JPS6030670B2 - Novel compounds useful in arrhythmia treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 5-endo-(3-indolecarponyloxy)-N-[ami/(lower)-alkyl]-bicyclo[ 2.2.1] Concerning the hebutane-2,3-gend-carboxylic acid imide series.

Cardiac arrhythmia, a phenomenon commonly associated with coronary heart disease or myocardial infarction, is a common affliction for humans, especially the elderly.

The mechanism of cardiac arrhythmia is thought to be caused by abnormal "lesions" in the ventricles that send nerve signals faster than necessary for normal heart beats. Unbalanced arrhythmia causes muscular vibrations that can lead to death. 5-Endo-(3-indolecarbonyloxy)-N-[amino(lower)alkyl]-bicyclo[2.2.1]-heptane-2.3
It has now been discovered that a series of compounds of the present invention, named endocarboxylic acid imides, are useful therapeutic or prophylactic agents for the suppression of abnormal deviated heartbeats.

Therefore, the present invention provides a compound represented by the formula 1: [wherein R4 and R5 are the same or different and are each alkyl or (lower) alkyl, and n is an integer from 2 to 4], its levorotatory or dextral The present invention provides a rotary isomer or a pharmaceutically acceptable acid addition salt of the above compound [1] or an isomer thereof.

Compound 1 theoretically exists in the following isomeric forms: ■ Endo-3-indolecarbonyloxy: Endo-substituted imide: 'B) Exo-3-indolecarbonyloxy: Exo-substituted imide (X): Ni' Endo-3- Indole carbonyloxy: Exo-substituted imide: ■' Exo-3-indole carbonyloxy: Endo-substituted imide: These isomers each have two optical isomers: levorotary and dextrorotatory.

The distinction between isomers is determined by the mutual position of the constituent bonds in the 2, 3 and 5 positions of the bicyclo ring system.

If these bonds (ie, the constituent bonds at positions 2, 3, and 5) are on the same side as the 7-bridge, they are exo-exo isomers.

These bonds (i.e. the constituent bonds at positions 2, 3 and 5) are on opposite sides of the C7 bridge or the carbon atoms 2,
If it is in the cage formed by 3, 5 and 6, it is an end-end isomer. The constitutive bond at position 5 is C7
If it is on the same side as the bridge and constituent bonds 2 and 3 are on the opposite side from the C7 bridge, it is an endo-exo isomer. An illustrative exo-exo isomer is a compound with the formula x.

An exemplary end-end is a compound having formula 1.
The only isomers claimed in this invention are the end-end isomers represented by formula 1 and their dextrorotatory and levorotatory isomers.

The end-end isomers were originally produced exclusively by the synthetic methods described in section 2). Optical isomers of compounds having formula 1 can be isolated, for example, by fractional crystallization of air isomer salts produced using (10)- or (1)-tartaric acid or D-(10)-camphorsulfonic acid.

Although this is probably better, the optical isomer of compound 1 has the formula m:
[However, in the above formula, n is an integer of 2 to 4, and R4 and R5 are H or (lower) alkyl] Compound 5
-endohydroxyl-N-[amino(lower)-alkyl]bicyclo[2,2,1]-heptane-2,3-Gendo-rupoxylic acid imide is decomposed, for example (
Compound 1 can be produced by performing a fractional crystallization process on a transparent isomer salt produced using (1) or (1)-tartaric acid or D-(10) camphor sulfonic acid and then esterifying it.

As used herein, "(lower)alkyl" is defined as an alkyl group having 1 to 6 carbon atoms.

The alkyl group may be branched or straight chain, for example n-propyl, isopropyl and the like. n is 2 to 4-(
The expression C-2n)- can be used to refer to any variable group, such as -C
It shall include ratio 1CH21CH2-, *etc.

"Pharmaceutically acceptable acid addition salts" are defined as any inorganic acid salts of the compounds of this invention that are commonly used to prepare substantially non-toxic salts of pharmaceuticals with amine functionality. .Illustrative examples include compounds with formula 1: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphorous acid, hydrobromic acid, maleic acid,
Mixed with malic acid, ascorbic acid, citric acid or tartaric acid, pamoic acid, lauric acid, stearic acid, palmitic acid, oleic acid, myristic acid, lauryl sulfonic acid, naphthalene sulfonic acid, linoleic acid, linolenic acid, etc. These salts formed. Compounds of the invention have been described by Applicants' colleagues, Sadao. Oki and Ichiro. Natsuo U.S. Patent Nos. 3,850,922 and 38
It is closely related to what was published in No. 50921.

Such compounds have the formula: [However, in the above formula, R1, R2 or R3 is
r, F, (lower) alkyl, nitro, OH or (lower)
Alkoxy: n is an integer of 2 to 4: and R4 and R
5 is (lower) alkyl, or when nitrogen is also included, it is a group having the formula:

As is clear, these compounds are esters of compound m.

As a result of the applications identified above, compounds with formula m, in particular (
10) -5-Endo-penzoyloxy(3-dimethylaminopropyl)-bicyclo[2.2.1]-hebutane-2.3-endodicarboxylic acid imide hydrochloride has excellent long-term effects on rodents. It was found to have moderate anti-arrhythmic properties, but only short-term activity in humans due to the special sensitivity of esterases present in human serum.

Apparently the compound with the formula is rapidly hydrolyzed to an inactive species identified as compound ma. In the wake of this knowledge, great efforts have been made to discover compounds that counteract this enzymatic hydrolysis. It has been found that 3-indolecarponyloxyesters are particularly effective against this in vivo hydrolysis.

A preferred embodiment of the invention is a compound of formula 1, its levorotatory or dextrorotatory isomer, or a pharmaceutically acceptable salt of said compound 1 or said isomer.

The most preferred embodiment of the present invention is a compound of the above formula 1 in which n is 3 and R4 and R5 are each methyl, a levorotatory or dextrorotatory isomer thereof, or a pharmaceutically acceptable acid addition of the above compound or an isomer thereof. It's salt. Another preferred embodiment is an essentially pure levorotatory isomer of Compound 1.

The present invention further provides a method for producing a pharmaceutically acceptable salt of the compound of formula 1, its levorotatory or dextrorotatory isomer, or a pharmaceutically acceptable salt of the compound of formula 1 or its isomer. ) Formula m: (However, in the above formula, n, R4 and R5 are as defined above.

) in an organic solvent, preferably a solvent selected from the group consisting of benzene, toluene, xylene, pyridine, methylene chloride, chloroform or mixtures thereof, at a temperature of from about 0 to about 600C; At least one 3-indole carbonyl halide, preferably at about room temperature, of the formula (where x is chlorine, bromine or iodine, but preferably chlorine) or a chemical equivalent thereto. molar acylation to yield a compound of formula 1 and optionally {a} treatment of the above compound of formula 1 with a pharmaceutically acceptable acid to yield the corresponding acid addition salt to yield a compound of formula m; If the acid addition salt has not yet been decomposed, optionally decompose the acid addition salt into its optical isomers; After decomposition into isomers, the optional decomposed isomers are treated with a pharmaceutically acceptable acid to form the corresponding acid addition salts.

consists of things.

