e.g., impotence in males, and/or to enhance the sexual desire of a patient without a sexual dysfunction. As another example, the therapeutically effective amount may be administered to a bull (or other breeding stock), to promote increased semen ejaculation, where the ejaculated semen is collected and stored for use as it is needed to impregnate female cows in promotion of a breeding program.

The compounds of the present invention are effective antiarrhythmic agents. The compounds according to the present invention have been found to exhibit advantageously low Central Nervous System (CNS) toxicity whilst retaining high antiarrhythmic activity.

In another embodiment the present invention provides methods for the synthesis of compounds of the present invention such as those according to formula (IA), (IB), (IC), (D), or (IE), and in particular methods for the synthesis of the compounds;

(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base and the corresponding monohydrochloride;

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

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

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

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

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

(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-cyclohexane free base and the corresponding monohydrochloride;

Some general synthetic processes for aminocyclohexyl ethers have been described in WO 99/50225 and references cited therein.

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

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a reaction sequence whereby the following aminocyclohexyl ether compounds of the present invention may be synthesized:

• (1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane free base;
• (1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride (Compound 1);
• (1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane free base;
• (1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride (Compound 2);
• (1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dim ethoxyphenethoxy)-cyclohexane free base;
• (1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dim ethoxyphenethoxy)-cyclohexane monohydrochloride (Compound 3);
• (1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethox yphenethoxy)-cyclohexane free base;
• (1R,2R)/(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethox yphenethoxy)-cyclohexane monohydrochloride (Compound 4);
• (1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethox yphenethoxy)-cyclohexane free base;
• (1R,2R)/(1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethox yphenethoxy)-cyclohexane monohydrochloride (Compound 5);
• (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane free base;
• (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride (Compound 6);
• (1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane free base;
• (1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth oxy)-cyclohexane monohydrochloride (Compound 7);

FIG. 2 illustrates a synthetic methodology that may be employed to prepare a trans-aminocyclohexyl ether compound of the present invention.

FIG. 3 illustrates a synthetic methodology for preparing amine 1e required for the formation of amino alcohol 2e (as shown in FIG. 2).

FIG. 4 illustrates a synthetic sequence that may be used to prepare a cis-aminocyclohexyl ether compound of the present invention such as compound 25.

FIG. 5 illustrates a general reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 6 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 7 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure tans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

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

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

FIG. 10 illustrates a general reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (57).

FIG. 11 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

FIG. 12 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

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

FIG. 14 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

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

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

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

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

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

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

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

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

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

FIG. 24 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

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

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

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

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

FIG. 29 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

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

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

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

FIG. 33 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 34 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (69).

FIG. 35 illustrates a general reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1R,2R)-aminocyclohexyl ether compound of formula (66).

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

FIG. 37 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (55).

FIG. 38 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (64).

FIG. 39 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (67).

FIG. 40 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (71).

FIG. 41 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (53).

FIG. 42 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (62).

FIG. 43 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (52).

FIG. 44 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure compound of formula (61).

FIG. 45 illustrates a general reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 46 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexylether compound of formula (79).

FIG. 47 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 48 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 49 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 50 illustrates a general reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 51 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 52 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 53 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 54 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

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

FIG. 56 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 57 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (79).

FIG. 58 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 59 illustrates a reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (81).

FIG. 60 illustrates a general reaction scheme that may be used as a process for preparing a stereoisomerically substantially pure trans-(1S,2S)-aminocyclohexyl ether compound of formula (75).

FIG. 61 illustrates a reaction scheme that may be used as a process fo