DE3039304A1 - NEUROMUSCULAR BLOCKERS AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

DR. BERG DIPL.-ING. STAPF-DIPL.-ING. SCHWABE DR. DR SANDMAIR

PATENTANWÄLTE PO Box 860245 8000 Munich 86 3039304

Attorney's file: 31 199 Oct. 17, 1980

THE WELLCOME FOUNDATION LTD. LONDON N.W.l / UK

Neuromuscular blockers and their method of manufacture

13002 ''

r (089) 9 * 82 72 Tdejrtmme Binkkonten: Hypo-Bsnk Munich 4410122 850

981273 BERGSTAPFPATENT Munich. (BLZ 70020011) Swift Code HYPO DE MM

9 »» 274 TELEX: Biyet Vereinjbink Munich 453100 (BLZ 70020270)

9 * 3310 0524540 BERG d Posijcheck Munich 65343-808 (BLZ 70010080)

description

Used in anesthesia during surgical procedures and intubation of the trachea neuromuscular blockers are used to achieve relaxation of the skeletal muscles.

Two types of neuromuscular blockers are commonly used: non-depolarizing and depolarizing.

Non-depolarizing blockers include d-tubocurarine, pancuronium, gallamine, diallyl toxiferin, and toxiferin.

Depolarizing blockers include succinylcholine and decamethonium. All conventional non-depolarizing Blockers have a long duration of action in the relaxation of the skeletal muscles during surgical interventions, E.g. in humans 60 to 180 min. The depolarizing blockers, on the other hand, achieve a much shorter muscle relaxation than the niqht-depolarizing. E.g. has succinylcholine a duration of action of 5 to 15 minutes, while decamethonium provides muscle relaxation for 20 to 40 minutes in humans achieved.

The long duration of action of the non-depolarizing blocker is for many surgical procedures that take less than 1 hour need, undesirable because the patient is in general

130022/0888 - ' ⁸

not recovered from their effects in time, i.e. they cannot breathe on their own, for example.

All non-depolarizing blockers have inherent side effects. Gallamine and pancuronium can cause tachycardia, and d-tubocurarine and diallyl toxiferin cause a drop in blood pressure.

Cholinesterase inhibitors can act as antagonists against these drugs can be used, however, the administration of a second drug is necessary, which has its own side effects may have, e.g. bradycardia, intestinal cramps or bronchorrhea. It then has to be to the mentioned side effects of the To eliminate cholinesterase inhibitors, a third drug, an anticholinergic drug, e.g. atropine, may be given.

To the best of the applicant's knowledge there is for the depolarizing Blockers are not pharmacological antagonists. In most cases there is no need to see the effects the depolarizing blockers, but in certain patients the effects of succinylcholine are great extended because the patient has an abnormal metabolic situation for the blocker.

The depolarizing blockers are known to induce muscle contraction according to their mode of action and causes irritation of the smooth muscles, to some extent

130022 / 06S8 " ^{/ 9}

Sen cases have the following side effects: increased intraocular and intragastric pressure, cardiac arrhythmias, Potassium release and muscle pain.

These side effects of the depolarizing blockers do not occur with the non-depolarizing blockers. It is therefore it can be clearly seen that a new neuromuscular blocker is needed to reduce the short duration of action of the depolarizing with the relatively minor side effects and controllability of the non-depolarizing blockers with one another should unite.

It should be noted that non-depolarizing blockers In general, gallamine and pancuronium have few side effects, but tachycardia, and d-tubocurarine and diallyl toxiferin Can produce a drop in blood pressure.

The compounds according to the invention are surprisingly free of these side effects in the tests carried out to date at the dosages intended for their clinical use. Reference is made to the following publications ¹ , they contain a more detailed description of the neuromuscular blockers: The Pharmacological Basis of Therapeutics-5. Edition, Louis S. Goodman and Alfred Gilman, Editors. The McMillian Co., 1975, chapter 28, George B. Koelle.

130022/0688

-Λή.

Neuromuscular Blocking Activity of a New Series of Quaternary N-Substituted Choline Esters - British Journal of Pharmacology, 1971, 43, 107.

The Pharmacology of New Short Acting Non-depolarizing Ester Neuromuscular Blocking Agents: Clinical Implications. Anaesthesia and Analgesia .... Current Researches, 1973, 52, 982.

Potential Clinical Uses of Short-Acting Non-depolarizing Neuromuscular-Blocking Agents as Predicted from Animal Experiments. Anaesthesia and Analgesia .... Current Researches, 1974, 54, 669; and
U.S. Patent 3,491,099.

GB-PS 3 00 «+ 031 describes a group of laudanosinium salts, which are neuromuscular blockers of the non-depolarizing type.

BE-PS 869 415 describes a group of substituted tetrahydroisoquinolinium salts with a neuromuscular blocking effect of the non-depolarizing type and short duration of action. The ES-PS 477 257 describes a second group of tetrahydroisoquinolinium salts, which, as neuromuscular blockers of the non-depolarizing type, have a medium duration of action own. The compounds described in the above-mentioned patents include various mixtures of up to and trans isomers of undefined composition.

13002 2/0688 ^"m

A 1

The four centers of asymmetry in all of the compounds of the above-mentioned patents allow 16 stereoisomers. Because of the symmetry of the molecular structure, however, only 10 stereoisomers can actually occur: U d £ pairs (an alltrans, an all-cis, two ice, trans) and two meso forms (an all-cis, an all-trans). It was found that the synthetic route and also the more detailed experimental conditions determine the proportions of the cis / trans and stereoisomers. None of the granted patents relates on the question of stereoisomers, therefore methods for separating the different isomers are not given still suggested. The above-mentioned patents also do not address the problem that different efficacies, Duration of action or side effects may apply to the various isomers in the mixtures.

A process has now been discovered by which the all-trans (a d £. Pair, a meso form) and the all-cis (a d £ pair, a meso form) connections can be made. These dia stereomers show up as neuromuscular Blocker different effectiveness and / or duration of action. Compared with the corresponding all-cis compound, at the all-trans compounds have a 3 to 6 times stronger effect and a shorter duration of action in the cat. They were with the monkey Differences in potency not so clear, the duration of action of the all-trans compounds was considerably shorter

- / 12

130022/0688

-hl

(2 to 3 times) than that of the corresponding all-cis compounds. The unexpected differences in the duration of action can be explained by measuring the rate of hydrolysis by acetylcholinesterase in vitro. The hydrolysis of the cis compounds was slow compared to that of the corresponding trans form.

