FI94860B - Process for the preparation of therapeutically useful (+) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl] -1-phenyl-N, N-dimethyl-n-propylamine - Google Patents

Abstract

(+)-1-[(3,4,5-Trimethoxy)benzyloxymethyl]-1-phenyl- N,N-dimethyl-n-propylamine of formula <IMAGE> is a medicament which is useful in gastroenterology.h

Description

i 94860

The present invention relates to a medicament which, when administered orally, on the other hand, increases gastric acid in the gastrointestinal tract. depletion and, on the other hand, prevents convulsions, thus affecting a wide range of gastrointestinal diseases.

It is known that many compounds can increase or accelerate gastric emptying. Thus, metoclopramide, which has been used since 1964 as an anti-nausea drug and digestive modifier, has this property. However, this neuroleptic drug product should be used with caution, as indicated by the side effects, precautions to be taken during use, medical interactions, and undesirable effects mentioned in 15 "Dictionnaire Vidal", 1988 edition, p. 1320.

Thus, restrictions on its use with anticholinergic drug derivatives, parkinsonism drugs, and neuroleptic drugs with drug inhibitory effects as well as potential central nervous system interactions have been particularly limited. its indications.

25 Gu6, M. et al. (Gastroenterol. Clin, and Biol. 12 (1988) 2) have recently shown that two compounds hitherto known as analgesics increase gastric emptying in dogs when administered orally. The authors explain this phenomenon by the fact that these products, namely Trifluadom and U-50.488, have a specific affinity for kappa-type opiate receptors and are likely to act locally on these receptors in the gastric mucosa and cause increased emptying.

2,94860 However, these compounds are known to have a predominantly common opiate-type analgesic effect when administered orally (Pharmaprojects, V&D Publications, Ltd, May and August, 1988).

5 It has been reported that this effect is not addictive, such as morphine, but is associated with tolerance, which is why the product must be administered in increasing amounts to obtain the desired effect.

To date, these compounds have been used as only 10 pharmacological reagents and are not known to have been used as drugs in human therapy.

This invention relates to a medicament which acts on the gastrointestinal tract both to prevent convulsions and to increase gastric emptying, but these effects are essentially non-central nervous system effects and do not cause drug dependence.

The drug is characterized in that it contains as active ingredient the dextrorotatory enantiomer of ether amino oxide, (+) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl] -1-20 phenyl-N, N-dimethyl-n- propylamine of the formula 00.3 25 ^ cv0 ~ cH2 ~ ^ Cy- »dj cm / 'n \ 25 / \ ocH, CH3 CH3 1 2 or a pharmaceutically acceptable acid addition salt thereof.

3

Pharmacological experiments have shown that the ability of the 4 (+) - enantiomers of the formula I prepared according to the present invention to inhibit the effect of intestinal obstruction on gastric emptying in rats at a dose of 10 3 94860 mg / kg is ten times greater than that of the corresponding racemic (+/-) The ability of 1 - [(3,4,5-trimethoxy] benzyloxymethyl] -1-phenyl-N, N-dimethyl-n-propylamine, described in Example 2 of U.S. Patent 4,301,163.

The present invention has been carried out in a manner not previously described by successive studies, the essential features of which are described below.

In U.S. Patent No. 4,301,163, Applicant has claimed a patent for aminoethers having local anesthetic, anticonvulsant and analgesic effects.

In order to further define the latter property of the compound mentioned in Example 2, optical separation of this racemic product was performed to obtain, on the one hand, a dextrorotatory enantiomer which is a product of the present invention and, on the other hand, a levorotatory enantiomer.

It is generally accepted that in vitro study of opiate receptor binding affinity is a means of studying potential analgesic compounds (Simon, Eric J., Opiate receptor binding in Drug Research, in Receptor binding in Drug Research (1986) pp. 183-202, O ' Brien-Dekker, Robert A., eds.).

In this experiment, performed by Roman, F. et al., J. Pharm. Pharmacol. 39 (1987) 404-407, optically active compounds were used, as well as the compounds preferred in U.S. Patent No. U 50,488 and morphine as reference products.

At the end of the study, it was found that the iron product of the invention differs from other compounds in that it has receptor binding affinity for the mu-, delta- and kappa receptors studied, in contrast to the preferred compounds of the aforementioned U.S. patent, which exhibit predominantly mu-affinity. and compound U 50,488, which is reported to bind specifically to cap-4 94860 pa receptors. These results indicate the potential analgesic effects of these products (CRC Handbook of Stereoisomers: Drugs in Psychopharmacology, CRC Press Inc (1984) p. 402); thus, they were subjected to an in vivo test considered appropriate to determine this effect.