Compounds with the formula m can be prepared by the following sequential steps: Endolysis in water [2.2.1]
-hept-5-ene-2,3-dicarboxylic anhydride or exocys-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride, preferably endos-isomer suspension The solution is treated with excess concentrated sulfuric acid in the temperature range of 70-95 qo to produce an endo-compound of formula B: [1 mole of B' compound B is refluxed with at least 1 mole of thionyl chloride or phosphorus trichloride. temperature for 15 minutes or more to remove excess thionyl chloride or phosphorus trichloride in vacuo to produce an oily residue, {C
} The residual oa is expressed by the formula: (However, n, R4, and R5 in the above formula are as defined above.

) in an organic solvent, preferably a solvent selected from the group consisting of benzene, toluene, xylene, etc., at reflux temperature for at least 30 minutes, and the solvent is removed in vacuo to obtain an oily Isosumi ro b. The resulting retentate is heated with at least 1 mole of potassium hydroxide in a mixture of (lower) alkanol and water and heated at reflux temperature for at least 1 hour to form the formula m: n, R4 and R in the formula
5 is as above.

) and, if necessary, decompose it into its optical isomers.

The present invention also provides a pharmaceutically acceptable amount of a compound having formula 1, its levorotatory and dextrorotatory isomers, or a pharmaceutically acceptable acid addition salt of said compound 1 or its isomers in an amount sufficient to inhibit cardiac arrhythmias. A pharmaceutical composition for treating cardiac arrhythmia characterized in that it is mixed with an acceptable drug substance.

Further, the present invention provides mammals with a body weight of about 0.25 to about 3.0.
By administering up to 3 or 4 times a day a compound having formula 1 of o/k9, its levorotatory or dextrorotatory isomer, or a pharmaceutically acceptable acid addition salt of said compound 1 or its isomer. The present invention provides a method for treating cardiac arrhythmia in mammals.

The compounds of the present invention were tested in dogs for their restoring activity in arrhythmias caused by obain.

Anesthetized dogs were used to create ventricular arrhythmias induced by Obain. The arrhythmia was due to nodal or ventricular cardiac involvement. The methods used to determine arrhythmia and the standards used to examine anti-arrhythmic activity are generally those of Lucchesi.
J. hesi) et al. PhannaCol, Exp. me
rap. , 132, 372, 1961. Compound (soil)-1a produced in Example 2 below [
The anti-arrhythmic activity of (±)-BL-4712A] was compared with silaver lidocaine, disopyramide and aprindine by rapid intravenous injection (1.V.). The mean prolongation and recovery doses were as follows: *Values are mean mean standard errors; N is the number of animals. was also tested.

Harris (also ms) Circulationl: 1318
, 1950, created a multifocal ventricular deviation rhythm in dogs using the coronal venation technique. Two minutes after ventricular arrhythmia occurred, the test drug was infused at a rate of 0.2 females/kg/min. The approximate average dosage required to produce a 50% reduction in ventricular eccentric rate and reversal of ventricular arrhythmia is shown below. Contrary to compounds 1 and 2, no recovery was observed even with intravenous infusion administration of lidocaine or quinidine up to 50 9/k9. *Values are average values; N is the number of tests.

Bulbring et al., J. Pha skin a
co1. Exp. The p. , 85:7 & 1945 was used in sentient Guinea pigs to determine local anesthetic activity.

Thirty minutes after lidocaine and Compound 1 were intradermally injected into the back of the animal's back, the animal's response to stinging pain from a hypodermic needle was tested. The dosage required for a 50% reduction in pain response is shown below along with confidence limits. Acute toxicity test results LD5 by intravenous administration of compound Ex-la (Example 2)
The o values are as follows.

LD5o by oral administration of compound Tsujito la (Example 2)
The values are:

All compounds within the scope of this invention possess anti-arrhythmic activity.

The compounds of the present invention can be used in the treatment of cardiac arrhythmias in mammals, including humans, up to 3 or 4 times a day at a rate of about 0.25 9/k9 body weight.
It is useful as a prophylactic or therapeutic agent within a dosage range of 9 to about 3.0.

Starting material method A Bicyclo[2.2.1]butane-endo2.3-
Manufacture of dicarpoxylic acid-5-endohydroxy-y-lactone (0) 500-600 ml of water and 164 ml of endocyclic [2.2.1] hepto-5-en-2,3-dicarboxylic anhydride While stirring vigorously, 500 g of concentrated sulfuric acid was gradually added to the suspension.

The reaction was exothermic and the temperature rose to about 80-90 mm during the addition of sulfuric acid. Two hours of boiling water was added to the reaction solution and immediately filtered. As the furnace liquid cooled, colorless plate-like crystals of the title product formed. When the crystallization was completed, it was collected in a furnace, washed with cold water, and air-dried to obtain crystals of 138 mm. Melting point: 20,000. Method B General Preparation of 5-endohydroxy-N-[amino(lower)alkyl]-bicyclo[2,2,1]hebutane-2,3-endocarboxylimides (m) Lactones from Method A (0) 0.1 mole and thionyl chloride 5
The mixture of 0 and 0 was heated to reflux on a wound bath for 2 hours.

Excess thionyl chloride was removed in vacuo and the oily residue (Da) was
- Washed with hexane (or petroleum ether). The oily residue was dissolved in 50' of anhydrous benzene. To this solution was added a solution of a suitable amine, e.g. 0.12 mole of N.N-dimethylaminopropylamine, and 100 molar of anhydrous benzene. The mixture was then reflux distilled for about 5 hours and concentrated in vacuo. The resulting brown syrup substance (rob) was mixed into a 50% water-ethanol solution containing 0.12 mol of potassium hydroxide.
Reflux distillation was carried out for 5 hours in a Z of 0. The solvent was removed in vacuo and saturated potassium carbonate solution was added and the resulting solution was extracted repeatedly with chloroform or 1:1 ethyl acetate-benzene.
The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solution is concentrated in vacuo and the product having the formula m is obtained by crystallization, chromatography and/or
Or recovered by vacuum distillation. Method C Alternative production method of 5-endohydroxy-N-[ami/(lower)alkyl]-bicyclo[2.2.1]hebutane-2.3-di-endocarpoxylic acid imides (m) From Method A A mixed solution of 0.1 mol of lactone (0) and PC1330 was distilled under reflux for 2 hours on a hot water bath.