Accordingly, the invention relates to new neuromuscular blockers (sometimes called muscle relaxants) having the formula I.

• 2X "

in which B and C each represent a group of the formula II and are in the meta or para position to one another:

OCK.

OCH.

OCH.

II

130022/0688

- / 13

-AU-

wherein D is CHLCH «or CH = CH (preferably trans); Y alkyl having 1 to 4 carbon atoms (methyl, ethyl, propyl or butyl); E and FH or OCH ₃ ; X ~ is an anion, preferably a pharmaceutically acceptable anion, and the substituted benzyl and propyl groups in the nitrogen-containing ring are in the trans position relative to one another.

Preferred compounds are those in which Y is methyl.

Particularly effective compounds associated with a short duration of action are bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-1- (3,4,5-trimethoxybenzyl) -isoquinolinium] -propyl} - 1,3-phenylenedipropionate salts, especially in the form of the dichloride, diiodide or ditosylate salts.

Compounds with particularly high effectiveness, connected with a medium duration of action are bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-l- (3,4,5-tΓimeΐhoxybenzyl) -isoohinolinium] -propyl} -l, 4-phenylene- (E, E) -diacrylate- and bis- {3- [trans-l, 2,3,4-tetrahydro-6,7-dimethoxy-N-methyll- (3,4,5-trimethoxybenzyl) -isoquinoliniumJ-propyl} -l, 3-phenylene- (E, E) -diacrylate salts, especially in the form of the dichloride, diiodide or dimesylate salts.

- / 14

130022/0688 '

303330Α

Since the effectiveness of the compounds according to the invention is based on the dication, the type of anion X is relatively unimportant. Suitable pharmaceutically acceptable anions include iodide »mesylate, tosylate, bromide, chloride, sulphate, Phosphate, hydrogen phosphate, acetate, benzene sulphonate, Succinate, maleate, naphthalene sulphonate and propionate.

The compounds of the invention are as about 1: 1 Mixtures of the racemic (dS.) Pair and the meso isomer before. The invention also relates to processes for obtaining the compounds of formula I as one of the above Isomers essentially free of the other isomers, as well as mixtures of one of these isomers with either or both of the other isomers.

Preferably, the compounds of the invention are so produced that the quantitative ratio of the inventive trans, trans compound to the total amount of the various corresponding ice, ice and ice, trans compounds, present as impurities is at least 96: U.

The compounds of the formula I are used as neuromuscular blockers in surgical interventions or for tracheal purposes Intubation is used and given conventionally parenterally, e.g. intramuscularly or intravenously as a solution. The in formula I. compounds according to the invention shown are used in patients such as monkeys and humans and other mammals for

- / 15

130022/0688

Targeting a neuromuscular block supplied. The dosage for each type of patient must vary according to the specifics of the species. A suitable intravenous dosage level for compounds of formula I to achieve sufficient paralysis for surgery in monkeys and humans would be 0.05 to 1.5 mg / kg body weight and
preferably 0.1 to 1 mg / kg body weight, based on the weight of the dication as active ingredient.

The dose for intramuscular use is 2 to Η times that of the intravenous one. The compounds of the invention are usually re-administered every 5 to M5 minutes, depending on whether the duration of action of the compound is short or medium, preferably every 5 to 30 minutes after the first administration. They can also be administered as a continuous infusion according to the duration of the desired muscular block and according to the instructions of the treating anesthesiologist or surgeon. The action of the compounds according to the invention is reversible, including the conventional cholinesterase inhibitors
how neostigmine and edrophonium are used, and they
seem the side effects of depolarizing blockers
to avoid.

The compounds of the formula I can therefore be used to achieve a short or medium-length neuromuscular block will. The invention relates to a method to

- / 16

130 022/0688

such blocks in mammals, e.g., humans or monkeys, by intravenous injection of a dose of 0.05 to 1.5 mg / kg to achieve.

The compounds can be used in a pharmaceutical preparation for parenteral administration. The preparation can be an aqueous or non-aqueous solution or emulsion in a pharmaceutically acceptable liquid or liquid mixture, which Bacteriostats, antioxidants, buffers, thickeners, suspending agents or other pharmaceutically acceptable May contain additives. Such preparations usually come in unit dose form such as ampoules or disposable syringes or in the form of multiple doses, such as a bottle, from which the appropriate amount is withdrawn can be. All of these preparations should be sterile.

The compounds can be presented as a powder, such as a unit dose in a sealed ampoule to which the sterile water or other pharmaceutically acceptable sterile liquid carrier can be added, preferably with aseptic methods.

A suitable unit dose for achieving neuromuscular block in mammals, e.g., humans or monkeys, is about 1.0 mg to 300 mg, preferably 5.0 to 200 mg.

- / 17

130027/0688

- / it

The compounds according to the invention can, if desired, along with other non-depolarizing agents, such as. they are listed above.

A suitable pharmaceutical preparation for pareriteral Administration to humans therefore preferably contains 1.0 to 300 mg of the compounds of the formula according to the invention I in solution.

A simple and preferred preparation is a solution of the compound of the formula I in water. This can be done by simply Dissolve the compound in previously sterilized pure Water, i.e. in pyrogen-free water, under aseptic conditions and with subsequent sterilization the solution.

The compound of the formula I can also be administered as an infusion of a dextrose or saline solution, for example Ringer's solution will. The compounds can also be used in other solvents such as alcohol, polyethylene glycol and dimethyl sulfoxide administered. They can also be given intramuscularly as a suspension.

The compounds according to the invention lead to unexpected results lower doses to the same relative degree of neuromuscular blockage than those previously described eis / trans mixtures. Hence the possible occurrence

-718 130022/0680

of side effects such as abnormal drop in blood pressure, histamine release, tachycardia, etc. are significantly reduced. The invention also makes it possible _for mixtures with specified Isomerzusammensetzungen manufacture.