Surprisingly, the compound of the invention had essentially no analgesic activity in this experiment, in contrast to other products which proved to be active.

10 A final attempt to determine in vivo the properties of the product observed in vitro has now been made using an assay according to Gu6, M. et al. (Supra).

In an experiment, the product according to the invention has a clear effect of increasing gastric emptying from solids in 15 dogs. In addition, the observed effect is inhibited by compounds known to be opiate antagonists.

Thus, in an unexpected and peculiar manner, the compound of the invention having in vitro affinity for opiate receptors mu, delta and kappa does not have the expected central analgesic effect in vivo but a local effect on gastric opiate receptors, resulting in increased solids depletion in dogs.

In addition, it is also noteworthy that the product also has an anticonvulsant effect.

Thus, in aqueous solution at a molar concentration of 1.70 x 10 5, the product inhibited 50% of the intensity of seizures induced in the duodenum of rats. In this in vitro experiment, morphine is inactive at a concentration of more than five times the concentration of the product of the invention.

The dual effect of the product, as evidenced by the increased depletion of solids and the disappearance of intestinal cramps, is particularly significant because the effect extends to many layers of the gastrointestinal tract.

5,94860

Many diseases of the digestive tract can be well treated. Some examples are gastrointestinal diseases caused by long-term drug therapy, such as analgesics or neuroleptic drugs Hoi-5.

Thus, the product of the invention is to normalize gastrointestinal function in patients treated with morphine-type analgesics, are known to slow gastric emptying and to induce in a 10-tyjen intestinal muscle spasms (Goodman and Gilman's The

Pharmacological Basis of Therapeutics ", 6th ed., (1980) pp. 503-504).

The above experiments and results, which form the basis of the invention, are described in detail below.

Comparative experiments which enabled the product of the invention, in particular the preferred (+) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl] -1-phenyl-N, N-dimethyl-n-propylamine D - (- ) tartrate has been performed with racemic compounds according to U.S. Patent No. 4,301,163, namely (+/-) - 1 - [(3,4-dimethoxy) benzyloxymethyl] -1-phenyl-N, N-dimethyl -n-propylamine, (+/-) - l-bentsyloksimetyyli-. 1-phenyl-N, N-dimethyl-n-propylamine, (+/-) - 1 - [[(3,4,5-trimethoxy) benzyloxymethyl] -1-phenyl-N-methyl-n-propylamine and (+/-) - 1- (p-chlorobenzyloxymethyl) -1- (p-methoxyphenyl) -N, N-dimethyl-n-ethylamine in Examples 1, 3, 12 and 13 of said patent publication, respectively , described and preferred. 30 products.

»

In addition, the following were used as reference products: the levorotatory enantiomer of the compound of the invention, namely (-) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl] -1-phenyl-N, N-dimethyl-n-propylamine, 35 is described in the experimental part of the text.

• 9,94860 trimebutine (DCI), which is (+/-) - 2-dimethylamino-2-phenyl-n-butyl-3,4,5-trimethoxybenzoate, the subject of FR Patent Publication No. 2,369 M, and having a chemical structure similar to that of the racemic compound corresponding to the product of the invention, a compound having the code U 50,488 and described above as affecting gastric emptying, this is trans-3,4-dichloro-N-methyl-N- [2- (1-pyrrolidinyl) cyclohexyl] phenylacetamide, a centrally acting analgesic and antiepileptic drug (Pharmaprojects, published August 1988).

Finally, morphine has been used as a reference analgesic in these experiments.

Thus, the effect of the enantiomer has been compared with the effect of racemic compounds. However, it is known in practical experiments that these receptors are stereoselective and that they are sensitive to the action of only one enantiomer while the other is inactive, as in the CRC Handbook of Stereoisomers, Smith, Donald 20 F., ed. (1984) ss. 401-440: Opiates Agonists and Antagonists: Pharmacological Behavioral, and Neurochemical Effects of Stereoisomers "has been described. In experiments and comparisons, this has been taken into account and the racemic value of this compound is multiplied by two and the dose of racemic product two before comparing the result with that obtained with the compound of the invention.

As already mentioned, the binding affinity of the products for opiate receptors mu, delta and kappa was measured according to the method described by Roman, F. et al. (Cited above).

