CA1276153C - Therapeutically active, membrane stablizing compounds - Google Patents

Abstract

ABSTRACT

Novel substituted piperidines of the formula are disclosed:

Description

The present invention relates to new subs-tituted piperidines, methods for their preparation, and pharmaceutical preparations and methods employing such compounds for membrane stabilization in mammals, including man.
Membrane stabilizing agents, such a lidocaine and mepivacaine, have been shown to possess good local anesthetic effects. These compounds, however, offer short durations of the local anesthetic activity. It would be desirable to provide local anesthetic agents which have a long duration, especially when used as spinal or topical anesthetics, which, have therapeutic effects against cardiac arrhythmic conditions, and which can be administered either parenterally or orally.
SU~MARY OF THE INVENTION

It has been found in accordance with the present invention that advantageous membrane stabilizing effects are provided by compounds of the formula (I) ~o 1~ ` : ~ ~ H OR (I), Il R

wherein Rl is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, and 2-hydroxy-ethyl and wherein R is selected from the group consisting - . . . .

- - , : , , , , . ' - ,.
: . , ' ' '' ', 1, . ..
, of a substituted or unsubstitute~d phenyl group R

~R
R R

or a substituted or unsubstituted cyclohexyl group R
~4 R R
in which R2, R , R and R5 are the same or different and are each selected from the group consisting of hydrogen and methyl. The membrane stabilizing effect of these com-pounds make them useful as spinal anesthetics, topical anesthetics, local anesthetics, antiarrhythmics, inhibitors of interneurons and antiepileptic agents. The compounds can be administered, for example, perorally as well as in parenteral form. The compounds of the invention can thus be employed in effective amounts to provide such activities in pharmaceutical preparations along with a pharmaceutically acceptable carrier and in methods of treating mammals, such as man.
DETAILED DESCRIPTION OF THE INVENTION

As noted above, R in the compounds of the inven-tion can be hydrogen, methyl, ethyl, n-propyl, n-butyl or , . . .
:, .

2-hydroxyethyl. R can be R R
~O~R ,and ~ -R

R R R R
wherein R2, R3, R4 and R5 are the same or different and are each independently selected from hydrogen or methyl.
Examples of suitable R groups include 2,6-xylyl, 2,4-xylyl, 2,5-xylyl, phenyl, 2-methylphenyl, and 2,6-dimethyl-cyclohexyl.
As is evident from the formulas above, the compounds of the invention have an asymmetric center.
Thus, they can be resolved into optially active isomers.
The present invention includes racemates as well as optically active isomers of the compounds.
The compounds of the invention can be prepared by various processes. For example, a compound of the formula (II) -X (II) Rl wherein R is as defined above and X is a halogen atom other than fluorine can be reacted with a compound of the formula (III) r~R (III) :

~76~3 .4_ wherein R is as defined above and M is Na or K. M can also be hydrogen provided a sodium or potassium ~ontaining base such as sodium hydroxide, sodium carbonate, etc., is present in the reaction mixture.
In another method, a picolylhalogenide of the formula (IV) ~ cH2 x (IV) wherein X is as defined above above can be reacted with an alkali metal phenolate of the formula MO-R (III) wherein M and R is a substituted or unsubstituted phenyl group as defined above in the presence of a lower alkanol and water to form the compound of the formula (V) ~L CH2--R (V) which can be hydrogenated to give a compound of formula (VI) Q CH20R (VI) H

~, :

- .
.- : .

~t7~j~5~

If Rl is to be other than hydrogen, the compound of formula (VI) can then be a~.kylated or ethoxylated to provide the desired R1 groups. Also, the compound of formula (VI) can be further hydrogenated to give a compound of formula (I) above wherei.n R is a substitu-ted or unsubstituted cyclohexyl group.
Also, a compound of formula (VII) N (VII ) can be reacted with a compound of formula (VIII) X-R (VIII) wherein R is a substituted or unsubstituted cyclohexyl group, and wherein X is as defined above to form a compound of formula (V) which is then hydrogenated. If R1 is to be other than H, the resultant compound of formula (VI) can be alkylated or ethoxylated to provide the desired Rl group.
Further, a compound of the formula (IX) o}~ (IX) - ': - .: : ' , . , , . :