The compounds of Formula I can be made by the following methods getting produced; a substituted tetrahydroisoquinolinium salt is used for this purpose, which is defined above possesses trans configuration.

Procedure 1

Benzy! Tetrahydroisoquinolines are known from homoveratrylamine or mescaline and homoveratric acid or 3,4,5-trimethoxyphenylacetic acid with Bischler-Napieraliski reaction and reduction / alkylation produced.

The tertiary benzyl tetrahydroisoquinoline is converted into quaternary form with a suitable 1,3-dihalopropane, for example 1-bromo-3-chloropropane, 3-chloro-1-iodopropane or 3-bromo-1-iodopropane. From the obtained N-alkyl-N-3-halopropyl-benzyl-tetrahydroxsoquinoline halide, the trans-isoquinoline halide is separated off and boiled in water with the silver salt of the suitable diacid to give silver halide and the benzy-tetrahydroisoquinolineum salt of the acid. This salt reacts with the corresponding ester ¹ when heated, preferably to 90 to IUO ⁰ C. The generalized reaction is shown below as an example:

1300.22 / 0688 ' ^{/ 19}

oca.

D-COO Ag

π + y

(CH ₉ ) ^ OOC-D

Ag ~ OOC-D

I. Exchange (AgBr ppt) 2. Heat

, D-COO (CH ₂ )

.2Cl '

OCH

OCH,

Supreme Court

OCH,

here D, Y, E and F have the meanings given above. The desired salts are then prepared by ion exchange using conventional methods such as metathesis with HX or a silver salt, an anion exchange resin, etc. can be used.

- / 20

130022 / 06S8

Procedure 2

The suitable 1-benzyl tetra prepared according to method 1 hydroisoquinoline is treated with a 3-halopropanol such as e.g. 3-iodine, 3-bromo- or 3-chloropropanol in quaternary form leads. This is shown below, E, F, X and Y have the meaning given above.

F.

OCH.

OCH,

This process can be carried out in a variety of solvents (e.g. acetonitrile, lower alcohols, DMF, water, aromatic hydrocarbons, etc.) and in a range between ambient temperature to reflux temperature
will. The trans isomer is separated as described below.

The bis-acid chloride of a suitable meta- or para-phenylenedicarboxylic acid is prepared in a conventional manner by treatment with a reactant such as thionyl chloride.

- / 21

130022/0688

3033304

The bis-acid chloride is then esterified, e.g., by two moles the appropriate quaternary salt containing a 3-hydroxypropyl chain. This process is illustrated below, D, E, F, X and Y have the meanings given above.

OCH-

-COCl

Cl-CO- D

P-COO- (CK ₂ ) 3

OCH,

OCH.

For the production of all-trans to quaternary salts with reinforced Effectiveness and fewer side effects must be a trans-N-S-hydroxypropyl-N-alkyltetrahydroisoquinolinium salt

- / 22

130022/0688

with a total of U up to 6 methoxy groups (as shown in formula II) for coupling with the meta- or para-phenylenedipropion- or diacrylic acids are produced. For example, trans and cis N-3-hydroxypropyl-5'-methoxylaudanosinium salts are Diastereomers and theoretically with physical methods, e.g. crystallization, to separate. However, it appears from the literature that this separation is difficult. So described e.g. Stenlake et al. (J.B. Stenlake, W.D. Williams, N.C. Dhar and 1.6. Marshall, Eur. J. Med. Chem. - Chemica Therapeutica, 9, 233 (197H)) the synthesis of mixtures of trans- and cis -N-ethyllaudanosinium iodides, but it was impossible to separate these: "All attempts to separate the components Separation of these mixtures by crystallization and chromatographic methods were unsuccessful. "

A number of solvents for the recrystallization of the trans / cis mixtures of N-3-Hydroxypropy1-5'-methoxylaudanos inium iodid (trans / cis ratio about 2.5-2.7 / 1), created by quaternization of 5'- Methoxylaudanosine with 3-hydroxypropyl iodide (see Table I) ₇ was investigated. Most types of solvents were unsatisfactory. The mixture of trans / ice quaternary iodides was largely insoluble in ethers (tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane), esters (ethyl acetate, ethyl propionate), ketones (acetone, 2-butanone) and aromatic hydrocarbons (benzene, Toluene, xylene). The insoluble residues showed little or no accumulation in the trans isomer. To the for

130022/0688 " ^{/ 23}

The separation of useful solvents included acetonitrile, some chlorinated hydrocarbons (e.g. Di chlorine than, 1,2-dichloroethane), some alcohols (e.g. ethanol, 2-propanol) and water. Water is the most preferred solvent. Once the enrichment in the trans isomer has succeeded (e.g. by recrystallization from water), then further recrystallization from a number of solvents is sufficient (e.g. acetonitrile, ethanol) or trituration with acetone to increase the trans content to about 98% or more.

- / 24

130022/0688

If-

Table I Separation of trans / cis -N-3-hydroxypropyl-5'-methoxylaudanosinium iodide

A sample of trans / cis iodide (2.6 / 1 according to HPLC) was heated in a solvent, filtered hot, ^{cooled to 25 °} C. and filtered again.

trans / cis ratio (yield)

solvent

Tetrahydrofuran

1,4-dioxane

1,2-dimethoxyethane

acetone
2-butanone

Ethyl propionate
Ethyl acetate

Acetonitrile

Di chloromethane
chloroform

Carbon tetrachloride
1,2-dichloroethane

Nitromethane
Nitroethane

benzene
toluene
Xylene

Methanol

Ethanol

2-propanol

2-methoxyethanol

Formamide

N, N-dimethylformamide

N-ethylacetamide

Dimethyl sulfoxide

Hexamethylphosphorami d

water

Concentration ml / g

10 10 10

10 10

10 10

10

2 2

10 5

2 2

10 10 10

2 5 5 2

2 2 2

2 2

6.74

insoluble salts

recrystallized salts

2.7 / 1
2.8 / 1
2.6 / 1

2.7 / 1
3, H / l

2.7 / 1
2.6 / 1

(90%)
(71%)
(83%)

(81%)
(82%)

(96%)
(88%)

