MXPA00002969A - Mixtures of enantiomers of aminocyclohexylamides to produce simultaneous analgesia with local anaesthesia or antiarrhythmia. - Google Patents

Abstract

The present invention provides compositions and methods for providing analgesia during the treatment of cardiac arrythmias or the induction of local anaesthesia. The compositions of the present invention include a plurality of vicinal aminocyclohexylamide enantiomers in ratios of stereo-specific configurations.

Description

MIXTURES OF AMANCILLERS OF AM I NOCIC LOH EX! LAM I DAS TO PRODUCE SIMULTANEOUS ANALGESIA WITH ANESTHESIA LOCAL OR ANTIARRHYTHMIA FIELD OF THE INVENTION The present invention relates generally to the use of mixtures of enantiomers of adjacent aminocyclohexylamides to produce local anesthesia and / or antiarrhythmia, while at the same time producing an appropriate level of analgesia. This invention, more particularly, relates to the treatment of cardiac arrhythmias and the induction of local anesthesia, with an appropriate amount of analgesia.

BACKGROUND OF THE INVENTION It is known that the compounds produce local anesthesia and / or antiarrhythmic effects. It may be desirable to simultaneously produce an appropriate analgesic effect. Therefore, there is a need in the art to identify new compositions that produce the desired combination of effects. The present invention satisfies this need, and further provides other related advantages.

