DD143254A5 - PROCESS FOR PREPARING TETRAHYDROISOCHINOLINE DERIVATIVES - Google Patents

Description

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Tetrahydro-isoquinoline derivatives, processes for their preparation and agents containing the derivatives

Anv / end un ^ 3 ft; area of the invention ^

The invention relates to a process for the preparation of novel and improved neuromuscular blocking agents, also referred to as muscle relaxants, based on tetrahydroisoquinoline derivatives.

Characteristic eri stic of the known technical solutions;

In anesthesia, neuromuscular blocking agents are used for the relaxation of skeletal muscle during surgery and during incubation of the trachea.

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Typically, two types of neuromuscular blocking agents are used, non-depolarizing and depolarizing. The non-depolarizing agents include b-'ubacurarine, pancuronium, gallamine and dialiyltoxyferins and toxifarin. The depolarizing agents capture succinylcholine and decamethonium.

All conventional non-depolarizing agents, when used during mammalian surgery, result in skeletal muscle relaxation of about 60 to 180 minutes.

The depolarizing agents cause muscle relaxation with a shorter duration of action than the non-depolarizing agents at doses commonly used during surgery.

Succinylcholine carries e.g. During a relaxation time of about 5 to 15 minutes, while the decamethoniura causes a relaxation time of the muscles of about 20 to 40 minutes.

There are no known non-depolarizing agents for clinical use which have a short duration of action.

In the following, a time of less than about 10 minutes when used in monkeys is defined as a short duration of action.

The long duration of action of the non-depolarizing agents is undesirable for many surgical procedures lasting less than 1 hour, since the patient should not be exposed to the effect of the agent for longer than necessary, as the patient should after surgery as possible

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should absorb the self-breathing quickly.

The known non-depolarizing agents have inherent side effects. Thus s.B, gallainin and pancuronium tachycardia and d-tubucurarine and diallyltoxiforin cause hypotension.

Since these agents pharmacologically counteract the anticholinesterase agents, it is often necessary to administer a second agent, which in turn has its own side effects, such as bradycardia, intestinal spasm and bronchorrhea. In order to eliminate the above side effects of the anticholinesterase agents, a third agent, an anticholinergic drug such as atropine, must be administered.

The depolarizing agents have no pharmacological antagonists. In the. In most cases there is no reason to counteract the effects of depolarizing agents. In some patients, the effect of succinylcholine is prolonged due to an abnormal metabolism of the agent in the patient.

Depolarizing agents cause initial skeletal muscle contraction and smooth muscle stimulation due to their effects. However, they also have the following effects in some cases: Increased intraocular and intragastric tension, cardiac arrhythmia, release of potassium and muscle pain "These side effects of depolarizing agents are not caused by non-aepolarizing agents. Thus, it is desired to have a novel neuromuscular blocking agent which has the short duration of action of the depoicing agents and the relatively low side effects and reversibility of the non-depolarizing agents.

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However, if the known non-depolarizing agents have little side effects, gallamine and pancuronium tachycardia and d-tubocurarine and diallyltoxiferin may cause hypotension.

Surprisingly, it has been found by clinical trials with conventional doses that the compounds of the invention do not have these side effects.

The prior art relating to neuromuscular blocking agents is referred to the following references:

The Pharmacological Basis of Therapeuties, 5 · Edition, Louis S. Goodman and Alfred Gilman, 1975, chapter 28, author George B, Koelle; Neuromuscular Blocking Activity of a New Series of Quaternary N-Substituted Choline Esters, British Journal of Pharmacology, September 1971, VoI, 43, no. 1, page 107;

The Pharmacology of New Short Acting Nondepolarizing Ester Neuromuscular Blocking Agents: Clinical Implications, Anesthesia and Analgesia .... Current Researches, Vol. 52, no. 6, page 982, Nov. - Des. 1973; Potential Clinical Uses of Short-Acting Nondepolarizing Neuromuscular Blocking Agents to Predicted from Animal Experiments, Anesthesia and Analgesia .... Current Researches, VoI * 54, no. 5, page 669, Sept. - Oct. 1974;

The object of the invention is to provide novel and improved neuromuscular blocking agents which have the mode of action of the non-depolarizing agents, a short duration of action and the necessary reversibility required for clinical use in surgery, and a method for the preparation thereof.

Parieg'un ^ the essence of the invention;

The neuromuscular blocking agents of the invention are characterized by the general formula I, wherein C is preferably in the m-position to B, as shown in the following labeile II or p-position to B, as shown in the formula III, and wherein B and G is the following radical of formula IY, t7orin in 2, 3 or 4, in particular 2, R-, R2, R-2, R /, Rc, Rg and Rj are the same or different and are hydrogen or alkoxy with 1 to 4 C atoms, in particular methoxy, ethoxy, propoxy or butoxy, Y is alkyl having 1 to 4 C atoms, in particular methyl, ethyl, propyl or butyl,

η is 2, 3 or 4, in particular 3 and X is a pharmaceutically acceptable anion, provided that at least one dor radicals R ^ to R ^ each ITiedrigalko: -q / and at least one of the radicals Rc to Rj is in each case a lower alkoxy radical ,

The preferred compounds of the invention are those in which Rr to Rj are lower alkoxy.

The preferred compounds of the invention are those of formula IJ. or III, in which X is methyl, m is 2 _S η 3, R ₁ -, Rg and R _{7 are} methoxy radicals in the 3, 4 and 5 positions of the phenyl radical of the benzyl group, R- and R, hydrogen "Atoms and Rg and R-, methoxy radicals are because these compounds are hydrolyzed less rapidly than the dimethoxyboazy! Compounds." The m compound (s, Formula II) is preferred over the corresponding p compound because it is a much shorter molecule Has effective time. The preferred compounds have minimal side effects and high potency.

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As the anions for the compounds of the present invention, e.g. the following ions are suitable:

J _o did, mesylate, tosylate, bromide, chloride, sulfate, phosphate, hydrogen phosphate, acetate, benzenesulfonate, liitrobenzolsulfon, Naphthylsulfosaat and propionate. The mesylate and chloride cations are the preferred ions due to the compounds prepared with these ions in water. Since the mode of action of the compounds of the invention is characterized by the cation portion of the compound, the door of the anion is of little importance as long as it is a pharmezeutisch compatible anion acts.

The compounds of formula I, II or III are used as neuroinuscular blocking agents in the operation or intubation of the trachea by conventional parenteral administration, that is, intramuscular or intravenous administration in solution. The compounds of the invention according to the formulas I, II or III are in patients, for example, monkeys or humans or other mammals; administered to cause neuromuscular block. The dose for the particular patient depends on the nature of the species. The suitable intravenous amount or dose of the compounds according to the invention of the formulas I, II or III is from 1.0 to 4.0 mg / kg body weight in monkeys and from 0.2 to 3 * 0 mg / kg body weight in humans, in particular 0 , 5 to I ₅ 5 mg / kg body weight. The amounts are based on the weight of the cation which is the active ingredient.

The dosage for intramuscular administration is two to four times v; ie intravenous Do3is _a erfindungsgemäßon The compounds v / normally all ground

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5 to 20 minutes, especially 5 to 15 minutes after the initial administration, or administered by continuous infusion depending on the desired duration of muscular block. The mode of administration is determined by the anesthesiologist and the surgeon.

