CZ20001495A3 - Bis-quaternary ammonium derivatives - Google Patents

Abstract

Alkoxy- and acyloxy-substituted aralkyl- and aralkenyl-bisquaternary ammonium derivatives of cyclic alkanol diesters. Process for the production and use of these compounds as muscle relaxants and pharmaceutical compositions containing these compounds.

Description

Technical area

The present invention relates to compounds useful as muscle relaxants. In one of the more preferred embodiments, the invention relates to a series of alkoxy- and acyloxy-substituted aralkyl and aralkenyl-bisquaternary ammonium derivatives of cyclic alkanol diesters. The present invention also relates to a process for the preparation and use of these compounds as muscle relaxants and pharmaceutical compositions containing these compounds.

State of the art

During surgical procedures, it is advantageous to have the patient's muscles as relaxed as possible. Although general anesthesia will render the patient unconscious, it rarely provides sufficient skeletal muscle relaxation. A number of muscle relaxants, also known as neuromuscular blocking agents, are used to relax muscles during surgical procedures. One muscle relaxant that has been widely used in the past is succinylcholine, which has a very rapid onset of action and a short duration of clinical action. However, succinylcholine causes "depolarization" of muscle membranes, which makes this compound less useful. In addition, serious side effects can occur.

Several other so-called "non-depolarizing" muscle relaxants are known and are used in anesthesia and surgery. These chemically distinct non-depolarizing muscle relaxants include, among others: tubocurarine, pancuronium, atracurium, cisatracurium, vecuronium, mivacurium and rocuronium. A common structural feature of these compounds is one, usually two, quaternary nitrogen atoms. These

The substances are clinically acceptable because they cause only mild or no side effects. However, their onset of action is slow and the duration of action is too long. Thus, without exception, these substances do not meet the requirements of an “ideal” surgical muscle relaxant.

Hungarian Patent No. 142,597, issued September 15, 1955, describes a series of compounds containing a pair of tropine groups linked by an ester bond to an aliphatic or aromatic diacid. The nitrogens on both tropines are quaternized by alkyl groups or ^by unsubstituted or monosubstituted benzyl groups.

io Some naturally occurring alkaloids consist of esters of azabicycloalkanols with dicarboxylic acids, such as belladonine, which is a bis-tropine ester, and thesin, which is a bisoxymethylpyrrolizidine ester. Only the ethyl quaternary derivatives of belladonine and the methyl quaternary derivatives of thesin are reported as muscle relaxants.

Several other neuromuscular blocking agents are reported in the literature which contain pairs of quaternary nitrogens as part of a tropane h ring system. In these compounds the tropinyl groups are linked by bridging two quaternary nitrogen atoms. U.S. Pat. No.

2,746,964 (1953) describes esters of 3-piperidinol with dicarboxylic acids and their alkyl quaternary derivatives.

The object of the present invention is to provide new and improved muscle relaxants which are characterized by a very rapid onset and short duration of neuromuscular blocking action.

The essence of the invention

During the inventors' research to find the "ideal" muscle relaxant, it was found that generally di- or poly- alkoxy- or acyloxy-substituted aralkyl- and aralkenyl quaternary ammonium derivatives of cyclic amino alcohol diesters either had minor side effects or

-3- ·· effects such as lowering blood pressure and increasing heart rate or higher potency than other substances containing alkyl, unsubstituted aralkyl or monosubstituted aralkyl quaternary groups. In particular, the alkoxy- and acyloxy-substituted aralkyl and aralkenyl quaternary derivatives of cyclic diesters of amino alcohols had a rapid onset and shorter duration of action than any previously known "non-depolarizing" muscle relaxant. This discovery was completely unexpected and unforeseen and therefore forms the essence of the present invention.

The present invention consists of a series of di- or polyalkoxy- or acyloxy-substituted aralkyl and aralkenyl bis-quaternary ammonium derivatives of cyclic alkanol esters of dicarboxylic acids as neuromuscular relaxants, a process for their production and pharmaceutical compositions containing them.

A first embodiment of the present invention is a group of compounds

15- 1/a of the following general formula:

R,-7-<CH ₂ )n (CHJn-r--R, ^{1 R} 'V po—AO-^ „· yR,·

R ₄ --2X- (CH,)m- ^L -R/

A second embodiment of the present invention is a group of compounds 1/b of the following general formula:

R, Λ \ /

-{CHJn

R--N-τ ⁺ / \ (O4,)P )-°- ^A -° \ /·'(CHj)n--NR,'

R;

X (CH.)mr;

-4A third embodiment of the present invention is represented by a group of compounds 1/c of the following general formula:

• · 9 9 9 • · · · ···

R,

R ₃ -N-(CH,)n (CHj)n—Νς-F (CHj)p -OAO-/ (CHj)p

R _t -—(CHj)m ~ _ (CHj)m-/

X where A is alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl, polycycloalkanedicarbonyl, aromatic dicarbonyl, substituted alkenedicarbonyl, substituted alkynedicarbonyl, substituted bicycloalkanedicarbonyl, substituted bicycloalkanedicarbonyl or substituted aromatic dicarbonyl; Ri and Rr are di- or polysubstituted aralkyl or aralkenyl, in which at least one of the substituents is alkoxy or acyloxy; R2 and Ri are alkyl or alkenyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; _R3 and _R3 are H, _CH3 or lower alkyl; _R4 and _R4 - are H, _CH3 or lower alkyl; R ₃ and R ₄ can also be -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) k -, -epoxy- or -(CH ₂ ) hS-(CH ₂ ) k -, where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and R ₃ · and R ₄ · can also be

About / \

-(CH ₂ ) _g -, -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) _k -, -CH—CH-, or -(CH ₂ ) hS-(CH ₂ ) k, where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; X is a pharmaceutically acceptable anion; R-ι and Rr may be the same or different; similarly R ₂ and R ₂ ·, R ₃ and R ₃ ·, and R ₄ and R ₄ · may be the same or different.

A fourth embodiment of the present invention is a method of using compounds of general formula 1/a to 1/c as neuromuscular relaxants.

A fifth embodiment of the present invention is a pharmaceutical composition comprising compounds of general formula 1/a to 1/c and a pharmaceutically acceptable excipient.

Description of preferred embodiments

Definition

As used herein, the term "alkyl" means a hydrocarbon radical having 1 to 20 carbon atoms. In the present invention, alkyl may be unsubstituted, such as methyl, butyl, octyl, and dodecyl.

As used herein, the term "alkenyl" refers to any hydrocarbon radicals containing from 1 to 20 carbon atoms containing at least one carbon-carbon double bond at any position.

Examples include ethenyl, 2-butenyl, 5-octenyl, and 2,10-dodecenyl.

As used herein, the term "alkynyl" refers to hydrocarbon radicals containing from 1 to 20 carbon atoms containing at least one carbon-carbon triple bond at any position.

Examples include acetylenyl, 2-butynyl, 5-octynyl and 1,7-decanediinyl.

As used herein, the term "aryl" refers to aromatic hydrocarbon radicals. Examples include phenyl, naphthyl, and anthracyl.

As used herein, the term "aralkyl" refers to aryl hydrocarbon radicals including an alkyl moiety as defined above. Examples include benzyl, phenylethyl, and 6-naphthylhexyl.

···· ··

- 6 As used herein, the term "aralkenyl" refers to aryl hydrocarbon radicals including the alkenyl moiety as defined above. Examples include styryl, 3-benzylpropenyl, and 6-naphthyl-2-hexenyl.

As used herein, the term "cycloalkyl" refers to any alkyl having carbon atoms arranged in a ring. Examples include cyclohexyl, cyclobutyl, and cyclododecyl.

As used herein, the term "cycloalkenyl" refers to an alkenyl having carbon atoms arranged in a ring. Examples are cyclohexenyl and

1,5-cyclododecadienyl.

As used herein, the term "bicycloalkyl" refers to an alkyl having carbon atoms arranged in two rings. Examples include decahydronaphthyl, norbornyl, and bicyclo[2.2.2]octyl.

As used herein, the term "bicycloalkenyl" refers to an alkenyl having carbon atoms arranged in two rings. Examples are norbornenyl and 1,2,3,4,5,6,7,8-octahydronaphthyl.

' As used herein, the term "polycycloalkyl" refers to an alkyl having carbon atoms arranged in three or more rings.

As used herein, the term "polycycloalkenyl" refers to an alkenyl having carbon atoms arranged in three or more rings.

