HK1120798A - Substituted pyrrolidin-2-ones, piperidin-2-ones and isothiazolidine-1, 1-dioxides, their use as kv1.5 potassium channel blockers and pharmaceutical preparations comprising them - Google Patents

Description

Substituted pyrrolidin-2-ones, piperidin-2-ones and isothiazolidine-1, 1-dioxides, their use as Kv1.5 potassium channel blockers and pharmaceutical preparations comprising them

The invention relates to compounds of formula (I), to their preparation and to their use, in particular in medicine,

wherein A, R1, R2, R3, R4, R5, R6, R7 and n have the meanings indicated below.

The compounds of the invention of the formula I have not been described before. They act on the so-called Kv1.5 potassium channels and suppress potassium currents, which are called ultrafast activation delayed rectifiers in the human atria. In addition, the compounds also act on other atrial specific potassium channels such as acetylcholine dependent potassium channel KACh and the two-pore (2P) domain potassium channel TASK-1. The compounds are therefore very particularly suitable as antiarrhythmic active ingredients, in particular for the treatment and prophylaxis of atrial arrhythmias, for example Atrial Fibrillation (AF) or atrial flutter.

Atrial Fibrillation (AF) and atrial flutter are the most common persistent arrhythmias. Incidence increases with age and often leads to fatal outcomes, such as stroke. AF affects, for example, about 3 million americans and causes over 80000 strokes per year in the united states. Although the currently used type I and type III antiarrhythmic drugs can reduce the recurrence rate of AF, their use is limited due to their potential proarrhythmic side effects. For this reason, there is a great medical need to develop better drugs for treating atrial arrhythmias.

It has been shown that a so-called reentry depolarization wave lays the basis for most supraventricular arrhythmias. Such reentry occurs if the conductivity of the heart tissue is slow and at the same time has a very short refractory period. Increasing the refractory period of the myocardium by prolonging the action potential is a well-established mechanism for terminating arrhythmias and preventing their development. The duration of the action potential is essentially determined by the K flowing out of the cell through the various K + channels⁺The degree of repolarization of the current. Of particular importance in this connection are the so-called delayed rectifiers I_KIt consists of 3 different components: IK (Internet Key exchange)_r、IK_sAnd IK_ur。

Most known type III antiarrhythmics(e.g., dofetilide or d-sotalol) blocks predominantly or exclusively the rapidly activating potassium channel IK_rThe potassium channel IK_rHas been detected in both human ventricular and atrial cells. However, it has been shown that: when the heart rate is slow and normal, these compounds have an increased risk of proarrhythmia, especially those known as torsades de pointes, which have been observed. In addition to this high risk of mortality in certain low heart rates, it has been found that: IK (Internet Key exchange)_rThe potency of the blocking agent decreases in the case of tachycardia, and this potency is required at the very moment (negative use-dependency).

Delay rectifier IK corresponding to Kv1.5 channel_urThe "extremely fast" activation component and the extremely slow deactivation component of (ultra-fast activation delay rectifiers) are extremely important to the human atrial depolarization duration. Thus, with IK_rOr IK_sInhibition of IK_urInhibition of potassium efflux represents a particularly effective method of prolonging atrial action potential and thereby terminating or preventing atrial arrhythmia. Mathematical model of human action potential suggests: IK is precisely under the pathological conditions of chronic atrial fibrillation_urThe positive effects of blockade should be particularly pronounced (M.Courtemanche, R.J.Ramirez, S.Nattel, Cardiovasular Research 1999, 42, 477-489: "drug therapy ion target and atrial fibrillation induced electrical remodeling: exploration using mathematical models").

And IK_rAnd IK_sAlso occurs in the human ventricle for contrast, IK_urPlays an important role in the human atria, but not in the ventricles. For this reason, if IK is suppressed_urThe risk of electrical currents, proarrhythmic effects on the ventricle, is excluded from the outset, which is in contrast to IK_rOr IK_sIn contrast (Z.Wang et al, Circ.Res.73, 1993, 1061-1076: "outward flow induced by continuous depolarization in human atrial myocytes"; G.R.Li et al, Circ.Res.78, 1996, 689-696: "two delayed commutations K in human ventricular myocytes⁺-evidence of current composition "; G.J.amos, etcHuman, j. physiol.491, 1996, 31-50: "difference between the outward flow of human atrial and subcardial ventricular myocytes").

However, to date, selective blockade of IK by the atrium has been used_urAntiarrhythmic drugs of the current or Kv1.5 channels are not yet on the market. Although the effect of numerous active pharmaceutical ingredients (e.g. quinidine, bupivacaine or propafenone) to block the kv1.5 channel has been described, in each of these cases the kv1.5 block represents only a side effect in addition to the other major effects of these substances.

A number of patent applications have described a variety of substances as kv1.5 channel blockers in recent years. A compilation and detailed discussion of these substances has been recently published (J.Brendel, S.Peukert; Curr.Med.Chem. -Cardiovasular & hematology Agents, 2003, I, 273-287; "Kv1.5 channel blockers for the treatment of atrial arrhythmias"). However, all kv1.5 blockers disclosed to date and described therein have a completely different type of structure from the compounds invented in this application. Furthermore, to date, no clinical data on the efficacy and tolerability of any of these compounds disclosed to date has been published for humans. Experience has shown that: only a small fraction of the active ingredients successfully overcome all clinical obstacles from preclinical studies to drugs, and there is a continuing need for new promising substances.

It has now surprisingly been found that: the compounds of formula I of the present invention and/or their pharmaceutically acceptable salts are potent blockers of the human kv1.5 channel.

Furthermore, the compounds of the formula I and/or their pharmaceutically acceptable salts also act on the acetylcholine-activated potassium channel KACh and on the TASK-1 channel, which likewise predominantly occurs in the atria (Krapivinsky G., Gordon E.A., Wickman K., Velimiroviric B., Krapivinsky L., Clapham D.E.: G-protein-gated atrial K)⁺Channel I_KAChIs two inward commutations K⁺Heteropolymers of channel proteins, Nature 374(1995) 135-141; liu, w., Saint, d.a.: "quantification of adults and embryos by real-time polymerase chain reactionRat heart diplopore K⁺Heterologous expression of channel genes ", clin. exp. pharmacol. physiol.31(2004) 174-; jones s.a., Morton, m.j., Hunter m., Boyett m.r.: "pH sensitive diplopore Domain K in rat myocytes⁺Expression of the channel TASK-1 ", am.J.Physiol.283(2002) H181-H185).

Due to the combined effect on a variety of atrial-specific potassium channels, the compounds of formula I and/or their pharmaceutically acceptable salts are therefore useful as novel antiarrhythmic agents with particularly advantageous safety profiles. The compounds are particularly suitable for the treatment of supraventricular arrhythmias, such as atrial fibrillation or atrial flutter.

The compounds of formula I and/or pharmaceutically acceptable salts thereof may also be useful in the treatment and prevention of diseases in which atrial specific potassium channels, such as Kv1.5, KACh and/or TASK-1, are only partially inhibited, for example by using lower doses.

Compounds of formula I and/or pharmaceutically acceptable salts thereof are useful for preparing compounds having K⁺Channel blocking effect, treatment and prevention of K⁺A drug for a channel-mediated disease. The compounds of formula I and domains thereof and pharmaceutically acceptable salts thereof may further be used for the treatment or prevention of cardiac arrhythmias which may be abrogated by prolonging the action potential.

The compounds of formula I and/or pharmaceutically acceptable salts thereof may be used to terminate existing atrial fibrillation or flutter to restore sinus rhythm (cardioversion). Furthermore, the substance reduces the susceptibility to develop new fibrillation events (maintenance, prevention of sinus heart rate). It has further been observed that said substances are effective in preventing life-threatening ventricular arrhythmias (ventricular fibrillation) and are capable of protecting against sudden cardiac death without causing an undesired prolongation of the so-called QT interval.

The compounds of formula I and/or pharmaceutically acceptable salts thereof are useful for the preparation of medicaments for the treatment or prevention of reentry arrhythmias (reentry arrhythmias), supraventricular arrhythmias, atrial fibrillation and/or atrial flutter.

The compounds of formula I and/or their pharmaceutically acceptable salts may further be suitable for the preparation of medicaments for the treatment or prophylaxis of heart failure, in particular diastolic heart failure, and for increasing atrial contractility.

Compounds of formula I and/or pharmaceutically acceptable salts thereof inhibit the TASK potassium channels, for example the subtypes TASK-1 and TASK-3, and especially the subtype TASK 1. Due to the TASK-inhibiting properties, the compounds of formula I and/or pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of diseases caused by TASK-1 activated or activated TASK-1, as well as diseases secondary to TASK-1 related injuries.

Due to the effect of these substances on the TASK channel, the compounds of formula I and/or their pharmaceutically acceptable salts are also suitable for the preparation of medicaments for the treatment or prevention of the following diseases: respiratory disorders, in particular sleep apnoea, neurodegenerative disorders and cancer, such as sleep-related respiratory disorders, central and obstructive sleep apnoea, Cheyne-stokes respiration, snoring, impaired central respiratory drive, sudden infant death, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders associated with altitude adaptation, acute and chronic lung disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, alzheimer's disease, parkinson's disease, huntington's chorea, cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

The invention relates to a compound of formula I and pharmaceutically acceptable salts and trifluoroacetates thereof,

wherein each meaning is:

a C, S or S ═ O;

n 0, 1, 2 or 3;

r1 phenyl, pyridyl, thienyl, naphthyl, quinolyl, pyrimidinyl or pyrazinyl,

wherein each of these aryl groups is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylhydro groups;

or

R1 cycloalkyl having 3, 4, 5, 6 or 7C atoms;

r2 phenyl, pyridyl, thienyl, naphthyl, quinolinyl, pyrimidinyl, or pyrazinyl, wherein each of these aryl groups is unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, COOMe, CONH₂Alkoxy having 1, 2, 3 or 4C atoms, OCF₃OH, methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino;

R3 C_pH_2p-R8；

p 0, 1, 2, 3, 4 or 5;

R8 CH₃、CH₂F、CHF₂、CF₃cycloalkyl having 3, 4, 5, 6 or 7C atoms, C.ident.CH, C.ident.C-CH₃Alkoxy having 1, 2, 3 or 4C atoms, phenyl or pyridyl,

wherein phenyl and pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms, alkoxy having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r4 hydrogen or alkyl having 1, 2 or 3C atoms;

r5 hydrogen or alkyl having 1, 2 or 3C atoms;

r6 and R7

Independently of one another, hydrogen, F or alkyl having 1, 2 or 3C atoms.