The compounds of the invention are reversible using conventional aaticholinesterase agents, e.g. Neostigmine and HJdrophonium and have no side effects that show up with the use of depolarizing agents.

The inventions of formulas I, II or III are therefore suitable for causing short-term neuromuscular bleeding, z.3. in mammals such as humans or monkeys, wherein the mammals are injected with a dose of 0.05 to 4.0 mg / kg intravenously.

The compounds of the invention may be prepared in the form of the pharmaceutical formulation for parenteral administration. The forakulation may be an aqueous or non-aqueous solution or emulsion in a pharmaceutically acceptable liquid or mixture of liquids containing bacteriostatic agents, antioxidants, buffering agents, thickening agents, suspending agents or other pharmaceutically-acceptable additives. Such formulations are usually presented in unit dosage form, e.g. Ampoules or self-priming units or in a multidose form, e.g. in bottles from which the appropriate dose is withdrawn. These formulations must be kept sterile.

The compounds of the invention can be used as powder, Z ₉ Ii. in a jjinmaldosis in a sealed ampoule

be packaged, with sterile water or other pharmaceutically acceptable sterile carrier fluid is added by means of a needle into the vial.

A suitable single dose for neuromuscular blocking in mammals e.g. Humans or monkeys is about 10 mg to 400 mg, especially 50 to 300 mg. '

The compounds of the invention may be administered, if desired, together with other non-depolarizing agents as indicated above.

A suitable pharmaceutical parenteral preparation preferably contains 10 to 400 mg of the compounds according to the invention of the formulas I, II or III in solution.

A simple and preferred formulation is a solution of the compound of formula I, II or III in J. Yasser prepared by simply dissolving the compound in preferably sterile pure water, that is, pyrogen-free water under aseptic conditions and sterilizing the solution has been.

The compounds according to the invention of the formulas I, II or III can be administered as an infusion in a dextrose solution or a saline solution, e.g. Ringers' solution administered.

The compounds of the invention may also be used in other solvents, e.g. Alcohol, polyethylene glycol and dime thy isulf oxide be administered. It is also possible to use them as a suspension intramuscularly.

The compounds according to the invention of the formulas I, II or III can be prepared by the following methods ».

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Procedure I

Benzyltetrahydroisoquinolines are prepared in the usual way from suitably substituted phenylethylamines and phenylacetic acid *! on the Bischler ITapieralski reaction. The tertiary benzylisoquinoline is quaternized with a suitable ώ- bromo-oj-chloroalkane, tl- iodo-oj-chloroalkane or <6-iodo-cj-bromoalkane. The resulting H-methyl-il-co-haloalkyl-1-benzyltetrahydroisoquinoline halide is heated in water with the silver salt of the corresponding dicarboxylic acid »silver bromide and the benzylisoquinoline being obtained as the acid. The salt is converted to the corresponding ester by heating. The general reaction sequence is exemplified by using o-broin-co-chloroalkane as Reaction Scheme I:

wherein Z is a (GHg) _1n -GrUpPe and R- to R ^ have the meanings given above »

Other salts are usually prepared by reacting the di-chloro salt via an ion-exchange reaction with a suitable salt of the desired anion, e.g. made of silver mesylate.

The temperature for the conversion into the ester is preferably 90 to 140 C.

Procedure 2

The bis-acid chloride of a suitable phenylenedicarboxylic acid is prepared in the usual manner by treating the acid with thionyl chloride. The acid chloride is treated with a suitable O-hydroxy- u? esterified, wherein, as shown below, the desired phenylenedicarboxylic acid bis-CJ ~ iodoalkyl ester of the formula I is obtained

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The di-ester is refluxed with an excess of, for example, 2 moles of a suitable 1-benzyl-tetrahydroisoquinoline according to the Bischler-Uapieralski reaction as described in Method 1. The desired bis-benzyl-isoquinolinediiodide (disalt) is obtained, as shown in greater detail in Reaction Scheme II: viorin Z is a (CHg) -GrUpPe and R- to R ~ have the meanings given above. The desired salts are then "described by a usual ion exchange reaction me in the process 1 was prepared. Bromine or chlorine may iodine in the <£ hydroxy replace -jodalkan ω, if desired. The reaction course is the same as above *

Method 3

The appropriate 1β- benzyl-tetrahydroisoquinoline prepared by Method 1 is quaternized with the appropriate Cu- halide-hydroxy alkane. This process can be carried out in various solvents, for example acetonitrile, lower alcohols, DMF, aromatic hydrocarbons, etc., at room temperature to reflux temperature, as shown in Reaction Scheme III.

The bis-acid chloride of a suitable m- or p-phenylenedicarboxylic acid is prepared in the usual manner by treatment with an appropriate reagent, e.g. Thionyl chloride produced. The bis-acid chloride is then treated with e.g. 2 moles of the corresponding quaternary salt containing a hydroxyalky! Chain esterified. The desired salts are prepared by ion exchange using conventional methods ζ.-B. Metathesis with a silver salt, an anion exchange resin, etc .;

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Method 4

In an alternative method, the product of the Bischler ITapieralski reaction is quaternized with 3-rom-1-propanol in acetone at room temperature. By reduction with zinc, a tetrahydroquinoline containing a 2-hydroxypropyl substituent is obtained. This aminoalcohol is acylated with the desired acid chloride in chloroform at room temperature and then refluxed for 30 minutes. The chloroform is stripped off in vacuo, the residue is slurried in water, made alkaline by addition of excess potassium carbonate and then extracted with ether. The ether is concentrated and the tertiary ester is dissolved in acetone. Add excess methyl iodide and allow the solution to stand overnight, add ether in excess to precipitate the quaternary ester, filter off and dry the ester as shown in Reaction Scheme IV, then add tertiary aminoalcohol the appropriate acid chloride prepared according to Method 2 or 3, under the conditions of Procedure 3, to give the desired tertiary ester, This product is then treated with alkane halide to produce the desired bis-quaternary ester.

m- and p-phenylenediacetic acids are commercially available (illdrich). The m- and p-phenylenediacrylic acids are prepared by Knoevenagel-Doebner condensation of isophthalic acid and terephthalaldehydes with malonic acid. Terephthalaldehyde ( 150mM ) and malonic acid ( 180mL ) Yienaene are mixed with pyridine ( 45mL ) and piperidine ( 1.5mL ). The mixture is then warmed up on the water bath (85 bio 95G) for 3 hours is then cooled to room temperature and distilled in vacuo to remove the pyridine »The solid residue is

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washed in warm iaopropanol (70 C) to remove the remaining pyridine. The product obtained, p-phenylenediacrylic acid, was filtered and dried (mp> 275 ° C),

in-phenylenediacrylic acid was prepared from isophthalaldehyde in the same manner (3 pp> 275 ° C).

m- and p-phenylenedipropionic acids may be removed by conventional methods by catalytic reduction, e.g. by reaction of the corresponding diacrylic acid with hydrogen at 2.8 to 3.15 kg / cm pressure in the presence of 5 / Sigem palladium / activated carbon in dilute methanol or dimethylformamide at room temperature to 55 C. Further methods are described in Wagner & Zook, Synthetic Organic Chemistry, 1973, page 431, method 26.

The compounds of the invention may under some circumstances contain water of hydration in various amounts, e.g. 1 to 5 molecules or more of water per quaternary grouping. These compounds are also the subject of the application.

The invention is further illustrated by the following examples. The temperatures are given in ⁰ C.