As used herein, the term "substituted" refers to a hydrocarbon radical selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, polycycloalkyl, polycycloalkenyl, and all groups as defined above, wherein one or more hydrogen atoms have been replaced by an alkyl, fluoride, chloride, bromide, iodide, hydroxy, mercapto, alkoxy, acyloxy, alkylthio, arylthio, acetamido, amino, or nitro group or groups.

The term "substituted" also means a hydrocarbon radical selected from the group of alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, polycycloalkyl, polycycloalkenyl and all groups as defined above, where one or more carbon atoms have been replaced by an atom or atoms of oxygen, sulfur, nitrogen or silicon. In the case of quaternizing aralkyl or aralkenyl groups, the term "disubstituted or polysubstituted" means two or more substituents, one or more of which will be alkoxy or acyloxy and the other(s) will be one or more of the same or different substituents selected from the group: alkyl, alkenyl, aryl, aralkyl, halogen, hydroxy, mercapto, alkoxy, aryloxy, acyloxy, acetamido, amino, alkylthio, arylthio, imino or nitro, which replace two or more carbon atoms of the aralkyl or aralkenyl group.

As used herein, the term "alkyl-cycloalkyl" means a hydrocarbon radical including an alkyl and a cycloalkyl group. Examples include 3-methylcyclohexyl and 4-hexylcycloheptyl.

As used herein, the term "alkanedicarbonyl" means a radical containing an alkyl as defined above and two carbonyl groups. Examples include succinyl, glutaryl, sebacyl, 1,11-dicarboxyundecanyl, and the like.

As used herein, the term "alkenedicarbonyl" means a radical containing at least one carbon-carbon double bond and two

2o carbonyl groups. Examples include 1,3-dicarboxypropenyl, 1,6-dicarboxy-3-hexenyl and traumatyl(1,10-dicarboxy-2-decenyl).

As used herein, the term "alkynedicarbonyl" refers to a radical containing at least one carbon-carbon triple bond and two carbonyl groups. Examples include 1,2-dicarboxypropynyl, 1,6-dicarboxy-225 -hexynyl, and the like.

As used herein, the term "bicycloalkanedicarbonyl" means a radical containing a bicycloalkenyl as defined above and two carbonyl groups. Examples include 5-norbornane-2,3-dicarbonyl, decahydronaphthalene-1,5-dicarbonyl, and 9,10-dihydro-9,10-ethano30 anthracene-11,12-dicarbonyl.

···· ·· ·· 99 99 99

9 9 9 9 9 9 9 9 9

9 9 9 9 999 9 9 9 · • · ··· · 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9

99 99 99 99 99

- 8 As used herein, the term "bicycloalkenedicarbonyl" refers to a radical containing a bicycloalkenyl as defined above and two carbonyl groups. Examples include 3,6-endiamine-1,2,3,6-tetrahydrophthaloyl and 1,2,3,4,5,6,7,8-octahydronaphthalene-1,5-dicarbonyl.

As used herein, the term "aromatic dicarbonyl" means a radical containing an aromatic group substituted with two carbonyl groups. Examples include phthalyl, terephthalyl, 1,4-dicarboxynaphthyl, and the like.

As used herein, the term "acyloxy" means the group RC(O)O-, in which R is a normal or substituted hydrogen atom, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl or bicycloalkenyl. Examples include acetoxy, propionyloxy, 2,3-difluorobutyryloxy, benzoyloxy, cyclopropylacetoxy and chloroacetoxy.

As used herein, the term "tropine" refers to tropine (8-methyl-8-azabicyclo[3.2.1]octan-3a-ol), also known as alpha- or endotropine; and pseudotropine (8-methyl-8-azabicyclo[3.2.1]octan-3p-ol), also known as beta- or exotropine, depending on the configuration of the hydroxyl group attached to the C3 atom of tropine.

As used herein, the term "granatanol" means 9-methyl-9-azabicyclo[3.3.1]nonan-3β-ol or 9-methyl-9-azabicyclo[3.3.1j-nonan-3β-ol and the term "granatanin" means 9-methyl-9azabicyclo[3.3.1]nonane. It is understood that the nitrogen atom of tropine and granatanol is already substituted with a methyl group. Therefore, if the nitrogen atom of tropine or granatanol is referred to as substituted, such as N-methyltropinium iodide, it will be understood that the nitrogen atom is a quaternary nitrogen atom and the halide is present for charge balancing.

As used herein, the term "pharmaceutically acceptable anion" refers to an anion that has little or no toxic effects and does not significantly affect the pharmacological action of the drug.

·< · · pharmaceutically administered doses. Examples include chloride, bromide, iodide, nitrate sulfate phosphate, sulfonate, mesylate, besylate, tosylate, etc.

For many compounds within the scope of the present invention, a variety of optical isomers, enantiomeric pairs, and diastereomeric pairs exist.

The present invention therefore encompasses all such compounds as well as all mixtures of optical isomers, enantiomeric pairs and diastereomeric pairs for each structural variant, including all pure compounds and racemic mixtures.

The cis and trans geometric isomers are also within the scope of the present invention.

Syntheses

Various methods for synthesizing the compounds of the present invention will now be described. These synthesis schemes will be illustrated in

N-methyl-8-azabicyclo[3.2.1]octan-3a-ol (tropine) as an example of a starting material. Other suitable cyclic amino alcohols can also be used.

Synthesis scheme A

HIM

AND

about \

(equation A) *Ul ···· «* ·· ·· ·· ·· »····· . ·· .

• · · · · ··· e · · * ·· « « · r · ··· *· · · • · · · · · · · · · « · ·· ·· ·· .« . .··ς

- 10 + 2 RX

(equation B)

Regarding equation A in synthesis scheme A, the process is carried out as follows; to a cooled solution of one equivalent of the corresponding diacyl halide (II) in dry methylene chloride in an ice bath, two equivalents of tropine in dry methylene chloride are added dropwise, and then the mixture is allowed to warm to room temperature. After the reaction, the mixture is poured into cold water, the pH of the aqueous layer is adjusted to pH 10-11 with 6N aqueous NaOH solution, and the mixture is extracted with chloroform.

The diester (III) is then purified by chromatography.

In equation B, one equivalent of the purified diester (III) is transferred to a slightly polar aprotic solvent such as acetone or acetonitrile. Two and a half equivalents of the appropriate alkoxy-, acyloxy- or alkoxyacyloxy-substituted aralkyl- or aralkenyl halide RX (IV) are added. The resulting solution is heated to a temperature between 50 and 150 °C for 6 to

12 hours depending on the reagents. The quaternary salts obtained are filtered and purified by recrystallization.

Synthesis scheme of B/ ^CH'R ,. + /

I + IV (equation C)

HO in

(equation D)

10.

In the reaction described by equation C in synthesis scheme B in the alternative synthesis scheme, one equivalent of the appropriate tropine (I) and 1.25 equivalents of the desired alkoxy-, acyloxy- or alkoxyacyloxy-substituted aralkyl- or aralkenyl halide (IV) are heated together in a slightly polar aprotic solvent such as acetone or acetonitrile for between 6 and 12 hours and at a temperature between 50°C and 100°C. The resulting quaternary ammonium salt (V) is filtered and purified by recrystallization.

As shown in equation B, two equivalents of the recrystallized quaternary salt (V) are reacted with one equivalent of the appropriate organic diacyl halide (II) in dry methylene chloride in a closed vessel. The components are heated in a closed vessel at 80-100°C. After removal of the solvent, the residue is purified by recrystallization to give the pure compound of formula 1/a, 1/b and 1/c.

The compounds of formula 1/a to 1/c according to the invention may also be in the form of asymmetric diammonium esters. These compounds may be prepared as follows: not more than one equivalent of the first, alkoxy- or acyloxy-substituted aralkyl- or aralkenyl halide (RX) and one equivalent of the diesters (III) in acetone • · · · • ·

or acetonitrile are heated at 50°C for 12 hours; a second, quaternizing compound RX (IV) is added to the reaction mixture. The reaction mixture is then heated again at 80-100°C for 12 hours. The precipitate obtained is purified by recrystallization.

An alternative synthesis route according to Scheme A is illustrated in Synthesis Scheme C.

Synthesis scheme of C

HCI

VI □H ci—a—α

Π (Equation E) vn vil + 2RX ► Formula 1/c (p. 4) (Equation F)

Other suitable hydrochlorides of cyclic aminoalkanols, such as tropine or granatanol hydrochloride, may also be used.