1.1 / 1
1.1 / 1

NP NP NP

NP NP

CS

1 / 15.8 (21%)

CS

2.6 / 1 (96%)
1 / 1.2 (30%)

CS
CS

2.7 / 1
2.7 / 1
2.5 / 1

1 / 2.6 (28%)

1 / 6.2 (2%)

NP 4/1 (58%)

1/1 (30%) 2.3 / 1 (89%)

100%) NP 100%) NP 100%) NP

CS

9.8 / 1 (27%)
12.7 / 1 (38%)
CS

CS
CS
CS

CS
CS

CS

6.8 / 1
1.9 / 1
1.5 / 1
2.8 / 1

2.6 / 1

(9%) (58%) (25%) (31%)

NP NP (96%)

NP NP

1 / 5.17 (31%)

Abbreviations:

NP = no precipitate, CS = completely dissolved, HPLC = high performance liquid chromatography

- / 25

130 0 2 2/0688

In another attempt, the trans / ice quaternary salt mixtures to separate, the iodide initially received a different anion. The iodide mixtures were prepared using standard procedures (Anion exchange chromatography, metathesis with silver chloride, and metathesis with HCl gas) to the corresponding Chlorides and a number of solvents were investigated to separate the isomers (see Table II). Again, most of the solvents were unsatisfactory. Of the ethers, only Ι, Μ-dioxane was selective. Ketones, esters and aromatic hydrocarbons were ineffective. Nitroalkanes (nitromethane, nitroethane), acetonitrile, some alcohols (especially ethanol and 2-propanol), some chlorinated hydrocarbons (e.g. dichloromethane, 1,2-dichloroethane), Dimethyl sulfoxide, hexamethylphosphoramide, and N-substituted amides are useful solvents for a to obtain quaternary chloride enriched with the trans isomer. N-substituted amides (e.g. N, N-dimethylformamide, Ν, Ν-dimethylacetamide, N-formylpiperidine, N-formylmorpholine, N-methylformamide, N-methylacetamide and N-ethylacetamide) are preferred solvents for the trans / cis separation. These amides can be used as recrystallization solvents or solvents can be used to slurry enriched trans mixtures to further increase the trans isomer content.

- / 26

130022/0688

'ft

Table II

Separation of trans / cit: -N-3-hydroxypropyl-5'-methoxylaudanosinium chloride

A sample of trans / cis chloride (2.9 / 1 according to HPLC) was heated in a solvent, filtered hot, ^{cooled to 25 °} C. and filtered again.

solvent

Concentration ml / g

Tetrahydrofuran 10

1,4-dioxane 10

1,2-dimethoxyethane 10

Acetone 10

2-butanone 10

Ethyl propionate 10

Ethyl acetate 10

Acetonitrile 10

Dichloromethane 10

Chloroform 2 carbon tetrachloride 10

1,2-dichloroethane 10

Nitromethane 5

Nitroethane 10

Benzene 10

Toluene 10

Xylene 10

Methanol 2

Ethanol 5

2-Propanol 10 2 - Me th oxy e th ano 1

Formamide 2

N, N-dimethylformamide 5

N-ethylacetamide 2

Dimethyl sulfoxide 2 hexamethylphosphoramide xd IO

Water 2

trans / cis ratio (yield)

insoluble salts

recrystallized salts

2.6 / 1 (97%)

132/1 (67%)

3.3 / 1 (96%)

3/1 (95%)

3.8 / 1 (97%)

3.4 / 1 (99%)

3.3 / 1 (95%)

NP

1/6 (24%) NP

1/15 (2%) 1/11 (3%)

NP NP

100/1 (50%) 8.6 / 1 (6%)

101/1 (36%)

CS

2.4 / 1 (99%)
6/1 (76%)

CS
80/1 (42%)

2.9 / 1 (99%)
3.1 / 1 (97%)
2.4 / 1 (96%)

CS
CS
69/1 (30%)

CS
CS
CS

CS
7/1 (40%)

CS

NP NP NP 1 / 2.9 (12%)

9.4 / 1 (56%) NP

NP NP NP

NP

17/1 (32%) 9.1 / 1 (18%)

NP

6.7 / 1 (54%) 8.8 / 1 (76%)

18/1 (34%) NP

NP

Abbreviations:

NP = no precipitate, CS = completely dissolved, HPLC = high performance liquid chromatography

- / 27

130 0.2 2/0688

■ It

It has been found that a particularly good separation of the trans isomer from the crude cis / trans mixture can be achieved if the N- (3-hydroxypropyl) -N-methyl compound is used in the form of the iodide ( ice / trans mixture) crystallized from water. The cis isomer preferentially crystallizes. If necessary, then the trans-enriched
Filtrate can be converted to the chloride, for example by means of
conventional anion exchange chromatography (e.g. using Dowex 1-X8 chloride resin), the solute can be recovered and slurried with dimethylformamide if the cis isomer preferentially dissolves giving a product containing only a trace of the cis isomer.

With the help of fractional crystallization, the trans / cis mixtures of N-3-hydroxypropyllaudanosinium iodide, N-3-hydroxypropyl-8-methoxylaudanosinium iodide and N-3-hydroxypropyl 1-5 ', 8-dimethoxylaudanosinium iodide separately.

It is preferred to use an intermediate having less than about 2% of the corresponding cis isomer to obtain a compound of Formula I which is less than 4% of the
Contains ice, ice and ice, the trans isomer. This level of separation can easily be achieved using the methods described above.

- / 28

130 0.2 2/0688

- 2 * -

Procedure 3

The suitable 1-benzyltetrahydroisoquinoline prepared according to Method 1 is treated with a 3-halopropanol, e.g. 3-iodo-, 3-chloro- or 3-bromopropanol in quaternary form transferred, and the trans-N-3-hydroxypropyl-1-benzyltetrahydroisoquinolinium salt is separated from the cis isomer according to method 2.