Excess PC13 was removed in vacuo and washed with n-hexane. The oily residue is dissolved in 50 g of chloroform or methylene chloride, and a solution of 0.12 mol of a suitable amine, e.g. I added while doing so. After 2 hours of incubation, the mixture was distilled under reflux for one more step to warm it up to room temperature. The solution was washed with saturated potassium carbonate solution, cooled and separated. The separated organic phase was washed with saturated sodium chloride solution. The organic liquid was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product then collected was the title compound with formula m. Method ○ 5-Endohydroxy one day (3-dimethylaminopropyl)-bicyclo[2.2.1]hebutane 2.3
- Preparation of endocarboxylic acid imide (wind a) The title product is prepared by replacing the "appropriate" amine used in B and C with an equimolar amount of N.N-dimethylamino-propylamine and ethanol. Colorless plate-like crystals were obtained from -n-hexane by the crystallization method at 8°C (1).

) Matama・540o (,/3 ratio ○), yield 26-37%
. C. 4th 2203N2.1 Analysis value: Calculated value:
C, 56.42: Day, 8.79: N, 9.40 Measured value:
C, 56.70: day, 8.76: N, 9.11C, 4 days Analysis value for 2203N2・1/XLO: Calculated value: C
, 61.76; Sun, 8.45: N, 10.29 Measured value:
C, 61.93; Sun, 8.76; N, 10.40 Method E
5-Endohydroxy-N-(2-dimethylaminoethyl)bicyclo[2.2.1]hebutane-2.3
The title product was prepared by substituting an equimolar amount of N.N-dimethyl-aminoethylamine for the "appropriate" amine used in Methods B and C for the preparation of carboxylic acid imide (mb). Ta.

The free base was collected as colorless platelets by crystallization from ethanol-n-hexane. Melting point: 141.5°C, yield: 50%. C, 3 days 2.

Analysis value for 03N2 1/3LO: Calculated value: C, 6
0.46: day, 8.13; N, 10.85 measurement value: C,
60.71: Sun, 8.04; N, 10.95 Method F5-endohydroxy-N-(2-dimethylaminoethyl)bicyclo[2.2.1]hebutane-2.3-endocarboxylic acid Preparation of imidophenolphthalinate (mc) Substituting an equimolar amount of N.N-dimethylaminoethylamine for the "appropriate" amine used in Method B gave the title product as a yellow oil.

Boiling point 213-220oo/pentapod Hg, yield 37%. The product was further characterized as a phenolphthalinate salt.
Melting point 137-138.800. C fake day 4007N2-・
Analysis value for Seasonal 〇: Calculation: C, 67.04; Day, 6
．． 91; N, 4.48 measurement: C, 67.38; day, 7.
41; N, 4.23 Method G5-endohydroxy-N-(3-diethylaminopropyl)bicyclo[2
・2.1] Equimolar amount of N・N-jethyluamino in place of the “appropriate” amine used in the production method B of hebutane-2,3-endocarboxylic acid imidophenolphthalinate (md) centre.

The title product was obtained as a yellow oil using lopylamine.
Boiling point 228-230°C (6 willow Hg) 34% yield, the product was further characterized as a phenolphthalinate salt. Melting point: 155-158q○. c38th 42o7N2.1 Analysis value: Calculation: C, 67.39; Day, 7.02; N
, 4.36 measurement: C, 67.77; day, 7.79; N,
4.36 Method Day 5-Endohydroxy-N-(3-
piberidinopropyl) bicyclo[2,2,1)butane-2,3-gendocarboxylic acid imide (m
The title product was prepared in the form of colorless plates by crystallization from isopropyl-n-hexane using an equimolar amount of 3-piveridinopropyl-amine in place of the "appropriate" amine used in process B or C of preparation e). Obtained crystals.

Melting point 121.500. C, 7th 2603N2・1/44
Analysis value for 0: Calculation: C, 65.70; Day, 8.5
3; N, 9.01 measurement: C, 66.05: Sun, 9.03
:N, 9.06 Method I5-endohydroxy-N-
(2-morpholinoethyl)-bicyclo[2.2.1
] Hebutane-2,3-diendocarboxylic imide hydrochloride (mf) used in production method B or C.
The title product was prepared using an equimolar amount of morpholinoethylamine in place of the appropriate amine and collected as the hydrochloride salt.

The hydrochloride salt was prepared by dissolving mf in a minimal amount of diethyl ether and adding dry RCI gas to the mf solution while stirring vigorously. The hydrochloride salt was collected as colorless plate-like crystals from water-ethanol by the crystallization method. Melting point 280-2
8 is 0. Yield 30-34%. C, Rainbow 2204N2・HC
Analysis value for I: calculation: C, 54.43: day, 7.0
0; N, 8.46 measurement; C, 54.26; day, 7.66
:N, 8.50 Method J5-endohydroxy-N-(3-morpholinopropyl)-bicyclo[2.2.
1] “Appropriate” used in method B for producing hebutane-2,3-diendo-carboxylic acid imide (mg)
The title product was obtained as a yellow oil by replacing the amine with an equimolar amount of morpholinopropylamine.

Boiling point 260-27000/4 side Hg, yield 50%, product further characterized as methiodide salt. Melting point 233
00. Analysis value for C, JH2404N2-CH31: Calculated: N, 6.20 Measured: N, 6.28 Method K 1] Hebutane-2,3-endocarboxylic acid imides (L
) (Starting material) 5-endohydroxy-N-[amino-(lower)alkyl]bicyclo[2.2.1]-heptane-2.3-di-endocarboxylic acid imide (m) ( 0.01 mol) of a suitable benzoyl halide, e.g.
．． 0.12 moles of a 100:1 pyridine-piveridine solution.

The resulting mixture was left in a freezer overnight or warmed in water or oil bath. The mixture was poured into ice water, saturated with sodium carbonate, and then extracted with chloroform or 1:1 benzene-ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solution was filtered in an oven and concentrated in vacuo to give the desired title product (L). Method L (Method) -5-Endobenzoyloxy-N-(3-dimethyl-aminopropyl)bicyclo[2.2.1]hebutane-2.3-diethodocarboxylic acid imide (
Lb)'s production failure The "appropriate" penzoylha used in Manpo K.

The title product was prepared using an equimolar amount of penzoyl chloride in place of the genide and an equimolar amount of ma in place of the dicarboxylic acid imide m and collected as the hydrochloride salt. [B}
The free base was dissolved in near-boiling ethanol (700 g) and 90 g of ethanol saturated with hydrochloric acid gas was added.