Applicability

Compounds of formulae 1/a, 1/b and 1/c have significant activity as neuromuscular blocking agents. These agents are typically administered intravenously. The form of administration may be a single injection, a series of injections or the composition may be administered as a component of • ···

- 13 ··♦· ·· • · • · intravenous infusion. The compounds of the present invention are characterized by a rapid onset of action and a short duration of action to such an extent that they are clearly superior to any existing known muscle relaxants. In terms of side effects, the compounds of the present invention have significantly reduced cardiovascular side effects associated with succinylcholine, tubocurarine or gallamine, as earlier prototype muscle relaxants used in clinical practice.

The single dose may vary considerably from patient to patient as with other muscle relaxants, but based on animal experiments, a dosage of between 0.1 and 1.0 mg/kg body weight has been estimated. The exact dose must be determined after consideration of each individual case including the age, sex, weight and general condition of the patient and the degree of muscle relaxation required.

Dosage may be accomplished using a liquid solution, either for direct injection or for addition to intravenous fluid, or a solid powder or granular material may be used for reconstitution just prior to use. The liquid or solid may be formulated by any conventional means.

One or more pharmaceutically acceptable excipients or adjuvants, including pH adjusters, stabilizers, preservatives, biologically acceptable salts, sugars, etc., may be added to the formulation for clinical use.

The efficacy of these substances can be tested by any suitable method.

The applicability of the compounds of formulae 1/a, 1/b and 1/c has been tested on anesthetised rats and/or cats, rabbits, dogs, guinea pigs, pigs or monkeys. A leg-mounted traction device is connected to a transducer. An appropriate motor nerve, for example the sciatic nerve or the peroneal nerve, is stimulated. The resulting muscle contractions are recorded. When a neuromuscular blocking agent is administered ··*· ··

- 14 of the composition of the present invention into the vein, the response of muscle contractions to stimulation decreases. The decrease is measured in a dose-dependent manner. Similarly, the onset and duration of action can be determined in comparison with these values for known compositions used in clinical practice. Both electromyographic and mechanomyographic methods are also acceptable.

The invention can be better understood by reference to the following examples, which are given for illustrative purposes only and are not to be construed as limiting the scope of the present invention.

w Examples of embodiments of the invention

The following example illustrates the synthesis scheme of A.

Example 1 - Preparation of bis-tropan-3-yl-succinate

To a solution of 14.1 g (100 mmol) of tropine in 50 ml of methylene chloride was added dropwise 7.75 g (50 mmol) of succinyl chloride in 100 ml of methylene chloride while cooling in a water bath. The mixture was then allowed to warm to room temperature. After reaction, the mixture was poured into 200 ml of cold water, the pH of the aqueous layer was adjusted to pH 10-11 with aqueous 6N NaOH solution and extracted with chloroform. The oil obtained was purified by column chromatography (silica gel, 20% methanol in chloroform) to give 11.8 g (65%) of bis-tropan-3-yl succinate as a thick oil.

Similarly, it is possible to use a substance from the group:

malonyl chloride glutaryl chloride thiodiglycolyl chloride ( 25 2-ketoglutaryl chloride j adipoyl chloride sebacyl chloride 4,4'-dithiodibutyryl chloride 1,11-undecandicarbonyldichloride

- 15 ·»»* φφ • φ • φ • · · φ • φ ·φφφ • ΦΦΦ φφφφ ·· φφ φφ φφ φφ φ · · φ φ · φ « φ φ φ « φ φ φ φ « φ φφ φφ fumaryl chloride trans-traumatyl chloride acetylene dicarbonyl chloride trans-1,2-cyclobutane dicarbonyl dichloride

1,3-Cyclohexanedicarbonyldichloride

1,1-cyclopentanediacetyl dichloride phthaloyl chloride

4,5-dichlorophthaloyl chloride trans-3,6-endomethylene-1,2,3,6-tetrahydrophthaloyl chloride to obtain the following compounds:

bis(tropan-3-yl)-malonate bis(tropan-3-yl)-glutarate bis(tropan-3-yl)-thiodiglycolate bis(tropan-3-yl)-2-ketoglutarate bis(tropan-3-yl)-adipate bis(tropan-3-yl)-sebacate bis(tropan-3-yl)-4,4'-dithiodibutyrate .

bis(tropan-3-yl)-1,11-undecanedicarboxylate bis(tropan-3-yl)-fumarate bis(tropan-3-yl)-trans-traumate bis(tropan-3-yl)-acetylene dicarboxylate bis(tropan-3-yl)-cyclobutane-1,2-dicarboxylate bis(tropan-3-yl)-cyclohexane-1,3-dicarboxylate bis(tropan-3-yl)-cyclopentane-1,1-dicarboxylate Bis(tropan-3-yl) diacetate bis(tropan-3-yl)-4,5-dichlorophthalate bis(tropan-3-yl)-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate

Similarly, it is possible to obtain the corresponding dicarboxylic acid esters by substituting other cyclic amino alcohols for the tropine mentioned in formulas 1/a, 1/b and 1/c as the starting material and the mentioned acyl chlorides.

• ·

- 16 Example 2 - Preparation of bis[N-(3,4-diacetoxybenzyl)tropanium-35-yl]-succinate dibromide

To a solution of 5.0 g (13.7 mmol) of bis-tropan-3-yl-succinate in 100 ml of dry acetone was added 9.8 g (34.3 mmol) of 3,4-diacetoxybenzyl bromide (prepared from 3,4-dihydroxybenzaldehyde by acetylation of the hydroxy groups, reduction of the aldehyde to the corresponding alcohol and bromination). The mixture was then heated at 60-70 °C for 10 h. The precipitate was collected by filtration, washed with acetone and ether and dried in vacuo to give 9.6 g (75%) of bis-[N-(3,4-diacetoxybenzyl)tropanium-3-yl]>succinate dibromide as a white powder, which was further purified by recrystallization from a methanol-methylene chloride mixture.

It can be obtained similarly, for example, using another substance such as:

2,5-diacetoxybenzyl bromide

3.4.5- triacetoxybenzyl bromide

3.4-dipropionyloxybenzyl bromide

2,4-dibutyryloxybenzyl bromide

4-acetoxy-3-methoxybenzyl bromide

4-acetoxy-3,4-dimethoxybenzyl bromide

2,5-dimethoxybenzyl bromide

3.4.5-trimethoxybenzyl bromide

3,4-diethoxybenzyl bromide

3,4-diacetoxyphenylethyl bromide

3-(3,4-diacetoxyphenyl)-propenyl bromide, a

3.5-diacetoxy-2-naphthylmethyl bromide prepare:

bis[N-(2,5-diacetoxybenzyl)-tropanium-3-yl]-succinate dibromide • ·

- ¹⁷ bis[N-(3,4,5-triacetoxybenzyl)-tropanium-3-yl]-succinate dibromide bis[N-(3,4-dipropionyloxybenzyl)-tropanium-3-yl]-succinate dibromide bis[N-(2,4-dibutyryloxybenzyl)-tropanium-3-yl]-succinate dibromide bis[N-(2,5-acetoxy-3-methoxybenzyl)-tropanium-3-yl]-succinate dibromide bis[N-(4-acetoxy-3,5-dimethoxybenzyl)-tropanium-3-yl]-succinate dibromide bis[N-(3,4,5-trimethoxybenzyl)-tropanium-3-yl]-succinate dibromide and bis[N'-(3,5-diacetoxy-2-naphthylmethyl)-tropanium-3-yl]-succinate dibromide.

It will be apparent to one skilled in the art that both starting materials can be substituted. For example, if 4-acetoxy-3-methoxybenzyl bromide is replaced by .3,4-diacetoxybenzyl bromide and bis-tropan-3-yl glugarate, bis-tropan-3-yl sebacate, and bis-tropan-3-yl cyclobutane-1,2-dicarboxylate are replaced by bis-tropan-3-yl succinate, one can obtain: bis-[N-(4-acetoxy-3-methoxybenzyl)-tropanium-3-yl]-glutarate dibromide, bis-[N-(4-acetoxy-3-methoxybenzyl)-tropanium-3-yl]-sebacate dibromide, and bis-[N-(4-acetoxy-3-methoxybenzyl)-tropanium-3-yl]-cyclobutane-1,2-dicarboxylate dibromide.