~Z~6~i3 wherein Rl is as defined above can be reacted with a compound of formula (VIII) above wherein R and X are as defined above, to form a compound of formula (I).
In still another me-thod, a co~pound of 5 formula (X) ~ f, 2 Br- (CH2 ) 4 -C-NH2 CH2-0-R (X~

wherein R is as defined above can be ring-closed to form a compound of the formula (I), wherein R1 is not hydrogen.
The reaction is carried out in the presence of concentrated hydrochloric acid and elevated temperature.
In a similar manner, a compound of the formula (XI) H

(XI ) R NH (CH2 ) 4 f -Br wherein R and R are as defined above can be ring-closed in the presence of concentrated hydrochloric acid and at elevated temperature to provide a compound of formula (I).
A compound of the formula (V) above may also be alkylated or ethoxylated and then hydrogenated according to the following reaction scheme:

. . - , -,,, . .: , . .
. .
': - ~, ,' : '' , : . , ' ~
' : . ~ - ~ ' ; ,- i . . ' ~6~53 CH2-O-R + (CH3) 2S4 PtO2 + 3H2 CH2~0-R
N~ CH3COOH
H3C ~H30So37 ~C NaOH
N,~ H2-O-R
/ \ ~CE~30S03;~

O--CH2-0-R * NaOC020CH3 + H20 . .:- . , , ` . -` `: , ,: , . `
. - - , : , ` `
:. ~

~ ~J~ 5 Depending on the process conditions and the starting materials, the en~ product of these processes can be obtained ei~er as -the free base or as the acid addition salt, both of which are included within the scope of the invention. Thus, basic, neutral or mixed salts may be obtained, as well as hemi-, mono-, sesqui- or polyhydrates. The acid addition salts of the compounds of the invention may be transformed in a manner known per se into the free base by using basic agents such as alkali or by ion exchange. On the other hand, the free bases obtained may form salts with organic or inorganic acids.
In the prepapration of acid addition salts, preferably such acids are used which form suitable thçrapeutically acceptable salts. Such acids include hydrohalogen acids;
sulfuric acid; phosphoric acid; nitric acid; perchloric acid; aliphatic, alicylic, aromatic or heterocyclic carboxy or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic, ~O phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfanilic acids; methionine;
~5 tryprophane; lysine; or arginine. These or other salts, e.g., picrates, of the compounds of the invention may serve as purifying agents of the free bases ohtained.
Salts of the bases may be formed, separated from solution, and then the free base can be recovered from a new salt solution in a purer state.
The starting materials are known or may, if they should be new be obtained according to processes known per se.

~, :' . . ' '' :. ' -.

.. . . .

~7~ 3 g In clinical use, the compounds of the invention can be administered topically, orally, rectally or by injection. They may be administered in the form of a pharmaceutical preparation which contains an active 5 component either as a free base or as a pharmaceu-tically acceptable, non-toxic acid addition salt, such as hydro-chloride, lactate, acetate, sulfamate, in combination with a pharmaceutically acceptable carrier. The active component is included in the preparation in an amount effective to provide the desired antiarrhythmic, anti-convulsive, interneuronal inhibiting or anesthetic effect.
The carrier may be in the form of a solid, semisolid or liquid diluent, or a capsule. Usually the amount of active compound is between 0.1 and 99% by weight of the 15 preparation, between 0.01 and 20% by weight in preparations for injection and between 2 and 99% by weight in preparation for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present ~0 invention in the form of dosage units for oral administration, the compound(s) selected may be ~ixed with a solid pulverulent carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose deriva-tives or gelatin, as well as with an antifriction agent ~5 such as magnesium stearate, calcium stearate and poly-ethylene glycol waxes. The mixture is then pressed into tablets. If coated tablets are desired, the above prepared core may be coated with a concentrated solution of sugar, which may contain gum arabic, gelatin, talc, titanium dioxide; or with a lacquer dissolved in volatile organic solvent or mixture of solvents. To this coating, various dyes may be added in order to distinguish among tablets with different active compounds or with different amounts of the active compound present.