SUMMARY OF THE INVENTION In summary, the present invention provides compositions and methods for providing analgesia during the treatment of cardiac arrhythmias or the induction of local anesthesia in a patient in need of this. In one aspect, the present invention provides a composition containing a plurality of adjacent aminocyclohexylamide enantiomers, wherein said enantiomer composition is between about 85% to 99.99% of R, R configuration and between about 15% to 0.01% of S, S configuration. The compositions may optionally include a pharmaceutically acceptable carrier or diluent. In one embodiment, the plurality of enantiomers are compounds of the formula: where n is either 0 or 1; R ^ R2, R3, R4 are hydrogen, hydroxy, alkoxy of one to four carbon atoms, or splicing or fused five- or six-membered heterocyclic ring-containing points containing an oxygen or sulfur atom; R5 and R6 are either alkyl of one to five carbon atoms or, when taken together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl, tetrahydroisoquinolinyl, or hexahydroazepinyl ring; and Q is selected from the group consisting of substituents comprising: 3,4,5-trimethylphenoxy: wherein R7 is hydrogen, fluorine, chlorine, alkyl of one to six carbon atoms or aryl; Z is -CH2-, -O-, -S-, or N-R8, wherein R8 is hydrogen, alkanoyl of one to six carbon atoms, or alkyl of one to six carbon atoms; wherein X is CH2, O, or S, and R9 and Rio are independently hydrogen, fluorine, bromine, alkyl of one to six carbon atoms, or alkoxy of one to four carbon atoms; (? V) where X and R9 and R10 are as defined above; wherein X is as defined above, and R n and R 2 are independently hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, or aryl. In another aspect, the compositions of the present invention are provided for use as a medicament, and for use in the manufacture of a medicament for providing analgesia during the treatment of cardiac arrhythmias or the induction of local anesthesia. The present invention further provides a method comprising the administration, to a patient in need of treatment for cardiac arrhythmias or the induction of local anesthesia, of a composition according to the present invention. These and other aspects of the present invention will become apparent after reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION As noted above, the present invention is directed to mixtures of enantiomers of adjacent aminocyanohexylamides, which have a variety of uses. Such uses include induction of local anesthesia, treatment of arrhythmias and blockage of ion channels in vitro and in vivo. Amino-cyclohexylamides are known in the literature and include those described in the U.S.A. No. 5, 506,257 and the patent and the technical literature cited therein. As described in the present invention, compositions that include mixtures of at least two enantiomers of adjacent aminocyanohexylamides surprisingly produce a combination of desirable effects. Examples of adjacent aminocciohexylamides include the class of substituted aminocyclohexylamide compounds represented in formula I above. A nitrogen atom is an amine nitrogen substituted with R5 and R6 as defined above. Preferably, R5 is methyl and R6 is lower alkyl, most preferably methyl, or, when taken together with the nitrogen atom to which they are attached, R5 and R6 preferably form a pyrrolidinyl ring, a morpholinyl ring or a hexahydroazepinyl ring. The other nitrogen atom is a substituted N-methylamide as described above, wherein n is preferably 1. Preferably, R ,, R2, R3 and R4 are hydrogen or, R3 and R4 are hydrogen and R1 and R2 are an oxaspyran ring . As used herein, the term "aryl" means phenyl; phenyl substituted with alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, nitro, or trifluoromethyl; 2- or 3-thienyl; and, 2- or 3-thienyl substituted with alkyl of one to four carbon atoms or alkoxy of one to four carbon atoms. In formula II illustrated above, the bond joining the substituent to the rest of the compound of formula I is shown as intersecting both rings of the fused ring structure of substituent II. This indicates that the bond can be at any of the carbon atoms in the fused ring structure, except at the R7 position. The aminocyclohexylamides are represented by formula I above through a structural formula. Said structural formula contains one or more asymmetric carbon atoms and, therefore, the compounds exist in various stereoisomeric forms. In addition, the compound is capable of existing in different geometric isomeric forms. For example, the Ri substituent of the cyclohexane ring can be placed on the same side of the average plane of the ring as the amide nitrogen, or on the opposite side. In a preferred embodiment, the two nitrogens (amino substituents and N-methylamide) attached to the cyclohexyl ring are in a trans orientation. The present invention contemplates the use of geometrical and stereoisomeric forms of the compounds of the formula I. The compounds of the formula I can be used in the present invention as mixtures of individual enantiomers. Examples of individual enantiomers include compounds 2, 7 and 10 below. Examples of compounds that can be prepared as individual enantiomers, or that are prepared as racemic mixtures that are either separated into individual enantiomers or used as racemic mixtures, include the compounds listed below. The following compounds and racemic mixtures are examples of the compounds of the formula I: 1. (±) -trans-N-methyl-N- [2- (1-pyridinyl) cyclohexyl] benzo [b] thio faith n- 4 -acetamide; 2. (1R, 2R) - (+) - trans-N-methyl-N- [2- (1-pyrrole idin i I) cyclo or hexyl] benzo [b] thiof in -4 -acetamide; 3. [(±) - (1a, 2β, 4β, 5β)] - N-methyl-N- [4,5-di methoxy-2- (1-pyrrole id inyl) cyclohexyl] benzo [b] thiophene 4-acetamide; 4. [(±) - (1a, 2ß, 4ß, 5ß)] - N-methyl-N- [4,5-di methoxy-2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; 5. (±) -trans-N-methyl-N- [2- (1-hexahydroazepinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; 6. (±) -trans-N-methyl-N- [7- (1-pyrrol idini I) -1-oxaspiro [4.5] dec-8-i I] benzo [b] furan-4-acetamide; 7. [5R- (5a, 7a, 8ß)] - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] of c-8-yl] benzo [b] furan -4 - acetamide; 8. (±) -trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; 9. (±) -trans-N-methyl-N- [2- (1-pyridinyl) cyclohexyl] benzo [b] thio faith n-3-acetamide; 10. [5S- (5a, 7a, 8ß)] - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzo [b] furan-4-acetamide; 11. (1S, 2S) - (-) - trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4-acetamide; 12. (1R, 2R) -2- (indol-3-yl) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] acetamide; 13. (1S, 2S) -2- (ndol-3-yl) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] acetamide; 14. (1R, 2R) -2- (2,3-dichlorophenoxy) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl-ketamine; 15. (1S, 2S) -2- (2,3-dichlorophenoxy) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl-acetamide; 16. (1R, 2R) -N-methyl-2- (1 -naphthalenyloxy) -N- [2- (1-pyrrole-idinyl) -cyclohexyl-acetamide; 17. (1S, 2S) -N-methyl-2- (1-naphthalenyloxy) -N- [2- (1-pyrrole idyl) cyclohexylketcetamide; 18. [1S- (1a, 2β, 4β) -N-methyl-N- [4-methoxy-2- (1-pyrrolidinyl) cyclohexyl] benzo [b] furan-4-acetamide; 19. [1R- (1a, 2ß, 4ß) -Nm ethyl-N- [4-m-ethoxy -2 - (1-pi rro I idini I) ci cl oh ex i I] benzo [b] furan-4- acetamide; 20. (1R, 2R) -inden-2-yl-N-methyl-N- [2- (1,1-dimethylamino) cyclohexyl] carboxamide; 21. (1S, 2S) -inden-2-yl-N-methyl-N- [2- (1,1-dimethylamino) cyclohexyl] carboxamide; 22. (R, 2R) trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-3-acetamide; 23. [(1R, 2R) - (1a, 2β, 4β, 5β)] - N-methyl-N- [4,5-dimethoxy] -2- (1-pyrrolidinyl) c -clohexyl] benzo [b] thiophen -4-acetamide; 24. [(1R, 2R) - (1a, 2ß, 4ß, 5ß)] - N-methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; 25. (1R, 2R) -trans-N-methyl-N- [2- (1-hexahydroazepinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; 26. (1S, 2S) -trans-N-m ethyl-N- [2 - (1-pi rididinyl) cyclohexyl] benzo [b] thiophen-3-acetamide; 27. [(1S, 2S) - (1a, 2ß, 4ß, 5ß)] - N-methyl-N- [4,5-dimethoxy-2- (1-pi rro I idini I) cyclohexyl] benzo [b ] thiophen-4-acetamide; 28. [(1S, 2S) - (1a, 2ß, 4ß, 5ß)] - N-methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; and 29. (1S, 2S) -trans-N-methyl-N- [2- (1-hexahydroazepinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide. The compounds of the formula I can be prepared by known methods, including those described in the patents of E.U.A. above mentioned of Horwell (all references cited in the present application, including those of Horwell, are hereby incorporated by reference in their entirety). Suitable methods for the synthesis of diaminocyclohexane intermediates useful for the preparation of a variety of compounds identified above are described by Szmuszkovicz, J., and Von Voightlander, P.F. (1982) J. Med. Chem. 25: 1125-1126. The oxaspiro and methoxy-cyclohexanediamine intermediates useful for the synthesis of compounds 7, 10, 18 and 19 are described by Halfpenny, P.R., et al. (1990) J. Med. Chem. 33: 286-291. The preparation or sources of the carboxylic acids used in the final stage of the syntheses of the compounds listed above will also be found in the above references as well as by Clark, CR, et al. (1988) J. Med. Chem. 31: 831- 836 The last three references contain information on the three steps of the synthesis of the compounds listed above, and provide sufficient guidance for those skilled in the art to repeat the synthesis, isolation and purification of these and many other analogous compounds. The individual enantiomers are obtained from mixtures of the different forms through known resolution methods, such as the formation of diastereomers, followed by recrystallization. One of ordinary skill in the art will appreciate that there are a variety of ways to produce the blends of the present invention. For example, the synthetic method for the compounds can be modified in order to obtain the desired mixture of enantiomers. For example, instead of using a single enantiomer of a chiral starting material, a prescribed ratio of enantiomers can be used in order to produce the desired mixture of enantiomers in the product. The synthesis conditions can also affect the degree of enantiomeric purity of some compounds. A chiral compound can be synthesized as a pure enantiomer under certain conditions, but the alteration of these conditions can result in some racemization. Taking advantage of this, a mixture of the present invention is made possible through said alteration of the conditions of the chiral synthesis in order to produce the desired mixture of enantiomers in the product. Another procedure for obtaining the desired mixture of enantiomers results in the chiral synthesis of the two enantiomers, followed by the mixing of the two enantiomers in the desired ratio. Another method for obtaining the desired mixture of enantiomers requires (a) a chiral synthesis of the enantiomer that is required in the smallest amount in the final mixture, (b) a synthesis of the racemate, and (c) a mixture of the racemate with the individual enantiomer to give the desired final enantiomer ratio. Another method for obtaining the desired mixture of enantiomers is to separate a racemate solution using chiral separation techniques, such as liquid chromatography of preparation with a chiral column, then mixing the enantiomers in the desired ratio. The compounds of the formula I can be in the form of a