The following example illustrates the synthesis scheme of B.

Example 3 - Preparation of N-[3-S-trimethoxybenzoyl]-tropinium chloride

A mixture of 14.1 g (100 mmol) of tropine and 26.0 g (120 mmol) of 3,4,530-trimethoxybenzyl chloride in 300 ml of acetone is heated at 60-70 °C for 10 h in a sealed test tube. The precipitate is then filtered, washed and ··· ·

- 18 recrystallizes to obtain 28.6 g (80%) of N-3,4,5-trimethoxybenzyl)tropinium chloride as a white powder.

Similarly, it can be obtained using compounds such as:

2-Methoxy-5-nitrobenzyl bromide

4-acetoxy-3,5-dimethoxybenzyl chloride

3-(3,4-dipropionyloxyphenyl)propyl bromide

3,5-diacetoxy-2-naphthylmethyl bromide

4-acetoxy-3-chlorobenzyl bromide to produce:

N-(2-Methoxy-5-nitrobenzyl)-tropinium bromide

N-(4-acetoxy-3,5-dimethoxybenzyl)-tropinium chloride

N-(3-(3,4-Dipropionyloxyphenyl)-propyl)-tropiunium bromide

N-(3,5-diacetoxy-2-naphthylmethyl)-tropinium bromide and N-(4-acetoxy-3-chlorobenzyl)-tropinium bromide

Example 4 - Preparation of bis-[N-(3,4,5-trimethoxybenzyl)tropanium-3-yl]-succinate dichloride

N-(3,4,5-trimethoxybenzyl)-tropinium chloride (20.0 g, 56.0 mmol) 20 and 4.35 g (28.0 mmol) succinyl chloride in 100 ml dry methylene chloride are heated at 100 °C for 12 h in a sealed tube. After adding 5 ml methanol to the cooled reaction mixture, the solvent is removed on a rotary evaporator. The product is purified by recrystallization from methanol-methylene chloride, yielding 12.0 g (54%) of bis-[N25 -3,4,5-trimethoxybenzyl)-tropanium-3-yl]-succinate dichloride.

Similarly, it is possible to use compounds such as:

N-(2-Methoxy-5-nitrobenzyl)-tropinium bromide

N-[3-(3,4-dipropionyloxyphenyl)-propyl]-tropinium bromide

N-(3,5-diacetoxy-2-naphthylmethyl)-tropinium bromide

- 19 N-(4-acetoxy-3,5-dimethoxybenzyl)-tropinium chloride

N-(4-acetoxy-3-chlorobenzyl)-tropinium bromide for

N-(3,4,5-trimethoxybenzyl)-tropinium chloride, produce:

bis[N-(2-methoxy-5-nitrobenzyl)-tropanium-3-yl]-succinate dibromide bis[N-(3-(3,4-dipropionyloxyphenyl)-propyl)-tropanium-3-yl]w succinate dibromide bis[N-(4-acetoxy-3,5-dimethoxybenzyl!)-tropanium-3-yl]-succinate dichloride bis[N-(4-acetoxy-3-chlorobenzyl)-tropanium-3-yl]-succinate dibromide

The following example illustrates the preparation of an asymmetric diammonium ester.

Example 5 - Preparation of fN-(2,5-dimethoxybenzyl)-tropanium-3-yl, fN-(3,4-diacetoxybenzyl)-tropanium-3-yne succinate dibromide

To a solution of 18.2 g (50 mmol) of bis(tropan-3-yl)-succinate in 500 ml of dry acetone in a sealed bottle was added 11.6 g (50 mmol) of 2,5-dimethoxybenzyl bromide. After heating at 50 °C for 24 h, 14.3 g (50 mmol) of 3,4-diacetoxybenzyl bromide was added to the cooled mixture. The mixture was then heated again at 70-75 °C for another 10 h. The resulting white precipitate was separated by filtration and purified by recrystallization (2 x) from MeOH-methylene chloride to give 9.0 g (20%) of [N-(2,5-dimethoxybenzyl)-tropanium-3-yl], [N-(3,4-diacetoxybenzyl)-tropanium-3-yl]-succinate dibromide as a white powder.

• · » · • · • · ·

-20Similarly, for example, by replacing 3,4-dibromophenethyl bromide and 3-(4,6-dimethoxynaphth-2-yl)-propenyl bromide with 2,5-dimethoxybenzyl bromide or 3,4-diacetoxybenzyl bromide, it is possible to obtain [N-(3,4-dibromophenethyl)-tropanium-3-yl], [N-{3-(4,6-dimethoxynaphth-2-yl)propenyl}-tropanium-3-yl]-succinate dibromide

The following example illustrates the synthesis scheme of C.

Example 6 - Preparation of bis[quinuclidine-3-in-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate

To a solution of trans-3,6-endomethylene-1,2,3,6-tetrahydrophthaloyl chloride (2.63 g, 12.0 mmol) in 20 mL of methylene chloride in a sealed tube was added 3-quinuclidinol hydrochloride (4.50 g, 27.5 mmol). The heterogeneous mixture was heated to 80 °C overnight. After cooling, the mixture was poured into 100 mL of 2N aqueous NaOH and extracted with CHCl3. The combined organic layer was dried over MgSO4 and concentrated. The resulting oil was purified by column chromatography (silica gel, 10% MeOH in CHCl3) to give 4.0 g (83%) of bis[quinuclidin-3-yl]-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate as a white solid.

Example 7 - Preparation of bis(N-(4-acetoxy-3-methoxybenzyl)-quinuclidinium-3-vin-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate dibromide

A solution of bis[quinuclidin-3-yl]-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate (1.0 g, 2.5 mmol) and 4-acetoxy-3-methoxybenzyl bromide (1.6 g, 6.25 mmol) in 30 mL of acetone was heated at 60 °C in a sealed tube for 10 h. The white solid (1.22 g, 54%) that precipitated was collected under vacuum over 1 h. Elemental analyses of this compound and other representative compounds are given in Table 1, where the C, H, and N contents are given as weight percent. High-resolution mass spectroscopy data and melting points are given in Table 2.

• ·· ·

Similarly, by appropriate choice of starting materials, other symmetrical and asymmetrical bis-quaternary ammonium salts of general structures 1/a, 1/b and 1/c can be prepared, for example:

[N-ethyl,N(-4-acetoxy-3,5-dimethoxybenzyl)-nor-granataninium-5-3-yl], [N-ethyl,N(-3,5-dinitrobenzyl)-nor-granataninium-3-yl]-cyclobutane-1,2-dicarboxylate dibromide, bis[N-(2,5-dimethoxybenzyl)-quinuclidinium-3-yl]-isophthalate dibromide, bis[N-(3,4-dipropionyloxyphenethyl)-1,2,6-trimethylpiperidinium-4iq. -yl]-cyclopentane-1,1-dibutyrate dibromide ttttttt tttt tttt tttt tttt tttt • · · · · · ··· · • · · · · tttttt · tttt · tt· tttttt ·· · · · · · · • tttt · · ·· · · ·· ·

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- 30 Example 8 - Testing the biological activity of neuromuscular blocking agents in animals in vivo

The neuromuscular blocking effect and other effects (e.g. cardiovascular side effects) of selected compounds have been tested in several different experimental animals. This approach is necessary because, according to current knowledge, the pharmacodynamic and pharmacokinetic properties of these agents vary significantly from species to species. Therefore, most important aspects of the intended therapeutic utility of these compounds, such as neuromuscular blocking effects, onset, duration and duration of action, and side effects, cannot be evaluated "in vitro" using only a single animal species.

