OPTICAL ISOMER OF 1,4-BENZOTHIAZEPINE-1-OXIDE DERIVATIVE, AND PHARMACEUTICAL COMPOSITION PREPARED USING SAME

Abstract

The present invention provides: a novel compound which is characterized by being capable of increasing the number of heart beats or a blood pressure mildly to improve hemodynamics, and which is useful as a therapeutic or prophylactic agent for atrial fibrillation and heart failure; and a pharmaceutical composition which contains the compound. The present invention relates to: an optical isomer of a 1,4-benzothiazepine-1-oxide derivative represented by general formula [II]

##STR00001##

(wherein R represents a hydrogen atom or a hydroxy group; and * indicates the presence of an optical isomer) or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition which contains the optical isomer or a pharmaceutically acceptable salt thereof.

Claims

1. An optical isomer of 1,4-benzothiazepine-1-oxide derivatives represented by the following general formula [II] or a pharmaceutically acceptable salt thereof; ##STR00007## (in the formula, R presents a hydrogen atom or a hydroxyl group, and * indicates the presence of optical isomers).

2. The optical isomer of the 1,4-benzothiazepine-1-oxide derivatives or the pharmaceutically acceptable salt thereof according to claim 1, wherein the optical isomer of the 1,4-benzothiazepine-1-oxide derivatives is a first optical isomer component.

3. The optical isomer of the 1,4-benzothiazepine-1-oxide derivatives or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is hydrochloride salt or citrate salt.

4. A pharmaceutical composition comprising an optical isomer of the 1,4-benzothiazepine-1-oxide derivatives or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, wherein the optical isomer of the 1,4-benzothiazepine-1-oxide derivatives is a first optical isomer component.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is a therapeutic agent or a prophylactic agent for a heart disorder.

7. The pharmaceutical composition according to claim 6, wherein the heart disorder is arrhythmia or heart failure.

8. The pharmaceutical composition according to claim 7, wherein the arrhythmia is atrial fibrillation.

9. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is a therapeutic agent or a prophylactic agent for improving arrhythmia and heart failure by improving hemodynamics.

10. A method for producing each optical isomer represented by the following general formula [II] comprising: ##STR00008## (in the formula, R presents a hydrogen atom or a hydroxyl group, and * indicates the presence of optical isomers) resolving 1,4-benzothiazepine-1-oxide derivatives represented by the following general formula [I] by using a chiral column ##STR00009## (in the formula, R presents a hydrogen atom or a hydroxyl group); and collecting each optical isomer.

11. The optical isomer of the 1,4-benzothiazepine-1-oxide derivatives or the pharmaceutically acceptable salt thereof according to claim 2, wherein the pharmaceutically acceptable salt is hydrochloride salt or citrate salt.

12. A pharmaceutical composition comprising an optical isomer of the 1,4-benzothiazepine-1-oxide derivatives or a pharmaceutically acceptable salt thereof according to claim 2, and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising an optical isomer of the 1,4-benzothiazepine-1-oxide derivatives or a pharmaceutically acceptable salt thereof according to claim 3, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is a therapeutic agent or a prophylactic agent for a heart disorder.

15. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is a therapeutic agent or a prophylactic agent for improving arrhythmia and heart failure by improving hemodynamics.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0078] FIG. 1 illustrates that a change in the heart rate is compared as a difference compared to the previous value (i.e., control value) after administering (0.1 mg/kg/minute) the first optical isomer component of the present invention (in FIG. 1, expressed with an empty circle A) and the second component as the other enantiomer thereof (in FIG. 1, expressed with a solid circle B), respectively. As for the statistics, a significant difference between the first optical isomer component (in FIG. 1, expressed with an empty circle A) and the second component (in FIG. 1, expressed with a solid circle B) was examined by a t test. * indicates the significant difference P<0.05 between the first component and the second component.