The results are shown in Table 1 below and are expressed as CI50 values representing nanomolar concentrations of the dissolved product capable of inhibiting 50% of the binding of a specific radioactive ligand to the receptor under study.

7 94860

table 1

Binding affinity of compound and reference products for mu, delta and kappa receptors 5 Test compound mu-delta-recappa-receptor receptor receptor

Product according to the invention: (+) - enantiomer 196,540,232 10 (-) - enantiomer 580 12,320 2,630 U.S. Pat. No. 4,301,163 e.g. 1,110 7,800 1,110 e.g. 3,190 14,700,560 e.g. 1,260 2,250 2,280 e.g. 13,250 4,390,900 15 Trimebutine 146 1,750 1,460 U. 50,488 1,028 14,610 66

Morphine 7 152 127

Looking at these results even after the above correction for racemic compounds has been made, which is not mentioned in Table 1, it is surprising that the dextrorotatory enantiomer of the invention is the only compound with considerable potency in addition to morphine. to the receptor studied.

On the other hand, looking only at the mu receptor, the compounds of Examples 3, 12, and 13 of U.S. Patent No. 4,847,607, as well as trimebutine, are equally active if not even more active. The same is true for U. 50,488 if; 30 only the kappa receptor is considered.

Because the affinity of a compound for opiate receptors (in vitro) often corresponds to analgesic, pharmacological properties (CRC Handbook of Stereoisomers, cited above), the products were subjected to an experiment suitable for demonstrating this analgesic effect in general in 35 vivo.

8,94860 This experiment, performed in mice according to the method of Roster, R. (Fed. Proc. 18 (1959) 412), involves examining the effect of oral products on the manifestations of pain induced by an acetic acid solution administered intraperitoneally to animals.

In this case, the animals, in groups of ten animals, are not allowed to eat or drink for 20 hours before the experiment. However, they receive the test products as an aqueous solution in an amount of 2 ml of solution per 100 g of body weight, followed ten minutes later by intraperitoneal injection of 0.25 ml of 0.5% (v / v) acetic acid solution kept at 37 ° C. . Three minutes after this injection, the number of abdominal cramps in the animals is counted for ten minutes. Animals are considered to be less painful 15 if they have less than half the average number of seizures in the control group. In the experiment, the products were administered at a dose of 50 mg / kg, and the oral analgesic dose of 10 mg / kg of the reference morphine is 78%.

20 Table 2 shows the results of this study. They demonstrate and confirm the properties of the product according to the invention, which has a very low analgesic effect compared to the other products studied. These findings are even more significant if the proposed correction is made for these racemic compounds. In this case, the dextrorotatory enantiomer of the invention (17.60%) is substantially three times less analgesic than trimebutine (24.3 x 2 = 48.6%) and five times less analgesic (44.0 x 2 to 88.0%). %) Than the compound of Example 12 of U.S. Patent No. 9,94860

Table 2

In vivo analgesic effect (50 mg / kg orally) 5 Test compound Pain sensitivity% (p)

Product of the invention: (+) - enantiomer 17.6 (*) 10 U.S. 4,301,163 e.g. 3 27.6 (*) e.g. 12 44.0 (***) e.g. 13 27.9 (* **)

Trimebutine 24.3 (**) U. 50,488 90.0 (***) 15 _ (p) probability, Student's T-test (*) p <0.05 (**) p <0.01 (** *) P <0.001 20

The study of the local effect of the product of the invention on opiate receptors of the gastric mucosa has been performed according to the method described by Gue, M. et al. (Cited above).

25 The authors investigated the effect of mu- and kappa-type opiate compounds in dogs after oral administration. At low doses, they show no effect with mu-agonist compounds, whereas kappa-agonist-type compounds (such as U. 50,488) increase gastric emptying of food solids in dogs. The opiate antagonist compounds naloxone and MR 2266, which are known to be antagonistic of both mu and kappa receptors (Römer, D. et al., Life Sciences 31 (1982) 1217-120), had otherwise inhibited this effect.

35 In this study, the authors suggest that 10,94860 kappa agonist-type opiate compounds, such as trifluomom and u. 50,488, when administered orally, modify gastric emptying due to a local effect.

In an attempt to demonstrate such an effect with the product of the invention, it has been used in this experiment and compared to its levorotatory enantiomer and tri-mebutin, which is known for its regulatory effect on gastrointestinal function.