Selected compounds of the present invention were examined in detail, first in "systematic screening" experiments on rats for neuromuscular blocking ability. The selected compounds were then tested for specific effects, such as time to onset of action, duration of action and side effects, in other selected animal species, such as cats, pigs, monkeys, rabbits and dogs. The methods used in rats and cats are described below. These methods were also used in other species where appropriate.

a) Adult male albino rats were anesthetized by intraperitoneal injection of pentobarbital. A cannula was inserted into the trachea for artificial respiration with a small animal respirator. A cannula was inserted into the carotid artery for recording blood pressure using a transducer and heart rate using a cardiotachograph on a polygraph machine. One external jugular vein was cannulated for i.v. drug administration. Neuromuscular function was monitored by electromyography, recording responses of the tibialis anterior muscle as a result of supramaximal nerve stimulation consisting of a single rectangular pulse or consecutive rectangular pulses of 0.1 to 0.2 ms duration every 10 to 12 s, which ···· ·· tt · • tt • · · • tt tt

- 31 were delivered to the sciatic or peroneal nerve by a laboratory nerve stimulator. Another method of stimulation involved repeated stimulation at a frequency of 0.1 Hz or 1 Hz. Vagal heart block, a side effect of some muscle relaxants, was evaluated by peripheral stimulation of the transected cervical vagus nerve and by determining the possible blocking effect against vagal-induced bradycardia. The agents were dissolved in saline and injected intravenously at appropriate time intervals. The intensity, onset, duration of neuromuscular block and its type were also determined for each agent. By administering several doses, doses corresponding to 50%, 80% and 90% neuromuscular block were determined. All agents were compared with selected standard neuromuscular blocking compounds, such as succinylcholine, pancuronium, mivacurium or rocuronium. The resulting data are shown in Table 5, where:

ED ₅₀ = intravenous dose in pg/kg that causes 50% neuromuscular block.

in minutes required to achieve 80 to 85% neuromuscular block.

'RI = recovery index in min, spontaneous recovery to 25 to 75% of neuromuscular response.

VB = percentage vagal block at 80 to 85% of the neuromuscular blocking dose.

AHR = percentage change in heart rate at 80 to 85% of the neuromuscular blocking dose.

ΔΒΡ = change in arterial blood pressure in percent at 80 to 85% of the neuromuscular blocking dose.

No = number of animals tested.

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- 32 b) Adult cats were anesthetized with a mixture of 70 mg/kg alphachloralose and 0.5 g/kg ethylurethane intraperitoneally. One thigh was fixed in a vertical position with a nail at the lower end of the femur. Needle electrodes were placed on the sciatic or peroneal nerve. The tendon of the tibialis anterior muscle was connected to a pressure transducer and the muscle responses elicited as described in paragraph a) were recorded. Both electromyographic and mechanomyographic responses were measured. Blood pressure and heart rate were measured in the arteries using pressure transducers and a cardiotachograph using appropriately inserted cannulas. The resulting data are contained in Table 4.

» The procedures described in paragraphs a) and b) were used as appropriate for other species, with the modification that young pigs were initially anesthetized by inhalation of halothane (Table 5) and monkeys were initially sedated by intramuscular injections of ketamine before induction and maintenance of general anesthesia using pentobarbital and propofol administered intravenously (Table 6). Data for rabbits are presented in Table 7 and data for dogs in Table 8.

If we consider all animal experiments together, the new neuromuscular relaxants are two to ten times faster and have a shorter duration of action than the comparator compounds.

Fig. 1 illustrates the neuromuscular blocking effect of bis[N-(3,4-diacetoxybenzyl)-tropanium-3-yl]-cyclobutane-1,2-dicarboxylate dibromide compared to succinylcholine and rocuronium in the monkey. The EMG response for muscle relaxation and the blood pressure response as a function of time in minutes are shown.

Blood pressure is given in mmHg, where 1 mmHg = 133 Pa.

It will further be apparent to those skilled in the art that the present invention may be embodied in other specific forms without departing from the scope of the invention.

3o to deviate from its essence or key features. Although the foregoing description of the present invention only describes ···· ·· φφ »< φφ ·· • φ φ · φ · φφφφ φφφ » φ ·ΦΦ φ φ φ * φ φφ φ φφ φ · φφ · φφ φφ »« φφ ·· ··

- 33 some of its embodiments are given as examples, it should be understood that other variations are within the scope of the present invention. The present invention is therefore not limited to the specific embodiments that are described in detail in the description. The present invention will be defined based on the appended claims.

• ·

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• ••4 ··

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Claims (24)