Preferred compounds of the formula I in one embodiment are those in which the meanings are as follows and the pharmaceutically acceptable salts and trifluoroacetates thereof:

a C, S or S ═ O;

n 0, 1, 2 or 3;

r1 phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,

wherein each of these aryl groups is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino;

or

R1 cyclohexyl;

r2 phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,

wherein each of these aryl groups is unsubstituted or selected from the group consisting of 1, 2 or 3Substituted with a substituent of group (d): F. cl, Br, I, CN, COOMe, CONH₂Alkoxy having 1, 2, 3 or 4C atoms, OCF₃OH, methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino;

R3 C_pH_2p-R8；

p 0, 1, 2, 3, 4 or 5;

R8 CH₃、CH₂F、CHF₂、CF₃cycloalkyl having 3, 4, 5, 6 or 7C atoms, C.ident.CH, C.ident.C-CH₃Alkoxy having 1, 2, 3 or 4C atoms, phenyl or 2-pyridyl,

wherein phenyl and 2-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms, alkoxy having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r4 hydrogen or alkyl having 1, 2 or 3C atoms;

r5 hydrogen or alkyl having 1, 2 or 3C atoms;

r6 and R7

Independently of one another, hydrogen, F or alkyl having 1, 2 or 3C atoms.

Particularly preferred compounds of the formula I are those in which the meanings are as follows and the pharmaceutically acceptable salts and trifluoroacetates thereof:

a is C or S ═ O;

n is 0, 1, 2 or 3;

r1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl,

wherein each of these aryl groups is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of

Substituted by substituent groups: F. cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃And alkyl having 1, 2, 3 or 4C atoms;

or

R1 is cyclohexyl;

r2 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl,

wherein each of these aryl groups is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: cl, Br, I, CN, CF₃Alkyl having 1, 2, 3 or 4C atoms;

r3 is C_pH_2p-R8；

p is 0, 1, 2, 3 or 4;

r8 is CH₃、CH₂F、CHF₂、CF₃Cycloalkyl having 3, 4, 5 or 6C atoms, C.ident.CH, C.ident.C-CH₃Alkoxy having 1, 2, 3 or 4C atoms, phenyl or 2-pyridyl,

wherein phenyl and 2-pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: F. cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms and alkoxy having 1, 2, 3 or 4C atoms;

r4 is hydrogen or alkyl having 1, 2 or 3C atoms;

r5 is hydrogen or alkyl having 1, 2 or 3C atoms;

r6 and R7

Independently of one another, hydrogen, F or alkyl having 1, 2 or 3C atoms.

One embodiment describes compounds of formula I wherein a is defined as C or SO, e.g., C.

Yet another embodiment describes compounds of formula I wherein n is 1 or 2.

A further embodiment describes compounds of the formula I, in which R1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl or cyclohexyl, preferably phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl or cyclohexyl, for example phenyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 8-quinolyl or cyclohexyl, wherein each of the aryl groups, for example phenyl, is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino, preferably F, Cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃And alkyl having 1, 2, 3 or 4C atoms; r1 is defined as, for example, phenyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 8-quinolyl or cyclohexyl, wherein phenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: F. cl, methoxy, OCF₃Methylsulfonyl or CF₃。

Yet another embodiment features compounds of formula I wherein R2 is phenyl, 2-pyridyl, 3-pyridyl4-pyridyl group, 2-thienyl group, 3-thienyl group, 1-naphthyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 2-pyrimidyl group, 4-pyrimidyl group, 5-pyrimidyl group, 2-pyrazinyl group, 3-pyridazinyl group or 4-pyridazinyl group, preferably phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-thienyl group, 3-thienyl group, 1-naphthyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group or 8-quinolyl group, such as phenyl, 2-pyridyl, 3-pyridyl, 2-thienyl or 8-quinolyl, wherein each of these aryl groups is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, COOMe, CONH₂Alkoxy having 1, 2, 3 or 4C atoms, OCF₃OH, methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino, preferably F, Cl, Br, I, CN, CF₃Alkyl having 1, 2, 3 or 4C atoms; r1 is defined as, for example, phenyl, 2-pyridyl, 3-pyridyl, 2-thienyl or 8-quinolyl, wherein phenyl and 2-thienyl are unsubstituted or substituted by 1 or 2, preferably 1, substituent selected from the group consisting of F and methyl.

One embodiment describes compounds of formula I wherein R3 is C_pH_2p-R8, wherein p is 0, 1, 2, 3 or 4, e.g. 0, 1, 2 or 3, R8 is CH₃、CH₂F、CHF₂、CF₃Cycloalkyl having 3, 4, 5 or 6C atoms, C.ident.CH, C.ident.C-CH₃Alkoxy having 1, 2, 3 or 4C atoms, phenyl or 2-pyridyl, e.g. CH₃、CH₂F、CF₃Cyclopropyl, C.ident.CH, C.ident.C-CH₃Phenyl or 2-pyridyl, wherein phenyl and 2-pyridyl, for example phenyl, are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: F. cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms, alkoxy having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylAcylamino, preferably F, Cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms and alkoxy having 1, 2, 3 or 4C atoms, such as Cl, CN, COMe and methoxy; r3 is defined as, for example, CH₃、CH₂F、CF₃Cyclopropyl, C.ident.CH, C.ident.C-CH₃Phenyl or 2-pyridyl, wherein phenyl is unsubstituted or substituted with 1 or 2, preferably 1, substituents selected from the group consisting of Cl, CN, COMe and methoxy.

Yet another embodiment describes compounds of formula I wherein R4 is hydrogen or methyl, for example hydrogen.

Yet another embodiment describes compounds of formula I wherein R5 is hydrogen or methyl, for example hydrogen.

Yet another embodiment describes compounds of formula I wherein one of the substituents R4 and R5 is methyl and the other is hydrogen, or both R4 and R5 are hydrogen.

Yet another embodiment describes compounds of formula I wherein R6 and R7 are independently from each other hydrogen or methyl, for example hydrogen. Yet another embodiment describes compounds of formula I wherein one of the substituents R6 and R7 is methyl and the other is hydrogen, or both R6 and R7 are hydrogen.

The compounds of formula I may exist in stereoisomeric forms. The asymmetric centers present may, independently of one another, have the S configuration or the R configuration. The present invention includes all possible stereoisomers, such as enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, such as enantiomers and/or diastereomers, in any ratio. Thus, the invention includes, for example, the enantiomers in the form: enantiomerically pure form, the levorotatory and dextrorotatory forms can be obtained in the form of a mixture of the two enantiomers in different ratios or in the form of a racemate. The mixtures can be fractionated to prepare the individual stereoisomers by conventional methods or, for example, by stereoselective synthesis, as desired.

If a mobile hydrogen is present, the invention also includes all tautomeric forms of the compounds of formula I.

The invention also includes derivatives of the compounds of formula I, e.g., solvates, such as hydrates and alcohol adducts, esters, prodrugs and other physiologically acceptable derivatives of the compounds of formula I as well as active metabolites of the compounds of formula I. Likewise, the present invention includes all crystalline forms of the compound of formula I.

The alkyl and alkylene groups may be straight or branched. This also applies to formula C_pH_2pAn alkylene group of (a). Alkyl and alkylene groups may also be straight-chain or branched if they are substituted or present in other groups, for example in alkoxy or in fluoroalkyl. Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Divalent groups derived from these groups, such as methylene, 1-ethylene, 1, 2-ethylene, 1-propylene, 1, 2-propylene, 2-propylene, 1, 3-propylene, 1-butylene, 1, 4-butylene, and the like, are examples of alkylene groups. One or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen atoms of the alkyl or alkylene group may be replaced by fluorine atoms. Substituted alkyl groups may be substituted at any position.

Likewise, the cycloalkyl group may be branched. Examples of cycloalkyl having 3 to 7C atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cycloheptyl and the like. One or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, hydrogen atoms in the cycloalkyl group may be replaced by fluorine atoms. Substituted cycloalkyl groups may be substituted at any position. Cycloalkyl groups may also be alkylcycloalkyl or branched forms of cycloalkylalkyl, such as methylcyclohexyl or cyclohexylmethyl.

The phenyl group may be unsubstituted or substituted one or more times, for example one, two or three times, by the same or different groups. If the phenyl group is substituted, it preferably has one or two identical or different substituents. Monosubstituted phenyl may be substituted in position 2, 3 or 4, disubstituted phenyl is substituted in position 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-, trisubstituted phenyl is substituted in position 2, 3, 4-, 2, 3, 5-, 2, 3, 6-, 2, 4, 5-, 2, 4, 6-or 3, 4, 5-. The corresponding statements also apply analogously to N-containing heteroaromatic systems, such as pyridyl, quinolyl, pyrimidinyl or pyrazinyl, naphthyl and thienyl, for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl.

If the radicals are di-or trisubstituted, the substituents may be identical or different.

If the compounds of the formula I contain one or more basic groups or one or more basic heterocycles, the invention also encompasses the corresponding physiologically, pharmaceutically or toxicologically acceptable salts, in particular the pharmaceutically acceptable salts, and also the trifluoroacetates. Thus, the compounds of the formula I having one or more basic, i.e. protonatable, groups or containing one or more basic heterocycles may also be used in the form of their physiologically tolerated acid addition salts with inorganic or organic acids, for example the hydrochloride, phosphate, sulfate, methanesulfonate, acetate, lactate, maleate, fumarate, malate, gluconate and the like. Salts may be obtained from compounds of formula I by conventional means, for example by combining with an acid in a solvent or dispersant or by anion exchange with other salts. The compounds of the formula I can also be deprotonated at the acidic group and used, for example, as alkali metal, preferably sodium or potassium, or ammonium salts, for example with ammonia or organic amines or amino acids.

The invention also relates to a process for the preparation of compounds of formula I. The compounds of formula I can be prepared by various chemical methods, for example starting from 2-amino-1, 2-diarylethanol of formula II as shown in scheme 1 or 2, wherein A, R1, R2, R3, R4, R5, R6, R7 and n have the meanings indicated above, and in the case of the aliphatic group R3Y is a leaving group such as Cl, Br, I, tosylate, mesyl ester, and in the case of the aromatic group R3Y can additionally be F.

Scheme 1

For the conversions shown in scheme 1, the compound of formula II is initially reacted with the compound of formula III in the presence of a base, such as sodium hydroxide. The resulting compound of formula IV is then reacted with a compound of formula V in the presence of a base, such as sodium hydride or potassium hydroxide, to give the desired compound of formula I.

Scheme 2

For the transformations shown in fig. 2, the compound of formula II is initially reacted with the compound of formula III in the presence of a base, such as sodium bicarbonate. The resulting compound of formula XVI is then mixed with a base, such as sodium hydroxide, and the mixture is reacted with a compound of formula V to provide the desired compound of formula I.

Yet another process for preparing compounds of formula I is in scheme 3 below, wherein A, R1, R2, R3, R4, R5, R6, R7 and n have the meanings given above, and in the case of the aliphatic group R3, Y is a leaving group such as Cl, Br, I, tosylate, mesyl ester, and in the case of the aromatic group R3, Y can additionally be F.

Scheme 3

As shown in scheme 3, to prepare the compound of formula I, the bromoketone of formula XVII is initially reacted with NHE₃Mixed and subsequently reacted with a compound of formula III. The resulting compound of formula XVIII is reacted with NaBH₄Reduction to give the compound of formula XVI. The resulting compound of formula XVI is then mixed with a base, such as sodium hydroxide, and the mixture is reacted with a compound of formula V to provide the desired compound of formula I.