The principle of the experiment is to measure the stomach content of the animals 10 one hour after the animals have eaten a meal containing 400 g of solids and containing 21.7% of the following dry matter: 7.7% protein 4.5% fat 15 6.9% carbohydrates 2.6 % mineral salts and 20 g of sheep liver containing radiolabelled cyanocobalamin. The animals enjoy the meal in about five minutes. After one hour, the contents of the stomach are recovered using a small tube placed in a gastric port of about 10 cm before the experiment.

The collected sample is weighed and homogenized. Its radioactivity is measured and the amount of gastric emptying pro-. . expressed in cents is calculated according to the following formula: (cpml · P1 - cpm2 · p) x 100% depletion = - cpml · P1 30 • · where: cpml is the radioactivity in grams of mixed, radiolabelled liver, P1 is the radioactivity added to the food the weight of the liver labeled with isotope 35, • 11,94860 cpm2 is the radioactivity in grams of the sample collected after one hour, p is the weight of the sample collected after this hour.

In practice, each experiment is performed on three dogs 5 and given 20 minutes before the meal described above a capsule containing 0.25 ml / kg of animal body weight of the test product or a placebo capsule to determine the control of emptying in the animal. Each of the three dogs is treated twice in a random 10 order. Finally, in the last series of experiments, three dogs receive an intravenous solution of MR 2266 or naloxone in an amount of 0.1 mg / kg body weight. The meal is administered and eaten 20 minutes after administration of the capsule containing the test product. Solids depletion values are measured as described above and compared using the Mann and Whitney test (U-test). The difference compared to the control values is considered significant when p is <or = than 0.05.

The effect of the test products is made objective 20 using a percentage variation calculated according to the following ratio: (test compound control compound \

caused - caused by empty- I

empty% nys% J

/ x 100% variation = _% depletion by control compound 30 The results obtained in this study are shown in Table 3.

12 94860

Table 3

Effects of products on gastric emptying from solids in dogs 5 Test compound (*)% variation

Product of the invention: (+) - enantiomer + 110% above + naloxone + 5% 10 above + MR 2266 + 14% (-) - enantiomer + 26% trimebutine - 4% ♦ Excluding trimebutine, which was administered in an amount of 5 mg / kg, the products were administered at a dose of 0.25 mg / kg according to the protocol described above.

The effect of the product according to the invention cannot be ruled out: it doubles the gastric emptying of solids in dogs after one hour after 20 doses, while the effect of its levorotatory enantiomer is four times less significant. In addition, the observed effect is simultaneously inhibited by naloxone, in particular a mu receptor antagonist, and MR 2266, a kappa receptor antagonist, which makes it possible to read the depletion effect as a general agonist-type effect on local opiate receptors in the gastric mucosa and more specifically mu-receptors. .

The anticonvulsant effect of the product of the invention in the D - (-) - tartrate form has been studied in vitro in the rat duodenum, which is an integral part of the intestine of this animal.

In the study, a seizure is induced in a fragment of this tissue by an anticonvulsant, in this study by barium chloride, followed by a decrease.

13 94860 anyone the concentration of the product solution (IC50) that is able to inhibit 50% of the intensity of the convulsions caused.

The results of the study are presented in Table 4.

5

Table 4

In vitro anticonvulsant effect in rat duodenum (Anticonvulsant BaCl2) 10 _

Test product IC50 (mol / l)

Product of the invention: (+) - enantiomer 1.70. 10'5 15 Papaverine 2.74. 10s

Morphine Inactive pi in 10 "4

Although morphine is inactive in this experiment, the product of the invention is slightly more active than papaverine, which is considered to be a reference compound for anticonvulsant activity.

Finally, the study of the acute toxicity of the product of the invention is also significant, especially with respect to its left-handed enantiomer.

This toxicity has been studied orally in male mice. The test products are given in an amount of 2 ml of their aqueous solution per 100 g of animal weight. The animals are then observed for three hours after administration and then updated for 14 to 14 days, at which time they are sacrificed and necropsied.

LD50 values (lethal doses that cause 50% death in animals) have been calculated by the team of Reed, J.

L. and Muench, H. (Am. J. Hyg. 27 (1939) 493) according to method 35.

14 94860

The results obtained are shown in the following Table 5 and show that the toxicity of the product of the invention is about half that of its levorotatory enantiomer in this experiment.