The solution was cooled with ice to obtain colorless plate-like crystals of the hydrochloride having the formula B. Although it has a melting point of 239°C, it was decomposed by the crystallization method from methanol-acetone. Yield 90%. C2, day 270
Analysis value for 4N2・1'XLO: Calculation: C, 61.
07: Sun, 6.83: N, 6.95 measurement: C, 60.6
3; day, 6. Iso; N, 7.33 Method M(±)-5-Endobenzoyloxy-N-(3-dimethyl-aminopropyl)bicyclo[2.2.1]hebutane-2.3-endocarboxylic imide hydrochloric acid Decomposition of salt (Lb) 1 (1)-Production of optical antipode A (±)-5-endo-penzoyl-N-(3-dimethyl-aminopropyl)bicyclo[2.2.1]hebutane-2. 3-Diene-carboxylic acid imide (Lb) A mixed solution of hydrochloride of Lb (10 ml) was added to 150 ml of water and 200 ml of ether, and neutralized by adding sodium carbonate.

The aqueous layer was re-extracted with ether. The combined ether extracts (2 x 200) were washed with water, washed with saturated aqueous sodium chloride solution three times, and dried. (Sodium sulfate) ether was removed to obtain colorless crystals of racemic base Lb. (93rd evening) Melting point 106-107.5°C. B(1)-5-endobenzoyloxy-N-(3-dimethyl-aminopropyl)
Ethanol (3) containing (10)-10-1 camphor sulfonate water (175 [
．． Racemic base Lb (441.1 evening, 1.1 evening) in
(9 mol) in ethanol (1.1 mol) to a hot solution containing (9 mol) (
10)-10 Camphorsulfonic acid (276.5 evenings,
A hot solution containing 1.19 mol) was added.

The solution was heated to near the boiling point and then rapidly cooled to 20°C. 2
The colorless crystals formed during 3 hours at 0° C. were collected and washed with cold ethanol (600° C.) to give the title product of 325.3 hours.

Melting point: 221-226 qo. This salt was recrystallized from acetonitrile to give 282.6 mm of colorless needle crystals. Melting point 23
0-233℃. The ethanol mother liquor was saved for (10)-isomer isolation. C(1)-5-endobenzoyloxy-N-(3-dimethylaminopropyl)bicyclo[2.2.1]hebutane-2,3-di-endocarboxylic acid imide [(1)-Lb] From step B of camphor sulfonate (282.6 μl) was partitioned between a flocculation mixture of water (3 μl) containing ethyl acetate (3.5 μl) and sodium bicarbonate (150 μl).

The aqueous layer was further extracted with ethyl acetate (600 ml). The ethyl acetate extract was washed with saturated aqueous sodium chloride solution (bulb) and dried.

Removal of ethyl (sodium sulfate) acetate gave the title product as colorless crystals. (173.3 evening) Melting point 131.5-1
32.500 [Q] Color 5-Vulgar. 53.

(c.4.20 ethanol) D(1)-5-endo-
Step C of penzoyloxy-N-(3-dimethylaminopropyl)bicyclo[2.2.1]hebutane-2,3-endocarboxylic acid imide hydrochloride (V) in 95% ethanol (3.5 min) (4-)-isomer from (
On the evening of 173.3, a solution of 475' containing 95% ethanol (0.4 paper moles) in hydrochloric acid (0.4 total moles HCI) was added to a near-boiling solution of 0.4 total moles HCI.

The liquid was cooled with ice. The colorless crystals were collected, washed with cold 95% ethanol (600%) and dried to give the title product, 182.6%. Melting point 207-209qo, [Q] customer -85.5
6 (c.1.5 water) was further recrystallized from 95% ethanol, but the melting point and rotation did not change much. 0 (10)
Preparation of one optical enantiomer A(10)-15-endobenzoyloxy-N-(3-dimethyl-aminopropyl)bicyclo [2.2.1]
(1)-tartrate of hebutane-2,3-gendocarboxylic acid imide The ethanolic mother liquor of step IB above was stored at 0°C for 9 hours to further produce a crystalline substance (237.2 nights).
I got it.

Melting point: 183-186°C. Concentrate the furnace liquid to further produce colorless crystals (
119.9 pm) was obtained. Melting point 168-177°C. The two crystals were combined and partitioned between ethyl acetate and aqueous sodium carbonate as described in IC above (10)- and (1)-
The isomer (221.4 min) was obtained.

Melting point 125-129°C, greatly increased in (10)-optical enantiomer. Ethanol (3.6〆) containing water (40')
During (10)-increased mixture (221.4 evening, 0.59
(6 mol) of (1)-tartaric acid (89.6 mol)
In the evening, 0.596 mol) was added.

The mixture was heated to near boiling and then cooled to 25° C. for 4 hours. Collect colorless crystals and use 95% cold ethanol (500%
(10) - Optical enantiomer tartrate (2)
91.6〆) was obtained. Recrystallization from acetonitrile, melting point 157-16ro (decomposition) gave 247.2% pure tartrate. Melting point: 162-164°C (decomposition) B(10)-15-endo-penzoyloxy-N-(3-dimethylaminopropyl)bicyclo[2.2.1]hebutane-2.3-
Diendocarboxylic acid imide [(10)-Lb] The (10)-optical enantiomer generated by decomposing the tartrate salt (247.2) from Step A with an aqueous sodium carbonate solution was dissolved in ethyl acetate as described in IC. Extracted.

Removal of ethyl acetate gave the (10)-isomer (171.6 evening)
was obtained as colorless crystals. Melting point 111-133.500.
[Q] Capacity +77.740 (C.1,89 eta/-r)C
(10) 15-Endobenzoyloxy-N-(3-dimethylaminopropyl)bicyclo[2.2.1]hebutane-2.3-endocarboxylic acid imide hydrochloride (in) ID (1) - (10) - Optical enantiomer from step B as described for the optical enantiomer (171.
6 was treated with an equivalent amount of ethanolic hydrochloric acid to obtain colorless crystalline (10)-optical antipode hydrochloride.

(188.2 evening) Melting point 207-20900 [Q] Customer 18
5.8 (c.1.30 water) Method N 5-endohydroxy-N-(4-dimethylaminobutyl)-bicyclo[2.2.1]hebutane-2.3
- Preparation of endocarboxylic acid imide (mk) Dry C ratio CI 2100 ) (15.2
In the evening, thionyl chloride (25 cm) and DM (3 drops) were added to a mixed solution containing 0.144 mol of DM.

The mixture was strained and distilled under reflux for 3 hours. Then, the reaction solution was diluted with 2
The mixture was cooled to 0 and the solvent was removed under reduced pressure. The residual yellow oil was taken up in 50' of benzene and dried under reduced pressure to give a pale yellow solid. Dissolve the solid in 100' CH2C12 to obtain a C ratio CI250
4-dimethylaminobutylamine (20 evening, 0.
A solution containing 173 mol) was added dropwise. After the addition was completed, the reaction mixture was prayed to by two steps with a carp. The reaction mixture was then saturated with K2C
03 solution and the phases were separated.