[0079] FIG. 2 illustrates that a change in blood pressure is compared as a difference compared to the previous value (i.e., control value) after administering (0.1 mg/kg/minute) the first optical isomer component of the present invention (in FIG. 2, expressed with an empty circle A) and the second component as the other enantiomer thereof (in FIG. 2, expressed with a solid circle B), respectively. As the result of statistic analysis between the first optical isomer component (in FIG. 2, expressed with an empty circle A) and the second component (in FIG. 2, expressed with a solid circle B), the significant difference P<0.05 indicated by *, the significant difference P<0.01 indicated by **, and the significant difference P<0.001 indicated by *** were exhibited.

[0080] FIG. 3 illustrates that a change in myocardial contraction function (max dP/dt) is compared as a difference compared to the previous value (i.e., control value) after administering (0.1 mg/kg/minute) the first optical isomer component of the present invention (in FIG. 3, expressed with an empty circle A) and the second component as the other enantiomer thereof (in FIG. 3, expressed with a solid circle B), respectively. As the result of the statistic analysis between the first optical isomer component (in FIG. 3, expressed with an empty circle A) and the second component (in FIG. 3, expressed with a solid circle B), the significant difference P<0.05 indicated by *, the significant difference P<0.01 indicated by **, and the significant difference P<0.001 indicated by *** were exhibited.

[0081] FIG. 4 illustrates that a change in myocardial relaxation function (min dP/dt) is compared as a difference compared to the previous value (i.e., control value) after administering (0.1 mg/kg/minute) the first optical isomer component of the present invention (in FIG. 4, expressed with an empty circle A) and the second component as the other enantiomer thereof (in FIG. 4, expressed with a solid circle B), respectively. As the result of the statistic analysis between the first optical isomer component (in FIG. 4, expressed with an empty circle A) and the second component (in FIG. 4, expressed with a solid circle B), the significant difference P<0.05 indicated by * was exhibited.

[0082] FIG. 5 illustrates that a change in atrial effective refractory period is shown as % change rate compared to the previous value of 100% (i.e., control value) after administering (continuous administration for 10 minutes at 0.1 mg/kg/minute, and subsequently, continuous administration for 20 minutes at 0.05 mg/kg/minute) the first optical isomer component of the present invention (in FIG. 5, expressed with an empty circle A) and the second component as the other enantiomer thereof (in FIG. 5, expressed with a solid circle B), respectively. As the result of the statistic analysis between the first optical isomer component (in FIG. 5, expressed with an empty circle A) and the second component (in FIG. 5, expressed with a solid circle B), the significant difference P<0.05 indicated by *, and the significant difference P<0.01 indicated by ** were exhibited.

[0083] FIG. 6 illustrates that a change in ventricular effective refractory period of the first optical isomer component (in FIG. 6, expressed as A on left side) and the ventricular effective refractory period of the second component as the other enantiomer thereof (in FIG. 6, expressed as B on right side) is shown as % change rate compared to the previous value of 100% (i.e., control value). An asterisk (*) indicates that there is a significant difference P<0.05 between the first component (in FIG. 6, expressed as A) and the second component (in FIG. 6, expressed as B).

[0084] FIG. 7 illustrates an elution pattern when the compound [I] is applied to chromatography using a chiral column. The first optical isomer component of the present invention is eluted at 8.1 minutes approximately, and the second optical isomer component as the other enantiomer thereof is eluted at 11.4 minutes approximately, showing that they are completely separated from each other.

[0085] FIG. 8 illustrates an elution pattern when the collected first optical isomer component of the present invention is applied to chromatography which uses the same chiral column as the one used for resolution.

[0086] FIG. 9 illustrates an elution pattern when the second optical isomer component as the other enantiomer of the first optical isomer component of the present invention is applied to chromatography which uses the same chiral column as the one used for resolution.

DESCRIPTION OF EMBODIMENTS

[0087] The optical isomers of the present invention represented by the general formula [II] include a compound which has a hydrogen atom as R in the general formula [II] and a compound which has a hydroxyl group as R in the general formula [II]. Preferred examples of the compound include a first optical isomer component of 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide that is represented by the following formula [IV] or a pharmaceutically acceptable salt thereof.