pharmaceutically acceptable acid addition salt. Said salts include the salts of hydrochloride, sulfate, phosphate, citrate and other salts known in the art. The pharmaceutical compositions of the enantiomers of compound I or salts of compound I may contain pharmaceutically acceptable carriers or diluents, which are well known in the art. The compositions of the present invention are prepared by mixing together two or more enantiomers of adjacent aminocyclohexylamide. The aminocyclohexylamides may be adjacent in positions 1,2; 2,3; 3,4; 4,5; 5.6; 6.7; 7.8; etc.; depending on the rest of the structure of the compound as a whole. The resulting mixture produces useful compositions where analgesia is needed at the same time as local anesthesia or antiarrhythmia. In a preferred embodiment, the aminocyclohexylamide enantiomers are present so that approximately 85% -99.99% are in the R, R configuration and approximately 15% -0.01% are in the S, S configuration. For example, an R, R enantiomer is present in a mixture at about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98%, 99% (and numbers between the integers) or up to 99.99%, with the remaining percentage as an S, S enantiomer. In a particularly preferred embodiment, about 99.5% are R, R and about 0.5% are S, S. In order to determine whether a mixture has the pharmacological activity required within the present invention, it must be tested using methodology known in the art. For example, the antiarrhythmic activity of a compound can be estimated against arrhythmias induced by coronary artery occlusion in anesthetized rats. It is expected that a good arrhythmic compound will have antiarrhythmic activity at doses that have minimal effects either in ECG, blood pressure or heart rate. Similarly, it can be determined that a mixture is an anesthetic using a standard test for local anesthetic effects. The following is a general description of that test. Typically, a 20 microliter injection of the drug (or the carrier vehicle as a control) is made near the base of the tail of a mouse. The needle is advanced until the tip makes contact with the caudal vertebra, then the solution is injected. After two minutes, the pin prick test is conducted both near and far on both sides of the injection site. If a small spot response occurs in the queue, a response of "Yes" is recorded If there is no response, a "No" is recorded, indicating local anesthesia, Similarly, a mixture can be determined to be an analgesic using a standard test. for analgesic effects The following is a general description of this test: Typically compounds were administered on a dose scale (or vehicle control), intravenously, to mice weighing 20-30 g. or 15 minutes after the injection, a clip was placed at the base of the tail of the animal and each animal was observed for a maximum period of 40 seconds, if the animal turns and bites the bra this indicates a lack of analgesia; If the bra is not turned over or bites, there is analgesia, the number of responses in each group is determined and a dose that produces 50% analgesia of the animals (ED50) is then calculated. The compounds of the present invention can be used to treat the rhythm of a heart or prevent arrhythmias from occurring in a heart that is susceptible to arrhythmia. Methods for administering effective amounts of antiarrhythmic agents are well known in the art and include administration of an oral or parenteral dosage form. Said dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants and transdermal delivery systems. Generally, oral or intravenous administration is preferred. The amount of dose and frequency are selected to create an effective level of the agent without harmful effects. It will generally vary from a dose of about 0.1 to about 100 mg / kg / day, and typically from about 0.1 to 10 mg / kg, which will be administered orally or intravenously for an antiarrhythmic effect. To be used as a local anesthetic, a 0.1% to 1% solution injected at a local site is typical. When the mixtures of the present invention are used to induce local anesthesia, the administration means may be the same as described above in the case of arrhythmia treatment., except that the use of oral administration in the form of tablets or capsules will generally not be appropriate. Topical application of the local anesthetic agent, for example, in the form of an ointment or an aerosol spray, may be employed. The means of administering local anesthetics are well known in the art. The administration of the mixtures of this invention can be carried out in combination with the administration of other agents. For example, one may wish to administer another antiarrhythmic agent or local anesthetic. The present invention also includes a commercial kit containing a pharmaceutical composition, which includes two or more isomeric compounds of formula I or, their pharmaceutically acceptable salts, in addition to any pharmaceutically acceptable carrier or diluent. The commercial equipment also includes instructions for the use of the pharmaceutical composition for the treatment of arrhythmia or for the induction of local anesthesia. Preferably, the commercial package will contain one or more doses of the pharmaceutical composition. For example, said unit dose may be an amount sufficient for the preparation of an intravenous injection. It will be apparent to those skilled in the art that compounds that are sensitive to light and / or air may require a special packaging and / or formulation. For example, a package that is opaque to light, and / or sealed to be out of contact with ambient air, and / or formulated with suitable covers or excipients can be used. The following examples are provided by way of illustration and not by way of limitation.