The aqueous phase was extracted with CH2CI3 (2 x 125 [)] and CQ
The C12 phases were combined, washed with saturated NaCl solution, dried over Na2S04, oven and vacuum to remove the solvent. The resulting pale yellow oil was treated with boiling ethyl acetate, and the decanted ethyl acetate solution was removed under reduced pressure to yield a pale yellow solid. This was recrystallized from ethyl acetate to obtain bright yellow crystals mk. (13.3 evening,
33.3%) Melting point 108-10 pi○. C, 5th 2403
Analytical value for N2: Calculated: C, 64.26; Days, 8.
63; N, 9.99 measurement: C, 64.21: day, 8.4
6:N, 10.02 (corrected for ratio 01.61%.

) Example 1 5-endo-(3-indolecarbonyloxy)-N
-[Amino(lower)alkyl]bicyclo(2.2.1
]-General method for preparing heptane-2,3-di-endocarboxylic acid imides (1) Appropriately substituted indole-3-carponyl halide (0.011 mol) in methylene chloride containing about 1 pyridine; For example, the dried liquid of indole-3-carbonyl chloride is added to this (
15-endohydroxy-N-[amino(lower)alkyl]bicyclo[2.2.1]-heptane-2
・3-endocarboxylic acid imide (m) (0.
01 mol) was added.

The resulting mixture was left in a refrigerator overnight or warmed in a water or oil bath. The mixture was poured into ice water, saturated with sodium carbonate, and then extracted with chloroform or 1:1 benzene-ethyl acetate. The combined organic extracts were dried with saturated sodium chloride solution over anhydrous sodium sulfate. The solution was filtered and concentrated in vacuo to give the desired title product (1). Example 2 5-endo-(3-indolecarbonyloxy)-N
-(3-dimethylaminopropyl)-bicyclo[2.
2.1]-heptane-2,3-di-endocarboxylic acid imide hydrochloride [(±)-1a] Indole-
Thionyl chloride (3.6', 0.05 mol) was added to a suspension of 3-carboxylic acid (6.44 mm, 0.04 mol), and the mixture was heated in an anhydrous state for 2 hours.

The solvent and excess thionyl chloride were removed by evaporation at 25-30q0 vacuum to obtain an oil. Dry the oil further (CQC day 2)
20 and removal as above to give a solid whose infrared spectrum was consistent with the desired indole-3-carbonyl chloride. This acid chloride (7.16 night, 0.04 mol) was added to dry CQC1210 containing 13 drops of dry pyridine.
Dissolved in 0'.

Alcohol ((shi) ma (5.32 evening, 0.02 mol)
The mixture was stirred at 25° C. for 5 hours to form a solid precipitate, and 20% of dry pyridine was added to form a solution. After distilling the mixture under reflux for about 10 minutes, a precipitated product was obtained. After cooling in a cooling furnace, 7.6 hours (86% yield) of the crude title compound was obtained.
This was purified by recrystallization from 20:ICH3CH20H/CH30 days. Melting point 25 is ○. C23rd 27N304・
Analytical value for HCI: Calculated: C, 62.09; Day, 6
．． 12; N, 9.44; CI, 7.97 Measurement: C, 62
．． 27; Sun, 6.19:N, 9.39:CI, 7.95
Example 3 5-endo-(3-indolecarbonyloxy)-N
-(2-dimethylaminoethyl)bicyclo[2.21
1] Preparation of hebutane-2,3-diendocarboxylic acid imide [(±)-lh] Indole-3-carboxylic acid (452 mmol, 28 mmol) was converted to the acid chloride in a conventional manner.

The acid chloride was redissolved in CH2CI2 (100 ml) and then alcohol (4.8 min, 19 mmol) and dry pyridine (1 Z) were added with stirring. After distilling the mixture under reflux for 70 minutes, a white solid product precipitated. (6.
7 evening, 81.6%) 2:1 isopropyl alcohol C
An analytical sample was obtained by recrystallization from day 30. Melting point 259 - 26100 (decomposition) C22 days 2bu304 Analysis value for HCI: Calculation: C, 61.18: days, 6.07: N,
9.73 measurement: C, 61.53; Sun, 6.10: N, 9
．． Example 85 Production of 45-endo-(3-indolecarbonyloxy)-N-(3-methylaminopropyl)bicyclo[2.2.1]-heptane-2.3-gendocarboxylic acid imide hydrochloride (li) 5-endo-[1-(2,2,2-trichloroethoxycarbonyl)-3-indolecarbonyloxy]-N[3-(2,2,2-trichloroethoxycarbonyl)-3-methyl Aminopropyl Bicyclo [2.2.
1]-heptane-2,3-diendo-carpoxylic acid imide Compound) la (8
．． Trichloroethyl chloride formate (45 mmol, 9.53 pm) was added little by little to the solution containing 21.5 mmol) over 15 minutes.

After the 2nd birthday speech at 20qo, 60-65pm at Yu Yuchu.
was heated for 75 minutes.

The clear amber liquid was then cooled and the solvent removed under reduced pressure at 45°C. The residue was dissolved in CQC12 (300) and washed successively with ice, cold dilute hydrochloric acid, water, 5% Na2C03 solution and brine. Drying (over MgSO4) and removal of the solvent gave an amber rubbery 5-endo-[1-(2,2,2-trichloroethoxy-carponyl)-3-indolecarbonyloxy]-N-(3-dimethylaminopropyl). )-hicyclo[2.2.1]-hebutane-2.3-endocarboxylic acid imide (7a) and 5-endo[1
-(2,2,2-trichloroethoxycarponyl)
-3-indolecarbonyloxy]-N-[3-(2
・2,2-trichloroethoxycarponyl)-13-methylaminopropyl)bicyclo[2,2,1]hebutane-2,3-diendocarboxylic acid imide (7b
) was obtained. (16th evening) The white solid obtained by grinding with (CH3CH2)20 was ethyl acetate/(CH3CH2).
2) Recrystallization from 20 (filtering off a small amount of undissolved material) gave essentially pure 7b (5.6 min, 35% yield).

Melting point 178-1820. (Disassembly) Tsukuda 5-end-(3
-indolecarbonyloxy)-N-(3-methylaminopropyl)bicyclo[2.2.1]-heptane-
2.3-Gendocarboxylic acidimide hydrochloride (l
j) 7b (1.95 mmol, 2.61 mmol) was suspended in 90% acetic acid (100%) and zinc powder was added with stirring for 1 minute.