##STR00005##

[0088] (in the formula, * indicates a chiral center).

[0089] In the compound of the present invention, the bond (SO) between the sulfur atom (S) in the heterocyclic group and the oxygen atom (O) forms a polar atomic group showing strong electronegativity. Further, as it is a coordination bond, to show that the bond between the sulfur atom and oxygen atom is a coordination bond, it can be described as the arrow of heterocyclic S.fwdarw.O. Furthermore, this coordination bond can be expressed as heterocyclic S+—O.sup.−.

[0090] In general, if group R.sup.1 and R.sup.2 are different from each other in a sulfoxide compound represented by R.sup.1—S(O)—R.sup.2, it is known that the central chirality is present by having the sulfur atom as a chiral center. Namely, it is known that there are 2 types of stereoisomers, i.e., a compound in which the oxygen atom is bonded from the bottom side of a horizontal plane and a compound in which the oxygen atom is bonded from the top side of a horizontal plane. Furthermore, by ignoring the involvement of d orbital and assuming that an imaginary atom with atomic number of 0 is bonded at the position of the electron pair of the sulfur atom, it is possible to denote either R configuration or S configuration depending on the rule of order set by R—S nomenclature.

[0091] At the moment of the present invention, it is not analyzed whether the stereoisomer named as the first component of the present invention has R configuration or S configuration. However, as shown in FIG. 7, the compounds represented by the general formula [I] are found to have include two compounds that are stably and clearly separated at a temperature of 40° C. at a ratio of about 1:1 by a chiral column. Furthermore, as the collected two compounds exhibit the same behaviors according to instrumental analysis, the compounds are believed to be two types of stereoisomers based on central chirality resulting from chiral center.

[0092] In the present specification, the component eluted at 7 minutes to 9 minutes (retention time of about 8.1 minutes) when the compounds represented by the general formula [I] are loaded onto a chiral column (CHIRALPAK AD-H (manufactured by Daicel) 0.46 cm I.D.×25 cm L.) which uses MeOH/MeCN/DEA=90/10/0.1 (v/v) as a mobile phase with flow rate of 1.0 mL/min to elute the compounds at 40° C. is referred to as the first component (alternatively, also simply referred to as (A)). Further, the component subsequently eluted at 10 minutes to 13 minutes (retention time of about 11.4 minutes) is referred to as the second component (alternatively, also simply referred to as (B)). As described above, at the moment of the present invention, it is not analyzed whether the stereo configuration of the enantiomer named as the first component of the present invention has R configuration or S configuration. However, it can be collected as shown in FIG. 7 and FIG. 8, and it has been obviously isolated.

[0093] Meanwhile, an oxalate of the compound [Ia] described below forms crystal, and considering that stereoisomers at the amide portion are confirmed to be present at a ratio of about 2:3 according to .sup.1H-NMR spectra recorded at room temperature, the possibility of having a nitrogen atom as the chiral center of the stereoisomers represented by the general formula [II] of the present invention cannot be completely ruled out. However, the free form of the compound [Ia] described below does not form crystal but are amorphous, and the presence of stereoisomers of which chiral center is a nitrogen atom are not confirmed.

[0094] Taken together, it is believed at the present moment that the chiral center is a sulfur atom as described above.

[0095] Since the compound of the present invention has a basic nitrogen atom, it can form an acid addition salt in this position. As an acid for forming this acid addition salt form, if it is pharmaceutically acceptable, it is not particularly limited. As a preferable acid addition salt of the present invention, examples include an inorganic acid addition salt such as hydrochloric acid salt, hydrogen bromide acid salt, sulfuric acid salt, phosphoric acid salt, or nitric acid salt; an organic acid addition salt such as oxalic acid salt, acetic acid salt, propionic acid salt, succinic acid salt, glycolic acid salt, lactic acid salt, malic acid salt, tartaric acid salt, citric acid salt, maleic acid salt, fumaric acid salt, methanesulfonic acid salt, benzene sulfonic acid salt, p-toluene sulfonic acid salt, or ascorbic acid salt; and an amino acid addition salt such as an aspartic acid salt or glutamic acid salt. Furthermore, the compound of the present invention or its acid addition salt may be a solvate like a hydrate.