A process for the preparation of bis-3 - / ^"l; i'-methyl-l- (3,4,5-trimethoxybenzyl) -S, 7 ~ dimethoxy-2,3 '4-tetrahydroisochinolin.7-p ^ opyl- m-'phenylene-3,3 ^l -dipropionate dichloride (HHlO). '

1. Preparation of silver m-phenylene dipropionate

m-phenylenedipropionic acid 4.4 mg - 40 meq vol. 60 ml

LIi-heel eye 40 ml

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The mixture is brought to boiling temperature and if necessary, the pH Y / ert is adjusted to 7.0 with the appropriate acid. To the yellow heat solution is added 6.8 mg = 40 mils of silver nitrate. It immediately forms a heavy precipitate. The mixture is cooled and filtered and the filter cake is washed with water, filtered again and dried. The yield is quantitative. The product is an amorphous light colored powder. This product is powdered for use in the next stage.

2. Preparation of 5'-methoxylaudanosine (Formula VI)

3,4-Dimeihoxyphenylethylamin and 3,4,5-Trimethosyphenylessigsäure be heated in a flask to I65 to 190 ⁰ G until water bubbles settle. The obtained H- (3 »4,5-T- ^ iEiethoxyphenylacetyl) homoveratrylainin is recrystallized from methanol. The yield is 80 % ₉ mp = 94 ⁰ C.

3.9 iog (10 mK) RL (3,4,5 ^"f 2rirüehtoxyphenylacetyl) -homover ~ toluene .atrylamin held together with 5 ^ l Pocio for 2 hours at reflux in 15 ml. The settling semi-solid product is carefully separated (POCl, in excess) and the free base prepared by adding excess sodium hydroxide solution The free base is extracted with benzene to give the obtained 6,7 ~ Dimethc: ry-l- (3 ', 4 *, 5 ¹ -trimethoxybensyl ) -

-3 '4 ~ dinydroisochinolin is held in acetone or benzene with an excess of methyl iodide at reflux * The quaternary salt, 6 _s 7-Dimethoxy-l- (3', 4 ', 5 ^f -trimethoxybenzyl) -2-raethyl-3 _> 4-dihydroiaoquinoline iodide precipitates as a solid. (Pp. ~ - 224 ° G).

1 mg (10 iiM) of 6,7-dimethoxy-l- (3 ^1, 4 ', 5 ^f -triinethoxybenzyl) -2 ~ metnyl-3,4-dihydrochinolinoodid vdrd in 80 ml of water

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and 16 ml of concentrated hydrochloric acid are dissolved. Zinc dust (1.1 mg) is added in small portions to the boiling, stirred solution. The yellow color disappears. The reaction time is about 15 to 20 minutes. The mixture is filtered warm from unreacted zinc and alkalized with concentrated sodium hydroxide. It is impractical to filter off the partially precipitated zinc hydroxide. In order to avoid the formation of an emulsion, the entire mixture is shaken gently with chloroform. The residue of the chloroform solution is again dissolved in ether and the ethereal insoluble part is filtered off. The ether residue does not crystallize on standing. This amine is a gummy substance which hardens on standing. The tube amine is used in the next stage of the process.

3. Preparation of! I- (3-chloropropyl) -5'-methoxylaudanosine bromide

1.4.mg = 4 mM 5'-methoxylaudanosine is dissolved in 8 ml of dimethylformamide with gentle heating. 1.2 mg (about 100 % excess) of 1-bromo-3-chloropropane are added and the mixture is allowed to stand at room temperature for 5 days. Sometimes a part of the unreacted 5 ^! -Methox: / laudanosine in the form of crystals of ₅ which, however, mostly dissolve again.

The reddish orange solution is treated with a large amount of ether and the precipitated gummy quaternary salt is decanted off and slurried in fresh ether, when left to stand in ether for 1 day, a low-melting solid is obtained. The yield is 1.6 mg, about SO % of theory.

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4. Preparation of m-Phenylene-Dipropionic Acid of Il-P.Propyl-S'-methoxylaudanosine (HHlO) (Formula VII) (Horensein-Pahlicke-Ssterbildung)

iT- (3-Cbloropropyl) -5 ^L -ethethozylaudanoaidbromide 2,1'mg «4 Silver m-phenylene dipropionate 0,85 mg = 4

V / asser ^; about 150 ml

The mixture is heated in an open beaker for about 10 to 15 minutes, stirring by hand from time to time. At the boiling temperature, the silver salt is readily soluble and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered and the aqueous solution is concentrated to dryness on the water bath. The residue then vird continuously heated for 2 hours on a water bath (90 ⁰ C). Thereafter, the conversion into the Bater is complete (Reaction Scheme V) ·

The amorphous residue is heated with isopropanol (about 40 ml) and filtered to remove traces of mechanical impurities. At room temperature, a rubbery solid precipitates from the filtrate. "Precipitation is excessively exceeded at about -3 ° C when left to stand. The supernatant phase is decanted off. The rubbery material, which is now semi-solid, is now filtered off. After careful drying at 75 ° C., the rubbery mass solidifies. At this stage the mass still contains certain amounts of water. The yield is 1.0 mg (about 40%). Yields vary from batch to batch. The melting point is 80 h ± B SO ⁰ G (decomposition). ·

Analysis. (.%) Calculated (%) found {%)

O 52.99 53.22

H 6,46 5,94

N 1.99 2.00

J 18.06 19.38

The calculations were made assuming 2 molecules of water per quaternary group.

Example _n 2

Preparation of bis-3- / -1-methyl-1- (3,4,5-trimethoxybenzyl) -6,7-dimethoxy-l, 2,3,4-tetrahydroisoquinoline-7-propyl-p-phenylene-3,3 ' dipropionate dichloride (HH177)

1. Preparation of silver p-phenylene dipropionate

p-phenylenedipropionic acid 4 ^ 4 mg = 40 meq (Aldrich)

Y / asser 60 ml

1-N-potassium hydroxide solution. 40 ml

The mixture is heated to boiling and, if necessary, adjusted to the pH of 7.0 with the same acid. 6,8 mg (40 raid) silver nitrate are added to the yellow Tjarmen solution. It immediately falls a heavy plague st of f. out. The mixture is cooled and filtered and the filter cake, washed with water, filtered again and dried. The yield is quantitative. The product is an amorphous, slightly yellow colored powder. "This product is powdered for use in the next process step.

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2. Preparation of 5 ^t -methoxylaudanosine of the formula YIII:

3,4-Dimethoxyphenylethylainin ^{un <i} 3,4,5-Triiaethoxyphenylessigsaure yjerden on 1œ5 to 19O ⁰ G heated in a flask to form water bubbles. The B- (3,4,5-2rimethoxyphenylacetyD-honioveratrylamin is unikristallisiert from methanol »The yield is 80 % (pp = 94 ⁰ C).

3.9 cig (10 ffili) N-3,4,5-1-trimethos: yphenylacetyl) -hoiaoveratrylamia is dissolved in 15 ml of toluene together with 5 ml of POCl-. refluxed for 2 hours. The settling semisolid material is carefully separated (PQClO in excess) and the free base is liberated by addition of excess liatanlau.ge and extracted with benzene. The sjy-dimethoxy-lO ', 4 ^f * 5'-trimethoxybenzyl) -3 | 4-dih: ydroisochinolin viird held in acetone or benzene with an excess of methyl iodide at reflux. It precipitates the quaternary salt, the 6,7-Din-iethoxy-l- (3 ^f , 4 * , 5 ¹ -trimethoxybensyl) -2-methyl-3> 4-dihydroisochinolinjodid from (mp = 224 ⁰ C).