After 21 hours at 20:00 (with some exotherm), excess zinc and salts were removed and the cake was washed with 30' of 90% acetic acid. Evaporate the furnace liquid at ~40qo and saturated the residual rubber with N.
It was treated with aHC03 solution (saturated) and then INNaOH solution was added until it became clearly alkaline. 2 with ethyl acetate
After extraction twice, the organic liquid was washed with water and brine. After drying (Mg
S04) The rubber obtained by removing the solvent (0.833 mm) was
:1 Dissolved in anhydrous EtOH/Et20 and treated with HCI gas. The solvent was removed and the crude hydrochloride (0.622 m, 55 m
．． 4% yield) was obtained. Melting point 243-247℃ (decomposition) 3
:ICH3CN/boiled in anhydrous ethyl alcohol (
Pure li was obtained twice by diluting with C ratio CH2)20. Melting point 246-249℃ (decomposition) C22 days 25N304
・HCI analysis value: calculation: C, 61.18: day, 6.0
7; N, 9.73 measurement: C, 60.98; day, 6.03
:N, 10.06 Example 55-endo(3-indolecarbonyloxy)-N-(3-aminopropyl)
Production of bicyclo[2.2.1]hebutane-2.3-di-endocarboxylic acidimide (lk) ■ 5-endohydroxy-bicyclo[2.2.1]hebutane-endo2[N-(2 -cyanoethyl)] lactone lactone (X
X) Lactonic acid (18.2 min, 0.1 mol), SOC
A mixture of 12150' and CH2CI2250M and 4 drops of dimethylformamide (DMF) was heated under reflux at 60 pm for 3 hours.

After evaporation to dryness, benzene was added and removed under reduced pressure. Acid chloride is C
After the comparison with CI235 was completed, a solution of CH2CI2150 containing 3-aminopropionitrile (0.21 mol, 15.3 m) was added to the bottle while stirring vigorously. The resulting reaction mixture was distilled under reflux for 2 hours. It was cooled, filtered to remove impurities, and the furnace liquid was evaporated to dryness. Add a small amount of CH to the obtained residue.
A slurry was made with 3CN and ether was slowly added to it.
A crystalline product was thus obtained with a yield of 85.5%. melting point 12
9-135qo. Analytically pure material was obtained by recrystallization from Cucumber CN. Melting point 145-1470. C, 2nd, 4N20
Analysis values for 3: Calculated: C, 61.52; Day, 6.02; N, 11.96
Measurement: C, 61.54: Day, 6.28; N, 11.96
Leg 5-endo-(3-indolecarbonyloxy)
-N-(2-cyanoethyl)bicyclo [2.2.1]
Hebutane-endo-2,3-dicarboxylic acid imide (
M) Drying (CQC day 2) Indole-3-carboxylic acid (9.4 evening, 0.0 globular mole) in 20 (200 [)]
Add thionyl chloride (15 drops) and DMF (3 drops) to the solution containing
added.

After heating at 23qC for 3 hours, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to obtain a dark-colored solid.

The solid was taken up to dry in 2 CI2 (150 cm) and mixed with pyridine (2') and 5-endo-hydroxy-bicyclo[2.2.1] butane-endo[N-(2-cyanoethyl)] Dorendo 3-carpoxylic acid y-lactone XX (9.0 min, 0.038 mol) was added.

The reaction mixture was reflux distilled for one vowel and filtered. The desired product X was obtained from the residue obtained by evaporating the furnace liquid under reduced pressure by the crystallization method from the C ratio CN. (6.8 pm, 48% yield) Melting point 230-2
31℃. Analysis value for C2, Sun, Bu 304: Calculation: C, 66.83; Sun, 5.07: N, 11.13
Measurement: C, 67.00: Day, 5.01; N, 10.78
) 5-endo-(3-indolecarbonyloxy)
-N-(3-aminopropyl)bicyclo[2.2.1
] Hebutane-endo-2,3-dicarboxylic acid imide hydrochloride (lk) Nitrile
mol) and 30% palladium on poppy, algae, and one night of catalyst were shaken in a Pan hydrogenator at 50 pounds of hydrogen pressure.

After 6 feeding hours of shaking, the hydrogen pressure in the apparatus had dropped by 19 pounds.

The reaction mixture was taken out and heated in a furnace. The filtrate was evaporated to dryness under reduced pressure, treated with 5% Na2C03, and evaporated to dryness. Wash the remaining bamboo with C ratio CI2 (150' x 4) and add the washing rice bran solution.
It was dried over 2S04, filtered and evaporated to dryness. Residue CH2
CI2/Skelly Soap B (trademark of Skelly Oil Co., Ltd.)
Recrystallization from n-hexane (boiling point 60 to 68 degrees) yielded 0.84 g of the free base. This was taken during the 20th CQC day and saturated with HCI gas (CH3
Injected into CH2)20. A gel-like mixture was obtained. The gel was evaporated to dryness, and the residue was heated in a CH3CH oven with charcoal for 20 days and removed under reduced pressure. In this case, the substance was an ethanol solvate. To remove solvates, the material was boiled with the following solvents: ethyl acetate, CI2, and Skelly C (trademark of Skelly Oil Co., consisting essentially of n-hexane, boiling point 90-10,000). The material was consistent with the desired primary amine similar to 11 at this point in elemental analysis, mass vector and 10 zNM old. Compound is 100
CH2CI solvate analyzed by MHzNM old 0.12
I found out it was a mole. When boiled with ethyl acetate, the compound was present as a 0.18 molar ethyl acetate solvate. Heat and vacuum also failed to remove this solvate. (0
．． 84 pm, 84% yield, melting point 185-190 pm) C2
, Analysis value for day 23N304: Calculation: C, 60.3
6; Sun, 5.79: N, 10.06; CI, 8.49 measurement: C, 59.61; Sun, 5.86; N, 10.02:
CI, 9.03 (1.24% water and 1.67% CH2
Corrected for CI2.

) Example 6 (10)-5-endo(3-indolecarbonyloxy)-N-(3-dimethylaminopropyl)bicyclo[2.2.1]-heptane-2.3-endocarboxylic acid imide hydrochloride [( 10)-la] A(10)-15
-Endo-hydroxy-N-(3-dimethylaminopropyl)bicyclo[2.2.1]hebutane-2.3-
G-endocarboxylic acid imide [(10)-ma] (
10) 15-Endo-penzoyloxy-N-(3-dimethylaminopropyl)bicyclo[2.2.1]hebutane-2.3-endocarboxylic acid imide hydrochloride (3.65 min, 0.0086 120-1250 mole) [(10)-Lb] was suspended in 18.8 moles of INNaOH.
The mixture was heated under reflux for 4 frames while being lit in an oil bath.