PATENT CLAIMS 1. Bis-quaternary ammonium derivatives selected from the group of compounds of the general formula and. — ⁷⁷ R,— N — R ₂ )-OAO-(ΟΗ,)η (CHJn ₂ ,. yRj'—N — R,' R/ Rr 2 X* (CHJm•R/ b. R ₃ -N * Ύ (CHJp (CHJn (CH.)n\ ⁺ -O-A-O-( (CH-)p \ /·' n—r; (CHJm 2 X* (CH ₂ ) mr; %-—U-(CHJn (CH ₂ )p YΪ,-- ⁵ -(CHj)m -A2 X" where R1 and R2 are di- or polysubstituted aralkyl or aralkenyl, provided that at least one of the substituents on each aralkyl or aralkenyl group is alkoxy or acyloxy; R2 and R2 are alkyl or alkenyl; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, IP ·· ···· ·· ·· ·· ·· • · · · · · · · · · • · · · · ··· · · · · • · · · · * · · · · ·· · • · · · · · · · ···· ·· ·· ·· ·· ·· ·· - 59 bicycloalkanedicarbonyl, bicycloalkenedicarbonyl, polycycloalkanedicarbonyl, polycycloalkenedicarbonyl, or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; R ₃ and R ₃ are H, CH ₃ or lower alkyl; R ₄ and R ₄ are H, CH ₃ or 5 lower alkyl; R ₃ and R ₄ together can also mean -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) _k -, O / \ -CH—CH-, or -(CH ₂ ) h S-(CH ₂ ) _k , ío where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; Ri and Rt , R ₂ and R ₂ , R ₃ and R ₃ , and R ₄ and R ₄ may be the same or different; and X is a pharmaceutically acceptable anion. 2. A bis-quaternary ammonium derivative according to claim 1, wherein R 1 is the same as 15 as R/, R ₂ is the same as R ₂ , R ₃ is the same as R ₃ , and R ₄ is the same as R ₄ . 3. The bis-quaternary ammonium derivative according to claim 1, wherein the group A is selected from the group of trans-3,6-endomethylene-1,2,3,620 tetrahydrophthaloyl, 1,9-nonanedicarbonyl, cyclobutane-1,2-dicarbonyl, cyclohexane-1,3-dicarbonyl, oxalyl, malonyl, succinyl, glutaryl, adipoyl, pimeloyl and suberoyl. 4. A bis-quaternary ammonium derivative according to claim 1, wherein R ₁ is the same as 25 as RL and represents aralkyl substituted by an alkoxy group, aralkyl substituted by an acyloxy group or aralkyl substituted by an alkoxyacyloxy group; A is trans-3,6-endomethylene-1,2,3,6-tetrahydrophthaloyl; R ₂ is the same as R ₂ and represents methyl; nam = 1; R ₃ and R ₄ together represent a group 30 -(CH ₂ ) ₂ - and R ₃ and R ₄ together mean -(CH ₂ ) ₂ -. • · ···· ·· ·< • · 4 4 4 · 4 4 · 4 4 4 4 4 4 444 4 4 4 4 •4 4 · 4 * · 444 44 4 • ·4 4 4 44 4 4 4 4 4 5. A bis-quartet ammonium derivative according to claim 4, which is [N-(2,5-dimethoxybenzyl)-tropanium-3a-yl]-trans-3,6-endo-methylene-1,2,3,6-tetrahydrophthalate dibromide. 6. The bis-quaternary ammonium derivative according to claim 4, which is bis[N-(4-acetoxy-3,5-dimethoxybenzyl)-tropanium-3a-yl]-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate dibromide. 7. The bis-quaternary ammonium derivative according to claim 4, which is bis[N-(4-acetoxy-3-methoxybenzyl)-tropanium-3a-yl]-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate dibromide. 8. The bis-quaternary ammonium derivative according to claim 4, which is bis[N-(3,4-diacetoxybenzyl)-tropanium-3a-yl]-trans-3,6-endo-methylene-1,2,3,6-tetrahydrophthalate dibromide. 9. The bis-quaternary ammonium derivative according to claim 4, which is bis[N-(3,4-diacetoxybenzyl)-tropanium-3β-yl]-trans-3,6-endo-methylene-1,2,3,6-tetrahydrophthalate dibromide. 10. A bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as R< and represents aralkyl substituted by an alkoxy group, aralkyl substituted by an acyloxy group or aralkyl substituted by an alkoxyacyloxy group; A is 1,9-nonanedicarbonyl; R2 is the same as _R2 and represents methyl; nam = 1; R3 and R4 together represent the group -( _CH2 ) _2- and _R3 and _R4 together represent -(Chhh- 61 ···· ·· «♦ ·· • · 11. A bis-quaternary ammonium derivative according to claim 10, which is bis[N-(3,4,5-trimethoxybenzyl)tropanium-3a-yl]-1,9-nonanedicarboxylate dibromide. 12. The bis-quaternary ammonium derivative according to claim 10, which is bis[N-(4-acetoxy-3,5-dimethoxybenzyl)-tropanium-3a-yl]-1,9-nonanedicarboxylate dibromide. yes 13. A bis-quaternary ammonium derivative according to claim 3, wherein R 1 is the same as R 1' and represents aralkyl substituted with alkoxy, aralkyl substituted with acyloxy or aralkyl substituted with alkoxyacyloxy; A is cyclobutane-1,2-dicarbonyl; R ₂ is the same as R 2 and represents methyl; nam = 1; 15 R3 and _R4 together represent the group -( _CH2 )2- and R3 and _R4 together represent -( _CH2 ) _2- . 14. A bis-quaternary ammonium derivative according to claim 13, which is bis[N-(4-acetoxy-3,5-dimethoxybenzyl)-tropanium-3a-yl]20-cyclobutane-1,2-dicarboxylate dibromide. 15. A bis-quaternary ammonium derivative according to claim 13, which is bis[N-(4-acetoxy-3-methoxybenzyl)-tropanium-3a-yl]-cyclobutane-1,2-dicarboxylate dibromide. 16. The bis-quaternary ammonium derivative according to claim 13, which is bis[N-(3,4-diacetoxybenzyl)-tropanium-3a-yl]-cyclobutane-1,2-dicarboxylate dibromide. ···· you · - 62 ·· ·· it · • · • it 17. The bis-quaternary ammonium derivative according to claim 13, which is bis[N-(3,4-dipropionyloxybenzyl)-tropanium-3a-yl]-cyclobutane-1,2-dicarboxylate dibromide. 18. A bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as R1' and represents aralkyl substituted with alkoxy, aralkyl substituted with acyloxy or aralkyl substituted with alkoxyacyloxy; A is cyclohexane-1,3-io-dicarbonyl; _R2 is the same as _R2 and represents methyl; nam = 1; R ₃ and R ₄ together represent the group -(CH ₂ ) ₂ - and R ₃ and R ₄ together represent -(CH ₂ ) ₂ -. * 19. A bis-quaternary ammonium derivative according to claim 18, which is 15 bis[N-(3,5-dimethoxy-4-propionyloxybenzyl)-tropanium-3a-yl]-cyclohexane-1,3-dicarboxylate dibromide. 20. A bis-quaternary ammonium derivative according to claim 18, which is bis[N-(4-acetoxy-3-methoxybenzyl)-tropanium-3a-yl]20-cyclohexane-1,3-dicarboxylate dibromide. 21. The bis-quaternary ammonium derivative according to claim 18, which is bis[N-(3,4-diacetoxybenzyl)-tropanium-3a-yl]-cyclohexane-1,3-dicarboxylate dibromide. 22. A bis-quaternary ammonium derivative according to claim 3, wherein Rt is the same as _RT and represents an aralkyl substituted with an alkoxy group, an aralkyl substituted with an acyloxy group or an _aralkyl substituted _with an alkoxyacyloxy group; A is glutaryl _; R2 is _· *·· «· • · _{·· ·} 23. A bis-quaternary ammonium derivative according to claim 22, which is bis[N-(3,4-diacetoxybenzyl)-tropanium-3a-yl]-glutarate dibromide. 24. A bis-quaternary ammonium derivative according to claim 22, which is bis[N-(3,4-dipropionyloxybenzyl)-tropanium-3a-yl]-glutarate 10 dibromide. 25. A bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as R1' and represents aralkyl substituted with an alkoxy group, aralkyl substituted with an acyloxy group or aralkyl 15 substituted with an alkoxyacyloxy group; A is adipoyl; R ₂ is the same as R ₂ and represents methyl; nam = 1; R 3 and R ₄ together represent the group -(CH ₂ ) ₂ - and R ₃ and R ₄ together represent -(CH ₂ ) ₂ -. 26. The bis-quaternary ammonium derivative according to claim 25, which is bis[N-(3,4-dipropionyloxybenzyl)-tropanium-3a-yl]-adipate dibromide. 27. A bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as 25 as R-ι' and represents aralkyl substituted by an alkoxy group, aralkyl substituted by an acyloxy group or aralkyl substituted by an alkoxyacyloxy group; A is glutaryl; R ₂ is the same as R ₂ and represents methyl; nam = 1; R3 and R ₄ together tttt·· «« • tt • · 64 tttt tttt ·· • « · · tt • · tt tt·· · • · ttttt tttt ttttt tt · · • tttt tttttt tt··· ·· ·· tttt ttttt tt··· ·· ·· tttt tttt '· · · • · · represent the group -(CH ₂ )3- and R3 and R ₄ together represent -(CH ₂ ) ₃ -. 28. A bis-quaternary ammonium derivative according to claim 27, which is 5 bis[N-(3,4-diacetoxybenzyl)-granataninium-3-yl]-glutarate dibromide. 29. A bis-quaternary ammonium derivative according to claim 27, which is bis[N-(3,4-dipropionyloxybenzyl)-granataninium-3-yl]-glutarate 10 dibromide. 30 Bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as Ri’ and represents aralkyl substituted with an alkoxy group, aralkyl substituted with an acyloxy group or aralkyl 15 substituted with an alkoxyacyloxy group; A is adipoyl; R ₂ is the same as R ₂ and represents methyl; nam = 1; R 3 and R ₄ together represent the group -(CH ₂ ) ₃ - and R ₃ and R ₄ together represent -(CH ₂ ) ₃ -. _31. The bis-quaternary ammonium derivative according to claim 30, which is bis[N-(3,4-diacetoxybenzyl)-granataninium-3-yl]-adipate dibromide. 