EXAMPLES EXAMPLE 1 rfl? JVS-N-METHYL-2-M-PIRROLIDINIL) CYCLOHEXYLAMINE This compound was prepared based on the method of the patent of E.U.A. No. 4,579,863. (i) Cyclohexene oxide (202 ml, 2 moles) was added dropwise to aqueous methyl amine (466 ml or 40% solution, 6 moles) for 70 minutes. After a further 90 minutes, the temperature of the reaction mixture was 48 ° C and reduced to 30 ° C by cooling in a water bath. After 2 more hours, the mixture was returned to room temperature. It was stirred overnight, and then refluxed for 3 hours. The mixture was saturated with sodium hydroxide (cooled during the addition), extracted several times with diethyl ether (total of 500 ml), the diethyl ether layer was dried over sodium sulfate overnight, and the diethyl ether was removed on a rotary evaporator. The remaining diethyl ether and cyclohexene oxide were removed by partial vacuum distillation. Distillation under complete vacuum yielded a colorless fraction with a boiling at 95 ° C, (± -trans-2- (methylamino) cyclohexenol: 217 g (84%). (Ii) A mixture of (±) -frans-2- (methylamino) cyclohexanol (200 g, 1.55 mol) and diethyl ether (400 ml) in a 3 liter beaker was stirred and cooled in an ice bath as chlorosulfonic acid was added dropwise (103 ml, 1.55 moles) After adding approximately 25 ml, it was necessary to stir the thickened mixture with a spatula, and after adding an additional 40 ml of acid, more diethyl ether (200 ml) was added. The thick mixture was stirred by hand and left at room temperature for 2.5 hours, the mixture was filtered, and the solid was washed with 300 ml of diethyl ether.A solution of sodium hydroxide pellets (216 g) 1 liter of water was cooled in an ice bath, and then slowly added to the cooled solid. being less viscous the addition could be completed in 20 minutes. The mixture was allowed to stand overnight, then was emptied into a 2 liter flask and steam distilled, adding water from a dropping funnel to keep the volume constant in the distillation vessel. After having distilled the diethyl ether, an organic product was co-distilled with the water at a head temperature of 92-100 ° C (600 ml of a colorless 2-phase mixture was collected), to leave a small amount of material Dark amber color on the surface of the remaining water in the distillation vessel. The distillate was saturated with sodium hydroxide and extracted with diethyl ether (8 x 100 ml), the diethyl ether layer was dried over sodium sulfate and the diethyl ether was stirred on a rotary evaporator to leave a crude product (133 g. ), which was distilled under reduced pressure to give 7-methyl-7-azabicyclo [4.1.Ojheptane (77.9 g, 43%). (ii) A solution of ammonium chloride (1.6 g) in 100 ml of water was added to 7-methyl-7-azabicyclo [4.1.O-heptane (70 g, 0.59 mol) under nitrogen. Pyrrolidine (210 ml, 2.5 moles) was added and the mixture was stirred and refluxed under nitrogen for 20 minutes. Sodium dioxide was added to saturate the aqueous phase and the mixture was extracted with diethyl ether 11 x 100 ml). The combined organic extracts were washed with water (2 x 10 ml), and dried over sodium sulfate. The diethyl ether was stirred on a rotary evaporator and the excess pyrrolidine (60 ml) was distilled off under vacuum. The product frans-N-metll-2- (1-pyrrolidinyl) cyclohexylamine was distilled under a complete vacuum (46-48 ° C). Yield 86 g (77%).