1 mg (10 mM) of 6,7-diciethoxy-1- (3 ^L , 4 ^F , 5 ^F -trimethoxy-benzyl) -2-methyl-3,4-dihydroisoquinoline iodide is dissolved in 80 ml of water and 60 ml of concentrated hydrochloric acid solved. 1.1 mg of zinc dust is added in small portions to the boiling, stirred solution. The yellow color disappears. "The reaction time is about 15 to 20 minutes. The mixture is filtered off from unreacted zinc and made alkaline with concentrated xiaol · Eo is impractical to filter off the partially precipitated zinc hydroxide. To prevent emulsion, shake the entire mixture gently with chloroform. The residue of the chloroform solution is dissolved in ether, and filtered with ether insoluble in ether. The ether residue does not crystallize on standing. * This amine consists of a gmr-raiartigen material »the

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Standing hardens. The raw Ainin will be used in the next Yerfahrenaatufe.

3. Preparation of 1T- (3-chloropropyl) -5'-methoxylaudanosine bromide of the formula IX

1.4 mg (4 mM) 5 ^f -Methoxylaudanosin is dissolved in 8 ml of dimethylformamide under gentle warming. Bs are added 1.2 mg (about 100 % excess) of 1-bromo-3-chloro-propane and the mixture is allowed to stand at room temperature for 5 days. (Sometimes part of the unreacted laudanosine precipitates in crystal form, but it partially dissolves again).

The reddish orange solution is treated with a large amount of ether and the precipitated gummy quaternary salt is decanted off and slurried with fresh ether. After being left in ether for one day, a low-melting solid is obtained. The yield is 1.6 mg, about 80 % of theory.

4. Preparation of p-phenylene dipropiondiester of the IT-propyl-5 ^{-metho2: ylaudanosins (HH177) of the Pormel X (Horenstein-Pahlicke-Ssterbildung)

H ~ (3-chloropropyl) -5 ^t -methoxylaudanosine bromide 2.1 mg = 4 silver p-phenylenedipropionate 0.85 mg = 4

Water about 150 ml

The mixture is heated in an open beaker for about 10 to 15 minutes while being manually stirred from time to time. At the boiling point, the silver salt dissolves readily and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered and the aqueous solution concentrated to dryness on a water bath. The residue is continuously on the

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Water bath (SO ⁰ G) for about 2 hours, after which the conversion to the ester is complete (Reaction Scheme VI)

The amorphous residue is warmed with isopropanol (about 40 ml) and filtered hot from undissolved mechanical impurities, a gummy mass precipitates from the mushroom at room temperature and the precipitate is quenched at about -3 ° C. when left to stand over water floating layer is decanted and slurried material in 3thylacetat twice. the rubbery material is semisolid and can be filtered off, "earth" Hach careful drying at '75 ⁰ G solidifies the gummy mass. in. this stage still contains the mass of a certain amount of V The yield is 1.0 mg (about 40 %) The yields vary from batch to batch The melting point is Pp = SO to 90 ° (decomposition)

Example 3

Preparation of Bis-3- / ~ N "methyl-l- (3,4-dimethoxy: x: ybenzyl) -6,7-diiaethox7-l, _2} 3J4-tetrabydrcisochinolin7-piOpyl ~ p-phenylene-3 '3 ^f -dipropionatdichlorid (HH121)

1. Preparation of silver p-phenylenedipropionate

p-phenylenedipropionic acid 4 »4 mg = 40 meq (purchased from Aldrich)

Water 60 ml

1-H-caustic solution 40 ml

The mixture is boiled and, if necessary, brought to a pH of 7.0 with the same acid.

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Add 6.8 mg (40 mM) of silver nitrate Börden to the warm yellow solution. It immediately precipitates a heavy solid. The mixture is cooled and filtered and the filter cake washed with water, filtered again and dried. The yield is quantitative. The product consists of an amorphous lightly colored powder. It is used in powder form in the next stage of the process.

2. Preparation of N- (3-Chloropropyl) -Laudanosine Bromide (Formula SI):

I »4 mg (4 mM) laudanosine is dissolved in 3 ml dimethylformamide with gentle warming. 1.2 mg (approx. 100 % excess) of 1- (bromo-3-chloroporpan are added and the mixture is allowed to stand at room temperature for 5 days (sometimes some of the unreacted Laudanosin crystals precipitate, some of which precipitate) to solve).

The reddish-orange solution is treated with a large amount of ether and the precipitated gummy aiatic salt is decanted off and slurried in fresh ether. After standing in ether for 1 day, a low-melting solid is obtained. The yield is 1.6 mg, about 80 % of theory. '

3. Preparation of N-propyl-laudanosine (KH121) p-Phenylene-Dipropionic Diea (Formula 21I)

N- (3-chloropropyl) -laudanosine bromide 2.1 mg = 4 mM silver p-phenylene dipropionai; 0.85 mg = 4 ml of water. about 150 ml

The mixture is stirred in an open beaker for about 10 to 15 minutes and stirred from time to time by hand. At boiling temperature, the silver salt is light

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soluble and reacts with the quaternary bromide. The mixture is cooled to room temperature, filtered, and the aqueous solution is evaporated to dryness on a water bath. The residue is then heated continuously for about 2 hours, after which the conversion to the ester is complete (Reaction Scheme VII).

The amorphous residue is warmed in isopropanol (about 40 ml) and traces of mechanical impurities are separated. From the filtrate precipitates at room temperature, a rubbery pesticide. The precipitation is terminated at about -3 ° C on standing overnight. The supernatant phase is decanted off and the material is slurried in ethyl acetate zv / eirnal on. The resulting rubbery material is semi-solid and can be filtered, and after careful drying at 75 ° C., the rubbery mass solidifies. In this statium a certain amount of water is retained in the material. The yield is 1.0 mg (about 40 %) . Yields vary from batch to batch. The melting point is Pp. = 80 to 90 ⁰ O (decomposition)

analysis calculated % found % C 53.57 53.62 H 6.44 6.06 ii 2.08 2.10 I 18.87 18.87

The calculation was based on the assumption of 2 molecules Y / a per per quaternary group.

Preparation of Bia-3 - / "-1-liethyl-1- (3i-4-dimethoxybenzyl) ~ 6,7-diiriethoyl-1 _J 2.3} 4-tetrahydroisoquinoline / -" Oropyl-ia-phenyleri ~ 3.3 ^! -Dipropionate dichloride (KH35)

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1. Preparation of silver m-phenylenediproinate

ni-phenylene-dipropionic acid 4.4 mg = 40 meq (relative to Aldrich)

Water 60 ml

1-N-potassium hydroxide solution 40 ml

The mixture is heated to boiling temperature and, if necessary, adjusted to a pH of 7.0 with the same acid. 6.8 mg (40 ml) of silver nitrate are added to the warm yellow solution. It immediately precipitates a heavy solid. The mixture is cooled and filtered and the filter cake washed with water, filtered again and dried. The yield is quantitative. The product is present as an amorphous light colored powder. It is used in powdered form in the next stage of the process.