The 2-amino-12, -diarylethanol of the formula II used is commercially available, known from the literature or can be prepared analogously to the synthetic methods disclosed in the literature for the 1, 2-aminoalcohols. Exemplary methods for synthesizing compounds of formula II and subsequent conversion to compounds of formula I of the present invention are detailed in the experimental section below. Likewise, the compounds of formulae III, V and XVII are commercially available, known from the literature or can be prepared by synthetic methods known to the skilled person.

Work-up and, if desired, purification of the products and/or intermediates is carried out by customary methods such as extraction, chromatography or crystallization and customary drying.

The use of compounds of formula I and pharmaceutically acceptable salts thereof as medicaments is claimed.

The compounds of the formula I according to the invention and their pharmaceutically acceptable salts can therefore be used as medicaments on their own, in mixtures with one another or in the form of pharmaceutical preparations for animals, preferably for mammals and in particular for humans.

The invention also relates to compounds of formula I and pharmaceutically acceptable salts thereof for the treatment and prevention of the aforementioned diseases, and their use for the preparation of medicaments for the aforementioned diseases and medicaments having a K + channel blocking effect.

Also claimed are pharmaceutical formulations comprising an effective amount of a compound of formula I and/or a pharmaceutically acceptable salt thereof, alone or in combination with other pharmaceutically active ingredients or drugs, together with pharmaceutically acceptable carriers and additives. The pharmaceutical preparations generally comprise 0.1 to 90% by weight of a compound of formula I and/or a pharmaceutically acceptable salt thereof. The pharmaceutical preparations can be prepared in a manner known per se. To this end, the compounds of the formula I and/or their pharmaceutically acceptable salts are converted, together with one or more solid or liquid pharmaceutical carriers and/or excipients and, if desired, in combination with other pharmaceutically active ingredients, into suitable dosage forms which can be used as medicaments in human medicine and veterinary medicine.

Furthermore, medicaments comprising a compound of formula I and/or a pharmaceutically acceptable salt thereof may be administered, for example, orally, parenterally, intravenously, rectally, transdermally, topically or by inhalation, and the preferred method of administration will depend on the individual condition, e.g. the particular manifestation of the disease. In addition, the compounds of formula I may be used alone or together with pharmaceutical excipients, especially in veterinary and human medicine. The amount of the medicament comprising the active ingredient of formula I and/or a pharmaceutically acceptable salt thereof is typically from 0.01mg to 1g per dosage unit.

The skilled worker is familiar, on the basis of his expert knowledge, with which excipients are suitable for the desired pharmaceutical formulation. In addition to solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, taste masking agents, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or colorants.

For oral use, the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by customary methods into suitable preparations, such as tablets, coated tablets, two-piece capsules (two-piece capsules), aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. The preparation can be carried out both as dry and as wet granules. Suitable as oily carriers or solvents are, for example, vegetable or animal oils such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or mixtures thereof. Examples of other excipients which are also used in other forms of administration are polyethylene glycol and polypropylene glycol.

For subcutaneous, intramuscular or intravenous administration, the active compounds are converted, if desired, into solutions, suspensions or emulsions with substances customary for this purpose, such as solubilizers, emulsifiers or other excipients. The compounds of formula I and/or their pharmaceutically acceptable salts can also be lyophilized and the resulting lyophilizates used, for example, for the preparation of injection or infusion products. Examples of suitable solvents are: water, physiological saline or alcohols, for example ethanol, propanol, glycerol, and sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Pharmaceutical preparations suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of formula I and/or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water or a mixture of such solvents. The formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and also propellant gases, if desired. Such formulations contain the active ingredient in a typical concentration of about 0.1 to 10% by weight, especially about 0.3 to 3% by weight.

The dose of the active ingredient to be administered or the dose of a pharmaceutically acceptable salt thereof depends on the individual case and should be adjusted to the individual case to achieve the optimum effect. It therefore naturally depends on the frequency of administration and on the potency and duration of action of the particular compound used for therapy or prophylaxis, but also on the type and severity of the disease to be treated, the sex, age, weight and individual response of the human or animal to be treated and whether the therapy is acute or prophylactic.

For a patient weighing about 75kg, the daily dosage of a compound of formula I and/or a pharmaceutically-acceptable salt thereof will generally be at least 0.001mg/kg to 100mg/kg body weight, preferably 0.01mg/kg to 20 mg/kg. Even higher doses may be required for acute episodes of the disease, such as in an intensive care unit. It may be necessary to reach 800mg daily, especially when used intravenously, for example in case of infarcted patients in intensive care units. The dose may be in the form of a single dose or divided into a plurality, e.g. two, three or four, of single doses. Parenteral administration by injection or infusion, for example continuous intravenous infusion, may be advantageous, in particular in the treatment of acute cases of cardiac arrhythmias, for example in intensive care units.

The compounds of formula I and/or their pharmaceutically acceptable salts can also be combined with other pharmaceutically active ingredients to achieve a beneficial therapeutic effect. Thus, in the treatment of cardiovascular disorders, advantageous combinations with substances acting on the cardiovascular system are possible. Suitable examples of such combination partners which are beneficial for cardiovascular disorders are other antiarrhythmic agents, e.g. type I, type II or type III antiarrhythmic agents, such as IK_rChannel blockers, e.g. dofetilide, or additional substances which lower blood pressure, such as ACE inhibitors (e.g. enalapril, captopril, ramipril), angiotensin antagonists, K⁺Channel activators and alpha-and beta-receptor blockers, and also sympathomimetic and adrenergic compounds, and Na⁺/H⁺Exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances with positive inotropic (positive inotropic) action such as digitosides or diuretics. In particular with beta receptor blockers or IK_rCombinations of channel blockers are particularly advantageous.

List of abbreviations:

TMSCl trimethylsilyl chloride

TFA trifluoroacetic acid

Et Ethyl group

DMF N, N-dimethylformamide

TEA Triethylamine

DMSO dimethyl sulfoxide

THF tetrahydrofuran

The compounds of formula I can be prepared by various methods. The preparation processes used for the preparation of the examples are described below, where R1, R2, R3, R4, R5, R6 and X have the same meaning as in the compounds of the formula I.

The compounds of formula I can be prepared by various methods. The preparation processes used for the preparation of the examples are described below, where A, R1, R2, R3, R4, R5, R6, R7 and n have the same meaning as in the compounds of formula I.

Preparation of 2-amino-12-diarylethanol

The following 2-amino-12, -diarylethanols were obtained from commercial sources:

(1S, 2R) -2-amino-1, 2-diphenylethanol,

(1R, 2S) -2-amino-1, 2-diphenylethanol,

(1R, 2R) -2-amino-1, 2-diphenylethanol and

(1S, 2S) -2-amino-1, 2-diphenylethanol.

All other 2-amino-12, -diarylalcohols were prepared by one of the following methods a1, a2, or A3.

General procedure for the Synthesis of 2-amino-12-diarylethanol

Method A1:

under argon, 1 molar equivalent of the specific aldehyde of formula VI is added to a solution of 1.5 molar equivalents of tert-butyl carbamate and 1.5 molar equivalents of sodium p-toluenesulfinate in acetonitrile. While cooling at 0-10 ℃, 2 molar equivalents of trimethylchlorosilane were added dropwise and the mixture was left at room temperature overnight. After addition of 400ml of water, the precipitated product of the formula VII is filtered off with suction and dried at 50 ℃ under vacuum. 0.9-1.0 molar equivalents of an aldehyde of the formula VIII are added to 1 molar equivalent of the resulting compound of the formula VII in dichloromethane in the presence of 0.1 to 0.3 molar equivalents of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide and 15 molar equivalents of triethylamine, and the mixture is heated at 35 ℃ until the reaction is complete (2-8 hours). The resulting reaction product of formula IX is reduced with 1 molar equivalent of sodium borohydride in methanol and the tert-butoxycarbonyl group is removed with hydrochloric acid or trifluoroacetic acid. 2-amino-1, 2-diarylethanol is obtained in the form of a mixture or 2 diastereomers, wherein the diastereomer of the formula IIa shown is usually predominant, in a proportion of 70 to 90%.

Method A2:

1 molar equivalent of the aldehyde or ketone of the formula X and 1.2 molar equivalents of the isocyanate of the formula XI dissolved together in THF are added dropwise over the course of 15 minutes to a solution of 1.2 molar equivalents of potassium tert-butoxide in 50ml of THF, cooled in an ice bath. After removal of the ice bath, stirring was continued for one hour, followed by addition of dilute hydrochloric acid to terminate the reaction. If desired, the oxazolidinethione of the formulae XIIa and XIIb obtained in this way can be separated into diastereoisomers, which can be achieved first by chromatographic methods and by fractional crystallization. In most cases the diastereomers are prepared in a ratio of about 50: 50. The purified oxazolidinones of the formulae XIIa and XIIb (e.g. 7mmol) are usually dissolved in methanol and 2N sodium hydroxide solution and then in excess of 35% H₂O₂And (6) processing. The solution became very hot and was allowed to cool to room temperature and stirred for an additional 1-3 hours. After removal of most of the methanol, the resulting oxazolidinones of the formulae XIIIa and XIIIb are crystalline and can be filtered off with suction. The subsequent hydrolysis of the amino alcohol of formula IIc or IId takes place under the following conditions: 1 molar equivalent of an oxazolidinone of formula XIIIa or XIIIb is dissolved in ethanol and 9 molar equivalents KOH in water are added. The mixture was boiled under reflux for 8 to 24 hours.

Method A3:

a solution of 81 molar equivalents of sodium nitrite in water is added dropwise at room temperature to a solution of 1 molar equivalent of the 1, 2-diarylethanone of the formula XIV in water/concentrated hydrochloric acid (8: 1). After 2 hours, the solution was neutralized with sodium carbonate. The resulting oxime of formula XV is dissolved in ethanol and, after addition of 3 mole percent platinum oxide, hydrogenated at atmospheric pressure until no more hydrogen is absorbed. After filtration and concentration of the solution, 2-amino-1, 2-diarylethanol is obtained as a mixture of two diastereomers of the formulae IIa and IIb. Depending on the aromatic groups RI and R2, diastereomers can be separated in this step or one of the following steps by chromatography or crystallization. General procedure for the Synthesis of 1-Cycloamido-2-alkoxy-1, 2-diarylethane from 2-amino-1, 2-diarylethanol

Method B1:

2-3 molar equivalents of triethylamine and 1 molar equivalent of an omega-haloalkylcarbonyl chloride or sulfonyl chloride of formula III (e.g., 5-chlorobutyryl chloride) are slowly added dropwise to a solution of 2-amino-1, 2-diarylethanol of formula II in DMF. After stirring for 20 minutes, a 10 molar equivalent sodium hydroxide tablet was added at 0 ℃ and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and the precipitated product was filtered off with suction or isolated by extraction with ethyl acetate. The alcohol of formula IV is subsequently reacted with 1 molar equivalent of a compound of formula V, wherein Y is preferably chlorine, bromine or iodine if R3 is an aliphatic group, or may also be fluorine if R3 is an aromatic group, i.e. for example with bromoalkane or an arylfluoride compound such as cyclopropylbromomethane or p-fluorobenzonitrile. The reaction is carried out with at least 1 molar equivalent of sodium hydride in DMF or potassium hydroxide as base in DMSO. Depending on the progress of the reaction, a further amount of compound of the formula V and base is subsequently added until the reaction is complete.