The trans-quaternary salt is by direct esterification with the appropriate meta- or para-phenylenedipropionic acid coupled. This procedure can also be used to do the trans-quaternary salt with meta- or para-phenylenediacrylic acid however, this response is slower. The process is carried out in a suitable solvent (e.g. 1,2-dichloroethane) using an acidic catalyst (e.g. p-toluenesulfonic acid). The reaction will by removing water with the help of drying agents (e.g. molecular sieves) or azeotropic distillation to completeness brought. The temperatures can be between ambient and return temperature. The final salt can, if desired, using conventional anxon exchange techniques be changed.

As already mentioned, the compounds of formula I exist in three stereoisomeric forms, which, if desired, with the aid can be separated from each other by conventional methods

- / 29

1 3 0 0.2 2/0 6 8 8

W— 'W

can. For example, the nieso isomer can be separated from the (dJO pair by fractional crystallization or preparative HPLC (high performance liquid chromatography), and the d and ε isomers from one another by conversion to a salt of a certain isomer of an optically active acid and subsequent fractional crystallization The product can then be converted to an alternative salt using conventional anion exchange techniques, if desired.

m- and p-phenylenediacrylic acids were produced by means of the Knoevenagel-Doebner condensation of isophthalic and terephthalic aldehydes with malonic acid. 150 mmol of terephthalic acid aldehyde and 180 mmol of malonic acid were mixed with kB ml of pyridine and 1.5 ml of piperidine. The mixture was heated in the steam bath (85-95 ⁰ C) for 3 hours. The solution was then cooled to room temperature and distilled in vacuo to remove pyridine. The solid residue was washed out in hot 2-propanol (70 ^° C.) to remove residual pyridine. The product, p-phenylenediacryic acid, was filtered off and dried (melting point> 275 ^° C.).

m-Phenylenediacrylic acid was obtained in exactly the same way from isophthalic acid aldehyde (melting point> 275 ^° C.).

m- and p-Phenylenedipropionic acids can be mixed with conventional Process can be produced by catalytic reduction, e.g. by reacting the corresponding phenylenediacrylic acid

ei 28-31.5 N / cm in the presence of

130022/0683 "/ 30

2 salts with hydrogen at 28-31.5 N / cm in the presence of

5% palladium on charcoal in water or dimethylformamide, at room temperature up to 55 ^° C. For another method see Wagner & Zook, Synthetic Organic Chemistry 19 7 3, 431, method 26.

The compounds of the invention can sometimes be water of hydration contained in various amounts, and the invention therefore also relates to such compounds containing water of hydration. The following examples are intended to explain the invention in more detail. The specified temperatures are in C. (uncorrected).

The primary analysis of the quaternary salt intermediates and the di-quaternary salt end products were carried out with the aid of high performance liquid chromatography (HPLC). Samples were dissolved in methanol and placed on a 25 cm χ 4 mm silica gel column and eluted with acidic methanol. The determination was based for absorbance at 2 80 nm; Percentages were calculated by integrating the areas under the curves. NMR spectra, Combustion analyzes and Karl Fischer water analyzes were carried out as required in order to determine the structures to support. The stereochemistry of the cis and transquaternary salts was determined by X-ray crystallography of the cis iodide and the trans-perchlorate of the N-3-hydroxypropyl-5'-methoxylaudanosinium salts confirmed.

- / 31 130 0.2 2/0688

example 1

50 g (73% trans) N-3-hydroxypropyl-5'-methoxylaudanosinium iodide (BE-PS 869 415 and West German Offenlegungsschrift No. 2833505) were dissolved in hot water, cooled, and the solids were filtered off and placed in a vacuum oven (60 ⁰ C, 3 h) dried; this gave 15.5 g of solid, HPLC analysis gave 84% ice. The trans-rich filtrate was applied to a 5 × 60 cm column filled with 110 g of Dowex 1-X8 chloride in water and eluted with 100 ml of water. The eluate was concentrated to dryness in vacuo. The residue was triturated with acetone, filtered off, and the solid in vacuo (60 ⁰ C, 3h), giving 28 g of crude trans-chloride afforded. The crude product was slurried in warm DMF, cooled and filtered off. The solids were washed out with cold DMF and hot acetone. The suspension was cooled, filtered, and the solids washed out with cold acetone and dried in a vacuum oven, yielding 24.7 g (80.5%) of trans-N-3-hydroxypropyl-5'-methoxylaudanosinium chloride, m.p. 209-211 ° C. HPLC analysis indicated that this material was 99.3% in trans form.

Example 2

412 g (95.1% pure, 71.9% trans according to HPLC) of crude N-3-hydroxypropyl-5 ^1- methoxylaudanosinium iodide was crystallized from water. The trans-rich mother liquor was chromatographed on 1.00 kg of Dowex 1-X8 chloride. The eluate and the

- / 32

1300.22 / 0688

- 5? -

Wash solutions were combined and vacuumed to a viscous one concentrated oil. The residue was triturated with acetone, the volume was reduced, cooled and filtered off, giving 225 g of crude trans chloride (97.7% trans). The crude product was slurried in warm DMF, cooled and filtered off. The cake was washed out with the DMF liquors and then with acetone. Eventually it got damp Product slurried in refluxing acetone, cooled, filtered and dried, yielding 206 g (87.0%) of trans-N-3-hydroxypropyl-5'-methoxylaudanosinium chloride (99.9% trans by HPLC).

Example 3

50 g (72.5% trans, 26.7% ice) N-3-Hydroxyρropy1-5'-methoxylaudanosinium iodide were dissolved in 337 ml of hot water. The solution was ^{cooled at 25 °} C. for 3 hours. The mixture was filtered off and gave 15.5 g of cis-iodide (83.8% ice - purified (> 99% ice) by recrystallization from methanol). The filtrate was concentrated to dryness in vacuo and gave the trans iodide (95.6% trans by HPLC). The crude trans iodide was purified by recrystallization from dry acetonitrile (2.5 ml CH 2 CN / g) to give 99 , 6% trans iodide (71% yield). In similar experiments, 94.5% trans iodide gave 99.3% pure trans (67% yield) and 97% trans gave 99.6% trans (86% yield). Trans iodide was also purified by trituration with acetone (3 ml / g):

- / 33 130022/0688

92.7% trans gave 97.7% trans (95% yield). Ethanol (95%, 4 ml / g) could also be used as a solvent for recrystallization used: 9 7.7% trans gave 99.6% trans (61% yield).