'- .
.. . ..
..
.: . .,: - : ~ .

~6~53 Soft gelatin capsules may be prepared which cap-sules contain a mixture of the active compound or compounds of the invention and vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.
Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance in a mixture with a neutral fat base, or they may be prepared in the form of gelatin-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.
Liquid preparations for oral administration may l~ be prepared in the form of syrups or suspension, e.g., so-lutions containing from 0.2% to 20% by weight of -the active ingredient and the remainder consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain ~o coloring agents, flavoring agents, saccharin and carboxy-methylcellulose as a thickening agent.
Solutions for parenteral administration by in-jection may be prepared as aqueous solutions of a water soluble, pharmaceutically acceptable salt of the active compound, preferably in a concentration from 0.01% to 10%
by weight. These solutions may also contain stabilizing agents, agents that affect the duration of the therapeutic effect, such a vasoconstrictors (e.g., vasopressin or derivatives), dextranes, potassium ions, Na henzoate, agents that affect the weight of the solutions, such as sugars, and/or buffering agents and may be manufactured in different dosage units.
The precise dosage administered will depend upon the intended application, i.e., as a spinal anesthetic, .. - , . . : .
- ~
. .
' - . . . .
, ~ ~ ' ' ' . .
.

7~ ~53 topical anesthetic, local anesthetic, antiarrhythmic, interneuronal inhibitor and/or antiepiletic. Typically, as a spinal anesthetic and local anesthetlc, the compounds of the invention will be employed as from about .1 to about 10% by weight solutions. The topical anesthetic used in the compounds are from, for example, from about .1 to about 20% by weight of the preparation, e.g., a cream or lotion. For antiarrhythmic, interneuronal inhibitors and anticonvulsive applications, the compound of the invention may be administered by single or repeated parental or oral administration of from about 20 to about 1,000 mg of the compound, with the actual dosage being titrated to the individual.
The following examples are intended to illustrate but not to limit the invention. Temperature is given in degrees Centrigrade~
~XAMPLE 1 Two hlmdred and forty-five (2~5) g of 2,6-xylenol were transformed into the potassium salt thereof by reacting with 113 g of KOH in 545 mls of water.
To this solution were added dropwise 139 g of 2-chloromethyl pyridine hydrochloride dissolved in 1470 mls of methanol. The reaction was carried out for 7 hours at boiling temperature. The mixture was cooled to 15C, ~5 treated with 5 g of active carbon, and filtered. The filtrate was evaporated in vacuo and the residue was -distilled ln vacuo at about 2 mm Hg and 1~0C. The product obtained was 2-[(2,6-xyloxy)-methyl]pyridine.
Twenty-nine (29) g of 2-[(2,6-xyloxy)methyl]-pyridine were hydrogenated in 250 mls of concentrated acetic acid using hydrogen in the presence of 1.0 g PtO2.

The hydrogenation -took place by introducing hydrogen to theoretical volume at 70-80C in an autoclave at a pressure of 5-10 atmospheres. ~he catalyst was filtered off, and the acetic acid evaporated. Twenty-four (24) g of 2-[(2,6-xyloxy)methyl]piperidine were obtained. The acetic acid sal-t produced was dissolved in 300 mls of wa-ter and was purified with active carbon, whereupon the product was precipitated as the base using ammonia. The base product was dried and dissolved in 150 mls of methyl ethyl ketone, whereupon the hydrochloride was obtained by neutralizing with dry HCl. The hydrochloride of 2-[(2,6-xylyoxy)-methyl]piperidine melted at 227-229C.