Method B2:

the solution of the aminoalcohol compound of formula II or its hydrochloride salt is dissolved in dichloromethane and the same volume of saturated aqueous sodium bicarbonate solution is additionally added. 1.05 molar equivalents of the omega-haloalkylcarbonyl chloride or sulfonyl chloride of formula III were added to the vigorously stirred mixture, and the mixture was stirred at room temperature for a further 60 minutes. The organic phase is then separated off and the compound of formula XVI is isolated therefrom by crystallization. The compound of formula XVI is dissolved in DMSO and 10-100 molar equivalents of powdered NaOH are added. After stirring for 10 to 30 minutes at room temperature, 3 to 5 molar equivalents of a compound of the formula V are added, where Y can have the meaning described in method B1. The mixture is stirred at room temperature for 1-10 hours and, if desired, an additional amount of the compound of formula V is added until alkylation is complete.

General procedure for the synthesis of 1-cycloamido-2-alkoxy-1, 2-diarylethanes from bromoketones

The method C comprises the following steps:

strong NH is generated₃The gas stream is passed through a vigorously stirred solution of the bromoketone of formula XVII (wherein R2 and R1 are substituted) in dimethylformamide for 15 to 20 minutes, followed by a stream of intense air for 30 minutes to remove again the excess NH from the solution₃. Subsequently, 1.1 molar equivalents of triethylamine and 1.1 molar equivalents of the ω -haloalkylcarbonyl chloride or sulfonyl chloride of formula III are added to the mixture. The compound of the formula XVIII obtained in this case is isolated in a conventional manner and subsequently reduced with sodium borohydride in methanol.

The aminoalcohol of formula XVI obtained in this way is dissolved in DMSO, 10 to 100 molar equivalents of powdered NaOH are added. After stirring for 10 to 30 minutes at room temperature, 3 to 5 molar equivalents of the compound of the formula V, where Y can have the meaning described in method B1, are added. The mixture is stirred at room temperature for 1-10 hours and, if desired, an additional amount of the compound of formula V is added until alkylation is complete.

The starting compounds described in the synthetic methods, such as compounds of formulae III, V, VI, VIII, X, XI, XIV and XVII, are commercially available or can be prepared by or analogously to methods described in the literature and known to the skilled worker.

Work-up and, if necessary, purification of the products and/or intermediates is carried out by customary methods such as extraction, chromatography or crystallization and customary drying.

Examples Using general synthetic methods

Example 1: 1- [ (1R ', 2S') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-quinolin-8-ylethyl ] -piperidin-2-one (general procedure Synthesis: A1+ B1)

a) [ (4-fluorophenyl) (toluene-4-sulfonyl) methyl ] carbamic acid tert-butyl ester

15.0g (121mmol) of 4-fluorobenzaldehyde are added under argon to a solution of 21.3g (184mmol) of tert-butyl carbamate and 32.3g (181mmol) of sodium p-toluenesulfinate in 430ml of acetonitrile. While cooling to 0-10 ℃, 26.3g (242mmol) of trimethylsilyl chloride was added dropwise, and the mixture was left at room temperature overnight. After addition of 400ml of water, the precipitated product is filtered off with suction and dried in vacuo at 50 ℃. 36.3g of tert-butyl [ (4-fluorophenyl) (toluene-4-sulfonyl) methyl ] carbamate are obtained.

b) [1- (4-fluorophenyl) -2-oxo-2-quinolin-8-ylethyl ] carbamic acid tert-butyl ester

1.9g (5.1mmol) of tert-butyl [ (4-fluorophenyl) (toluene-4-sulfonyl) methyl ] carbamate, 255mg (1.0mmol) of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide, 10.5ml (76mmol) of triethylamine and 0.72g (4.55mmol) of 8-quinolinecarboxaldehyde are mixed at room temperature in 44ml of dichloromethane and then heated at 35 ℃ for 3 hours. After the reaction of the aldehyde was completed, 25ml of a saturated ammonium chloride solution was added, and the reaction mixture was stirred for 15 minutes. After removal of the aqueous phase, the organic phase is washed with 0.5M sodium hydroxide solution and saturated sodium chloride solution to give 1.7g of tert-butyl [1- (4-fluorophenyl) -2-oxo-2-quinolin-8-ylethyl ] carbamate and the reaction is continued without purification.

c) 2-amino-2- (4-fluorophenyl) -1-quinolin-8-ylethanol

0.48g (13mmol) of sodium borohydride are added to a solution of 4.9g (13mmol) of tert-butyl [1- (4-fluorophenyl) -2-oxo-2-quinolin-8-ylethyl ] carbamate in 75ml of methanol at 0-5 ℃. After 1 hour, the reaction mixture was concentrated, diluted with ethyl acetate and water, and the organic phase was washed with saturated ammonium chloride and sodium bicarbonate solution. The residue after drying and concentration of the organic phase is dissolved in 40ml of dichloromethane and 9ml of trifluoroacetic acid are added. After 2 hours, ice water was added and the product was extracted into the aqueous phase. The aqueous phase is basified and the product is extracted with dichloromethane, yielding 1.5g of 2-amino-2- (4-fluorophenyl) -1-quinolin-8-ylethanol.

d)1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] piperidin-2-one

0.43g (2.7mmol) of 5-chlorovaleryl chloride are slowly added dropwise to a solution of 0.75g (2.7mmol) of 2-amino-2- (4-fluorophenyl) -1-quinolin-8-ylethanol and 0.41g (4.0mmol) of triethylamine in 17ml of DMF. After stirring for 20 minutes, 1.3g (33mmol) of sodium hydroxide pellets were added at 0 ℃ and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice-water and the precipitated product was filtered off with suction and recrystallized from heptane/ethyl acetate. 600mg of 1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] piperidin-2-one are obtained as a single diastereomer.

e)1- [ (1R ', 2S') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-quinolin-8-ylethyl ] piperidin-2-one

26mg (0.55mmol) of sodium hydride are added at-10 ℃ to a solution of 0.2g (0.55mmol) of 1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] piperidin-2-one in 4ml of DMF. After stirring for 1 hour, 222mg (1.6mmol) of cyclopropylmethyl bromide are added. After stirring overnight, 26mg of sodium hydride and 222mg of cyclopropylmethyl bromide were added in each case until the starting materials had reacted completely. The residue after concentration in vacuo is taken up in 20ml of water and 20ml of ethyl acetate and the organic phase is washed with saturated sodium bicarbonate solution. Drying and concentration in vacuo gave 0.23g1- [ (1R ', 2S') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-quinolin-8-ylethyl ] piperidin-2-one.

Example 2: 1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-pyridin-3-yl-2- (4, 4, 4-trifluorobutoxy) -ethyl ] pyrrolidin-2-one (general procedure Synthesis: A1+ B1)

a) [1- (4-fluorophenyl) -2-oxo-2-pyridin-3-ylethyl ] carbamic acid tert-butyl ester

10.0g (26.4mmol) of tert-butyl [ (4-fluorophenyl) (toluene-4-sulfonyl) methyl ] carbamate, 665mg (2.6mmol) of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide, 55ml (395mmol) of triethylamine and 5.6g (26.4mmol) of 3-pyridinecarboxaldehyde are mixed in 230ml of dichloromethane at room temperature and then heated at 35 ℃ for 3 hours. After the reaction of the aldehyde was completed, 100ml of a saturated ammonium chloride solution was added, and the reaction mixture was stirred for 10 minutes. After removal of the aqueous phase, the organic phase is washed with 0.5M sodium hydroxide solution and saturated sodium chloride solution. 9.7g of tert-butyl [1- (4-fluorophenyl) -2-oxo-2-pyridin-3-ylethyl ] carbamate are obtained and the reaction is continued without purification.

b) (1S ', 2R') -2-amino-2- (4-fluorophenyl) -1-pyridin-3-ylethanol

0.36g (9.6mmol) of sodium borohydride are added at 0-5 ℃ to a solution of 3.2g (9.6mmol) of tert-butyl [1- (4-fluorophenyl) -2-oxo-2-pyridin-3-ylethyl ] carbamate in 40ml of methanol. After 3 hours, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried and the concentrated residue suspended in 60ml dichloromethane and 18ml of saturated HCl in dioxane was added. After 2 hours, the precipitated product is filtered off with suction to give 1.7g of (1S ', 2R') -2-amino-2- (4-fluorophenyl) -1-pyridin-3-ylethanol as the hydrochloride salt.

c)1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-hydroxy-2-pyridin-3-ylethyl ] pyrrolidin-2-one

0.87g (6.1mmol) of 5-chlorobutyl chloride is slowly added dropwise to a solution of 1.7g (6.1mmol) of (1S ', 2R') -2-amino-2- (4-fluorophenyl) -1-pyridin-3-ylethanol hydrochloride and 1.6g (15.4mmol) of triethylamine in 40ml of DMF. After stirring for 30 minutes, 3.1g (77mmol) of sodium hydroxide pellets were added at 0 ℃ and the mixture was stirred at room temperature for 3 hours. The mixture was poured into 100ml of ice water, and extracted with ethyl acetate. After washing the organic phase with saturated ammonium chloride and brine solution, 1.57g of 1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-hydroxy-2-pyridin-3-ylethyl ] pyrrolidin-2-one was obtained.

d)1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-pyridin-3-yl-2- (4, 4, 4-trifluorobutoxy) ethyl ] -pyrrolidin-2-one

0.26g (6.6mmol) of 60% sodium hydride and 1.26g (6.6mmol) of 4, 4, 4-trifluorobutyl bromide are added at 0 ℃ to a solution of 1.98g (6.6mmol) of 1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-hydroxy-2-pyridin-3-ylethyl ] pyrrolidin-2-one in 60ml of DMF. The mixture was allowed to stand at room temperature for 5 days, during which time 50% of the initial amount of sodium hydride and 4, 4, 4-trifluorobutyl bromide were added daily. The residue after the water treatment was purified by chromatography and the resulting product was recrystallized from ethyl acetate and heptane. This gave 710mg of 1- [ (1R ', 2S') -1- (4-fluorophenyl) -2-pyridin-3-yl-2- (4, 4, 4-trifluorobutoxy) ethyl ] -pyrrolidin-2-one.