32. The bis-quaternary ammonium derivative according to claim 30, which is ₂₅ bis[N-(3,4-dipropionyloxybenzyl)-granataninium-3-yl]-adipate dibromide. 33. A bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as R1' and represents an aralkyl substituted with an alkoxy group, - 65 • •toto «· • · • · >· • » « • · »·· • · • to » to · · ·· ·· • · < «· ·· aralkyl substituted with an acyloxy group or aralkyl substituted with an alkoxyacyloxy group; A is pimeloyl; R2 is the same as R2 and means methyl; nam = 1; R3 and _R4 together mean the group -(CHUb- and _R3 and _R4 together mean -( _CH2 ) _3- . 34. The bis-quaternary ammonium derivative according to claim 33, which is bis[N-(3,4-diacetoxybenzyl)-granataninium-3-yl]-pimelate dibromide. 35. The bis-quaternary ammonium derivative according to claim 33, which is bis[N-(3,4-dipropionyloxybenzyl)-granataninium-3-yl]-pimelate dibromide. 15 36. A bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as R< and represents aralkyl substituted with alkoxy, aralkyl substituted with acyloxy or aralkyl substituted with alkoxyacyloxy; A is suberoyl; R2 is the same as _R2 and represents methyl; nam = 1; _R3 and _R4 together 20 represent the group -(CH ₂ ) ₃ - and R ₃ and R ₄ together represent -( _CH2 ) _3- . 37. A bis-quaternary ammonium derivative according to claim 36, which is bis[N-(3,4-diacetoxybenzyl)-granataninium-3-yl]-suberate 25 dibromide. 38. A bis-quaternary ammonium derivative according to claim 3, wherein R1 is the same as R< and represents an aralkyl substituted with an alkoxy group, an aralkyl substituted with an acyloxy group or an aralkyl substituted with an alkoxyacyloxy group; A is cyclobutane-1,2-dicarbonyl; _R2 is the same as _R2 and represents methyl; nam = 1; _R3 and _R4 together represent the group -( _CH2 ) _3- and _R3 and _R4 together represent -( _CH2 ) _3- . 39. The bis-quaternary ammonium derivative according to claim 38, which is bis[N-(3,4-diacetoxybenzyl)-granataninium-3-yl]-cyclobutane-1,2-dicarboxylate dibromide. 40. A bis-quaternary ammonium derivative according to claim 38, which is bis[N-(3,4-dipropionyloxybenzyl)-granataninium-3-yl]-cyclobutane-1,2-dicarboxylate dibromide. 41. A bis-quaternary ammonium derivative according to claim 1, wherein A is 315-methyladipoyl; R1 and R2 are different and represent aralkyl substituted with alkoxy, aralkyl substituted with acyloxy or aralkyl substituted with alkoxyacyloxy; _R2 , _R3 , _R4 , _R2 , R3 and _R4 represent methyl; anam = 1. 20 42. A bis-quaternary ammonium derivative according to claim 41, which is [N-methyl, N-(2,5-dimethoxybenzyl)-2,6-dimethylpiperidinium-4-yl], [Ν’-methyl, N’-(3,5-diacetoxy-2-naphthylmethyl)-2,6-dimethyl-piperidinium-4-yl]-3-methyladipate dibromide. 25 43. A bis-quaternary ammonium derivative according to claim 3, wherein A is cyclobutane-1,2-dicarbonyl; R1 and R2 are the same and represent aralkyl substituted with alkoxy, aralkyl substituted with acyloxy or aralkyl substituted with alkoxyacyloxy; _R2 is the same as _R2 and represents ethyl; nam = 1; R ₃ and R ₄ together represent the group -(CH ₂ ) 3 - and R 3 and R ₄ together represent -(CH ₂ ) ₃ -. 44. A bis-quaternary ammonium derivative according to claim 43, which is bis[N-ethyl, N-{3-(4-acetoxy-3-methoxyphenyl)propenyl}-nor-granataninium-3-yl]-cyclobutane-1,2-dicarboxylate dibromide. 45. A bis-quaternary ammonium derivative according to claim 1, wherein A is fumaryl; R1 and R2 are the same and represent aralkyl substituted with an alkoxy group, aralkyl substituted with an acyloxy group or aralkyl substituted with an alkoxyacyloxy group; _R2 is the same as _R2 and represents methyl; n, map = 1; _R3 and _R4 together represent the group -( _CH2 ) _2- and _R3 and _R4 together represent -( _CH2 ) _2- . 46. The bis-quaternary ammonium derivative according to claim 45, which is bis[N-(3,5-dimethoxy-4-propionyloxybenzyl)-6-azabicyclo[3.2.1]octanium-3-yl]-fumarate dibromide. 47. A bis-quaternary ammonium derivative according to claim 1, wherein R1 and R2 are the same and represent 4-acetoxy-3-methoxybenzyl; and A is selected from the group consisting of malonyl, 1,1-cyclohexyldiacetyl and trans-3,6-endomethylene-1,2,3,6-tetrahydrophthaloyl. 48. A bis-quaternary ammonium derivative according to claim 47, which is bis[N-(4-acetoxy-3-methoxybenzyl)-quinuclidinium-3-yl]-trans-3,6-endomethylene-1,2,3,6-tetrahydrophthalate dibromide. 49. Method for producing bis-quaternary ammonium derivatives of the general formula • to • to - 68 *3-y'— < ^CH 2) ⁿ (CH,)n ______ R ₃ R —*N-Ri -OA--OZ R _z -VR ₄ ^R <--<CH ₂ )m {CH,)mZR ₄ where Ri is di- or polysubstituted aralkyl or aralkenyl, R ₂ is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or aromatic dicarbonyl; n is 0., 1 or 2; m is 0, 1 or 2; R ₃ is H, CH ₃ or lower alkyl; R ₄ is H, CH ₃ or lower alkyl; R ₃ and R ₄ together can also be -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) hO-(CH ₂ ) _k -, or -(CH ₂ ) _h -S-(CH ₂ ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of the formula is carried out R,-— (CH^n N—Rj)-OH \ / R*--{CH^m 25 with a compound of the formula CI-A-CI to obtain the first reaction product of formula i? • tt · · · · tttttttt • · Λ R<- (CH^n (CH^m O-A——O R ₂ —— N \ / and the reaction of the former with a compound of the reaction product formula is carried out RiX to obtain a second reaction product of formula / ^{7 -- <CH2)n} (CH^n _____ R ₃ R f—*N — ^r 2 V— ⁰ --AO-ý R ₂ —\f Rí \ / \ / _Rí - _2χ _ (CH ₂ )mL--R, 15 50. Method for the production of bis-quaternary ammonium derivatives of the general formula Rí • - N ^R rr ₂ (CHJn {CHi) _p •(Chem A-O 2X· Rí / (CH^nN (CH-)m where R1 is di- or polysubstituted aralkyl or aralkenyl, _R2 is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is _an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, - 70 • ·· · ·· • * bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; R3 is H, CH3 or lower alkyl; _R4 is H, _CH3 or lower alkyl; R3 and _R4 together can also be -( _CH2 ) _g , -CH=CH-, -( _CH2 ) _h -O-( _CH2 ) _k- , or -( _CH2 ) _h -S-( _CH2 ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of the formula is carried out Rz AND Rj-N 7“ (CHj),, (CHJn •OH (CHJm with a compound of the formula CI-A-CI to obtain the first reaction product of the formula R,- N-τ— (CHJn (CHz)p -Oc?(CHJn - N\ (CH ₂ )„ -(CHJm (CHJmR*) and reacting this first reaction product with a compound of the formula R1X to obtain a second reaction product of the formula • * ·« 71 R, Ra Ri Rj O ξ (CH,), (CH ₂ )m--R, 51. A process for the preparation of bis-quaternary ammonium derivatives of the general formula wherein R1 is di- or polysubstituted aralkyl or aralkenyl, R2 is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl' or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 1; R3 is H, _CH3 or lower alkyl; _R4 is H, CH3 or lower alkyl; R3 and _R4 together can also be -( _CH2 ) _g , -CH=CH-, -( _CH2 ) _h -O-( _CH2 )k-, or -( _CH2 ) _h -S-( _CH2 ) _k> where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of the formula • toto· ·· *· ** • « to · toto ··· ·« to·· ···· · ·· 4 •to ·· ·· «to 72 ·· ·· to «to · • to· · • ··· • ·· · ·· ·· R— N —(CH^n ¹ / (CH ₂ ) _p H Rr -(CH-)m with a compound of the formula CI-A-CI to obtain the first reaction product of the formula R=-N--(CHJn / \ (CH ₂ ) _p V\ Γ R<-*(CHJn-N-R_ J ^X Λ <CH ₂ ) _p (CH ₂ )m--R _x and the reaction of this first reaction product with a compound of the formula is carried out RiX to obtain the second reaction product of the formula R ₃ -fi (CHJn (CHjp y (CHJm 2X (CHJn-N (CHJm\ (CH ₂ ) _p 52. Method for producing bis-quaternary ammonium derivatives of the general formula ···· rr ^3 -Ri ·· ·· « · * · · · • · · · · ·«· ·· · · · · · • · · « ···· ·· ·· ·· ·· -73·· ·· • · R · • c · * • · · 9 • · · · ·· ·· FROM Kτ-’Ν—*2 AND R ₄ {CHjJn {CHJm 2 X (CHjJn Ri—Ν' L where R1 is di- or polysubstituted aralkyl or aralkenyl, _R2 is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; _R3 is H, _CH3 or lower alkyl; _R4 is H, _CH3 or lower alkyl; R ₃ and R ₄ together can also be -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) _k -, or -(CH ₂ ) _h -S-(CH ₂ ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of the formula