Fifty-eight (58) g of 2-[(2,6-xyloxy)methyl]-pyridine were added to 276 mls of xylene and were reacted with 26.4 mls of dimethylsulfate for 4 hours at 130C.
After isolation, purification and hydrogenation according to Example 1, 49 g of N-methyl-2-[(2,6-xyloxy)methyll-piperidine hydrochloride were obtained having a melting point of 171-173C.
EXAMPLES 3 A~D 4 The procedures of Examples 1 and 2 were repeated, but with the introduction of hydrogen being continued at an elevated temperature of 100C and an increased pressure of about 10 atmospheres. By this process, the corresponding 2-[(2,6-dimethylcyclohexyloxy)-methyl]piperidine (Ex~mple 3) and N-methyl-2-[(2,6-dimethylcyclohexyl)methyl]piperidine (Example 4) were obtained. Melting points of 155-157C and 162C, respectively, were obtained for these compounds as their hydrochlorides.

, ;, ,,' ~ i .
- . ~ .
.
, -~ ,~ : . ' ' ' : ~ ' , ',: ' '. .' ' .

-13-~27~3 By exchanging dime-thylsulfate in Example 2 above with diethylsulfate, N-ethyl-2-[(2,6-xyloxy)-methyl]piperi-dine is obtainecl, m.p. 163-164C (HC1).

N-(n-propyl)-2-[(2,6-xyloxy)methyl]piperidine was prepared in accordance with the procedure of Example 2 by employing dipropylsulfate in place of dimethylsulfate.
The product has a melting point of 167-168.5C (HCl).

N-(n-butyl)-2-[(2,6-xyloxy)methyl]piperidine was prepared by reacting n-butylaldehyde and the pyridine produced in Example l. The N-(n-bu-tyl)-2-[(2,6-xyloxy)-methyl]piperidine had a mel-ting point of ls4C (base).

In accordance with -the foregoing, the following compounds of formula I above having a substituted or unsubstituted phenyl R group were also prepared as indicated in Table l below:

'~2~

TABLE_]
. ~
E~ample ~1 R2 R3 R4 R5 Mel-ting Point . _ , ~ . . _ . _ _ . . . _ . _ .

8 CH3 3 H 3 H 174C (base) 9 CH3 H3 H H CH3 174C (base) CH3 H H H H 166C (base) 11 CH3 3 H H H 172 C (base) 12 ~OC2H4 CH3 CH3 H H 135 C (base) ,~

N-methyl-2-[(2,6-xyloxy)methyl)piperidine can be obtained by ring-closing an aliphatic compound in accor-dance with the following.
One hundred (100) g of 1-(~-bromobutyl)-1-(2,~-xyloxymethyl)methylglycinate are ring-closed while being boiled in 300 g of concen-trated hydrochloric acid for 4 hours. Five (5) g of active carbon are added and the solution is allowed to cool ~uring stirring for 0.5 hour.
The solution is then cooled to about 15C, is filtered and is evaporated to dryness. The residue is dissolved in 500 mls of water and is neutralized using a soluti~n of NaOH.
N-methyl-2-[(2,6~xyloxy)methyl]piperidine is extracted from the sodium chloride mixture using 2 x 150 mls of ligroin, which give the compound as a pale yellow oil after evaporation in vacuo. The base obtained can be . . _ . .. .

- , .
- .. ..
- . - ': ~ - ' ' ' ', ~ ' ' . . " ' :
- ' , ' . , - - : -. :
.. , ~ :

~;~7~53 further purified by treatmen-t with active carbon and by filtration when dissolved in 300 mls of methyl ethyl ketone.

-Fifty (50) g of 1-(~-methylaminobutyl)-1-bromo-2-(2,6-xyloxy)ethane can be ring-closed in accordance with Example 13 above, whereby N-methyl-2-[(2,6-xyloxy)methyl]-piperidine hydrochloride is obtained.