[0096] The compound as the first component of the optical isomers of the present invention can be produced by separating the compounds represented by the general formula [I] by a separation method using a chiral column or the like and collecting the separated compound.

[0097] The compounds represented by the general formula [I] of the present invention can be produced by the method described in Patent Document 11. More specifically, for example, by oxidizing the compound represented by the formula [V] of the following reaction formula with a suitable oxidizing agent, an oxide represented by the formula [Ia] can be produced. As an oxidizing agent, a peroxy acid, for example, peracetic acid, perbenzoic acid, and meta-chloroperbenzoic acid (mCPBA) can be used. As a solvent, halogenated hydrocarbon such as methylene chloride or chloroform can be used as appropriate. In order to prevent oxidation to a sulfone, the reaction temperature is preferably low temperature, for example, 0° C. to 5° C. or so. From a reaction mixture, separation and purification of a target product can be carried out by publicly known separation and purification means such as extract operation, chromatography, or distillation.

##STR00006##

[0098] Production can be made by oxidizing the sulfur atom of the heterocycle of 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine of the compound [V] by meta-chloroperbenzoic acid (mCPBA) as an oxidizing agent in chloroform (CHCl.sub.3) solvent.

[0099] According to the above-mentioned reaction pathway, the hydrochloric acid salt shown by formula [V] is oxidized in chloroform solvent with meta-chloroperbenzoic acid (mCPBA) as an oxidizing agent to provide 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide of the compound [Ia], which is then separated by silica gel chromatography using a chloroform-methanol mixture as a mobile phase. From the separated chloroform-methanol azeotropic solvent, the solvent is extracted by distillation and the residual solvent is removed in argon to give a final product. The compound represented by the above formula [Ia], which has been obtained as described above, has purity of 90% or more and has a molecular weight of 440.61, and it is an amorphous solid, stable to oxygen, humidity, acid, and alkali at a room temperature, is easily dissolved in ethanol and dimethyl sulfoxide (DMSO), and has a skin irritating property. Furthermore, the oxalate of the compound [Ia] is a crystal which has a molecular weight of 530.65, has purity of 90% or more and the melting point of 167 to 168° C., and it is soluble in water, ethanol, and dimethyl sulfoxide. It was confirmed by the analysis of the .sup.1H-NMR spectra at the room temperature that the stereoisomers in an amide portion exists at ratio of about 2:3.

[0100] Furthermore, 4-{3-[4-(4-hydroxybenzyl)piperidin-1-yl]propionyl}-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide which is a compound represented by the general formula [II] of the present invention having hydroxyl group as R, or a pharmaceutically acceptable salt thereof can be produced by the same oxidation reaction as described above while protecting the hydroxyl group, if necessary. Furthermore, a rat or a dog is administered with the 1,4-benzothiazepine derivative, which is the parent compound, and after adding water to the obtained urine or feces followed by homogenization, the supernatant can be subjected to component separation with retention time of 19 to 22 minutes by high performance liquid chromatography using a gradient elution, which uses reverse phase column using silica gel modified with octadecyl group (ODS) and, as a mobile phase, water containing 0.1% trifluoroacetic acid (TFA) as solution A and acetonitrile containing 0.1% TFA as solution B. The separated component has mass charge ratio (m/Z) of 457 according to mass spectrometry. Meanwhile, the compound of [Ia] can be also obtained by, according to the same method as above, the component separation with retention time of 27 to 30 minutes by high performance liquid chromatography using a gradient elution.