is carried out R,- ^(CH * ⁾ⁿ NR ₂ )-OH \ / R ₄ --(CHJm with a compound of the formula R-iX to obtain the first reaction product of the formula - 74 *3 R. ~7 *N—r ₂ (CH,)n H X* R<(CHJm) and reacting this first reaction product with a compound of the formula CI-A-CI to obtain a second reaction product of the formula Ri -y— (CHJn N—Ri )O-A-O 2 X* -Ri -r ₄ Method for producing bis-quaternary ammonium derivatives of the general formula Ri Rj F%- (Chyn <CH ₂ )p >A -(CH)m where R1 is di- or polysubstituted aralkyl or aralkenyl, R2 is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; R3 is H, _CH3 or lower alkyl; _R4 is H, CH3 or lower alkyl; R3 and _R4 together can also mean -( _CH2 ) _g , -CH=CH-, -( _CH2 )hO-( _CH2 ) _k- , or -( _CH2 ) _h -S-( _CH2 ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of the formula is carried out Rz (C^n (CH ₂ } _p )--OH \ / R*- ^k -(CH ₂ ) m with a compound of the formula R1X to obtain the first reaction product of the formula R, Rz and reacting this first reaction product with a compound of the formula CI-A-CI to obtain a second reaction product of the formula Ri Rz r ₃ (CHJn 49 4· » · · · · · · » 9 4 9 9 9 · · 9 ^R r (CH ₂ ) _p v -(CHJm 2X Ri Rz (CHJn — fi — / O-( (CH ₂ ) _b (CHJm- ^R * 54. Method for producing bis-quaternary ammonium derivatives of the general formula T ^-^-(CHJn (CH ₂ )p V A (CHJn — --R ₃ -O--A--O-( (CH ₂ )p -{CHJm 2X(CH)mwhere R1 is di- or polysubstituted aralkyl or aralkenyl, _R2 is alkyl or alkenyl provided that at least one 15 the substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or 20 aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; R ₃ is H, CH ₃ or lower alkyl; R ₄ is H, CH ₃ or lower alkyl; R ₃ and R ₄ together can also be -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) _k -, or -(CH ₂ ) _h -S-(CH ₂ ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is 25 a pharmaceutically acceptable anion, characterized in that it comprises the following steps; the reaction of the compound of the formula • · · · is carried out - 77 R— Ν —(CHj)n ³ / (CH,), H R is a compound of the formula RiX to obtain the first reaction product of the formula / (CH,), N—(CHj)n -OH χ· Rr and reacting this first reaction product with a compound of the formula CI-A-CI to obtain a second reaction product of the formula R* 55. Method for producing bis-quaternary ammonium derivatives of the general formula R,--γ—(CH ₂ ) n (CHJ n R ₃ R — *N—R? V-O-A-O-( Rz—N*—R, \ / \ / R ₄ ->-(CHjJm .(CH^ro- ^L -R _z where R 1 is di- or polysubstituted aralkyl or aralkenyl, R 2 is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; R 3 is H, CH 3 or lower alkyl; R ₄ is H, CH ₃ or lower alkyl; R 3 and R 4 can also together mean -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) hO-(CH ₂ ) k-> or -(CH ₂ ) _h -S-(CH ₂ ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of the formula (CH^n -S—7 Rj—n . HCl R ₄ - H with a compound of the formula CI-A-CI to obtain the first reaction product of the formula • · *3-— «W ⁿ !CH,)n _____ R ₃ tr R ₂ ——OAO-/ R ₂ —\ . I Rr—-(CHj)m (CH ₂ )m -R ₄ and reacting this first reaction product with a compound of formula 1 R-iX to obtain a second reaction product of the formula 15 56 R ₃ --77— (CH-,)n jCHJn _ R ₃ R — N- ^R i )-OAO-( R ₂ — N*—R1 \ / \ / „ R,--(CHj)m (CH,)m-1- _Rj * A Method for producing bis-quaternary ammonium derivatives of the general formula Rr Rj (CHJn (CHiJp IN -{CHpm 23C Ri Rj (CHJn — NR, “V (CH,)» (CH ₂ )m--R ₄ where R1 is di- or polysubstituted aralkyl or aralkenyl, R ₂ is alkyl or alkenyl provided that at least one 25 the substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted - 80 10 alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkanedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl . or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; R ₃ is H, CH ₃ or lower alkyl; R ₄ is H, CH ₃ or lower alkyl; R ₃ and R ₄ can also together mean -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) _k -, or -(CH ₂ ) _h -S-(CH ₂ ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of the formula is carried out R ₂ AND R,-N—7(CH ₂ ) _p r ₄ . HCl (CHjJn (CHjJm OH with a compound of the formula CI-A-CI to obtain the first reaction product of formula (CHj)n -N+(CH ₂ ) _p and react this first reaction product with a compound of the formula R^ to obtain a second reaction product of the formula - 81 Rí Rí (CHj) _P y \ -A — 2X Rí / -*3 Λ <ch ₂ ) _p (CH ₂ )m--R ₄ (CK)n 57. Method for producing bis-quaternary ammonium derivatives of the general formula Rj— N (CHj)n Rr(CHi)p A (OH,Ιπ — -R ₃ -AO( _CH2 ) _p 2X(CH ₂ ) m15 where R 1 is di- or polysubstituted aralkyl or aralkenyl, R ₂ is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkane20 dicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; R 3 is H, CH 3 or lower alkyl; R ₄ is H, CH 3 or lower alkyl; R 3 and R ₄ can also together represent -(CH ₂ ) _g , 25 -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) _k -, or -(CH ₂ ) _h -S-(CH ₂ ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, - 82 characterized in that it includes the following steps: the reaction of the compound with the formula .HCl is carried out R — N—(CHJn ⁵ / \ (CHJ _P )-OH R ₄ -*-(CH]m with a compound of the formula CI-A-CI 10 to obtain the first reaction product of the formula - (CHJn (CHJp R ₄ --(CHJm (CHJn —fy-Rj (CHJp (CHJm A—_r ₄ and reacting this first reaction product with a compound of the formula RiX to obtain the second reaction product of the formula Rf (CHJn (CHJp \ -{CHJm 2X' (CHJn (CHJm· -N\ (CHJp 25 58. Method for producing bis-quaternary ammonium derivatives of the general formula - 83 • * · · · · 9 9 9 9 * · · · · · 9 9 9 9 9 999 R, R ^R r ~7~ -*N-*2 A (CHJn (CHJm 2 X~ (CHJn (CHJm· FA R, ¹ FL' where R1 is di- or polysubstituted aralkyl or aralkenyl, _R2 is alkyl or alkenyl provided that at least one substituent on each aralkyl or aralkenyl group is an alkoxy or acyloxy group; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkanedicarbonyl, polycycloalkanedicarbonyl or aromatic dicarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; _R3 is H, _CH3 or lower alkyl; _R4 is H, _CH3 or lower alkyl; R ₃ and R ₄ together can also be -(CH ₂ ) _g , -CH=CH-, -(CH ₂ ) _h -O-(CH ₂ ) _k -, or -(CH ₂ ) _h -S-(CH ₂ ) _k , where g is 2, 3, 4 or 5, h is 1 or 2 and k is 1 or 2; and X is a pharmaceutically acceptable anion, characterized in that it comprises the following steps: the reaction of the compound of formula ~7 is carried out N—Ri A (CHJn (CHJm (CHJn_ -< Ri'—N / •R,' .RU with about one equivalent of a compound of formula R,X - 84 ··»· ·· ·· ·· • ♦ · · · · • · · · · «· and then reacting the obtained first reaction product with about one equivalent of a compound of formula R ₄ X to obtain a second reaction product of formula ^—7 R t—*N-«2 (CHJn (CH^n -OAO (CH ₂ )m (CH ₂ )m M A R ₂ ' —N*—Rl AND_"· Method for producing bis-quaternary ammonium derivatives of the general formula Ri Rz R,-(CKj) (CH ₂ ) _p )-OA--ORi' Rz* (CHj)n -ςΝ-- ^R '' ^R r 2X (CH ₂ ) _p _Z_Rr characterized in that it comprises the following steps: the reaction of the compound of the formula is carried out Rz R,- Hy— (Chyn (CH ₂ ) _p y (CFyn Rz· I _ M-R,· R* (CH ₂ ) _p _Z_RT with approximately one equivalent of a compound of the formula R-iX φφ • · · · · · · · φ φ φ β ·· · 4 Φ · 4 Φ 4 Φ · φ · • · · · · · · Φ Φ φφ Φ 85 - ** *· ·* ** ** ** and then reacting the obtained first reaction product with about one equivalent of a compound of formula R/X to obtain a second reaction product of formula Rz R-> — ty -7— (CHj)n (CH ₂ )„ -(CHJm ^R í -A—O 2Γ RV Rz' (CH^Jn -r ty~- ^R '' (CHz)p -L——RT 60. Method for the production of bis-quaternary ammonium derivatives of the general formula ^R r R,-^ - (OH,)η (CH2)p y \ -AND- 2X' (CHJn R,' AND -N\ (CH ₂ ), R<’ characterized by the fact that it includes the following steps: the reaction of the compound of formula r ₃ _ Ny— (CH-)n (CH ₂ ) _b )-OAO is carried out R—---(CHj)m (CHJn — N- ^R V -/ (CH2)p { _CH2 )ms approximately one equivalent of the compound of the formula - 86 4444 44 4 4 4 444 RiX and then reacting the obtained first reaction product with about one equivalent of a compound of formula RiX to obtain a second reaction product of formula *4R,-/#—<CH ₂ )n (CH ₂ )p V 2X (CHJn \ ( _CH2 ) _p 61. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient. -