Example 4

25.7 g (> 99% trans according to HPLC) of trans-N-3-hydroxypropyl-5'-methoxylaudanosinium chloride were suspended in 300 ml of 1,2-dichloroethane. The mixture was ^{cooled to about 70 °} C. and 6 g of 1,3-phenylenedipropionyl chloride (prepared by treating the corresponding acids with thionyl chloride) were added as a solution in dry 1,2-dichloroethane. The mixture was refluxed for 25 minutes; HPLC analysis found approximately 93% product. The reaction mixture was cooled, stirred over potassium carbonate for 2.5 hours, filtered off and concentrated to dryness in vacuo. The crude product was dissolved in 300 ml of chloroform, and the solution was washed twice with 5% sodium chloride and twice with water, dried over anhydrous sodium sulphate and concentrated in vacuo; this gave 24 g of bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1- (3,4,5-trimethoxybenzyl) isoquinolinium] propyl} - 1,3-phenylenedipropionate dichloride as a white amorphous solid (87.4% based on a dihydrate).

- / 34

130 02 2/0688

Example 5

124.6 g (> 99% trans according to HPLC) of trans-N-3-hydroxypropyl-5'-methoxylaudanosinium chloride were suspended in dry 1,2-dichloroethane and a solution of 32.7 g of 1,3-phenylenedipropionyl chloride in 100 ml of 1 , 2-dichloroethane was added. The mixture was stirred under reflux and cooled to 45 ⁰ C 8. 22.9 g of triethylamine were added,
and the mixture concentrated in vacuo. The residue was dissolved in 1800 ml of chloroform. The chloroform solution was washed out with 5% sodium chloride (2 × 450 ml), water (2 × 450 ml), dried over magnesium sulphate, clarified by treatment with charcoal and concentrated in vacuo until foaming occurred. The residue was triturated with hexane and the mixture again concentrated in vacuo until
Foaming occurred. This procedure was repeated 3 times until a solid product was obtained. The slightly oily product was placed in a mortar and triturated again with hexane, so that a granulated solid was obtained which was filtered off and dried (48 h at 40 ^° C.); this yielded 127.5 g (85.3%) bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1- (3,4,5-trimethoxybenzyl ) -isoquinolinium) -propyl} -l, 3-phenylenedipropionate dichloride.

- / 35

13002 2/0688

- -95-—

Example 6

5.06 g of trans-N-3-Hydroxypropy1-5'-methoxylaudanosinium chloride (> 99% trans according to HPLC) was with the method of
Example U with 1.27 g of EjE-ljU-phenylenediacryloyl chloride
coupled and gave 3.0 g (50.7% as dihydrate) bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-1- (3,4, 5-trimethoxybenzyl) isoquinolinium] propyl} -1, U-phenylene- (E, E) -diacrylate dichloride.

Example 7

0.58 g of 1,3-phenylenedipropionic acid, 3.2 g of trans-N-3-hydroxypropy 1-5 '-methoxy laudanosiniumchlorid, 1.75 g of p-toluenesulphonic acid monohydrate and 60 ml of dichloroethane were in a
Combined 100 ml flask fitted with a sintered glass Soxhlet apparatus with # 4 molecular sieve.
The mixture was heated to reflux and monitored by HPLC. After 35 hours the reaction mixture was cooled
and washed out 2 times with 50 ml of water. The dichloroethane layer was stirred with charcoal and magnesium sulphate (anhydrous) overnight. The mixture was filtered off and evaporated to dryness, yielding 3.11 g (84%) of bis- {3- £ trans-1,2,3, H-tetrahydro-6,7-dimethoxy-N-methyl-1- (3 , 4,5-trimethoxybenzyD-isoquinolinium] propyl} - !, 3-phenylene dipropionate ditosylate.

- / 36

1 30 0.2 2/06 88

3D39304

Example 8

5.00 g of trans-NS-hydroxypropyl-S ¹ -methoxylaudanosinium chloride, 1.08 g of 1,3-phenylenediacrylic acid and p-toluenesulphonic acid monohydrate were combined in 1,2-dichloroethane and reacted by the procedure of Example 7. After 99 hours under reflux, HPLC analysis showed 46.7% bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-1- (3,4,5 -trimethoxybenzyl) -isoquinoliniumj-propyl} -1, 3-phenylene- (E, E) -diacrylate ditosylate.

Example 9

5.07 grams of trans-N-3-hydroxypropyl-5'-methoxylaudanosinium chloride (> 99% according to HPLC) was with 1.29 g of 1,4-phenylenedipropionyl chloride coupled, which 4.7 g (79.6% from dihydrate) bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-1- (3,4, 5-trimethoxybenzy 1) -isoquinoline (T) -propyl} -1, 4-phenylene dipropionate dichloride revealed.

Example 10

To a solution of 0.65 g (prepared according to Example 4 using pure trans-iodide according to Example 3) bis- {3- £ trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-ΙΟ, 4,5-trimethoxybenzyl) isoquinolinium] propyl} -1,3-phenylenedipropionate diiodide tetrahydrate in 10 ml of acetonitrile was a solution of 0.22 g of silver methanesulphonate in 10 ml

- / 37 13-0022 / 0688

■ 31

Given acetonitrile. The mixture was stirred for 15 minutes and filtered to remove the silver iodide precipitate. The filtrate was concentrated in vacuo to a brown oil which was taken up in denatured ethanol (SD3A) and filtered to remove excess silver methanesulphonate. The alcohol was evaporated in vacuo and the residue was dissolved in acetonitrile and filtered. The acetonitrile was evaporated in vacuo and the residue dissolved in acetone. The acetone solution was filtered through Celite (filter aid) and evaporated to dryness, yielding 0.40 g (65%) of fluffy yellow crystals of bis- {3-ε trans-1,2,3,4-tetrahydro-6,7-dimethoxy -N-methy 1-1- (3,4,5-trimethoxybenzyD-isoquinolinium] propyl} -1,3-phenylenedipropionate dimethanesulphonate.
Calculated for C ₆₂ H ₈₂ N ₂ O ₁₄ .2CH ₃ O ₃ S.4H ₂ O:

C: 57.29; H: 7.21; N: 2.08; S: 4.79 Found: C: 57.37; H: 7.10; N: 2.09; S: 4.79.