Example 3: 1- [ (1R ', 2S') -2-cyclopropylmethoxy-2- (4-fluorophenyl) -1-quinolin-8-ylethyl ] -pyrrolidin-2-one (general procedure Synthesis: A1+ B2)

a) [ Quinolin-8-yl (toluene-4-sulfonyl) methyl ] carbamic acid tert-butyl ester

5.0g (32mmol) of 8-quinolinecarboxaldehyde are added under argon to a solution of 5.6g (48mmol) of tert-butyl carbamate and 8.5g (48mmol) of sodium p-toluenesulfinate in 112ml of acetonitrile. While cooling to 0-10 ℃, 6.9g (64mmol) of trimethylchlorosilane were added dropwise and the mixture was left at room temperature overnight. After addition of 130ml of water, the precipitated product is filtered off with suction and dried at 50 ℃ under vacuum. 11.4g of tert-butyl [ quinolin-8-yl (toluene-4-sulfonyl) methyl ] carbamate are obtained.

b) [2- (4-fluorophenyl) -2-oxo-1-quinolin-8-ylethyl ] carbamic acid tert-butyl ester

5.5g (13mmol) of tert-butyl [ quinolin-8-yl (toluene-4-sulfonyl) methyl ] carbamate, 336mg (1.3mmol) of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide, 27ml (200mmol) of triethylamine and 3.9g (13mmol) of 4-fluorobenzaldehyde are mixed at room temperature in 115ml of dichloromethane and then heated at 35 ℃ for 3 hours. After the reaction of the aldehyde was completed, 50ml of a saturated ammonium chloride solution was added, and the reaction mixture was stirred for 10 minutes. After removal of the aqueous phase, the organic phase is washed with 0.5M sodium hydroxide solution and saturated sodium chloride solution. After drying over magnesium sulphate and concentration of the organic phase, a semi-solid residue is obtained, which is stirred with 50ml of diethyl ether. The solid residue is filtered off with suction to yield 3.2g of tert-butyl [2- (4-fluorobenzene) -2-oxo-1-quinolin-8-ylethyl ] carbamate.

c) (1S ', 2R') -2-amino-1- (4-fluorobenzene) -2-quinolin-8-ylethanol

0.30g (7.9mmol) of sodium borohydride are added at 0-5 ℃ to a solution of 3.0g (7.9mmol) of tert-butyl 2- (4-fluorobenzene) -2-oxo-1-quinolin-8-ylethyl ] carbamate in 13ml of methanol. After 2 hours, the reaction mixture was diluted with ethyl acetate and water and the organic phase was washed with saturated ammonium chloride and sodium bicarbonate solution. The residue after drying and concentration of the organic phase is dissolved in 30ml of dichloromethane and 11ml of trifluoroacetic acid are added. After 2 hours, ice water was added and the product was extracted into the aqueous phase. After basification of the aqueous phase, the product is extracted with dichloromethane, yielding 1.8g of (1S ', 2R') -2-amino-1- (4-fluorophenyl) -2-quinolin-8-yl ethanol.

d) (1R ', 2S') -4-chloro-N- [2- (4-fluorophenyl) -2-hydroxy-1-quinolin-8-ylethyl ] butanamide

0.85g (6mmol) of 4-chlorobutyryl chloride are added at 0 ℃ to a solution of 1.8g (4.6mmol) (1S ', 2R') -2-amino-1- (4-fluorophenyl) -2-quinolin-8-ylethanol and 2ml triethylamine in 40ml DMF. After the mixture had been left overnight, it was treated with water and the reaction product was purified by chromatography with heptane/ethyl acetate 50: 50 to 25: 75. This gave 1.8g of (1R ', 2S') -4-chloro-N- [2- (4-fluorophenyl) -2-hydroxy-1-quinolin-8-ylethyl ] butanamide.

e)1- [ (1R ', 2S') -2-cyclopropylmethoxy-2- (4-fluorophenyl) -1-quinolin-8-ylethyl ] pyrrolidin-2-one

A solution of 1.8g of 4-chloro-N- [ (1R ', 2S') -2- (4-fluorophenyl) -2-hydroxy-1-quinolin-8-ylethyl ] butanamide, 560mg of potassium hydroxide and 1.0g of cyclopropylmethyl bromide in 15ml of DMSO is stirred at room temperature overnight. The crude product obtained after the water treatment was purified by chromatography on silica gel with heptane/ethyl acetate 50: 50 to yield 0.45g of 1- [ (1R ', 2S') -2-cyclopropylmethoxy-2- (4-fluorophenyl) -1-quinolin-8-ylethyl ] pyrrolidin-2-one.

Example 4: 4- [ (1R ', 2S') -1- (3, 4-difluorophenyl) -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) ethoxy ] benzonitrile (general procedure Synthesis: A1+ B1)

a) [ tert-butyl [2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-oxoethyl ] carbamate

30.0g (79mmol) of tert-butyl [ (4-fluorophenyl) (toluene-4-sulfonyl) methyl ] carbamate, 5.9g (23mmol) of 3-ethyl-5- (2-hydroxyethyl) -4-methylthiazolium bromide, 164ml (1.2mol) of triethylamine and 11.2g (79mmol) of 3, 4-difluorobenzaldehyde are mixed at room temperature in 700ml of dichloromethane and then heated at 35 ℃ for 6 hours. After the reaction of the aldehyde was completed, a saturated ammonium chloride solution was added and the reaction mixture was stirred for 15 minutes. After removal of the aqueous phase, the organic phase is washed with 0.5M sodium hydroxide solution and saturated sodium chloride solution to give 29.0g of tert-butyl [2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-oxoethyl ] carbamate, which is reacted further without purification.

b) [ (1R ', 2S') -2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-hydroxyethyl ] carbamic acid tert-butyl ester

3.0g (79mmol) of sodium borohydride are added portionwise at 5 ℃ to a solution of 29.0g (79mmol) of tert-butyl [2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-oxoethyl ] carbamate in 450ml of methanol. After 1 hour, the precipitate which had precipitated out was filtered off with suction to give 23.3g of tert-butyl [ (1R ', 2S') -2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-hydroxyethyl ] carbamate.

c) (1S ', 2R') -2-amino-1- (3, 4-difluorophenyl) -2- (4-fluorophenyl) ethanol

20ml of a saturated solution of HCl in dioxane were added to a solution of 23.3g of tert-butyl [ (1R ', 2S') -2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-hydroxyethyl ] carbamate in 400ml of dichloromethane and the mixture was left at room temperature for 3 hours. After cooling to 0 ℃ 17.0g of (1S ', 2R') -2-amino-1- (3, 4-difluorophenyl) -2- (4-fluorophenyl) ethanol hydrochloride precipitate.

d)1- [ (1R ', 2S') -2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-hydroxyethyl ] pyrrolidin-2-one

0.9g (9.1mmol) of triethylamine and 0.51g (3.6mmol) of 4-chlorobutyryl chloride are added dropwise at 0 ℃ to a solution of 1.1g (3.6mmol) of (1S ', 2R') -2-amino-1- (3, 4-difluorophenyl) -2- (4-fluorophenyl) ethanolic hydrochloride in 45ml of THF. After 1h, 1.8g (45mmol) of sodium hydroxide and 10ml of DMF are added and stirring is continued for 1 h. The mixture was added to ice water and the organic phase was washed with ammonium chloride solution and sodium chloride solution. Drying and concentration gave 0.89g of 1- [ (1R ', 2S') -2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-hydroxyethyl ] pyrrolidin-2-one.

e)4- [ (1R ', 2S') -1- (3, 4-difluorophenyl) -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) ethoxy ] -benzonitrile

0.13g (2.9mmol) of sodium hydride are added at 0 ℃ to a solution of 0.89g (2.6mmol) of 1- [ (1R ', 2S') -2- (3, 4-difluorophenyl) -1- (4-fluorophenyl) -2-hydroxyethyl ] pyrrolidin-2-one in 40ml of DMF. After 5 minutes, 0.32g (2.6mmol) of 4-fluorobenzonitrile was added and the mixture was stirred for 2 hours. The crude product was purified by chromatography to give 0.69g of 4- [ (1R ', 2S') -1- (3, 4-difluorophenyl) -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) ethoxy ] -benzonitrile.

Example 5: 1- [ (1R ', 2S') -2-cyclopropylmethoxy-2-phenyl-1-pyridin-2-ylethyl ] pyrrolidin-2-one (general procedure Synthesis: A3+ B1)

a) 1-phenyl-2-pyridin-2-ylethane-1, 2-dione 2-oxime

A solution of 8.75g (127mmol) of sodium nitrite in water is added dropwise at room temperature to a solution of 25g (127mmol) of 1-phenyl-2-pyridin-2-yl-ethanone in 250ml of water/concentrated hydrochloric acid (8: 1). After 2 hours, the solution was neutralized with sodium carbonate. The product crystallized overnight to give 25.3g of 1-phenyl-2-pyridin-2-ylethane-1, 2-dione 2-oxime.

b) 2-amino-1-phenyl-2-pyridin-2-ylethanol

25.3g of 1-phenyl-2-pyridin-2-ylethane-1, 2-dione 2-oxime are dissolved in 300ml of ethanol, and, after addition of 1.0g of platinum oxide, are hydrogenated at atmospheric pressure until no more hydrogen is taken up. The solution was filtered and concentrated to give 21.6g of 2-amino-1-phenyl-2-pyridin-2-ylethanol as a mixture of 2 diastereomers.

c) Cis-and trans-1- (2-hydroxy-2-phenyl-1-pyridin-2-ylethyl) pyrrolidin-2-one

35ml (252mmol) of triethylamine and 11.3ml (101mmol) of 4-chlorobutyryl chloride are added dropwise successively at 50 ℃ to a solution of 21.6g (101mmol) of 2-amino-1-phenyl-2-pyridin-2-ylethanol in 50ml of DMF. After 1 hour at room temperature, 48.4g of sodium hydroxide were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and extracted with dichloromethane, and the organic phase was washed with water and sodium bicarbonate solution. 3.0g each of the cis and trans diastereomers of 1- (2-hydroxy-2-phenyl-1-pyridin-2-ylethyl) pyrrolidin-2-one were isolated by chromatography on silica gel using ethyl acetate/ethanol 20: 1. The relative stereochemistry was determined by X-ray spectroscopy.

d)1- [ (1R ', 2S') -2-cyclopropylmethoxy-2-phenyl-1-pyridin-2-ylethyl ] pyrrolidin-2-one

A solution of 150mg (0.53mmol)1- [ (1R ', 2S') -2-hydroxy-2-phenyl-1-pyridin-2-ylethyl ] pyrrolidin-2-one, 86mg (0.64mmol) cyclopropylbromide and 0.69mg KOH in 2ml DMSO was stirred at room temperature for 4 hours. Water treatment and purification by preparative HPLC gave 30mg of 1- [ (1R ', 2S') -2-cyclopropylmethoxy-2-phenyl-1-pyridin-2-ylethyl ] pyrrolidin-2-one.