[0101] Furthermore, it is also possible to consider a method of producing a compound of the general formula [II] of the present invention by oxidizing 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine by the same method as above to obtain 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide, separating a stereoisomer therefrom by a chiral column, collecting one enantiomer, and carrying out amidation of the enantiomer at suitable reaction conditions.

[0102] The first optical isomer component of the compound represented by the general formula [II] of the preset invention or a salt thereof is useful as a therapeutic agent or a prophylactic agent for a heart disorder such as arrhythmia, heart failure, angina pectoris, or myocardial infarction, in particular, as a therapeutic agent or a prophylactic agent for a heart disorder such as arrhythmia, heart failure, angina pectoris, or myocardial infarction caused by atrial fibrillation or atrial flutter.

[0103] Thus, the first optical isomer component of the compound represented by the general formula [II] of the preset invention or a salt thereof can be used as an effective ingredient of a pharmaceutical composition. The pharmaceutical composition of the present invention can be administered orally, sublingually, or intravenously, or as a plaster, however, it is preferably administered by intracoronary artery injection.

[0104] When the pharmaceutical composition of the present invention is prepared as a solid dosage form for oral administration, it is possible to have a dosage form such as tablet, pill, powder, or granule form. In such a solid composition, one or more of the active ingredient is admixed with at least one inactive diluent agent, dispersing agent, adsorbent, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, or silicic anhydride powder, or the like, and the solid composition can be produced in accordance with a conventional method.

[0105] When solid dosage forms are prepared as a tablet or a pill, coating may be carried out with a membrane of stomach-soluble or intestine-soluble film consisting of white sugar, gelatin, hydroxypropyl-cellulose, or hydroxymethylcellulose phthalate, or the like, and the coating may be carried out to have two or more layers. It is also possible to be made from a capsule such as gelatin or ethylcellulose.

[0106] When liquid dosage forms for oral administration are prepared, it is possible to have dosage forms such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixir agents. As a diluent agent to be used, there is purified water, ethanol, vegetable oil, or an emulsifier, for example. Furthermore, the composition may be admixed with adjuvants such as permeation agents, suspending agents, sweetening agents, flavoring agents, aromatic agents, or antiseptic agents, in addition to the diluent agents.

[0107] When injection solutions for parenteral administration are prepared, sterile and aqueous or non-aqueous solution agents, solubilizing agents, suspensions, or emulsifiers are used. In case of aqueous solution agents, solubilizing agents, and suspensions, there are, for example, water for injection, distilled water for injection, physiological saline, cyclodextrin and its derivative, and organic amines such as triethanolamine, diethanolamine, monoethanolamine, or triethylamine, or inorganic alkali solutions.

[0108] When water-soluble solutions are prepared, for example, propylene glycol, polyethylene glycol, vegetable oil like olive oil, or alcohols like ethanol may be used. Furthermore, as a solubilizing agent, for example, surface active agents (for forming mixed micelle) such as polyoxyethylene hydrogenated castor oil or sucrose fatty acid ester, or lecithin or hydrogenated lecithin (for forming liposome) may be used. Furthermore, it is also possible to prepare emulsion agents which consists of non-water soluble solubilizing agents like vegetable oil, and lecithin, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol or the like.

[0109] The compound represented by the general formula [II] of the present invention or a salt thereof may be generally administered once daily or divided into several times per day and either orally or parenterally, within a range of 0.1 mg to 1 g, preferably 1 mg to 1 g or 0.1 mg to 0.5 g as a free compound per an adult patient per day, although it may vary depending on age, body weight, symptom, therapeutic effect, administration method, a treatment time, or the like.

[0110] Hereinafter, the present invention is further specifically explained in view of one example of the present invention. However, it is evident that the present invention is not limited at all by the following exemplifications and explanations.