5

Table 5

High oral toxicity in mice 10 Test product LD50 mg / kg

Product of the invention: (+) - enantiomer 407 (-) - enantiomer 255

The studies described above show beyond doubt the significance of the product according to the invention, and its special features, which are formed on the other agonist-20 type of local action on the opiate receptors in the gastric mucosa and on the other hand anticonvulsant effect particularly at intestinal level, proving its usefulness moderate gastrointestinal diseases. . involving gastric motility, such as from the stomach into the esophagus 25 back migration, gastric ulcers, ruuansulatushäi- disorders, gastritis, functional bowel disorder and biliary dysfunction treatment.

As the active ingredient of the medicament of the invention, a free amine which is (+) - 1 - [(3,4,5-30 trimethoxy) benzyloxymethyl] -1-phenyl-N, N-dimethyl-n- * propylamine or acid addition salts with pharmaceutically acceptable organic or mineral acids. Acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, as well as acetic acid, citric acid, gluconic acid and maleic acid are used.

15 94860

Of the organic acids, D - (-) - tartaric acid produces a preferred acid addition salt with a compound of the invention because, on the one hand, it is easy and efficient to purify by crystallization from ethanol and, on the other hand, is soluble in water and thus suitable for aqueous pharmaceutical forms without being hygroscopic. It has the necessary physicochemical stability necessary for use as a reagent in the pharmaceutical industry.

Another aspect of the invention is a process for preparing dextrorotatory aminoether oxide and its D - (-) - tartrate obtainable: using a preferred process similar to that described in U.S. Patent No. 4,301,163 and wherein (+) 2-Dimethylamino-2-phenyl-n-butanol prepared according to the method described in JP Patent Application Publication No. 16416/1980, issued May 1, 1980, is reacted with a 3,4,5-trimethoxybenzyl halide of the following formula -20 sa 00 * 3 xh2c-och3 25 '' och3 wherein X is a halogen atom which is chlorine, bromine or iodine.

More specifically, this means that the metal alcoholate of the right-rotating amino alcohol is therefore prepared by reaction with an alkali metal such as sodium, potassium or their hydrides or amides.

This reaction is generally carried out in aromatic solvents such as benzene, toluene and xylene, or in ether solvents such as diethyl ether, dioxane-1694860, and tetrahydrofuran, or in solvents such as dimethylsulfoxide, dimethylformamide, dimethylacetamide and acetonitrile, dimethonitrile, dimethonitrile. The salt formation reaction is carried out using 0.7 to 1.5 moles of metal-5 reagent per mole of alcohol, and preferably 0.9 to 1.2 moles of said reagent. The salt formation temperature is 0 to 140 ° C, more specifically 20 to 110 ° C.

The metal salt of the amino alcohol is formed after a reaction time of 0.5 to 6 hours, after which it is condensed with 3,4,5-trimethoxybenzyl halide at a temperature of 0 to 140 ° C, preferably 70 to 110 ° C. The condensation lasts 1 to 24 hours, preferably 2 to 6 hours, and can be monitored at the end of the reaction by thin-layer chromatography. The separation of the product formed is carried out using the conventional methods described in Illustrative Example 15.

The resulting dextrorotatory amino ether oxide can be salified using the appropriate acids already mentioned. Preferably, this reaction can be carried out using D - (-) - 20 tartaric acid at a concentration of 0.75 to 1.25 moles per mole of product to be salified. The reaction is performed in solvents such as low molecular weight ketones or alcohols. Ethanol is preferred in a concentration of 3 to 10 volumes per part by weight of isomer used.

Thus, 5-7 parts by weight of ethanol and 0.95 to 1.05 moles of D - (-) - tartaric acid are usually added to one mole. The reaction is carried out at a temperature of 20 to 80 ° C and lasts from 15 minutes to five hours, more specifically 0.5 to 1 hour at a temperature of 35 to 50 ° C. The crystallization of the salt is. After 48 hours at 20 ° C, the D - (-) tartrate of the dextrorotatory isomer of the invention can be obtained by filtration to a satisfactory purity for its therapeutic use. However, if necessary, the product can be purified by recrystallization from an ethano-35 list,

Il! Hill I! ! no • 17,94860, i.e. by separating the racemic amino ether oxide prepared in Example 2 of U.S. Patent No. 4,301,163.

In a conventional manner, this separation is carried out by separating the diastereoisomers obtained after salt formation with optically active acids. This method is commonly used. A particularly detailed composition of the reagents and their use can be found in the book "Optical Resolution Procedures for Chemical Compounds", Vol. 1: Amines and related compounds, 10 Newman, Paul, 1978.