2. Preparation of 3-chloropropyl-laudanosine bromide (Formula XIII):

1.4 mg (4 mM) of laudanosine is dissolved in 8 ml of dimethylformamide by gentle lukewarming. S3, 1.2 mg (about 100 % excess) of l ~ bromo ~ 3-c-chloropropane are added and the mixture is allowed to stand at room temperature for 5 days. Sometimes unreacted laudanosinkristalle form of _s which dissolve partially again.

The reddish orange solution is treated by a large amount of ether. The precipitated gum-like quaternary salt is decanted off and slurried in fresh ether. After standing in ether for one day, a fine solid is obtained. The yield is 1.6 mg, about 80 % of theory.

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3. Preparation of m-Phenylene-Dipropionic Acid of ll-Propyl-laudanosine (HH35) (Formula XIV): (Horenatein Pahlicke Ester Formation)

lT- (3-chloropropyl) -laudanosine bromide. 2.1 mg = 4 mM silver ia-phenylene-dipropionate 0.85 mg = 4 mM v / laser approximately 150 ml

The mixture is heated in an open beaker for about 10 to 15 minutes, stirring from time to time by hand. The further work-up is carried out as described in Example 3. When the residue is heated for about 2 hours on the water bath (90 ⁰ G), the ester formation according to the following reaction scheme. VIII finished.

The amorphous residue is warmed with isopropanol (about 40 ml) and filtered to remove residual mechanical impurities. The gum-like solid precipitated from the filtrate is worked up as described in Example 1. The yield is 1.0 mg (about 40%). The Auabeuten vary from approach to approach. The melting point is Pp. = 80 to 90 ⁰ G (decomposition).

Example 5

Preparation of bis-3- / N-methyl-1- (3,4-dimethoxybenzyl) ~ 5 _J 6 _J 7 -trimethoxy-1,2,3,4-tetrahydroisoquinoline-7-propyl-p-phenylene-3,3 ^1- dipropionate dichloride (LL37)

1. Preparation of silver p-phenylene dipropionate

p-phenylenedipropionic acid · 4 → 4 mg = 40 ineq

T / asser '60 ml

Ι-Ιϊ-ICalilauge 40 ml

24. -

207041

The mixture is heated to the boiling point and if necessary adjusted to the pH of 7.0 with the same acid; set. Ea 6.8 mg (40 πιΜ) of silver nitrate are added to the warm yellow solution. It immediately precipitates a heavy pesticide. The mixture is cooled and filtered and the filter cake is washed with water, filtered again and dried. The yield is quantitative. The product stands out as an amorphous lightly colored pulp. Sa is used in powder form in the next stage of the process.

2. Preparation of 5-metho-3-fluoroaudanosine / -H-methyl-l, - (3,4-dimethoxybenzyl) -5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline 7 (Formula XV);

2,3,4-Trimehtoxyphenylethylamin and 3,4-Dimethoxyphenylessigsäure are heated in a beaker to I65 to 190 ⁰ G erv / until water bubbles form. The IT- (3,4-dimethoxyphenylacetyl) -2,3,4-trimethoxyphenylenethylamine is recrystallized on methanol. The yield is 80 %, Pp = 101 ⁰ C.

3.9 mg (10 mM) of lT-3,4-dimethoxyphenylacetyl) -2,3,4-trimethoxyphenylethylamine are refluxed with 15 ml of toluene and 5 ml of POGIo for 2 hours. The settling product is carefully separated off (POCl- in excess) and the free base is released by adding excess sodium hydroxide solution and extracted with benzene. The 5 -6,7-trimethoxy-1- (3 ^L -4'-direthoxybenzyl) -3,4-dihydroisoquinoline is refluxed in acetone or benzene with excess ethyl iodide. The quaternary salt, 5 _S 6 _s 7-trimethoxy-l- (3 '> 4 ¹ -dimethoxybenzyl) -2-metbyl-3,4-dihydroisoquinoline iodide precipitates (Rp. = 165 ⁰ C).

-25 - 2070 41

I rag (10mM) 5,6,7-tria-ethoxy-1- (3 ', 4 ^l -di-ethyletho: γ, γ-benzyl) -2-methyl-3,4-dihydroisoquinoline; iodide is dissolved in 80 ml of water and 1β Dissolved ml of concentrated hydrochloric acid. 1.1 mg of zinc dust is added in small portions to the boiling, stirred solution. The separation of the unmolded zinc and the workup of the reaction product is carried out as described in Example 1. The crude amine is used in the next stage of the process.

3. Preparation of H- (3-chloropropyl) -5-methoxylaudanosine bromide

1.4 eig (4 ml.) Of 5-methoxylaudanosine are dissolved in 8 ml of dimethylformamide with gentle heating. Bs 1.2 mg (about 100 % excess) of l-bromo-3-chloro-prcpan are added and the mixture is allowed to stand at room temperature for 5 days. (Sometimes unreacted 5-ethoxylaudanosine crystals precipitate, some of which dissolve again).

The reddish orange solution is treated with a large amount of ether and the precipitated gummy quaternary salt is decanted off and slurried with fresh ether. After standing in ether for one day, a low-melting solid is obtained. The yield is 1.6 mg, about 80 % of theory.

4. Preparation of p-phenylenedipropionic acid diester of 1-propyl-5-methoxylaudanosine (1L37) Pormel XVI: (Listening to Tein-Pahlicke-rst Formation)

IT ~ (3-chloropropyl) -5-methphenylaudanosine bromide 2.1 mg = 4 mil silver p-phenylene dipropionate 0.85 mg = 4 diLi

Water . about 150 ml

- 26 -

- 26 - 207041

The mixture is heated in an open beaker for about 10 to 15 minutes, stirring from time to time by hand. The reaction mixture is worked up as described in Example 1. The Ssterbildung takes place by heating about 2 hours on the water bath, after which the conversion is completed in the ester (Reaction Scheme IX):

The amorphous residue is heated with isopropanol (about 40 ml) and filtered v / poor to separate the remains of mechanical impurities. Bsi room temperature precipitates from the mushroom a rubbery pesticide. The precipitation is completed at about -3 ⁰ O "on standing ITacht. The work-up of the reaction mixture is effected as described in Example 1. The yield is 1.0 mg (ca. 40%), the yields vary from batch to batch. The melting point is Pp. = 80 bio 90 ⁰ O (decomposition).

J2

Preparation of bis-3 - / "* 2i ^; 1-ethyl-1- (3> 4,5-trirethoxybenzyl) -5,6,7-trimethoxy-1,2,3,4-tetrahydroquinolino-7-propyl p-phenylene-3,3'-dipropionate dichloride (KK194)

1. Preparation of silver p-phenylene dipropionate

p-phenylenedipropionic acid 4 ₅ 4 mg = 40 mSq water 60 ml

l-l-T potassium hydroxide solution 40 ml

The mixture v; ith heated to the boiling point and, if necessary, the pH'Tert'auf ground 6.8 mg (40 rail) silver nitrate au varmen the solution is adjusted to 7.0 with the same acid, 'Za v / added. 2s f! I llt immediately a schvie-rer solid. The mixture is cooled

-27- 207041

and filtered and the filter cake is washed with water, filtered again and dried. The yield is quantitative. The product is an amorphous light colored powder. It is used in powder form in the next stage of the process.