Example 1

[0111] Production of the 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine-1-oxide of the compound represented by formula [Ia]

[0112] 30.0 g of hydrochloride salt of 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine, which is the compound shown by the above formula [V], was added to a reaction vessel, to which 800 ml of chloroform (CHCl.sub.3) as a solvent was added, and dissolved under stirring at room temperature. Subsequently, the reaction vessel was placed in an ice-cold water bath, and it was cooled until the temperature inside the vessel becomes 0 to 1° C. Six hundred ml of chloroform (CHCl.sub.3) solution dissolved with 14.0 g of meta-chloroperbenzoic acid (mCPBA) was gradually added dropwise thereto with dropwise addition time of 110 minutes while being careful not to have an increase of the reaction temperature. After completion of the dropwise addition, stirring was performed at 0 to 1° C. for 20 minutes approximately.

[0113] Subsequently, 200 ml of H.sub.2O solution dissolved with 4.14 g of Na.sub.2SO.sub.3 was added dropwise thereto at 0 to 5° C. over 1 minute. After completion of the dropwise addition, stirring was performed at 0 to 5° C. for 10 minutes. Subsequently, while maintaining it cool at 0 to 5° C., 1 mol/liter aqueous solution of NaOH was added dropwise thereto over 1 minute. After the dropwise addition, stirring was performed at 0 to 5° C. for 15 to 20 minutes. After separating out the organic layer, the aqueous layer was extracted with 600 ml of CHCl.sub.3. The organic layer was combined with extracts and washed once with 200 ml of H.sub.2O and once with 200 ml of saturated NaCl solution. The organic layer was dried with anhydrous Na.sub.2SO.sub.4, and then concentrated under reduced pressure.

[0114] By the silica gel chromatography, concentrated residue was eluted by ethanol for purification. The objective compound was obtained at 13 g as an amorphous to viscous oil phase.

[0115] IR (cm.sup.−1): 3452, 2919, 1643, 1594, 1022

[0116] .sup.1H-NMR (CDCl.sub.3, 300 MHz): δ

[0117] 1.1-2.95 (17H, m), 3.78 (3H, s), 3.86-4.16 (2H, m), 4.65 (2H, s), 6.8-7.65 (8H, m)

[0118] MS (FD-MS): 441 (M′)

Example 2

[0119] The first optical isomer component and the second component of the compounds represented by the formula [IV] of the present invention were prepared by separating the compound represented by the formula [Ia], which has been prepared in Example 1, and then by collecting, at the conditions described below.

[0120] Column: CHIRALPAK AD-H (manufactured by Daicel Corporation)

[0121] Size: 0.46 cm I.D.×25 cm L.

[0122] Mobile phase: MeOH/MeCN/DEA=90/10/0.1 (v/v)

[0123] Flow rate: 1.0 mL/min

[0124] Temperature: 40° C.

[0125] Detection wavelength: 245 nm

[0126] Injection amount: 10 μL

[0127] MeOH represents methanol, MeCN represents acetonitrile, and DEA represents diethylamine, respectively.

[0128] Meanwhile, as for the devices, the followings were used.

[0129] Pump: LC-20AD (manufactured by Shimadzu Corporation)

[0130] Detector: SPD-20A (manufactured by Shimadzu Corporation)

[0131] Auto sampler: SIL-20A (manufactured by Shimadzu Corporation)

[0132] From 10 g of the compound represented by the formula [Ia], it was possible to collect the first optical isomer component and the second component, each in an amount of 4 g.

[0133] Each of the collected components was applied to column chromatography at the same conditions as above. The results are shown in FIG. 8 and FIG. 9, respectively.

Example 3

[0134] Measurement of heart rate, blood pressure, left ventricular contraction function (max dP/dt), and left ventricular relaxation function (min dP/dt)

[0135] Test method: In the present test, by using an anaesthetized rat, the influence of the hydrochloride salt of the first optical isomer component (A) and the second optical isomer component (B), each administered intravenously and continuously, on a circulatory system was determined. The test was performed with n=5 for each group. Each of the first component (A) or the second component (B) was continuously administered for 20 minutes at 0.1 mg/kg/minute, and then the measurement of heart rate, blood pressure, max dP/dt, and min dP/dt was performed. Each parameter was measured at 0 minute, 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, and 40 minutes after the administration, and the result was expressed in terms of a difference compared to the 0 minute value (previous value (i.e., control value)). The measurement value was expressed in terms of mean value±SD.