Example 11

10 g of N-3-hydroxypropyl-5'-methoxylaudanosinium iodide (71% trans) was dissolved in 100 ml of methanol. The solution was heated to reflux and hydrogen chloride gas was released for 5 hours. long blown. The mixture was evaporated in vacuo and the residue left in a dryer overnight stored containing sodium hydroxide pellets. Acetone was added and evaporated in vacuo. Denatured alcohol (SD3A) was added and evaporated in vacuo, and the

130 0.2 2/0658 " ^{/ 38}

drive repeatedly a second time. After addition of acetone and seed crystals, 4 g of N-3-hydroxypropyl-5'-methoxylaudanosinium chloride (87% trans according to HPLC) were obtained. Slurrying in DMF gave the trans-quaternary chloride (> 9 8%
trans according to HPLC).

Example 12

5.06 g (> 99% trans by HPLC) of trans-N-3-hydroxypropyl-5'-methoxylaudanosinium chloride was coupled with 1.27 g of E, EI, 3-phenylenediacryloyl chloride using the method of Example 4, and yielded 6.0 g (100% as trihydrate)
bis- {3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1- (3,4,5-trimethoxybenzyl) isoquinolinium] propyl} -1, 3- phenylene (E, E) diacrylate dichloride.

Example 13

27.2 g of 5 ^f , 8-dimethoxylaudanosine and 27.2 g of 3-iodopropanol were refluxed in 150 ml of dry acetone for 21 hours. HPLC gave a cis / trans mixture of 1: 4.3.
The mixture was stripped to a gum and the excess iodopropanol extracted with ether. The ether was decanted off and the remaining gum was dissolved in SD3A (300 ml) with gentle warming. Cooling the alcoholic solution at 5 ° overnight gave a white crystalline solid which was filtered off and dried. The yield was 29.2 g (73%), which was 89.9% trans-N-3-hydroxy-

- / 39

130 0.2 2/0688

propyl-5 ¹ , 8-dimethoxylaudanosinium iodide and 10.1% cis-N-3-hydroxypropyl-5 ', 8-dimethoxylaudanosinium iodide. The mixture was recrystallized twice from 3.4 ml / g SD3A and gave 24.4 g (84% yield) of a mixture which, with the aid of HPLC, was determined to be 7.8% trans iodides and 2.2% cis iodides , mp. 160-163 ⁰ C. the mixture was dissolved in 300 ml of aqueous methanol, and the solution (75 g, Cl) through a Dowex 1-X8 ion exchange resin column filled passed. The column was rinsed with 150 ml of methanol and the eluate and wash solutions were combined, stripped to a white solid, triturated with acetone, filtered and dried. The yield was 18.1 g (87%), HPLC determination showed 100% trans.
Calculated for C ₂₆ H ₃₈ NO ₇ Cl ^ H 0:

C: 56.98; H: 7.72; N: 2.56; Cl: 6.47 Found: C: 56.9 7; H: 7.74; N: 2.52; Cl: 6.47.

Example 14

2.0 g of trans-N-3-hydroxypropy1-5 ', 8-dimethoxylaudanosinium chloride were with 0.48 g of 1,4-phenylenedipropionyl chloride coupled with the method according to Example 4, which gives 700 mg (31% as tetrahydrate) bis- {3- [trans-1,2,3,4-tetrahydro-6 , 7,8-trimethoxy-N-methyl-1- (3,4,5-trimethoxybenzyl) -isoquinolinium | -propyl} -1, 4-phenylenedipropionate dichloride revealed.

- / 40

130022/0683

- ¹ H.

Example 15

Following the procedure of Example 13, 34 grams of laudanosine were obtained converted into quaternary form with 26 g of 3-iodopropanol, which is a 3: 1 ratio of trans / cis-N-3-hydroxypropyllaudanosinium iodide revealed. Crystallization of the crude mixture gave the pure trans iodide, which led to the corresponding pure trans-chloride (> 99% according to HPLC) was converted. The yield for the quaternization was 87%, for the anion exchange 82%.

Example 16

3.6 g of trans-N-3-hydroxypropyllaudanosinium chloride were with 0.96 g of 1,4-phenylenedipropionyl chloride by the procedure coupled according to Example 4, and resulted in 2.8 (69% as tetrahydrate) bis- {3- (trans-l ^ S ^ -Tetrahydro-e ^ -dimethoxy-N-methyl-l- (3,4-dimethoxybenzyl) - isoquinolinium] propyl} -1, 4 ~ Phenyldipropionate dichloride.

Example 17

5.0 g of trans-N-3-hydroxypropyllaudanosinium chloride were with 1.35 g of EjE-ljU-phenylenediacryloyl chloride using the procedure coupled according to Example 4 and gave 2.3 g (40% as tetrahydrate) bis- {3-Jtrans-1,2, S ^ -Tetrahydro-e ^ -dimethoxy-N-methyl-1- (3,4-dimethoxybenzyl) -isoquinolinium] -propyl} -l, 4-phenylene- (E, E-diacrylate dichloride.

- / 41 130022/0683

Pharmacological effectiveness

Cynomolgus monkeys were given intramuscularly Thiopental (35-40 mg / kg) and diazepam (2-3 mg / kg) anesthetized. The anesthesia was with a mixture of halothane (0.25-0.75%), nitrous oxide (60%) and oxygen (40%) are maintained.

Bis- {3- {trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1- (3, H, 5-trimethoxybenzyl) isoquinolinium]] propyl} -1, 3 -phenylenedipropionate dichloride (Compound A), bis- {3- £ 1,2,3, U-tetrahydro-6,7-dimethoxy-N-methyl-1- (3,4,5-trimethoxybenzyl) -is ochinolinium] -propy1} -1,3-phenylenedipropionatdij odid (Mixture of cis and trans isomers, compound B) or

(3,4,5-trimethoxybenzyl) -isoquinolineunff-propyl} -1,3-phenylenedipropionate iodide (Compound C) were administered intravenously. The common peroneal nerve became supramaximal stimulated with square pulses of 0.2 ms duration at a frequency of 0.15 Hz. Muscle twitches were felt on the tendon of the Tibialis anterior measured.