More specifically, the process forms a salt from the corresponding racemic propylamine dissolved in a solvent, which may be a ketone or an alcohol having a boiling point below or close to 80 ° C, using a rotating organic (+) acid to give an insoluble (+) polyacrylic acid / (-) - propyyliamiinisuola; removing this insoluble salt by filtration to give a solution containing both (+) - acid and the (+) enantiomer of n-propylamine; evaporating the solvent of this solution to dryness to give a residue; dissolving the residue in water and basifying the solution to a pH close to or above 10 by adding an alkali metal, alkaline earth metal or ammonium hydroxide solution; extracting the free dextrorotatory n-propylamine as an organic solvent and then evaporating the extracted organic solvent to give the desired (+) - n-propylamine.

In carrying out this separation method, the enantiomers of tartaric acid are preferred. Using these, the diastereoisomers L - (+) - vii are formed in the first step. 30, then the diastereoisomer formed between the acid and the levorotatory enantiomer, which crystallizes, is removed by filtration and then the filtrate is treated to liberate its salt and separate the levorotatory isomer of n-propylamine, the isomer of which is the subject of the invention, and finally - ie 94860 dithio salt with D - (-) - tartaric acid, which salt can finally be purified as described above.

To separate one mole of racemic compound, 0.6 to 1.5 moles of L - (+) - tartaric acid are used to convert the amine to a salt in a solvent, preferably an alcohol or ketone having a low molecular weight and a boiling point of almost or below 80 ° C. This solvent should preferably be anhydrous. In most cases, absolute ethanol is used in a concentration of 3 to 30 parts by volume per one part by weight of the compound to be treated.

Salt formation is carried out by heating the resulting solution for five minutes to one hour under refluxing the solvent and then cooling, whereby the diastereoisomer formed from L - (+) - tartaric acid and the levorotatory enantiomer of the compound of the invention crystallize.

This salt, which is a by-product, is removed by filtration. The filtrate is then treated in a suitable manner to give the dextrorotatory enantiomer of the invention. In this case, the solvent is removed by distillation, the residue 20 is taken up in a sufficient amount of basic solution to obtain a pH close to or above 10, after which the product according to the invention is extracted with a suitable solvent such as ether or methylene chloride.

After evaporation of this extracted solvent, the dextrorotatory enantiomer of the invention is purified as described above by forming an addition salt, especially with D - (-) - tartaric acid, which is preferred, and then purifying this salt by crystallization.

These methods are illustrated in an unrestricted manner in the experimental section by the examples described in

i I

the method of preparation and the properties of the products according to the invention.

The utility of the product of the invention and its salts has been demonstrated in the treatment of a number of diseases of digestive motility. Depending on the nature and severity of the disease to be treated, the daily therapeutic dose should contain 5 to 1,000 mg, preferably 25 to 500 mg of product, which may be ingested once or several times a day.

The product is in a conventional pharmaceutical form, such as tablets, capsules or suppositories, or as solutions or suspensions suitable for oral, injectable or injectable use.

In galenic, i.e. so-called "dry" forms, the amount of active substance may be 5-80% by weight of the final product, and the total amount of excipients may be 95-20% by weight. In so-called "aqueous" forms (suspensions and solutions), the active ingredient may be present in an amount of 0.1 to 20% by weight of the composition, and the various additives in water account for 99.9 to 80% by weight of the final preparation.

The preparation of injectable solutions at a concentration of 0.5% (w / v) and the preparation of coated tablets containing 100 mg of the compound of the invention (-) - tartrate per unit 20 are presented to illustrate the invention.

Formulations

Solution for injection, 0.5% (w / v) Compounds required for the preparation of 100 ml of solution: (+) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl) - 0.500 g of 1-phenyl-N , N-dimethyl-n-propylamine (-) - tartrate sodium chloride for injection 0.850 g 30 distilled water for injections filling 100.0 ml

Manufacturing

The compounds are dissolved with stirring in about 95% of the distilled water to be prepared at a temperature of about 20 ° C. The resulting solution is filtered through a membrane with a pore size of 22 micrometers, after which the filtrate is made up to exact volume with distilled water, which is also filtered. The solution is packaged in an amount of 5 ml per ampoule, after which the ampoules are sealed, sterilized at 121 5 eC for 30 minutes.