The following procedure can be used to prepare N-methyl-2-[(2,6-xyloxy)methyl]piperidine hydrochloride:
Two hundred (200) g of 2-[(2,6-xyloxy)methyl]-pyridine are mixed with 300 g of dimethylsulphate whereupon 500 g of water are added at 100C during 3 hours. The excess of dimethylsulfate is removed by extraction using ether. The remaining solution is purified using active carbon and the resultant solution filtered.
N-methyl-2-[(2,6-xyloxy)methyl]pyridine methylsulfate is isolated as a salt by evaporation of the water ln vacuo.
Fifty (50) g of this quaternary compound are dissolved in 150 g of concentrated acetic acid and 1 g of platinum oxide is added. Hydrogenation with hydrogen gas is carried out at 600-800 kPa and 60-70C until the calculated amount of hydrogen is absorbed. The catalyst is filtered off and the acetic acid is distilled off in vacuo. The residue is dissolved in 250 g of water and is treated with active carbon (1 g), which then is filtered off. The filtrate is treated with a 10% solution of NaO~
to pH 8, whereby the base precipitates and is isolated by means of extraction using 2 x 100 mls of ether. The pure base is dissol~ed in ~200 mls of methyl e~hyl ketone .
.

whereupon the hydrochloride is precipitated by introducing gaseous HCl.

A syrup containing 2% (weight per volume) of active substance can be prepared from the following ingredients:

~ -[(2,6-xyloxy)methyl]piperidine-HC1 2.0 g Saccharine 0.6 g Sugar 30.0 g Glycerine 5.0 g Flavoring agent 0.1 g Ethanol 96% lO.0 g Distilled water added to 100.0 ml Sugar, saccharine and the active ether salt are dissolved in 60 g of warm water. After cooling, glycerine and a solution of flavoring agents dissolved in ethanol are added. To the mixture, water is then added to 100 ml.
The active substance in the above formulation may be replaced with other pharmaceutically acceptable acid addition salts in accordance with the invention.

N-methyl-2-[(2,6-xyloxy)methyl]piperidine hydro-chloride (250 g) is mixed with lactose (175.8 g) potatoe starch (169.7 g) and colloidal silic acid (32 g). The mixture is moistened with a 10% solution of gelatine and is granulated through a 12-mesh sieve. After drying, potatoe starch (160 g), talc (50 g) and magnesium stearate (5 g) are admixed and the mixture thus obtained is pressed .
-~ ~ . , ' ' .
: . . . . .
., , , . ~ . . : : , .

l~t~6~5~

into tablets (10,000) which contain 25 rng of ac-tive substance each. 'rhe tablets can be sold on the market provided with a breaking score to give another dose than 25 mg or to give multiples thereof when broken.

_ _ .

Granules are prepared from N-ethyl-2-[(2,6-xyloxy)methyl]piperidine hydrochloride (250 g), lactose (175.9 g) and an alcoholic solution of polyvinyl pyrrolidone (25 g). After drying, the granules are mixed with talc (25 g), potatoe starch (40 g) and magnesium stearate (2.50 g) and are pressed into 10,000 tablets being biconvex. These tablets are coated with a primary coating of 10% alcoholic solution of shellac and thereupon with a series of coating with an aqueous solution containing saccharose (45%), gum arabicum (5%), gelatine (4%) and dyestuff (0.2%). Talc and powder sugar are used for powdering after the first five coatings. The resultant coating is then further coated with a 66% sugar syrup and is polished with a 10% carnaube wax solution in carbon tetrachloride.

N-(n-propyl)-2-[(2,6-xyloxy)methyl]piperidine hydrochloride (1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g) are dissolved in sufficient amount of ~5 distilled water to give 100 ml of solution. This solution, which contains 10 mg of active substance on each ml, is used in filling ampoules, which are sterilized by heating at 120C for 20 minutes.

. J;~
..... . . ...

: ' . : . ' ' ', . .
,, ,,, . . ', . .

. .

~2~ i3 BIOLOGICAL EFFECTS
. . .. _ ..

T QX lcology The compounds according to Examples 1-12 have been tested as to their toxicological effects in mice.
LD50-values are given in Table 2 below ~or subcutaneous administration.

LD50-values in mice .. _ . . . .. _ . . , _ Compound according LD50(s.c.) to Example mg/kg :

l S 5 200 ~0 lO 150 Convulsive doses and lethal doses after intravenous administration for selected compounds of the invention and 25 for Bupivacaine are shown in Table 3 below.

.

., , ~ . ............ . ........................................ .
.

TABL,E 3 Convulsive and lethal doses of selected compounds administered intravenously at 1.0 mg/kg/min to rats (male; 250-300 g).