The liquid was then cooled and evaporated under reduced pressure to obtain a white solid.
The solid was triturated three times with 80 parts of ethyl acetate and the combined liquids were evaporated to give an oil which solidified on cooling. The solid was then suspended in 100 parts of cyclohexane and 15 parts of ethyl acetate and heated under reflux. The hot solution was heated in a furnace and cooled to 20°C to give a crystalline solid (1.53 min, 67% yield, melting point 121-12
○) was obtained, and it was determined to be (10)-ma. B(10)15-endo(3-indolecarbonyloxy)1N1(
3-dimethyl-aminopropyl)bicyclo[2.2.
1]-Heptane-2,3-JJENDO carboxylic acid imide hydrochloride [(10)-la] (CH3CH2)20(
40') indole-3-carboxylic acid (2.
6 days later, a solution containing 0.015 mol) of thionyl chloride (3.0 M) and anhydrous dimethyl formamide (D
MF) was added.

After boiling at 23 liters for 3 hours, excess chemicals and solvent were removed to obtain a crude chloride (2.6 min.) as a syrup close to a dark colored solid.

After drying the acid chloride in 2 CI2 and adding 5 drops of pyridine, (10)-ma. Lecole (2.0 evening, 0.007
5 mol) was added. The mixture was distilled under flask reflux in anhydrous conditions for 2 hours and the solvent was removed under reduced pressure. The colored residue was chromatographed through a basic alumina column (100%) and the product was chromatographed at 45% CHC13/45% (C ratio CH2)2.
Elution was performed with 0/10% CH for 30 days.

The yellow oil obtained by removing the solvent from the part containing the product was
CH3CH2) 20-25% CH3CH20 days and treated with HCI gas. Remove the solvent and convert the crude solid to CH8
It was recrystallized from CH20th and vacuum dried on P2Q at 7800 to obtain pure hydrochloride.

(0.921 min, 27.6% yield, melting point 193-195
00) Analysis value for C23 day 27N304・HCI:
Calculation: C, 61.95: Day, 6.33: N, 9.42:
CI, 7.95 measurements: C, 62.45; day, 6.41;
N, 9.74; CI, 8.13 (corrected for 1.65% water.

) [Q] 57.8 (c=0, 0.69 m; mother ○) Example 7 (1)-5-endo-1(3-indolecarbonyloxy)-N-(3-dimethylaminopropyl) Bicyclo[2.2.1]-heptane-2.3-diendocarboxylic acid imide hydrochloride [(1)-la]A(
1) -5-Endohydroxy-1N-(3-dimethyl-aminopropyl)bicyclo[2.2.1]hebutane-2.3-di-endocarboxylic acid imide [(1)-
[ma] Compound (1)-ma was prepared by using an equimolar amount of (1)-Lb in place of compound (10)-Lb used in the method described in the example.

Melting point: 119-120q○. B(1)-5-endo(3
-indolecarbonyloxy)-N-(3-dimethylaminopropyl)bicyclo[2.2.1]-heptane-2.3-gendocarboxylic acid imide hydrochloride indole-3-carboxylic acid (2.6 evenings, 0.015
mol) was converted to the crude acid chloride as described in the Examples.

As described in the example, (in CH2CI2/pyridine)
Compound (10)-la was treated with 4-ma alcohol (2.0 mL, 0.0075 mol) to obtain the crude product.

Chromatographed on a column of basic alumina (33% CHC13/12% (CH3CH2)20
/55% CH 30 days to give the pure free base. The solvent in the part containing the product was removed and the remaining crude oil was reduced to 75% (CH3
CH2) 20-25% CH was taken for 30 days and treated with HCI gas. The solvent was removed to obtain a brownish solid hydrochloride salt. CH
The product was recrystallized twice from day 3C and day 20, further ground with hot ethyl acetate, and vacuum dried on P205 at 78 qo to obtain a product. (1.47 pm, 44% yield, melting point 172-1740
0) Analysis value for C23 day 27N304・HCI: Calculation: C, 61.95: day, 6.33; N, 9.42: C
I, 7.95 measurement: C, 62.01: day, 6.07: N
, 9.52: CI, 8.22 (5.02% corrected for day 20.

) [Q] Closure = -58.2 (c = 0.052: ratio ○)
Example 85-Endo-(indole-3-carbonyloxy)-N-(2-dimethylaminopropyl)bicyclo[2.2.1]-hebutane-2.3-endocarboxylic acid imide hydrochloride, C ratio CH20 Solvent Compound (22) Lactonic Acid (8.0 t, 44 mmol),
SOC12 (12 [)] and dry DM Yen (2 Oran) were suspended in dry CH2CI2 (200%) and the mixture was distilled under reflux for 1.5 hours.

Crude acid chloride is produced by normal operation and dried with C ratio CI2 (
150 ml). Next, dry CH while stirring.
A solution containing 2-dimethylamino-n-propylamine (6.74 hours, 66 mmol) in 2CI250 was added dropwise over 10 minutes. After distilling the mixture under reflux for 3 hours, 1
After heating at o for 16 hours, add C ratio CI2 solution to 5% NaC03.
The solvent was removed by washing with liquid and saturated brine and drying (MgSO4). 5-Endohydroxy-N-(2-dimethylaminopropyl)bicyclo[2] as amber crude oil
．． 2.1]-hebutane-2.3-endocarboxylic acid was obtained.

Solid impurities were removed by milling with ethyl acetate Skerrysolve B and passing through an oven. Refined oil mm (11.49, 42.
8 mmol, 97.4% yield) was added to dry CH2CI2 (
200 () was added to a solution containing indole-3-carbonyl chloride (62 mmol of indole-3-carbonyl chloride (indole-3-COOHIO.0, 62 mmol) by the usual method). After heating under reflux for an hour, it was separated from the reaction mixture (6.71 evening, 35.2% yield) and recrystallized from anhydrous ethyl alcohol/(CH3C ratio) 20 to obtain purified product C, a broad CH20 solvent compound. Melting point 2
66-270o0 (decomposition) This solvate is 110qC
/0.05 or at the boiling point could not be removed by trituration with other solvent compounds such as ethyl acetate. Analysis value for C23rd 27N304・HC11CH3CH20th day: Calculation: C, 61.03: day, 6.97;
N, 8.54 measurement: C, 61.48; Sun, 6.63: N
, 8.76 Example 95-endo-(indole-3-carbonyloxy)-N-(4-dimethylaminobutyl)bicyclo[21211]hebutane-2,3-di-endocarboxylic acid imide hydrochloride (Siln) drying ( C&
Thionyl chloride (7.5') and DMF (2 drops) were poured into a solution containing indole-3-carboxylic acid (5.0 min, 0.031 mol) in CH2) 20 (100'). added.