2. Preparation of 5,5'-Dimetho: xylaudanosine (Formula XVII)

2,3 »4-Dimethoxyphenylethylamine and 3> 4,5-trimethoxyphenylacetic acid are heated in a flask at 165 to 190 C until they form bubbles. The ϊί- (3,4y5-trimethoxyphenylacetyl) -2,3,4-trimethoxyphenylethylamine is recrystallized from methanol. The yield is 80 % (Pp = 35 ⁰ C).

3.9 mg (10 mM) of K- (3,4,5-trimethoxyphenylacetyl) -2,3,4-trimethoxyphenylethylamine are refluxed with 15 ml of toluene and 5 ml of POGI for 2 hours. The settling semisolid product is carefully separated (POCIo in excess) and the free base is liberated by adding excess sodium hydroxide solution and extracted with benzene. The 5 »6,7-trimethoxy-l- (3 ', 4 ^f 5'-trimetho: q / benzyl) is held in acetone or benzene with an excess of Hethyljodid reflux -3> 4-dihydroisoquinoline. The quaternary salt, 5> 6,7-trimethoxy- »1- (3 ', 4 ^f 5 ^f -trimethoxybenzyl) -2-methyl-3,4-ditiydroiscchinolinjodid precipitates (mp = 181 ⁰ C).

10 mg of 5,6,7-trimethoxy-10: ¹ , 4 *, S'-trimbenzyl) -2-methyl-3,4-dihydroisoquinoline iodide are dissolved in 80 ml of water and 16 ml of concentrated hydrochloric acid , Bs, 1.1 mg of zinc dust are added in small portions to the boiling, stirred solution. The workup of the KeaktionsgeiTiisches is carried out as described in Example 1. The amine is a rubbery material that

207041

hardens on standing. The crude Amiη is used in the next stage of the process.

3. Preparation of li- (3-chloropropyl) -5 _} 5- ^t- dimethoxy laudanosine bromide

1.4 mg (4 mM) of 5, S'-dimethoxylaudanosine are dissolved in 8 ml of DimethyIformaraid with gentle heating. Bs are added .1.2 mg (about 100 % excess of 1-bromo-3-chloropropane and the mixture allowed to stand at room temperature for 5 days (sometimes unreacted 5 'S' -dimethoxylaudanosine crystals precipitate, but some of them precipitate again to solve).

The reddish orange solution is treated with a large amount of ether. The precipitated gummy quaternary salt is decanted off and slurried with fresh ether. After standing in ether for 1 day, easily melting pesticides are produced * The yield is 1.6 mg, about 80 % of theory.

4 "Preparation of the p-phenylenedipropionic diester of IT-propyl-S'-methoxylaudanosine (KIQ94) Formula XVTII; (Hearing stone Pahlicke-Ssterbildung)

H- (3_Chlorpropyl) -5 _i 5 ^t -diraethoxylaudano3idbromid

2.1 mg = 4 mM

Silver p-Phenylenedipropionaf 0.85 mg = 4 mM Vapor About 150 ml

The mixture is named for 10 to 15 minutes in an open beaker for about 10 minutes, but is stirred by hand from then on. The workup of the reaction solution is carried out as described in Example 1, Here is

- ²⁹ - 20 7 0 41

the formation of Sster after heating the residue for about 2 hours on the water bath (9O ⁰ C) ended (Scheme X).

Example 7

The pharmaceutical formulation (HHI10) is dissolved in water to prepare an injection solution at a concentration of 10 mg / ml. The solution is then poured into a 20 ml vial, which is then sealed.

Example 8

100 mg of the sterile powder HHI10 are aseptically packaged in a 20 ml ampoule and closed with a rubber stopper. Add 10 ml of sterile v / asser to the ampoule for the preparation of the injection solution for 3 seconds to prepare a 1 $ solution (10 mg / ml).

Example 9

The compounds HHI10, HH177, HH121 and HH35 were separately dissolved in a 0.9% saline solution at a concentration of 2 mg / ml. Cynomolgus monkeys were anesthetized with halothane, nitric oxide and oxygen. The maintenance concentration of halothane was 1.0 %. Arterial and venous catheters were connected to femoral vessels for administration of the agent, and arterial pressure was registered. The controlled ventilation was carried out by means of an endotracheal tube. The twitch and tetanic consensus of the tibialis arterial muscle were measured indirectly via the sciatics ITerv. Simultaneously, the arterial pressure electrocardiogram (display 1), the heart rate and the muscle function are recorded.

- 30 -

- 30 - 207041

The bis-3-methyl-1- (3, 4,5-trimethosyl-3-benzyl) -6,7-di-

Nylen-3 ', - dipropionate dimesylate was prepared by means of an ion exchange reaction by the reaction of HHIlO with silver racylate. For this purpose, the dichloride of HHIlO and silver silylate dissolved in acetonitrile. The reaction mixture is stirred at room temperature for 30 minutes, whereby the silver chloride precipitates. The reaction mixture is filtered through filter paper to separate the silver chloride. The mesylate salt remains in solution. Then the acetonitrile is removed in vacuo. «

The reaction product is then dissolved in ethanol and filtered to separate residual silver mesylate. The ethanol is removed under vacuum.

Example _m 11

Preparation of bis-3-Z "* ^ - ^ ^e thyl-l- (3,4,5-trimethoxybenzyl) -o, 7-dimethoxy-l, 2,3,4-tetrahydrochinolin7propyl -m-phenylene-3,3 'dipropionate-di3odid tetra, hydrate.

S, 3.2 g of ii- (3-hydroxyphenyl) -5'-methoxylaudanosine iodide were dissolved in dry acetonitrile and 4 g of molecular sieve were added. After stirring at room temperature for 24 hours, 0.78 g of m-phenylenediproionyldichloride were added (prepared by the reaction of thionyl chloride with m-phenylenedipropionic acid (3 Å, S. Kipping, J. Chem. Soc., 53, 21 (1888)) Another 4 g of molecular sieves (4 *) were added and the mixture was stirred at room temperature for 24 to 48 hours, filtered and concentrated to dryness. A dark brown oil was obtained in heated ethanol

20704t

dissolved and separated on cooling as a light brown oil. The oil solidifies after drying to a light brown amorphous pesticide. The yield was 60 %. *

This method would also be used to make correspondingly differently substituted compounds, e.g. by replacing the m-isomer with p-phenylenedipropionyl dichloride and the lT- (3-hydroxypropyl laudanosiujodida for dao 5'-methoxylaudanosine iodide.

Example 12

Preparation of n- (3-hydroxypropyl) -5'-metho2-ylaudano-sin-iodide

1 g of fj'-ilethoxylaudanosine (J * Russel Flack, II Hiller and PR Stermitz-Tetrahedron, 30, 931 (1974) in 200 ml of dry acetonitrile with 1.2 g of 1-iodo-3-propanoi (SY / awsonek, held J.Org. Ghem. 25, 2068 (I960) for 24 hours at reflux. the mixture was filtered, the solvent removed in vacuo and ether added to precipitate a yellow oily solid. iTach decanting off the ether, drying at 60 ⁰ C obtained a yellow powder in quantitative yield.

The same procedure was used to prepare ii- (3-hydroxy-propyl) -laudanosine iodide.

1,2,3,4-tetrahydroisoquinoline

These compounds were prepared by Gyclo bydratatio :: from β-phenylehtylamine to 3,4-dihydroxy-

-32 - 207041

quinolines quaternized with CHo groups. These compounds were then made by zinc. reduced in hot hydrochloric acid to the corresponding 1,2,3,4-tetrahydroisoquinolines.