Compound according Convulsive dose Lethal dose to Example mg/kg mg/kg 6 11 2~

Bupivacaine 9 13 ~ _ _ , , .. , .__ , . .
Pharmacology 1. Local anesthetic effects of the compounds of Examples 1-12 above were determined as discussed below.
lS A. Infiltration anesthetic effects.
The effects of the new compounds were tes-ted according to Aberg ~ Sydnes, Acta Anaesth. Scand., 1975, 19, 377 after intracutaneous injection to guinea pigs. The results are given in Table 4 below.
a. Nerve blocking effects.
The tests were carried out in vivo in rats after injection close to the sciatic nerve. The results are given in Table 4 below.
~5 C. Topical anesthetic effects.
Corneal tests were carried out on rabbits in vivo according to Henn. Acta Anaesth. Scand., 1960, 4, _____ _ 125. The results are given in Table 5 below.

~L27~ ;3 Local anesthetic effects of solutions containing 0.5% ~ ~ ht of the compound.
Compound Infiltration Nerve blockin~ effect according anes-thesia Sensorlc Motoric to Example duration blockade blockade (min) (min) (min) . .
l ~0 go 75 3 35 o O

ll 55 85 60 . _ Topical anesthetic effects on rahbit cornea : _ _. ~ _ .. ~ __ _ . _ _ . :
Compound Concentration Onset ~uration according (%) frequency (min) to Example . _ , ., _ : , . .~_ _ . .

~5 l l.O 9/10 24+~
2 1.0 7/10 14~4 l.O 9/lO 18+3 6 1.0 9/9 24~2 7 l.O lO/lO 27~4 .

,, ~ . . . .

-21 ~'~ 76~3 2. Antiarrhythmic effects.

Ventricular arrhythmias were induced in anesthe-tized dogs by intravenous injection of ouabain: initially ~g/kg bodyweight and thereafter 20 ~g/kg body-weight every 20 minutes until the ventricular arrhythmia was regarded as manifest. Thereupon, the test compounds were administered intravenously in the doses indicated in Table 6. Lidocaine was also tested by the same procedure.
The results are given in Table 6 below. The new compounds were compared with lidocaine, a known antiarrhythmic compound.

Antiarrhvthmic effects in anesthetized doas.
Compound Dose No. of Duration of regularization of Ex. No. (mg/kg) tests (min) , . . . . .
l 1 5 5 l 2 5 10 2 l 5 2 l 3 3 Lidocaine 1 5 2 Lidocaine 2 5 4 3. Interneuronblocking effects.
Tests were carried out in anesthetized cats (female;2.5 -3.5 kg bodyweight). The effects of the - : , , .., . - . : .
- . ~
~ ': ' : , ' - , ' ' , : . . . .

~7~3 compounds were studied on the lingomandibular reflex 7 which was provoked by means of electrical stimulation of the tongue. The mandibular reflex was registered from a transducer connected to the mandible. The compounds were administered intravenously in the doses indicated in Table 7. Phenyramidole was tested by the same procedure. As evident from the results shown in Table 7, the compound according to Example 2 of the invention is 10 times as potent as phenyramidole.

Compound Dose Maximal Duration of according mg/kg inhibition inhibi~ion to Example bodyweight % (min.) . .
2 0.~5 30 10 2 0.50 80 20 2 1.00 100 45 Phenyra-midole 2.5 40 5 2~ " 5.0 80 20 " 10.0 100 60 It will be understood that the embodiments described above are merely exemplary and that persons skilled in the art may make many variations and ~5 modifications without departing from the spirit and scope of the invention. All such modi~ications and variations are intended to be included within the scope of the invention as defined by the appended claims.

.. . - . . , - . . , ~ - . .~ . _ . .
- ~
, . .

~ '

Claims (11)

1. A compound of the formula (I) (I), or an optically active isomer thereof or a pharmaceutically acceptabls acid addition salt thereof, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, and wherein R is selected from the group consisting of in which R2 and R3 are both methyl, R4 and R5 are the same or different and are each independently selected from the group consisting of hydrogen and methyl.