The EDgrj i.e. the dose necessary for a 95% inhibition of the Muscle twitching was required for Compound A was 0.4-0.6 mg / kg, for Compound B 0.5-1.0 mg / kg and for Compound C 0.8-1.1 mg / kg (expressed as mg / kg cation).

End of description 130022/0688

Claims (1)

DR. BERG DIPI ..- ING. STAPF DIPL.-ING. SCHWABE DR. DR SAKDMAIR PATENTANWÄLTE PO Box 860245 8000 Munich 86 Attorney's file: 31 Claims 1. Compound of formula I .2X " wherein B and C each represent a group of the formula II OCH. OCH. D - COO - (CH ₂ ) ₃ - where D is CH ₂ CH ₂ or CH = CH; Y is an alkyl having 1 to t carbon atoms; E and FH or OCH., · And X ~ mean an anion, and the 13002 - / 0688 r (089) 988272 988273 988274 983310 Telegrams: BERGSTAPFPATENT Mllnchen TELEX: 0524560 BERG d - / 2 Buikkonir.ri; Hypo-Buik Munich 4410122850 (BLZ 70020011) Swift Code HYPO DE MM Bayet Vereinsbuik Munich 453100 (BLZ 70020270) Post check Munich 65343-808 (BLZ 70010080) substituted benzyl and propy! groups in the nitrogenous Ring are in trans position relative to each other. 2. A compound according to claim 1, characterized in that C to B is in the meta or para position stands. 3. Compound according to claim 1 or 2, characterized in that that Y is methyl. U. A compound according to any one of claims 1 to 3, characterized in that D is CH ₂ CH ₂ . 5. A compound according to any one of claims 1 to 3, characterized in that D means trans-CH = CH. 6. A compound according to any one of claims 1 to 5, characterized in that X is a means pharmaceutically acceptable anion. 7. A compound according to claim 6, characterized that X iodide, mesylate, tosylate, bromide, chloride, sulphate, phosphate, hydrogen phosphate, acetate, Means benzene sulphonate, succinate, maleate, naphthalene sulphonate or propionate. 13GO22 / QG8B 8. Pharmaceutically acceptable salt of bis- (3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1- (3,4,5-trimethoxybenzyD-isoquinolinium]) -propyD-1,3-phenylene dipropionate. 9. Pharmaceutically acceptable salt of bis- (3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-1- (3,4,5-trimethoxybenzyD-isoquinolinium] -propyl) -l, 4-phenylene diacrylate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-1- ( 3, U, 5-trimethoxybenzy 1) -isoquinoliniunT] -propy 1) -1, 3-phenylene diacrylate, bis- (3-ftrans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methy1-l- ( 3, 4-dimethoxybenzyl) isoquinoliniuni] propyl) -1, 3-phenylenedxpropionate, bis- (3- [trans-1,2,3,4-tetrahydro-6, 7,8-trimethoxy-N-methy 1- l- (3, U-dimethoxybenzyl) isoquinolinium] propyl) -1, 3 - phenylene dipropionate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7,8-trimethoxy-N-methyl-1- (3, U, 5-trimethoxybenzyl) -isoquinolinium] -propy1- 1,3-phenylenedxpropionate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1- (3,4-dimethoxybenzyl) -isoquinolinium] -propy1-1,4- phenylene dipropionate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7,8-trimethoxy-N-methyl-1- ( 3,4-dimethoxybenzyl) isochirioliniuin} propyl) - 1,4-phenylendipropionat, _ / ₄ 130022/0689 bis- (3- [trans-1,2,3,4-tetrahydro-6,7,8-tn'methoxy-N-methyl-1- ( 3, 4, 5-trimethoxybenzyl) -isoquinoline (T] -propyl) -1, 4-pheny lendipropionate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyll- ( 3,4,5-trimethoxybenzyl) -isoquinolinitini3-propyl) -l, 4-phenylene dipropionate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyll- (3,4-dimethoxybenzyl) isoquinolinium] propyl) -1,3 phenylene diacrylate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7,8-trimethoxy-N-methyl-1- ( 3,4-dimethoxybenzyl) isoquinolinium] propyl) -1,3-phenylene diacrylate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7,8-trimethoxy-N-methyl-1- ( 3,4,5-trimethoxybenzyD-isoquinolinium] propyl) -1,3-phenylene diacrylate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1- (3,4-dimethoxybenzyl) isoquinolinium] propyl) -1, 4- phenylene diacrylate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7,8-trimethoxy-N-methyl-1- ( 3, 4-dimethoxybenzyD-isoquinoline] - propyl) -1,4-phenylene diacrylate, bis- (3- [trans-1,2,3,4-tetrahydro-6,7,8-trimethoxy-N-methy1-1- (3, H, 5-trimethoxybenzy1) -isoquinolinium] -propy1) - 1,4-phenylene diacrylate. - / 5 130Ö22 / 080 8 10. A compound according to claim 8 or 9, characterized , caß it is a diiodide, dichloride or dimesylate. 11. A compound according to any one of the preceding claims, characterized in that it is in Form of the d, £ or meso isomer or a mixture consists of two or three of these isomers. 12. Pharmaceutical preparation for parenteral administration, characterized in that it contains an effective neuromuscular blocking amount of a compound according to any one of claims 6 to 11 as well contains a pharmaceutically acceptable liquid carrier. 13. Preparation according to claim 12, characterized in that it is in the form of unit doses. IU. Preparation according to claim 13, characterized that the amount of the compound is 1 mg to 300 mg. - / 6 130027/0688 15. Preparation according to one of claims 12 to 14, characterized in that it is in The form of a sterile aqueous solution of the compound of formula I is present. 16. Process for the preparation of a compound of the formula I according to claim 1, characterized in that that the trans isomer of a corresponding N- (3-hydroxypropyl) - or N- (3-halopropyl) -tetrahydroisoquinolinium salt separated from a mixture of the cis and trans isomers, the product with a suitable one Phenylenedicarboxylic acid or a reactive derivative thereof reacted and, if desired, the product an alternative salt is converted. - / 7 130022/0688