After the mixed solution was heated for 1 hour at 2mori○, it was filtered in a furnace and the solvent was removed from the furnace solution under reduced pressure. The remaining solid acid chloride (5.39, 0.
03 mol), CH2CI2 (130 mol) and pyridine (1
A dissolved 5-end alcohol (58.8 molar, 0.021 mol) was added to the mixture. After distilling the reaction mixture under reflux for 1 hour, the solvent was removed under reduced pressure. Next, the sample was mixed with a 5% aqueous potassium carbonate solution (200 ml) and ethyl acetate (200 ml).
0board)). The phases were separated and the aqueous phase was dissolved in ethyl acetate (2x
Extracted with 100'). The combined extracts were dried over M04, heated and evaporated under reduced pressure to obtain a dark brown residue. 1 remaining
:ICH3CH2〇H/(CH3CQ)2〇100 For me, I treated it with HCI gas. This liquid was removed under reduced pressure to obtain a brown solid. This solid was taken up in CH3CH20H/ethyl acetate and treated with charcoal to recrystallize. (3.7 pm, 38% yield, melting point 217 - 218 qo) C 24 days 2bu 304 H
Analysis value for C conversion: Calculation: C, 62.67; Day, 6.5
7; N, 9.14: CI, 7-71 measurement: C, 62.2
1: Sun, 6.87; N, 8.85; CI, 7.88. (
Corrected for 0.6% day 20.

) Example 10 5-endo(indole-3-carbonyloxy)-N-(3-isobropylaminopropyl)bicyclo[
2.2.1]-Hebutane-2,3-endocarboxylic acid imide hydrochloride (Sat 1o) {a) 5-endohydroxy-N-(3-isopropyl-aminopropyl)
Bicyclo[2.2.1]hebutane-2.3-endocarboxylic acid imide hydrochloride (melon) lactonic acid 0
(16.0 mmol, 88 mmol) was converted to the lactone acid chloride in a conventional manner.

The acid chloride was dissolved in dry CH 12 (120 I) and dissolved in dry CQC 12 (300) N-isopropyl-113-propanediamine (12.08 pm, 0.104
mol) over a period of 10 minutes. The mixture was distilled under reflux for 2 hours and then heated to 18°C for 1 hour.
6. I kept it immediately. It was then filtered to remove a small amount of solid amine salt. The solvent was removed from the furnace liquid under reduced pressure to obtain a syrup. This syrup was dissolved in hot ethyl acetate containing enough anhydrous ethyl acetate to make it liquid. Cooling to 4° C. gave the product mn (20.15 min, 72.3% yield) in two batches.

The product was obtained by recrystallization from ethyl acetate/absolute ethyl alcohol. Melting point 168-17 is ○. C, 5 days 24N20
3. Analysis value for HCI: calculation: C, 56.87: day, 7.95; N, 8.76 measurement: C, 56.63: day,
8.14:N, 8.76(b} 5-endohydroxy-N-(N'-benzyloxycarbonyl-3-isopropylaminopropyl) bicyclo[2.2.1]
Bebutane-2,3-gendocarpoxylic acid imide XX isopropylaminoalcohol mm (3.17 evening,
10 mmol) was dissolved in 12 ml of water, and anhydrous Na2C03 (3.18 pm, 30 mmol) was added while stirring.

After cooling the mixture to −5° C. (20°C on ice), carbobenzyloxy chloride (2.05°C, 12 mmol) was added dropwise over 1-2 minutes. A white solid precipitated from the mixture within 5 minutes.

The rope pestle was continued for one time at -5°C and then continued for one hour at 20qC. The white precipitate was taken out of the oven, washed with water and Skellysolve B, and air-dried. (March 09, 74.6%) Recrystallized from ethyl acetate Kelly solve B to obtain pure XX. (Melting point 96.5-10000) Analysis values for C23 days 3bu 205: Calculated: C, 66.64: days, 7.30; N, 6.76 Measured: C, 66.71; days, 7.42; N, 6.74 (c
) 5-endo (indole-3-carbonyloxy)
-N-(3-isopropylaminopropyl)bicyclo[2.2.1]-hebutane-2.3-gendocarboxylic acid imide hydrochloride (lo) indole in dry tetrahydrofuran (THF) (60%) 3-carpoxylic acid (0.644 hours, 4 mmol) and carbonyldiimidazole (1.3 hours, 8 mmol) were added and distilled under reflux for 3 hours.

The reaction mixture was concentrated to a volume of about 10.degree. C., cooled to 5.degree. C., heated in an oven and washed with 20.degree. C. (CH3C ratio) to obtain indole-3-imidazolide as a white solid. (Era, 0.485 evening,
57.4% yield) and then the imidazolide compound (0.57.4% yield).
37 min., 1.75 mmol) and carbobenzyloxy derivative XX (0.472 min., 1.14 mmol) in dry tetrachloroethane (75 min.) at 120 qo.
．． It was heated for 7 hours. The solvent was removed under reduced pressure and the residual oil was partitioned between ethyl acetate and water. After layer separation, the aqueous phase was further extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, dried (M is C4), and the solvent was removed to obtain a semi-solid rubber. (Cucumber CH2) 20 was ground to produce a white solid, which was separated by furnace. (Imidazo 1) Remove the solvent in the furnace and re-melt it to 20-CHC13 at 1:1 (CQC day 2) and pass it through a glass filter and a 3-inch layer of basic alumina in the furnace. 400's 1:1 (CQC day 2) 2
0-CHC13 was released in a 30-day solution of 12% CH.

Claims (1)

[Claims] 1 Formula [I]: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^4 and R^5 are the same or different and are each H or (lower) alkyl, and n is an integer from 2 to 4], its levorotatory or dextrorotatory isomer, or a pharmaceutically acceptable acid addition salt of the above compound [I] or its isomer. 2 A compound according to claim 1, wherein n is 3, a levorotatory or dextrorotatory isomer thereof, or a pharmaceutically acceptable acid addition salt of said compound or an isomer thereof. 3. The compound according to claim 1, wherein R^4 and R^5 are the same or different and each is H, methyl, ethyl or isopropyl, its levorotatory or dextrorotatory isomer, or the above compound, or Pharmaceutically acceptable acid addition salts of its isomers. 4 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim 1, its levorotatory or dextrorotatory isomer, or a pharmaceutically acceptable acid of the above compound or its isomer Added salt. 5 Formula: ▲ Numerical formula, chemical formula, table, etc.▼ Acid addition salts. 6. An essentially pure levorotatory isomer of the compound according to claim 4. 7. An essentially pure dextrorotatory isomer of the compound according to claim 4. 8. Essentially pure dextrorotatory isomers of the compounds according to claim 1. 9. Essentially pure levorotatory isomers of the compounds according to claim 1. 10 Formula [I]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^4 and R^5 are the same or different and are each H or (lower) alkyl, and n is an integer from 2 to 4 ], its dextrorotatory or levorotatory isomer, or a pharmaceutically acceptable acid addition salt of the above compound [I] or its isomer in a pharmaceutically acceptable amount sufficient to suppress cardiac arrhythmia. A therapeutic agent for cardiac arrhythmia, characterized in that it is mixed with a carrier.