EXAMPLE 2 MONOCLORHYDRATE OF (+) - rfl? MS-N-METHYL-N-r2-M-PIRROLIDINYL) CYCLOHEXIL1BENZOGB1TIOFEN-4-ACETAMIDE This compound was prepared according to the procedure described by C.R. Clark et al. In J. Med. Chem. 31: 831-836, 1988. A solution of 4-tianaphthalenacetyl chloride (prepared by refluxing 4-t-phthaleneacetic acid (1.94 g, 10 mmol) with an excess of thionyl chloride) in 10 ml of dichloromethane was added dropwise to a solution of (±) -frarts-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl-jimine prepared in Example 1 (1.84 g, 10 mmol) in 10 ml of dichloromethane at 0 ° C. After stirring at room temperature for 10 minutes, diethyl ether was added until there was no more precipitate. The crude product was collected by filtration, washed with diethyl ether and dried in vacuo. Recrystallized from methanol / diethyl ether, for the title compound, 3.3 g (85%). According to the proton and carbon-13 NMR data. Elemental analysis: calculated for C21 H29N2OCIS: C 64.18, H 7.44%, N 7.13%; it was found C 63.34, H 7.17, N 7.10.

EXAMPLE 3 MR.2R) - (±) -r / ??? fS-N- ETHYL-N-r2- (1- PYROLYLIDINYL) CICLOHEXIL1BENZ? RB1TIOFEN-4-ACETAMIDE A. Resolution of (±) -frai7s-N-methyl-N-r2- (1-pyrrolidinyl) cyclohexyl amine The racemic diamine (Example 1) (16.0 g, 87.9 mmol) was dissolved in 400 ml of boiling methanol. A solution of 2,3-di-p-toluoyl-D-tartaric acid (35.6 g, 92.1 mmol) in 400 ml of boiling methanol was added. Immediately a white precipitate formed. The mixture was cooled to room temperature, then the solid was filtered (40.4 g). This procedure was repeated two more times to obtain a total of 120 g of the crude tartaric acid salt. The salt was washed with 1 liter of hot methanol but the specific rotation of the free diamine was only -74 (liters, value: -96). Recrystallization from hot methanol in batches (5 g of salt in 600 ml of MeOH) provided 41.3 g of the salt. The salt was partitioned between 20% KOH (600 ml) and CH2CI2 (500 ml). The aqueous fraction was extracted back with additional CH2Cl2 (4 x 100 ml). The CH2Cl2 extracts were combined and washed with 50 ml of distilled water. The organic layer was dried by stirring over anhydrous sodium sulfate. The solvent was removed under vacuum to yield (-) diamine (13.5 g, 30%). Specific rotation: -93.

B. Synthesis of the Title Compound 1. Acid chloride formation 4-Tianaphthalene acetic acid (3.20 g, 17 mmol) in 18 ml of thionyl chloride was brought to reflux under nitrogen for 1 hour. After stirring at room temperature for one hour, the thionyl chloride was removed in vacuo to leave a brown oil, which was dissolved in 18 ml of dichloromethane. 2. Amide formation: The acid chloride solution was added through a cannula to a cooled solution of (-) diamine (2.90 g, 16 mmol) in 15 ml of dichloromethane. The reaction was stirred at 0 ° C for 15 minutes and then stirred at room temperature for an additional 45 minutes. 40 ml of ether was added to the solution. A whitish solid formed from the solution. The solid was filtered and washed with fresh ether (3 x 10 ml). The solid was recrystallized from hot methanol / ether (4.79 g, 77%). The specific rotation of free acetamide (not the HCl salt): +29.3 (liter, value: +30).