Example 6: (1R ', 2S') -1- [2- (4-chlorophenyl) -1-phenyl-2-propoxyethyl ] pyrrolidin-2-one (general procedure C Synthesis)

a) Make strong NH₃The gas stream was passed through a solution of 309mg (1mmol) 2-bromo-1- (4-chlorophenyl) -2-phenylethanone for 15 minutes and an intense stream of air was passed through for 20 minutes. Then, 0.2ml of triethylamine and 0.17ml of chlorobutyryl chloride were added, and the mixture was stirred at room temperature for one hour. The solution was diluted with 80ml of water and acidified to pH 1-2 with 2N hydrochloric acid. The DMF was stripped off in vacuo and the aqueous residue was extracted twice with ethyl acetate. The organic phase was washed with water until neutral, MgSO₄And (5) drying. Flash chromatography on silica gel was performed on the residue after evaporation of the solvent in vacuo. Elution with a heptane/ethyl acetate solvent mixture gave 230mg of acylated aminoketone 4-chloro-N- [2- (4-chlorophenyl) -2-oxo-1-phenylethyl]And (3) butyramide.

b) Dissolving the product of step a) in 4ml of methanol and adding 100mg of NaBH₄. After stirring at room temperature for 2 hours, the solvent was removed and the residue was treated with water to give racemic (1R ', 2S') -4-chloro-N- [2- (4-chlorophenyl) -2-hydroxy-1-phenylethyl in pure form]And (3) butyramide.

c) 1g of (1R ', 2S') -4-chloro-N- [2- (4-chlorophenyl) -2-hydroxy-1-phenylethyl ] butanamide is dissolved in 20ml of DMSO and stirred with 1g of powdered NaOH at room temperature for 1 hour. Then 0.5g of propyl iodide was added and every 45 minutes 0.3g of propyl iodide was added until the total amount of propyl iodide was 1.4 g. The reaction mixture was then acidified and extracted several times with ethyl acetate. The residue after evaporation of the solvent was subjected to flash chromatography on 50g silica gel. Heptane/ethyl acetate 7: 1 gives 670mg of the final product (1R ', 2S') -1- [2- (4-chlorophenyl) -1-phenyl-2-propoxyethyl ] pyrrolidin-2-one.

Example 7: (1S, 2R) -2- (1, 2-Diphenyl-2-propoxyethyl) isothiazolidine-1, 1-dioxide (general procedure B2 Synthesis)

a) 213mg (1mmol) of (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol were dissolved in 2ml of DMF and 164. mu.l of triethylamine (1.19mmol) and 137. mu.l (1.13mmol) of 3-chloropropanesulfonyl chloride were added. After stirring at room temperature for one hour, the reaction mixture was poured into water and filtered with suction. 310mg (88%) of the desired intermediate 3-chloro-N- [ (1S, 2R) -2-hydroxy-1, 2-diphenylethyl ] propane-1-sulfonamide are obtained.

b) 300mg of [ (1S, 2R) -2-hydroxy-1, 2-diphenylethyl ] amide are suspended in 8ml of 2N sodium hydroxide solution and stirred at 80 ℃ for 2 hours, during which the initial crystalline suspension is converted into an oily suspension. The mixture was cooled and acidified with a minimal amount of concentrated hydrochloric acid (pH 1-2). A crystalline precipitate of (1R, 2S) -2- (1, 1-dioxoisothiazolidin-2-yl) -1, 2-diphenylethanol) was obtained, which was suction-filtered (70mg, 0.221 mmol).

c) The product from step b) (70mg, 0.221mmol) was dissolved in 1ml DMSO, 110mg of powdered NaOH was added, followed by 169mg (0.995mmol) of n-propyl iodide. The reaction mixture was stirred at room temperature for 1.5 hours and then diluted with water. The crystalline precipitate thus obtained was filtered off with suction. After drying, the material was stirred with n-heptane several times to give 14.5mg of (1S, 2R) -2- (1, 2-diphenyl-2-propoxyethyl) isothiazolidine-1, 1-dioxide.

Example 8: 1- (2-Cyclopropylmethoxy-1, 2-diphenylpropyl) pyrrolidin-2-one (general procedure A2+ B2 Synthesis)

a) 2.63g of potassium tert-butoxide (24mmol) are dissolved in 50ml of THF and cooled in an ice bath. A mixture of 3.918g (24mmol) of α -methylbenzyl isothiocyanate and 2.123g (20mmol) of benzaldehyde was added dropwise to the stirred solution over 20 minutes. After addition of the reagents, the ice bath was removed and the mixture was stirred for one hour. The mixture was added to ice water, acidified with 2N HCl and extracted 3 times with diethyl ether. The residue was pre-purified by chromatography on silica gel. 1.1g each of the crude diastereomeric oxazolidinethione are obtained. The faster moving isomer 0.78g was isolated in pure form by trituration with diisopropyl ether. Only this isomer undergoes the subsequent reaction.

b) 0.74g (2.75mmol) of the oxazolidinethione obtained in step a) are dissolved in 15ml of methanol with 2N sodium hydroxide solution (7.5ml) and 2.5ml of 35% strength H₂O₂And (6) processing. The mixture was added to ice-water, the product was filtered off with suction and immediately KOH in 37ml of methanol (1.1g in 18.75ml of H)₂O) dissolved, boiled under reflux for 10 hours. The solvent was then distilled off, the residue was diluted with water and the resulting precipitate (1-amino-1, 2-diphenylpropan-2-ol, 470mg) was filtered off with suction.

c) Acylation of 330mg (1.452mmol) of 1-amino-1, 2-diphenylpropan-2-ol with 215mg (1.525mmol) of 4-chlorobutyryl chloride and triethylamine (154mg, 1.525mmol) in 3.5ml of DMF takes place in the usual manner to give 430mg (89%) of the corresponding chlorobutyramide.

d) 420mg (1.266mmol) of the chlorobutanamide obtained in step c) are dissolved in 4ml of DMSO, and 400mg of NaOH powder are added. After stirring for one hour, work-up is carried out in the usual manner and the mixture is purified on silica gel using the eluent ethyl acetate/n-heptane 1: 2. The ring-closed compound (350mg, 94%) was obtained.

e) 210mg of the ring-closure product from step d) (0.711mmol) are dissolved in 2.5ml of DMSO and stirred with 227mg of powdered NaOH and 239mg (1.774mmol) of bromomethylcyclopropane at room temperature for 4 hours. Silica gel chromatography was performed after conventional treatment. 1- (2-Cyclopropylmethoxy-1, 2-diphenylpropyl) pyrrolidin-2-one (18mg, 9%) was obtained in pure form using ethyl acetate/n-heptane.

Example 9: 4- [ (1S ', 2R') -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) -1-quinolin-8-ylethoxy ] benzonitrile (general procedure Synthesis: A1+ B1)

And example 10: 4- [ (1R ', 2R') -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) -1-quinolin-8-ylethoxy ] benzonitrile (general procedure Synthesis: A1+ B1)

a)4[1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] carbamic acid tert-butyl ester

0.314g (8.3mmol) of sodium borohydride are added in 4 portions to a solution of 3.16g (8.3mmol) of tert-butyl [1- (4-fluorophenyl) -2-oxo-2-quinolin-8-ylethyl ] carbamate in 45ml of methanol at 0-5 ℃. The reaction mixture was stirred at 0-5 ℃ for 0.5 hour, then at room temperature for 0.5 hour, and then poured into an aqueous solution of sodium dihydrogenphosphate (80 g/l). Extracted twice with ethyl acetate and then dried over magnesium sulfate. Concentration gave 2.78g of tert-butyl [1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] carbamate (diastereomer mixture: 80/20) (yield: 88%) as a pale yellow powder.

b) 2-amino-2- (4-fluorophenyl) -1-quinolin-8-ylethanol hydrochloride

2.78g (7.27mmol) tert-butyl [1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] carbamate are dissolved in 75ml dichloromethane and cooled to 0 ℃.18 ml of HCl (4N) in dioxane was added and the mixture was stirred at 0 ℃ for 20 minutes and allowed to reach room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was treated with diisopropyl ether. Filtered, then washed with diisopropyl ether and pentane and dried under vacuum. 2.75g of 2-amino-2- (4-fluorophenyl) -1-quinolin-8-ylethanol were obtained as the hydrochloride salt (mixture of diastereomers: 85/15) as a pale yellow, very hygroscopic powder (yield: quantitative). This material was used in the next step without further purification.

c)1- [1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] pyrrolidin-2-one

0.615ml (5.18mmol) of 4-chlorobutyryl chloride (95%) are slowly added dropwise to a solution of 1.5g (4.7mmol) of 2-amino-2- (4-fluorophenyl) -1-quinolin-8-ylethanol hydrochloride and 1.96ml (14.1mmol) of triethylamine in 15ml of DMF, cooled to-8 ℃. After stirring at-8 to-10 ℃ for 1 hour, 2.25g (56.3mmol) of a sodium hydroxide tablet and 156mg (0.94mmol) of potassium iodide were added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into an aqueous sodium hydrogen phosphate solution (80 g/l). Extracted twice with diisopropyl ether and then dried over magnesium sulfate. The residue after concentration in vacuo is purified by chromatography using petroleum ether/ethyl acetate 50: 50, then 30: 70 to 0: 100. This gave 845mg of 1- [1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] pyrrolidin-2-one (diastereomer A) (yield: 51%) and 127mg1- [1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] pyrrolidin-2-one (diastereomer B) (yield: 8%).

Diastereomer a: 1- [ (1S ', 2R') -1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] pyrrolidin-2-one

Melting point: 156 deg.C

Diastereomer B: 1- [ (1R ', 2R') -1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] pyrrolidin-2-one

Melting point: light yellow oil

e)4- [ (1S ', 2R') -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) -1-quinolin-8-ylethoxy ] benzonitrile (example 9)

41mg (0.86mmol) of sodium hydride (50% in oil) are added to a solution of 200mg (0.57mmol) of 1- [1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] pyrrolidin-2-one (diastereomer A) in 2ml of DMF at 0 ℃ under argon. After 5 minutes, 104mg (0.86mmol) of 4-fluorobenzonitrile were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into aqueous sodium hydrogen phosphate (80g/l) and extracted twice with diisopropyl ether. Dried over magnesium sulfate and concentrated. The residue was purified by chromatography using heptane/ethyl acetate 30: 70 to give 239mg of 4- [ (1S ', 2R') -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) -1-quinolin-8-ylethoxy ] benzonitrile (yield: 93%) as a white powder.

Melting point: 112 deg.C

f)4- [ (1R ', 2R') -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) -1-quinolin-8-ylethoxy ] benzonitrile (example 10)

47mg (0.98mmol) of sodium hydride (50% in oil) are added to a solution of 228mg (0.65mmol) of 1- [1- (4-fluorophenyl) -2-hydroxy-2-quinolin-8-ylethyl ] pyrrolidin-2-one (diastereomer B) in 2ml of DMF at 0 ℃ under argon. After 5 minutes, 118mg (0.97mmol) of 4-fluorobenzonitrile were added and stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous solution of sodium dihydrogenphosphate (80g/l) and extracted twice with diisopropyl ether. Dried over magnesium sulfate and concentrated. The residue was purified by chromatography using heptane/ethyl acetate 30: 70 to give 197mg of 4- [ (1R ', 2R') -2- (4-fluorophenyl) -2- (2-oxopyrrolidin-1-yl) -1-quinolin-8-ylethoxy ] benzonitrile (diastereomer B) (yield: 67%) as a white powder.