Ss was e.g. the laudanosine / ~ 'l - (3,4-dimethoxybenzyl) -2-methyl-l, 2,3,4-tetrah.hydroroquinoline7 is prepared in the following manner:

100 mM 3,4-dimethoxyphenylethylamine were mixed with 100 mM 3,4-dimethoxyphenyl acetic acid and heated to a temperature of 190 to 200 G until bubbling ceased. (20 minutes). The product obtained (Homoveratroylhomoveratrylamin) was cooled and recrystallized from methanol (yield = 85%, mp. = 122 G ^0), 100 mM Homoveratroylhomoveratrylarnin were mixed with 250 ml of toluene and 50 ml POGl- and heated to boiling for 2 hours and then cooled to room temperature. The crystalline precipitate was filtered off, rinsed with petroleum ether, dissolved in water and alkalized with excess ammonia and then extracted with benzene. The solution was dried with H 2 SO 4, filtered, and then excess methyl iodide was added. The solution was refluxed for 15 minutes, then allowed to stand at room temperature for 12 hours. Bs precipitated the quaternary salt, dihydropapaverine-methajodid. 100 mM of this quaternary salt was then reduced at boiling temperature with 12 mg zinc dust in βΟΟ ml and 120 ml concentrated hydrochloric acid for 1 hour and filtered warm to separate the unreacted zinc. Ammonia was added in excess for 3 seconds and the product was then extracted with chloroform. The chloroform is removed in vacuo and the Laudanoain extracted with petroleum ether, from which it crystallized on cooling (ΐ? Ρο = 114 to 115 ° C),

207041

In an analogous process to the laudanosine synthesis described above, the corresponding benzyliaquinoline compounds can be prepared starting from the analogous starting materials, e.g.

2,3,4-trimethoxyphenylethylairiin and 3> 4-dimethoxyphenyl acetic acid to 5-hetho: cylaudanosine; 3,4,5-trimethoxyphenylethylamine (mescaline) and 3,4-dimethoxy-phenylacetic acid to 8-methoxylaudanosine; 2,3,4-Trimethoxyphenylethylamin and 3> 4,5-Trimethoxyphenylessigsäure for 5> 5 ^! -öioiethoxylaudancsin; 3,4,5-trimethoxyphenylethylamine and 3 ', 4,5-trirethoxyphenylacetic acid to SjS'

The above compounds are reacted by the methods 1 to 4 to prepare the compounds of the present invention.

As shown in Table 1 below, the respective compound according to the invention was administered to 4 to 6 animals. Four other animals received succinylcholine chloride or d-tubocurarine chloride as a control. The table shows the doses necessary to produce a blocking of the Tvjitch reaction of the tibialis anterior nodule under the anesthesia conditions noted above in each animal series to which the agents were administered. The table also includes the duration of action of each compound in each animal series. The duration of exposure is defined as the time from the injection of the drug to the full recovery of the Tv / itch response of the tibial anterior muscle.

The duration of action of these compounds in monkeys is more informative about the possible duration of their use in monkeys.

- 34 - 20 7 0 41

compounds in humans than the studies on another species, e.g. on the cat and the dog, and for the following reason; ·.

It adopted Tniird that the compounds by an enzyme (plasma Gholinesterase), which is found in humans, the monkeys in the cat and dog "degraded (hydrolysed) are. Ba i7ird assumed that the rate of degradation of the compounds by this Bnzym It is known that the efficacy of monkey plasma cholinesterase is very similar to that of humans (CP Hobbiger and Peck, British Journal of Pharmacology 37, 258-271, 19-9).

Table I

Neuromuscular blocking potency of selected compounds in cynomolgus monkey

connection Number of tested animals 0.5 / kg Katio Duration of action \ (in minutes from injection to full recovery) - 8th HH 110 6 0.5 - 1.0 VJL - 12 HH 177 4 2.0 -1.0 8th - 6 HH 121 6 2.0 - 4.0 4 - 5 HH 35 4 1.0 - 4.0 3 - 6 Suocynylcholine 4 0.2 - 2.0 4 - 50 d-T about o curarin - 0,4 30

Necessary dose for the production of a 95% blocking of the Tvjitch reaction of the tibialis anterior muscle, indirectly stimulates the Sciatik iTerv at O ₅ 15 HZ via

- 35

-ho-

• 2x ~ co

C 2X

2 0 7 041 -Ή-

CH ₂ R ₄

R ₇ R ₆ .

(W)

COCI

2 HO (CH ₂ ) _η J

COCI

(S)

2HCl

COO (CH 2) _n J

CHO I OCH ₁ , ^0CH 3 (Vl)

H H-W

(VII)

CH ₀ O I OCH ₃ 3 OCH ^

CHP \ OCH ₃

HP ό

OCH ₃ , (VIII)

CH,

CH ₂ CH ₂ CH ₂ a

OCH

(IX)

ChF

<w

C CKCH ₇

CH,

HXO T OCH ^ OCH ₃

OCH,

CHCH

(XII)

OCH ₃

OCH,

(Jam)

'- (CHj-O-C-CH-CH

OCH

OCH,

C0 (CH ₂₎ -N *

OCH ₃

OCH

OCH ₃

"äs

- H5 ~

£ υ / ν **

(ZLX)

(ZX)

(C Η,) COO (CHJ

'm

(ΧΣΚ)

(CH ₂ ) QOC (CH ₂ )

'CH ₂ )

(YXYJJf)

CH ₂ R ₄

* 5

A? 7

* β

0OC (CHJ ₁

£ 77)

z

νηττ \

Ci (CHJn

CH ₂ R ₄

Rf

/ T ₀

Reaction scheme J

R ₁

2 CL (CH _£ ) _n

COOAg

CZ (CH ₂ )

CH ₂ ^R 4

R ₅

R ₅

COO (CH ₂ ) _n JZ

-f

COO (CH _z ) _n J

ICZIIIKA -ti.

R ₇ R ₆ R ₁

CH ₂ R ₄

Re ok ti'onssc h β m a M χ X

Reaction scheme e.g. laudanosine

OCH

Br '

OCH ₃ HO- (CH _z ) ₃ / V.

OCH ₃ HIGH CHBr 2 "~ 2 ~~~

OCH ₃

CH ₂

OCH

OCH

HO-CH ₂ CHfCH ₂

CH ₂

OCH ₃

OCH,

OCH ₃

tertiary aminoalcohol

*. * J V

COOAg

(CHA

Z ^J 2

COOAg

COO

(CH _z ) z COO '

OCH ₃

2Ag +

H ₃ CO

OCH ₃

HHW

ReaJhnschema Y.

H ₃ C-CL (CH /

4 ~ 3

OCH.

OCH

CH ₃ O

OCH.

OCH =.