EXAMPLE 4 ANTIARRHYTHMIA The antiarrhythmic efficacy was determined by investigating the activity of the compounds in the incidence of cardiac arrhythmias in anesthetized pentobarbital rats subjected to coronary artery occlusion. Arrhythmias were recorded as ventricular tachycardia (VT) and ventricular fibrillation (VF) and according to Curtis, M.J. and Walker, M.J. A. (1988) Cardiovasc. Res. 22: 656. A detailed description of the antiarrhythmic activity of certain of the compounds used in the compositions of the present invention can be found in the patent of E.U.A. No. 5,506,257 and the patent and technical literature cited therein. Table 1 describes the test result of Compound 7 described as an ED50 value (which is the dose required to produce 50% reductions in the arrhythmic activity referred to there). The initial results with compound 7 showed that at 2 and 8 μmol / kg, incidents of fatal arrhythmias (VF) were reduced to 25% and 0%, respectively, from a control value of 88%.

TABLE 1 Activity Compound VT 8 VF < 1 The results of a more detailed study in the pharmacological and antiarrhythmic activity of Compound 7 (the R, R enantiomer) and Compound 10 (S, S enantiomer) showed that both enantiomers (2 and 8 μmol / kg) also reduced arrhythmias in anesthetized rats subjected to occlusion of a coronary artery as presented in Table 2 (Pugsley, MK, et al. (1993) British J. Pharm., 1579-1585).

TABLE 2 Drug Dose (μmol / kq) Saline Arrhythmia Classification 5.0 + 0.6 Compound 7 2 3.0 + 0.7 Compound 7 8 1.3 ± 0J6 * Compound 10 2 1.1 + 0.6 * Compound 10 8 1.5 + 0.6 * Arrhythmia classification according to Curtis, M.J. Walker, M.J. A. (1988) Cardiovasc. Res. 22: 656. * p < 0.05 for comparison with saline.

EXAMPLE 5 A compound or compounds on a dose scale (or vehicle control) were administered intravenously to mice weighing 20-30 g. At 5 and / or 15 minutes after the injection, a fastener was placed at the base of the animal's tail, and each animal was observed for a maximum period of 40 seconds; if the animal turns and bites the bra, this indicates the lack of anesthesia; while if you do not turn or bite the bra this indicates analgesia. The number of responses in each group was then determined and a dose that produced analgesia in 50% of the animals (ED50) was then calculated. A mixture of enantiomers of Compound 1 (racemic mixture) was compared to the single enantiomer, Compound 2. The mixture of Compound 1 had an ED50 of 2 μm / kg, while Compound 2 failed to produce analgesia at sub-lethal doses. The analgesic activity of certain of the compounds used in the compositions of the present invention is described by Halfpenny, P.R., et al., (1990) J. Med. Chem. 33: 286-291. Compound 10 (the S, S enantiomer) with an MPE50 value (the dose required to produce 50%> of the maximum possible analgesic effect using a rat pressure test) of 0.024 mg / was determined. kg is approximately 100 times more effective than Compound 7 (the R, R enantiomer) with an MPE50 value of 2.5 mg / kg.

EXAMPLE 6 A NES T ESIA LOCAL A 20 microliter injection of the drug (or the carrier vehicle as a control) was made to the base of the tail of a mouse. The needle was advanced until the tip made contact with the caudal vertebra, then the solution was injected. After two minutes, the pin prick test was conducted both near and far on both sides of the injection site. If a response is presented with a small hit with the tail, a "Yes" is recorded. If there is no response, a "No" is recorded, indicating local anesthesia. Compound 2, tested at 0.05%, 0.1%, 0.2%, 0.4%, 1%, resulted in local anesthesia in 0%, 33%, 60%, 100% and 100% of the mouse population, respectively. Saline injection failed to produce local anesthesia. Lidocaine, as a positive control, at 0.1%, 0.5%? and 1%, produced local anesthesia in 17%, 17% and 100%) of the mouse population. The local anesthetic activity of certain of the compounds used in the compositions of the present invention is described in the U.S.A. No. 5,506,257. Compound 2 was evaluated for local anesthetic effects in a human phase II clinical trial. It was compared with lidocaine in a double-blind, randomized, placebo-controlled analysis. Drugs at various concentrations (Compound 2: 0.05%, 0.15% and 0.25%, lidocaine: 0.2%, 0.6% and 1.0%) were injected intradermally into one of the forearms of 40 healthy male subjects. Local anesthesia was determined in the eight intradermal grains (four grains / forearm) through a pin sting classification system and was recorded at 1, 10, 30, 60 and 120 minutes after the injection. The solutions of Compound 2 were four times more potent than those of lidocaine to produce local anesthesia with 10 minute start times (mean pin sting rating ± SEM at 10 minutes: Compound 2, 0.25%, 1.7 ± 0.07; lidocaine, 1.0%, 1.73 + 0.07, P = NS). These results demonstrated that Compound 2 is a potent local anesthetic in humans. From the foregoing, it will be apparent that, although specific embodiments of the invention have been described for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention.