Coated tablets containing 100 mg of substance per unit Formula per unit: (+) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl-100.0 mg of 10] - 1-phenyl-N, N-dimethyl-n- propylamine (-) - tartrate dicalcium phosphate 30.0 mg lactose 132.0 mg corn starch 80.0 mg 15 carboxymethylcellulose 10.0 mg polyvinylpyrrolidone 2516.0 mg microcrystalline cellulose 20.0 mg magnesium stearate 4.0 mg talc 8.0 mg 20 hydroxypropylmethylcellulose 4.4 mg titanium dioxide 1.1 mg total 405.5 mg

Manufacturing

The following ingredients are placed in a mixing vessel: 25 active ingredient 1750 g dicalcium phosphate 525 g lactose 2320 g maize starch 1400 g carboxymethylcellulose 175 g To moisten the resulting mixture, a solution containing 1.05 g of polyvinylpyrrolidone 25 in 770 ml of purified water is added. The mixture is ground to a granule with a device with a 2 mm mesh lattice, the granules are dried in an oven at 50 ° C and then calibrated by passing 35 through a 1 mm mesh lattice.

i «• <

Il rillit lii «'* · I. <21,94860 346 g of microcrystalline cellulose, 69 g of magnesium stearate and 139 g of talc are added to 6365 g of these granules in a mixer. After mixing, the product is compressed to 401.5 mg per unit, the resulting tablets are coated in 5 centrifuges at 40 ° C using a suspension of titanium dioxide and hydroxypropylmethylcellulose in water to give finished coated tablets with an average unit weight of 406.7 mg, each contains 100 mg of the product of the invention (-) - tartrate-10.

Experimental part

methods of Preparation

Example 1 (preferred) a) (+) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl] -1-15 phenyl-N, N-dimethyl-n-propylamine

60 ml of anhydrous dioxane and then 6.20 g of sodium hydride as an 80% by weight suspension (w / w) in paraffin (0.207 mol) are introduced into a reaction vessel protected from moisture and under a nitrogen atmosphere.

40 g (0.207 mol) of (+) - 2-dimethylamino-2-phenylbutanol [α] D = + 7.9 ° are added with stirring and without exceeding a temperature of 50 ° C; C - 1, ethanol). The suspension is stirred at 40 ° C for a further 45 minutes, after which it is cooled to about 20 ° C.

Within 2 hours and not exceeding 50 ° C, 44.9 g (0.207 mol) of 3,4,5-trimethoxybenzyl chloride in 5 ml of anhydrous dioxane are added. The reaction mixture is heated to 70-75 ° C and maintained at this temperature for five hours. Once the mixture has cooled, it will waste. After standing overnight, 200 ml of water are slowly added, keeping the temperature of the mixture below 20 ° C. After acidification to pH 1 with sulfuric acid, the mixture is extracted with 60 ml of toluene.

The toluene phase is isolated and removed. The acidic phase 35 is basified with concentrated sodium hydroxide solution, 22 9 4 8 6 0 and then extracted twice with 150 ml of methylene chloride.

The combined organic phases are washed with water and then dried over Na2SO4. The solvent is distilled off. The product 5 obtained is a pale yellow, viscous oil.

Weight: 70.30 g; yield 91%; 1 H, NMR, CDCl 3 (60 MHz, TMS int), chemical shifts ppm: 0.70 (triplet, 3H), 1.95 (quadruplet, 2H); 2.32 (singlet, 6H), 3.90 (singlet, 11H), 4.55 (singlet, 10H); 6.65 (singlet, 2H), 7.35 (broad, 5H), [α] D = + 16.5 ° (c = 6, ethanol).

b) Salt formation with D - (-) - tartaric acid 3.50 g (9.38 mmol) of the dextrorotatory enantiomer prepared above, 1.37 g (9.13 mmol) of D - (-) - tartaric acid 15 and 21 ml of absolute the ethanol is introduced into the reaction vessel.

The mixture is heated to 50 ° C with stirring and maintained at this temperature for 30 minutes. The solution is gradually cooled to about 10 ° C over 16 hours. The crystals are filtered and dried in vacuo at 50 ° C until their weight is constant.

Weight: 4.06 g; yield = 85%; mp. 147 ° C; [α] D = + 14.5 ° (c = 5, HCl N) A sample of this product is recrystallized from boiling ethanol (five volumes by weight). The melting point and optical rotation of the obtained crystals are identical to the untreated product. In conclusion, the values mentioned for the melting point and the optical rotation are considered to be characteristic of the purified product.