;,) / V ^J 'i? δ

COOAg CH ₂ CHz

CH ₂ CHz COOAg

2Ag Bt ^ ChI ₂ CH ₂ CH ₂ CL CH ₃

OCH ₃

COO CH ₂ CHZ

CL (CH ₃ ) ₃ W ₃ C

C CH ₂ COO '

OCH OCH _: OCH

OCH

¹ p

Reaction a

VI / KA-och

OCH ₃

COOAg (CH ₂ ) ₂

(CH ₂ ) ₂ COOAg

Ag Br

Ci (CH ₂ ) -

H ₃ CO

OCH ₃

CL (CH ₂ I ₃ -

H ₂ C

CH,

OCH ₃ OCH *

OCH ₃

COO '

OCH ₃

CH,

OCH ₃

OCH ₃

HH

Reacthnschsma HL

COOAg CCH _Z ) _Z

+

CCH ₂ ) _Z COOAg

CL (CHJ ₃ -N / 'H ₃ C

OCH

OCH

br

CH2

OCH.

OCH,

HH

OCH,

CH-

OCHj

OCH

OCH,

Reaction scheme YH

-A -f

fCH _z COO "Ag

- _Λ t

CH ₁ CH ₂ COO Ag

OCH

CH ₂ CH ₂ CL

• Br

CHD ³ OCH,

QChL

COO

CH ₂ , CH ₂

Cl CHCHCH.

CH ₂ CHz COO '

OCH ₁ OCH.

OCh '

OCH *

OCH

OCH,

OCH, 2Aq Br ^ _ LL

Reakvonsschema JK "

COQAg *

KK ? S

COO CH _Z CHo

CH,

CH ₃ O

J {- (CH ₂ ) ₃ ~ CL

Br '

OCH,

OCH,

OCH,

CH ₉ O I OChL ₁ ° OCH ₃

OCH,

OCH

CL (CHA

Reaktionssehema Ύ "

Ochi

Claims (29)

A process for the preparation of a compound of general formula I, v / orin B and C are each a radical of formula IV, wherein m2, 3 or 4, C is in p-pitch or Ei position to B, η 2 , 3, or 4, R-, R ^, ro, R ^, R _r, Rg and R ^ are the same or different and represent a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, Y represents an alky! group with 1 to 4 C atoms and X is a pharmaceutically acceptable anion, provided that at least one of R-, R4 is a lower alkoxy group and at least one of Rc to Rj is a lower alkoxy group, characterized in that a) a compound of general formula XIX with a compound of general formula XX, vvorin n, m, Y and each of the radicals R- ^ to Rr-, have the meanings given in point 1 and Q and Q ¹ for functional atoms or groups which react, react or react with each other to form an ester bridge b) a compound of the general formula XIvI in which Y and each of the radicals R- to Ry are those indicated in point 1. Meaning, by implementation with a compound of the general forms! XXII, wherein J is a Halogenatora and η and m have the meaning given in point 1, quaternized or c) the diteriary base of the general formula XXIII, viorin n, m and each of the radicals R- to R-, which has the meaning given in point or the corresponding monotertiary base in the Y has the meaning given in 'point 1 and having a the nitrogen atoms of Isochinolinrsates is alkylated with a suitable alkylating agent for the introduction of one or ζ ·. 7βί Y radicals, - 36 - -. 36 - 2 0 7 0 4 1 2. The method according to item 1, characterized in that one uses a salt of the following general Pormel XZIV, wherein ηj in, Y and En to Ry have the meanings given in point 1 of the formula (1) and Q is a halogen atom, 2 0 7 0 41 invention claim 3. The method according to item 2, characterized in that Q is a chlorine, bromine or iodine atom. 4-position on the phenyl ring. 4. Method according to item 2 or 3 », characterized in that .Q is a chlorine atom. 5. The method according to item 2, 3 or 4, characterized in that one heats the salt used, 6. The method according to item 5 », characterized in that one carries out the reaction at a temperature of 90 to 140 ^ 0. 7 «method according to the points 2 to 6, characterized in that the salt is prepared by reacting the silver salt of the anion with the halide of the cation. 8. The method according to item 7, characterized in that the halide used is a bromide. 9. The method according to item 1, characterized in that Q is a hydroxyl group and Q ^{f is} a carboxyl group or a reactive derivative thereof. 10, method according to item 9, characterized in that the acidic halide is used as a reactive derivative verv / ends. 11. The method according to item 10, characterized in that one uses an acid chloride. - 37 - 207041 12. The method according to item 9 to 11, characterized in that the reaction is carried out in an inert solvent in ird. 13 »Method according to item 1, characterized in that J is an iodide radical · 14, method according to point 12 and 13, characterized in that the Umse
is taken. that the reaction is carried out in an inert solvent. 15. The method according to item 1, 12 and 13, characterized in that the reaction components are heated to the reflux temperature of the reaction medium. 16. The method according to item 1, characterized in that one terminates as Alkylierungsmittel.einen reactive Bster of the alcohol YOH. 17. The method according to item 16, characterized in that the alkylating agent used is an alkyl halide. 18. The method according to item 17, characterized in that the alkylating agent used is an alkyl bromide, alkyl chloride or Alkyljcdid. 19. The method according to item 1, ΐβ to 18, characterized in that the reaction is carried out in an inert solvent v. Ird. 20. The method according to any one of items 1 and l6 to 19, characterized in that the Reaktionskona to the Rückflußterüperatur the Reaktionsmediuma erv / ärmt. 21. The method according to item 1, characterized in that in the compound of the general formula (I) the radical C is in the p-position to B. 22. The method according to item 1, characterized in that in the compound of formula (I) the radical C is in the m-position to B. 23. The method according to item l _s characterized in that in the compound of general formula (I) Σ is iodide, hesylate, tosylate, bromide, chloride, sulfate, phosphate, hydrogen phosphate, acetate or propionate. 24. The method according to item 1, characterized in that in the compound of general formula (I) m 2, 'η 3> Y is methyl, one or zv; ei of the radicals R-, to R ^ for a hydrogen atom and the aaderen Are radicals for a methoxy group and z \ 'ei or three of the radicals Rn to R ^ are methoxy radicals and zi? Ei of the radicals are methoxy groups, the others are hydrogen atoms. 25. The method according to item 1, characterized dadurhc that in the compound of general formula (I) m is 2, a is 3 _S Y is a methyl group, R- and R, hydrogen atoms and R2 and H, IJethoxygruppen are and Rc, Rg and Ιΐγ are iviethoxy groups in the 3- _s 4 ~ and 5-position on the phenyl ring. 26. The method according to item 1, characterized in that in the compound of general formula (1) m is 2, a is 3, "* · is a methyl group, R- and ϋ _Δ V / asserstoffatorae, Rp and R ^ Hethoxy groups are, R, - and Rg are LIethoxygruppen and Pw is a hydrogen atom. - 39 - 207041 27. The method according to item 1, characterized in that in the compound of general formula (I) m is 2, a is 3, Y is a methyl group, R ^ is a hydrogen atom, R ^ is a hydrogen atom, R ^ and Rg are methoxy groups and R ^ is a hydrogen atom or a methoxy group. 28. The method according to item 1, characterized in that in the compound of general formula (I) m is 2, η is 3 and Y is a methyl group, Rt, R2 and -R ^ are each a hethoxy group and R, is a hydrogen atom is, Ry is a hydrogen and R ₁ - is a hydrogen atom and Rg and Hj are methoxy groups in the 3- and 29. The method according to item 1, characterized in that in the compound of general formula (I) m is 2, η is equal to 3 » Y is a Llethylrest ,. R, R ₀ and Rd jev; are Eils Me thoxy groups and R. is a hydrogen atom, R ₁ -, Rg and Puj LIethoxygruppen in the 3-, 4- and 5-abutment condition are on the phenyl ring. Literature Formulas