Melting point: 188 deg.C

Example 11: 1- [ (1S ', 2R') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-naphthalen-1-ylethyl ] pyrrolidin-2-one (general procedure Synthesis: A1+ B1)

And example 12: 1- [ (1R ', 2R') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-naphthalen-1-ylethyl ] pyrrolidin-2-one (general procedure Synthesis: A1+ B1)

a) [1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] carbamic acid tert-butyl ester

0.72g (18.9mmol) of sodium borohydride are added in 4 portions to a solution of 7.2g (18.9mmol) of tert-butyl [1- (4-fluorophenyl) -2-naphthalen-1-yl-2-oxoethyl ] carbamate in 75ml of methanol at 0 ℃. The reaction mixture was stirred at 0-5 ℃ for 1 hour, and then poured into an aqueous solution of sodium dihydrogenphosphate (80 g/l). Extracted twice with ethyl acetate and then dried over magnesium sulfate. Concentration gave 7.4g of tert-butyl [1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] carbamate (diastereomer mixture: 85/15) (yield: quantitative) as a pale yellow oil. This material was used in the next step without further purification.

b) 2-amino-2- (4-fluorophenyl) -1-naphthalen-1-ylethanol hydrochloride

7.2g (18.9mmol) of tert-butyl [1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] carbamate are dissolved in 185ml of dichloromethane and cooled to 0 ℃. 47ml HCl in dioxane (4N) was added and the mixture was stirred at 0 ℃ for 15 minutes and allowed to reach room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was treated with diisopropyl ether. After filtration, it is washed with diisopropyl ether and pentane and dried under vacuum. 5.5g of 2-amino-2- (4-fluorophenyl) -1-naphthalen-1-ylethanol hydrochloride (diastereomer mixture: 85/15) (yield: 91%) were obtained as a white, very hygroscopic powder. This material was used in the next step without further purification.

c)1- [1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] pyrrolidin-2-one

2.15ml (18.1mmol) of 4-chlorobutyryl chloride (95%) are slowly added dropwise to a solution of 5.5g (17.3mmol) of 2-amino-2- (4-fluorophenyl) -1-naphthalen-1-ylethanol hydrochloride and 7.2ml (51.7mmol) of triethylamine in 55ml of DMF, cooled to-10 ℃. After stirring at room temperature for 2.5 hours, 8.3g (208mmol) of sodium hydroxide pellets and 862mg (5.2mmol) of potassium iodide were added, and the mixture was stirred at room temperature overnight. The mixture was poured into an aqueous solution of sodium dihydrogenphosphate (80 g/l). Extracted twice with diisopropyl ether and then dried over magnesium sulfate. The residue after concentration in vacuo is purified by chromatography using petroleum ether/ethyl acetate 50: 50. 3.8g of 1- [1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] pyrrolidin-2-one (diastereomer A) (yield: 63%) and 728mg of 1- [1- (4-fluorophenyl) -2-hydroxy-2- (1-naphthyl) ethyl ] pyrrolidin-2-one (diastereomer B) (yield: 12%) were obtained.

Diastereomer a: 1- [ (1S ', 2R') -1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] pyrrolidin-2-one

Melting point: 160 deg.C

Diastereomer B: 1- [ (1R ', 2R') -1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] pyrrolidin-2-one

Melting point: 190 deg.C

d)1- [ (1S ', 2R') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-naphthalen-1-ylethyl ] pyrrolidin-2-one (example 11)

124mg (2.58mmol) of sodium hydride (50% in oil) are added at 0 ℃ to a solution of 800mg (2.28mmol) of 1- [1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] pyrrolidin-2-one (diastereomer A) in 8ml of DMF. After stirring for 5 minutes, 335. mu.l (3.42mmol) of cyclopropylmethyl bromide were added. After stirring at room temperature for 2 hours, the mixture was poured into an aqueous solution of sodium dihydrogenphosphate (80 g/l). Extracted twice with diisopropyl ether and then dried over magnesium sulfate. The residue after concentration in vacuo is purified by chromatography using petroleum ether/ethyl acetate 70: 30. 835mg of 1- [ (1S ', 2R') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-naphthalen-1-ylethyl ] pyrrolidin-2-one (yield: 90%) are obtained as a white powder.

Melting point: 126 deg.C

e)1- [ (1R ', 2R') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-naphthalen-1-ylethyl ] pyrrolidin-2-one

(example 12)

149mg (3.1mmol) of sodium hydride (50% in oil) are added at 0 ℃ to a solution of 725mg (2.07mmol) of 1- [1- (4-fluorophenyl) -2-hydroxy-2-naphthalen-1-ylethyl ] pyrrolidin-2-one (diastereomer B) in 7ml of DMF. After stirring for 5 minutes, 300. mu.l (3.1mmol) of cyclopropylmethyl bromide were added. After stirring at room temperature for 2 hours, the mixture was poured into an aqueous solution of sodium dihydrogenphosphate (80 g/l). Extracted twice with diisopropyl ether and then dried over magnesium sulfate. The residue after concentration in vacuo is purified by chromatography using petroleum ether/ethyl acetate 60: 40. 715mg of 1- [ (1R ', 2R') -2-cyclopropylmethoxy-1- (4-fluorophenyl) -2-naphthalen-1-ylethyl ] pyrrolidin-2-one (yield: 85%) are obtained as a white powder.

Melting point: 150 ℃ C

Example 32: 1S, 2R-1- (Cyclopropoxy-1, 2-diphenylethyl) pyrrolidin-2-one

39mg (0.127mmol) of 1S, 2R-1- (1, 2-diphenyl-2-vinyloxyethyl) pyrrolidin-2-one (example 120) are dissolved in 2ml of anhydrous dichloromethane under argon. To this was added 0.63ml (0.69mmol) of a 1.1 molar solution of diethylzinc in toluene, followed by 169mg (0.63mmol) of diiodomethane. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with 2N hydrochloric acid and extracted with ethyl acetate. The solution dried over magnesium sulfate is evaporated in vacuo and the residue is purified chromatographically using heptane/ethyl acetate 6: 4 on 20g of silica gel. 34mg (83%) of 1S, 2R-1- (cyclopropoxy-1, 2-diphenylethyl) pyrrolidin-2-one are obtained.

Example 120: 1S, 2R-1- (1, 2-diphenyl-2-vinyloxyethyl) pyrrolidin-2-one

84mg (0.3mmol) of 1S, 2R-1- (2-hydroxy-1, 2-diphenylethyl) pyrrolidin-2-one plus 5mg (0.015mmol) of 4, 7-diphenyl [1, 9] phenanthroline and 5mg (0.015mmol) of palladium bistrifluoroacetate are dissolved in 1ml of butyl vinyl ether, and then 9mg (0.09mmol) of triethylamine is added under argon. The mixture was stirred at 70 ℃ for 3 hours under argon. The mixture was then poured into water and extracted several times with ethyl acetate. The combined organic layers were washed with water until neutral and dried over magnesium sulfate, then the solvent was evaporated under vacuum. The residue is chromatographed on 20g of silica gel with n-heptane/ethyl acetate as eluent. 25mg (27%) of 1S, 2R-1- (1, 2-diphenyl-2-vinyloxyethyl) pyrrolidin-2-one are obtained.

The following examples were prepared analogously to the above synthesis:

compounds with the so-called absolute stereochemistry are obtained as pure enantiomers of the described structure. The compounds referred to as two enantiomeric forms are obtained as racemic mixtures of two described enantiomers. No stereochemical structures are indicated as representing a racemic mixture of possible diastereomers.

Pharmacological study

Determination of Kv1.5 channel Activity

Human Kv1.5 channels were expressed in Xenopus oocytes. For this purpose, oocytes are first isolated from Xenopus laevis (Xenopus laevis) and the follicular membrane (deffoliculated) is removed. RNA encoding Kv1.5, synthesized in vitro, was then injected into these oocytes. After 1-7 days of Kv1.5 protein expression, the Kv1.5 current of the oocytes was measured using a double microelectrode voltage clamp technique. In this case, the Kv1.5 channel is usually activated to 0mV and 40mV with a voltage jump lasting 500 ms. A solution of the following composition was passed through the bath: NaCl 96mM, KCl 2mM, CaCl₂ 1.8mM、MgCl₂1mM, HEPES 5mM (titrated to pH 7.4 with NaOH). These experiments were performed at room temperature. Data acquisition and analysis were performed using the following instrument: geneclamp amplifiers (AxoInstructions, Foster City, USA) and MacLab D/A converters and software (ADInstructions, Castle Hill, Australia). The substances according to the invention were measured by adding them to the bath in different concentrations. The effect of the substance was calculated as the percentage inhibition of the kv1.5 control current obtained when no substance was added to the solution. The data were then extrapolated using Hill equation to determine the inhibitory concentration IC of each substance₅₀。

Determination of TASK-1 channel Activity

Human TASK-1 channels are expressed in Xenopus oocytes. For this purpose, oocytes are first isolated from xenopus laevis and the follicular membranes are removed. RNA encoding TASK-1, synthesized in vitro, was then injected into these oocytes. After TASK-1 protein is expressed for 2 days, a double microelectrode voltage clamp technology is usedThe TASK-1 current of the oocyte is measured. In this case, the TASK-1 channel is typically activated to 40mV with a voltage jump lasting 250 ms. A solution of the following composition was passed through the bath: NaCl 96mM, KCl 2mM, CaCl₂ 1.8mM、MgCl₂1mM, HEPES 5mM (titrated to pH 7.4 with NaOH). These experiments were performed at room temperature. Data acquisition and analysis were performed using the following instrument: geneclamp amplifiers (Axon Instruments, Foster City, USA) and MacLab D/A converters and software (ADInstructions, Castle Hill, Australia). The substances according to the invention were measured by adding them to the bath in different concentrations. The effect of the substance was calculated as the percentage inhibition of the TASK-1 control current obtained when no substance was added to the solution. The data were then extrapolated using Hill's equation to determine the half maximal Inhibitory Concentration (IC) of each species₅₀)。