Claims (20)

1. CLAIMS 1. A composition comprising a plurality of adjacent aminocyclohexylamide enantiomers, wherein said enantiomer composition is between about 85% to 99.99% of R, R configuration and between about 15% to 0.01% of S, S configuration, and optionally includes a pharmaceutically acceptable carrier or diluent. 2. A composition according to claim 1, wherein the plurality of enantiomers are compounds of the formula: where n is either 0 or 1; R (, R 2, R 3, R are hydrogen, hydroxy, alkoxy of one to four carbon atoms, or splicing or fused five- or six-membered heterocyclic ring sites containing an oxygen or sulfur atom; and Re are either alkyl of one to five carbon atoms or, when taken together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl, tetrahydroisoquinolinyl, or hexahydroazepinyl ring, and Q is selected from the group consists of substituents comprising: 3,4,5-trimethylphenoxy: wherein R7 is hydrogen, fluorine, chlorine, alkyl of one to six carbon atoms or aryl; Z is -CH2-, -O-, -S-, or N-R8, wherein R8 is hydrogen, alkanoyl of one to six carbon atoms, or alkyl of one to six carbon atoms; wherein X is CH2, O, or S, and R9 and Rio are independently hydrogen, fluorine, bromine, alkyl of one to six carbon atoms, or alkoxy of one to four carbon atoms; wherein X and R9 and R 0 are as defined above; wherein X is as defined above, and Rn and R12 are independently hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, or aryl. 3. A composition according to claim 2, wherein n = 1; R5 and R6 taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring; Rj, R2, R3 and R are hydrogen; and Q is selected from the group comprising substituents II, III and IV. 4. A composition according to claim 3, wherein Q is the substituent II. 5. A composition according to claim 2, wherein n = 1; R5 and R6 taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring; R3 and R4 are hydrogen; R ^ and R2 are selected from the group consisting of hydrogen and points of attachment of an oxaspyran ring; and Q is selected from the group comprising substituents II, III and IV. 6. A composition according to claim 5, wherein Q is the substituent II. 7. A composition according to claim 2, wherein an enantiomer is selected from the group consisting of the following compounds and racemic mixtures: (±) -trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophene-4-acetamide; (1R, 2R) - (+) - trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4-acetamide; [(±) - (1a, 2β, 4β, 5β)] - N-methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4 -acetamide; [(±) - (1a, 2β, 4β, 5β)] - N-methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichloro phenoxy) acetamide; (±) -trans-N-methyl-N- [2- (1-hexahydro azepinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; (±) -trans-N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzo [b] furan-4-acetamide; [5R- (5a, 7, 8β)] - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzo [b] furan-4-acetamide; (±) -trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; (±) -trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-3-acetamide; [5S- (5a, 7a, 8β)] - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] of c-8-yl] benzo [b] furan-4 -acetamide; (1S, 2S) - (-) - trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4-acetamide; (1R, 2R) -2- (indol-3-yl) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] acetamide; (1S, 2S) -2- (indol-3-yl) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] acetamide; (1 R, 2R) -2- (2,3-dichlorophenoxy) -N-methyl-N- [2- (1-pyrrole idyl) cyclohexylkethetamide; (1S, 2S) -2- (2, 3-dioxide rofenoxi) -N-met i l-N- [2- (1-pyrrolidinyl) cyclohexyljacetamide; (1R, 2R) -N-methyl-2- (1-naphthalenyloxy) -N- [2- (1-pyrrole-idyl) -cyclohexyl-acetamide; (1S, 2S) -N-methyl-2- (1-naphthalenyloxy) -N- [2- (1-pyrrolidinyl) -cyclohexyl-acetamide; [1S- (1a, 2ß, 4ß) -Nm ethyl-N- [4-m-ethoxy -2- (1-pi rro I id ini I) ci c I or hex i I] benzo [b] furan-4- acetamide; [1 R- (1 a, 2 b, 4 b) -N-m ethyl-N- [4-m and oxy -2- (1-pi rro I id in i I) cyclohexy I] benzo [b] furan-4-acetamide; (1R, 2R) -inden-2-yl-N-methyl-N- [2- (1,1-dimethylamino) cyclohexyl] carboxamide; (1S, 2S) -inden-2-yl-N-methyl-N- [2- (1,1-dimethylamino) cyclohexyl] carboxamide; (1R, 2R) trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-3-acetamide; [(1R, 2R) - (1a, 2β, 4β, 5β)] - N-methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] benzo [b] tofen 4-acetamida; [(1R, 2R) - (1a, 2β, 4β, 5β)] - N -methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; (1R, 2R) -trans-N-methyl-N- [2- (1-hexahydroazepinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; (1S, 2S) -trans-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-3-acetamide; [(1S, 2S) - (1a, 2ß, 4ß, 5ß)] - N-methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4-acetamide; [(1S, 2S) - (1a, 2ß, 4ß, 5ß)] - N -methyl- [4,5-dimethoxy-2- (1-pyrrolidinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide; and (1S, 2S) -trans-N-methyl-N- [2- (1-hexahydroazepinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide. 8. A composition according to claim 2, wherein an enantiomer is selected from the group consisting of the following compounds and racemic mixtures: (+) -fra / 7s-N-methyl-N- [2- (1 - pyrrolidinyl) cyclohexyl] benzo [b] thiophen-4-acetamide; (1 R, 2 R) - (+) - tra ns- N-methyl-N- [2- (1-pyridinyl) cyclohexyl] benzo [b] -thiophene-4-acetamide; [(+) - (1 a, 2 ß, 4 ß, 5 ßfrans- N-met i I- N - [4, 5-di methoxy] -2- (1-pyrrolidinyl) -cyclohexyl] benzo [b] thio n -4 -acetamide; [(±) - (1, 2ß, 4ß, 5ßíra / 7S-N-methyl-N- [4,5-dimethoxy-2- (1-pyrrolidinyl) -cyclohexyl] (3,4 -dichlorophenoxy) acetamide, and (+) - fra / 7s-N-methylene-N- [2- (1-hexahydroazepinyl) cyclohexyl] benzo [b] -thiophene-4-acetamide 9.- A composition according to claim 2, wherein an enantiomer is selected from the group consisting of: [5S- (5a, 7a, 8ß)] - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec- 8-yl] benzo [b] f-4 -acetamide: (1S, 2S) -2- (benzo [b] thiophen-4-M) -N-methyl-N- [2- (1-pyrrolidinyl) ) -cyclohexyl-acetamide; (1R, 2R) -2- (indol-3-yl) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] acetamide; (1R, 2R) -2- (2,3 -dichlorophenoxy) -N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] acetamide; (1R, 2R) -N-methyl-2- (1-naphthalenyloxy) -N- [2- (1- pyrrolidinyl) cyclohexyl] acetamide; [1S- (1a, 2ß, 4ß) -Nm ethyl-N- [4-methoxy-2- (1-pyrimidine I) ci cl oh ex i I] -benzo [b] furan -4-acet amide; and (1R, 2R) -inden-2-yl-N-methyl-N- [2- (1,1-dimethylamino) cyclohexyl] acetamide; 10. A composition according to claim 2, wherein an enantiomer is: (1 R, 2R) -trans- N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [b] thio fe n- 4-acetamide. 11. A composition according to claim 2, wherein an enantiomer is: (1R, 2R) - (+) - fra /? SN-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] benzo [bj-thiophene-3-acetamide. 12. A composition according to claim 2, wherein an enantiomer is: [(1R, 2R) - (1a, 2β, 4β, 5β-N-methyl-N- [4,5-dimethoxy-2- ( 1-pyrrolidinyl) -cyclohexyl] benzo [b] thiophen-4-acetamide. 13. - A composition according to claim 2, wherein an enantiomer is: [(1R, 2R) - (1a, 2β, 4β, 5β-N-methyl-N- [4,5-dimethoxy-2- (1- pyrrolidinyl) -cyclohexyl] (3,4-dichlorophenoxy) acetamide 14. A composition according to claim 2, wherein one enantiomer is: (1 R, 2R) -trans-N-met il-N- [ 2- (1-hexahydro azepinyl) cyclohexyl] (3,4-dichlorophenoxy) acetamide 15. A composition according to claim 2, wherein one enantiomer is: [5R- (5a, 7a, 8ß)] - N -methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzo [b] furan-4-acetamide 16.- A composition according to claim 2, in where an enantiomer is: [5S- (5, 7, 8ß)] - N-methyl-N- [7- (1-pyrrole-1-yl) -l-oxas piro [4.5] dec-8-yl] -benzo [b] ] f-4-acetamide 17.- A method for providing analgesia during the treatment of cardiac arrhythmias or the induction of local anesthesia in a patient with the need thereof, which comprises administering to said patient an effective amount of a composition according to claim 1. 18. The method according to claim 17, wherein the composition is according to any of claims 2-16. 19. A composition according to any of claims 1-16 for use as a medicament. 20. The use of a composition according to any of claims 1-16 for the manufacture of a medicament for providing analgesia during the treatment of cardiac arrhythmias or Induction of local anesthesia.