[0136] Test results: The result relating to a change in the heart rate is shown in FIG. 1. As shown in FIG. 1, the heart rate was mildly increased by the first optical isomer component (A) but the heart rate was decreased by the second optical isomer component (B), showing the pharmacological activities that are contradictory to each other.

[0137] The result relating to a change in blood pressure is shown in FIG. 2. As shown in FIG. 2, the blood pressure was mildly increased by the first optical isomer component (A) but the blood pressure was decreased by the second optical isomer component (B), showing the pharmacological activities that are contradictory to each other.

[0138] The change in left ventricular contraction function is shown in FIG. 3. As shown in FIG. 3, the left ventricular contraction function was enhanced by the first optical isomer component (A) but the left ventricular contraction function was reduced by the second optical isomer component (B), showing the pharmacological activities that are contradictory to each other.

[0139] The change in left ventricular relaxation function is shown in FIG. 4. As shown in FIG. 4, the left ventricular relaxation function was enhanced by the first optical isomer component (A) but the left ventricular relaxation function was reduced by the second optical isomer component (B), showing the pharmacological activities that are contradictory to each other.

[0140] For the data of FIG. 1 to FIG. 4, determination of a significant difference was carried out by using t test.

Example 4

[0141] Influence on Atrial Effective Refractory Period

[0142] Test method: In the present test, by using an anaesthetized beagle dog, the influence of hydrochloride salt of the first optical isomer component (A) and the second optical isomer component (B), each administered intravenously and continuously, on atrial effective refractory period was determined. The test was performed with n=5 for each group. The test compound was continuously administered for 10 minutes at 0.1 mg/kg/minute and then for 20 minutes at 0.05 mg/kg/minute. Measurement of atrial effective refractory period till 270 minutes after the termination of the administration was carried out. The pacing interval was 250 msec. The measurement value was expressed in terms of mean value±SD.

[0143] Test results: The test results are expressed in terms of % change rate when the previous value (i.e., control value) of atrial effective refractory period is set at 100%. The results are shown in FIG. 5. As shown in FIG. 5, the atrial effective refractory period was extended by the first optical isomer component (A) and also by the second optical isomer component (B), and the longer extension was obtained by the first optical isomer component (A).

[0144] For the data of FIG. 5, determination of a significant difference was carried out by using t test.

Example 5

[0145] Influence on Ventricular Effective Refractory Period

[0146] Test method: In the present test, by using an anaesthetized beagle dog, the influence of the first optical isomer component (A) and the second optical isomer component (B), each administered intravenously and rapidly, on ventricular effective refractory period was determined. The test was performed with n=5 for each group. The test compound was rapidly administered for 5 minutes at 1 mg/kg/minute. Measurement of ventricular effective refractory period was carried out immediately after the termination of the administration. The pacing interval was 250 msec. The measurement value was expressed in terms of mean value±SD.

[0147] Test results: The test results are expressed in terms of % change rate when the previous value (i.e., control value) of ventricular effective refractory period is set at 100%. The results are shown in FIG. 6. As shown in FIG. 6, the ventricular effective refractory period was not extended by the first optical isomer component (A), but it was significantly extended by the second optical isomer component (B) (P<0.05).

INDUSTRIAL APPLICABILITY

[0148] The present invention is to provide a compound having a specific stereo configuration and a property of an ideal therapeutic agent for atrial fibrillation which can extend atrial effective refractory period but does not extend ventricular effective refractory period and a pharmaceutical composition using the compound, and they are useful in the field of pharmaceuticals and medicines and thus have an industrial applicability.