Determination of KACh channel Activity

The effect of the substances on acetylcholine-activated potassium channels in isolated guinea pig atria was investigated by the technique of micro-puncture. After sacrifice by dislocation of the cervical vertebrae and disconnection of the spine, the heart was removed and the left atrium separated with fine scissors and fixed in the measuring chamber. Modified Krebs-Henseleit solution (in mmol/l: 136NaCl, 1.0KCl, 1.2 KH)₂PO₄、1.1MgSO₄、1.0CaCl₂5 glucose, 10HEPES, pH 7.4) was continuously passed through the tissue. The temperature in the measurement chamber was 37 ℃. The atrium is stimulated with 1 to 4 volt square wave pulses of 1 to 3 milliseconds duration at a frequency of 1 Hz. Action potentials were recorded using glass microelectrodes filled with 3mol/l KCl. The electrical signals were collected by an amplifier (model 309 microelectrode amplifier, Hugo Sachs, March-Hugstetten, Germany) and stored and analyzed in a computer. Summary of the experiments: after an equilibration time of 30 minutes, 1. mu. mol/l of carbachol was added to activate K by stimulating muscarinic receptors_AChAnd (3) ion channels. This results in a significant reduction in the action potential time course, 90% repolarization (APD)₉₀) About 150ms (without carbaryl) to 50ms after the addition of carbaryl (Gertjegerdes W., Ravens U., Zeigler A. (1979) "in the shadow of ouabain, calcium and stimulation ratesThe time course of the carbachol-induced response in the atria of guinea pigs was "j.cardiovasc.pharmacol.1: 235-243). In all further assays, bethanechol was present in the bath. After 30 minutes, 3. mu. mol/l of the test substance are added and after a further 30 minutes the action potential is recorded. To K_AChChannel blocking leads to APD₉₀And (5) prolonging. After a further 30 minutes, the substance concentration was raised to 10. mu. mol/l and the measurement was carried out after an exposure time of 30 minutes. Calculation of shortened APD caused by Carbamcholine₉₀The percentage elongation of the substance is set as the shortening by carbachol equal to 100%. Curve fitting with logistic function using calculated measurements: f (x) y_o+axⁿ/(cⁿ+xⁿ) Wherein c is IC₅₀And n is the Hill coefficient.

The following IC₅₀Values are determined for compounds of formula I:

example numbering	Kv1.5 IC-50[μM]	mTask-1 IC-50[μM]	KACh IC-50[μM]
				1	1.4		5.4
2	6
				3	0.5
4	3.9	2.3
				5	1.3
6	0.92
				7	0.6
8	1.2		5.8
				9	4.2	0.4	7.8
10	4.4
				11	0.2
12	0.5
				13	0.21		～10
14	0.33
				15	0.16
16	0.8
				17	0.3
18	0.4		4.2
				19	0.3
20	0.3
				21	0.8

Example numbering	Kv1.5 IC-50[μM]	mTask-1 IC-50[μM]	KACh IC-50[μM]
				22	0.5
23	0.65
				24	0.65
25	0.45
				26	1.0
27	0.6		～10
				28	0.9		～10
29	0.9
				30	1.1
31	1.4
				32	0.6
33	0.9
				34	1.0
35	0.5
				36	0.6
37	0.7
				38	0.7
39	1.1		7.4
				40	0.8
41	1.0
				42	0.6		4.4

Example numbering	Kv1.5 IC-50[μM]	mTask-1 IC-50[μM]	KACh IC-50[μM]
				43	1.4
44	0.5
				45	1.0
46	1.5	5.4
				47	1.0
48	2.1
				49	0.5
50	0.9
				51	0.9
52	2.0
				53	1.8
54	1.7
				55	1.1
56	0.8
				57	1.0
58	1.0		7.7
				59	1.9		6.7
60	1.3
				61	1.8
62	2.4
				63	1.7		5.6

Example numbering	Kv1.5 IC-50[μM]	mTask-1 IC-50[μM]	KACh IC-50[μM]
				64	1.83
65	1.5
				66	2.3
67	1.2
				68	0.5
69	1.6
				70	2.3
71	1.6
				72	2.1
73	1.0
				74	1.4
75	1.4		10.0
				76	2.7
77	2.7
				78	3.3
79	3.4
				80	1.4
81	3.2		5.3
				82	3.7
83	1.8
				84	2.4		～10

Example numbering	Kv1.5 IC-50[μM]	mTask-1 IC-50[μM]	KACh IC-50[μM]
				85	3.6
86	2.9
				87	4.2
88	4.0
				89	3.5
90	4.1
				91	4.0
92	3.8
				93	4.1
94	5.3
				95	5.2
96	5.1
				97	5.4
98	5.5
				99	6.3
100	5.4
				101	5.6
102	5.4
				103	6.6
104	6.7
				105	4.6

Example numbering	Kv1.5 IC-50[μM]	mTask-1 IC-50[μM]	KACh IC-50[μM]
				106	8.3
107	9.6
				108	9.0
109	9.6
				110	9.7
111	8.8
				112	～10
113	～10
				114	～10
115	～10
				116	～10
117	0.3
				118	0.8
119	0.8
				120	0.8
121	0.9

Claims (16)

1. Compounds of formula I and pharmaceutically acceptable salts and trifluoroacetates thereof,

wherein each meaning is:

a C, S or S ═ O;

n 0, 1, 2 or 3;

r1 phenyl, pyridyl, thienyl, naphthyl, quinolyl, pyrimidyl orPyrazinyl, wherein each of these aryl groups is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino;

or

R1 cycloalkyl having 3, 4, 5, 6 or 7C atoms;

r2 phenyl, pyridyl, thienyl, naphthyl, quinolyl, pyrimidinyl or pyrazinyl,

wherein each of these aryl groups is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, COOMe, CONH₂Alkoxy having 1, 2, 3 or 4C atoms, OCF₃OH, methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino;

R3 C_pH_2p-R8；

p 0, 1, 2, 3, 4 or 5;

R8 CH₃、CH₂F、CHF₂、CF₃cycloalkyl having 3, 4, 5, 6 or 7C atoms, C.ident.CH, C.ident.C-CH₃Alkoxy having 1, 2, 3 or 4C atoms, phenyl or pyridyl,

wherein phenyl and pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms, alkoxy having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r4 hydrogen or alkyl having 1, 2 or 3C atoms;

r5 hydrogen or alkyl having 1, 2 or 3C atoms;

r6 and R7

Independently of one another, hydrogen, F or alkyl having 1, 2 or 3C atoms.

2. Compounds of the formula I according to claim 1, in which the meanings are:

a C, S or S ═ O;

n 0, 1, 2 or 3;

r1 phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,

wherein each of these aryl groups is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino;

or

R1 cyclohexyl;

r2 phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl, 3-pyridazinyl or 4-pyridazinyl,

wherein each of these aryl groups is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CN, COOMe, CONH₂Alkoxy having 1, 2, 3 or 4C atoms, OCF₃OH, methylsulfonyl, CF₃Alkyl having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, acetyl and methylsulfonylamino;

R3 C_pH_2p-R8；

p 0, 1, 2, 3, 4 or 5;

R8 CH₃、CH₂F、CHF₂、CF₃cycloalkyl having 3, 4, 5, 6 or 7C atoms, C.ident.CH, C.ident.C-CH₃Alkoxy having 1, 2, 3 or 4C atoms, phenyl or 2-pyridyl,

wherein phenyl and 2-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: F. cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms, alkoxy having 1, 2, 3 or 4C atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

r4 hydrogen or alkyl having 1, 2 or 3C atoms;

r5 hydrogen or alkyl having 1, 2 or 3C atoms;

r6 and R7

Independently of one another, hydrogen, F or alkyl having 1, 2 or 3C atoms.

3. Compounds of formula I according to claims 1 or 2, as well as pharmaceutically acceptable salts and trifluoroacetates thereof, wherein:

a is C or S ═ O;

n is 0, 1, 2 or 3;

r1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl,

wherein each of these aryl groups is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: F. cl, Br, I, CN, alkoxy having 1, 2, 3 or 4C atoms, OCF₃Methylsulfonyl, CF₃And alkyl having 1, 2, 3 or 4C atoms;

or

R1 is cyclohexyl;

r2 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 1-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl,

wherein each of these aryl groups is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: cl, Br, I,CN、CF₃Alkyl having 1, 2, 3 or 4C atoms;

R3 C_pH_2p-R8；

p is 0, 1, 2, 3 or 4;

r8 is CH₃、CH₂F、CHF₂、CF₃Cycloalkyl having 3, 4, 5 or 6C atoms, C.ident.CH, C.ident.C-CH₃Alkoxy having 1, 2, 3 or 4C atoms, phenyl or 2-pyridyl,

wherein phenyl and 2-pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: F. cl, Br, I, CF₃、OCF₃、CN、COOMe、CONH₂COMe, OH, alkyl having 1, 2, 3 or 4C atoms and alkoxy having 1, 2, 3 or 4C atoms;

r4 hydrogen or alkyl having 1, 2 or 3C atoms;

r5 hydrogen or alkyl having 1, 2 or 3C atoms;

r6 and R7

Independently of one another, hydrogen, F or alkyl having 1, 2 or 3C atoms.

4. A compound of the formula I according to one or more of claims 1 to 3 and/or a pharmaceutically acceptable salt thereof for use as a medicament.

5. Pharmaceutical formulation comprising an effective amount of at least one compound of the formula I according to one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof as active agent, together with pharmaceutically acceptable carriers and additives.

6. Pharmaceutical preparation comprising an effective amount of at least one compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof as active agent, together with pharmaceutically acceptable carriers and additives and one or more further pharmacologically active ingredients or drugs.

7. A compound of the formula I as claimed in one or more of claims 1 to 3 and/orThe pharmaceutically acceptable salt thereof has K in the preparation⁺Channel blocking effect, use for treating and preventing K⁺Use in the manufacture of a medicament for a channel mediated disease.

8. Use of a compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prevention of cardiac arrhythmias which can be abrogated by prolongation of the action potential.

9. Use of a compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prevention of reentry arrhythmias.

10. Use of a compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prophylaxis of supraventricular arrhythmias.

11. Use of a compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prevention of atrial fibrillation or atrial flutter.

12. Use of a compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prophylaxis of respiratory disorders, neurodegenerative disorders and cancer.

13. Use of a compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prophylaxis of the following diseases: sleep-related respiratory disorders, central and obstructive sleep apneas, cheyne-stokes respiration, snoring, impaired central respiratory drive, sudden infant death, post-operative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after prolonged ventilation, altitude-adaptation-related respiratory disorders, acute and chronic lung disorders with hypoxia and hypercapnia, neurodegenerative disorders, dementia, Alzheimer's disease, Parkinson's disease, Huntington's chorea, cancer, breast cancer, lung cancer, colon cancer and prostate cancer.

14. Use of a compound of the formula I as claimed in one or more of claims 1 to 3 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prophylaxis of heart failure, in particular diastolic heart failure, and for increasing the atrial contractility.

15. Pharmaceutical preparation comprising as active ingredients an effective amount of at least one compound of the formula I according to one or more of claims 1 to 3 and/or a pharmaceutically acceptable salt thereof and a beta blocker, together with pharmaceutically acceptable carriers and additives.

16. Pharmaceutical preparation comprising an effective amount of at least one compound of the formula I according to one or more of claims 1 to 3 and/or a pharmaceutically acceptable salt thereof and IK_sChannel blockers as active ingredients, and pharmaceutically acceptable carriers and additives.