2. A compound according to Claim 1, wherein R is the group in which R2 and R3 are methyl and R4 and R5 are hydrogen.

3. A compound accoraing to Claim 1, which is N-(n-propyl)-2-[(2,6-xyloxy)methyl]piperidine, or an optically active isomer thereof or a pharmaceutically acceptable acid addition salt thereof.

4. A compound according to Claim 1, which is N-ethyl-2-[(2,6-xyloxy)methyl]piperidine, or an optically active isomer thereof or a pharmaceutically acceptable acid addition salt thereof.

5. A pharmaceutical composition consisting of an antiarrhythmically effective amount of a compound of the formula (I) (I) or an optically active isomer thereof or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, and wherein R is selected from the group consisting of in which R2 and R3 are both methyl, R4 and R5 are the same or different and are each independently selected from the group consisting of hydrogen and methyl, together with a pharmaceuti-cally acceptable carrier.

6. A pharmaceutical composition consisting of an anticonvulsive effective amount of a compound of the formula (I) (I) or an optically active isomer thereof or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, and wherein R is selected from the group consisting of in which R2 and R3 are both methyl, R4 and R5 are the same or different and are each independently selected from the group consisting of hydrogen and methyl, together with a pharmaceuti-cally acceptable carrier.

7. A process for preparing a compound of the formula (I) (I), characterized by the steps of (a), (b), (c), (d) or (e) below to form a compound of formula (I), wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl and 2-hydroxyethyl, and R is selected from the group consisting of a substituted or unsubstituted phenyl group or a substituted or unsubstituted cyclohexyl group wherein R2, R3, R4, and R5 are the same or different and are each independently selected from the group consisting of hydrogen and methyl:
(a) reacting a compound of the formula (II) (II) wherein R1 has the meanings given above and X is a halogen atom other than fluorine with a compound of formula (III) MO-R (III) wherein R is defined as above and M is Na or K, or hydrogen in the presence of a sodium or potassium containing base;
b) reacting a compound of the formula (IV) (IV) wherein X has the meaning given above, with a compound of formula (III) to form a compound of formula (V) (V) wherein R has the meanings given above, which compound of formula (V) is then hydrogenated to give a compound of formula (VI) (VI) wherein R has the meanings given above, which compound of formula (VI), if so desired is (i) alkylated or ethoxylated to give a compound of formula (I) wherein R1 is not hydrogen and/or (ii) if R is a substituted or unsubstituted phenyl group, further hydrogenated to give a compound of formula I wherein R
is a substituted or unsubstituted cyolohexyl group;

c) reacting a compound of the formula (VII) (VII) with a compound of the formula (VIII) X-R (VIII) wherein X has the meaning given above and R is substituted or unsubstituted cyclohexyl group to form a compound of formula (V) which is then hydrogenated to form a compound of formula (VI), and if so desired the compound of formula (VI) is alkylated or ethoxylated;
d) reacting a compound of the formula (IX) (IX) wherein R1 has the meaning given above with a compound of the formula (VIII), wherein R is a substituted or unsubstituted cyclohexyl group;
e) alkylating or ethoxylating a compound of formula (V) above and then hydrogenating the resultant compound to provide a compound of formula (I).

8. The use of a compound of formula (I), or an optically active isomer thereof or a pharmaceutically acceptable acid addition salt thereof for membrane stabilization in mammals, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, and wherein R is selected from the group consisting of in which R2 and R3 are both methyl, R4 and R5 are the same or different and are each independently selected from the group consisting of hydrogen and methyl.

9. The use according to claim 8, wherein R in said active compound is the group in which R2 and R3 are methyl and R4 and R5 are hydrogen.

10. The use according to Claim 8, wherein said active compound is N-(n-propyl)-2-[(2,6-xyloxy)methyl]piperidine, or an optically active isomer thereof or a pharmaceutically acceptable acid addition salt thereof.

11. The use according to Claim 8, wherein said active compound is N-ethyl-2-[(2,6-xyloxy)methyl]piperidine, or an optically active isomer thereof or a pharmaceutically acceptable acid addition salt thereof.