Example 2. . 30 a) Isolation of a racemic compound

To a moisture-protected reaction vessel are introduced 210 ml of absolute ethanol and 30 g (80.3 mmol) of (+/-) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl] -1-phenyl-N, N-dimethyl- style-n-propyl amine. 9.6 g of 35 - (64.2 mmol) of L - (+) - tartaric acid are then added to the mixture and it is heated with stirring; lii 23 94860 and refluxing for 15 minutes.

The resulting solution is allowed to gradually cool to 20 ° C, after which it is left to stir overnight.

5 Filter and remove the insoluble material. It contains essentially the L - (+) - tartrate of the levorotatory enantiomer of the product of the invention, which is purified to prepare a reference sample by crystallizing it from absolute ethanol at a concentration of five volumes per 10 parts by weight of the product until its optical rotation is constant: [a] D = -14.5 ° (c = 5, HCl N)

The alcohol filtrate from the first crystallization, which contains the product according to the invention, is evaporated in vacuo and the residue is dissolved in 160 ml of water.

The solution is basified to pH 10 with concentrated sodium hydroxide solution and then extracted twice with 120 ml of methylene chloride. The combined organic phases are washed with water and then dried over Na2SO4. After removal of the methylene chloride by distillation, a pale yellow oily residue is obtained which is enriched in the dextrorotatory isomer.

Weight: 16.50 g; yield: 55% by weight; [α] = + 14.7 ° (c = 6, ethanol); optical purity = 89% 25 b) Salt formation with D - (-) - tartaric acid

The procedure described in Example 1 (b) is followed using 12.6 g (33.7 mmol) of the previous product and 5.05 g (33.7 mmol) of D - (-) - tartaric acid in 110 ml of anhydrous ethanol. The crystallized product is filtered off and dried.

. Weight: 13.8 g, yield: 78% by weight; * · Mp = 143-145 ° C; [α] D 25 = + 13.8 ° (c = 5, HCl N); optical purity = 95%.

The product is recrystallized from 65 ml of ethanol at reflux.

After slowly cooling the solution to 20 ° C with stirring, the crystals are filtered off and dried in vacuo until their weight is constant.

Weight: 12.4 g; yield: 90% by weight; mp = 147 ° C; [α] D = + 13.8 ° (c = 5, HCl N) 5 The sample product is treated with an alkaline solution and extracted with methylene chloride. The optical rotation of the pale yellow oily residue obtained by evaporation is [a] D = + 16.6 ° at a concentration of 6% (w / v) in ethanol. When calculated, this value is considered to be characteristic of the optical purity of the dextrorotatory isomer of the invention.

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Claims (3)

A process for the preparation of a therapeutically useful (+) - 1 - [(3,4,5-trimethoxy) benzyloxymethyl] -1-phenyl-5N, N-dimethyl-n-propylamine of formula Ia, 2.0-Cl2 And ² and λ and ³ 3 ch 3 ch 3 and its pharmaceutically acceptable acid addition salts, such as a D - (-) - tartrate of a (+) - 1 - [(3,4,5) -trimethoxy) ben-syloxymethyl] -1-phenyl-N, N-dimethyl-n-propylamine, characterized in that a) (+) - 2-dimethylamino-2-phenyl-n-butanol of formula C, H - N 25 CH 3 Cl 3 is reacted with a 3,4,5-trimethoxybenzyl halide of the following formula J 94860 wherein X is a halide, preferably chlorine, bromine or iodine; or b) forming a site of the racemic propylamine corresponding to the compound of formula 1 dissolved in a solvent using an organic right-wielding (+) acid, wherein an insoluble (+) - acid / ( -) - propylamine salt is obtained, this insoluble site is removed by filtration to obtain a solution containing the bed (+) acid and (+) - enantiomer of n-propylamine, the solvent of this solution extends even further. dryness to obtain an ether residue, the ether dissolves in water and alkalizes the solution to a pH near or above 10 by the addition of a solution of alkali metal, alkaline earth metal, ammonium hydroxide, extracts the free right-turning n. the propylamine with an organic solvent and then replaces this extracted organic solvent to obtain the desired (+) propylamine of formula I. 2. A process according to claim 1, characterized in that a site of the racemic propylamine is dissolved which is dissolved in a solvent using an L - (+) - tartaric acid. Process according to Claim 1, characterized in that a site of the desired (+) propylamine is prepared using a pharmaceutically acceptable acid. • · *! L IKI- MH li Iti * ··!