FI61182B - FOERFARANDE FOER FRAMSTAELLNING AV FARMACEUTISKT AKTIVA BUTYLAMINDERIVAT - Google Patents

Description

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_. (44) Date of first publication. -

Patent- och regictaratyralMn Aniöktn utlmjd och utljkriften pubUcvrad 26.02.82 (32) (33) (31) Pyydetty vtuolkwii — B «(ird prtorttrt 20.05.71»

Belgium-Belgien (BE) 815273 (71) Sanofi, 40, avenue George V, 75008 Paris, France-France (FR) (72) Charles Pigerol, Saint-Ouen, Pierre Eymard, Fontaine, Jean-Claude Vernieres, La Tronche, Jean-Pierre Werbenec, Seyssinet, France-France (FR) (7 * 0 Oy Borenius & Co Ah (5 * 0 Process for the preparation of pharmaceutically active bitylamine derivatives - Formulation of pharmaceutically active pharmaceutical butylamine derivatives)

The invention relates to a process for the preparation of new pharmaceutically active n-butylamine derivatives.

The compounds of the invention are pharmaceutically active acid addition salts of n-butylamine derivatives, which n-butylamine derivatives can be represented by the general formula ch3-ch2-ch2

R 1 -C-NHO 1

O

wherein R represents an ethyl or n-propyl group and R 2 represents i) an ethyl, n-propyl, isopropyl, isobutyl or tert-butyl group, when R 1 represents n-propyl, or ii) an n-butyl or iso -butyl group when R 1 represents ethyl.

The invention relates to a process for the preparation of pharmaceutically acceptable acid addition salts of the compounds of formula I. Such are acid addition salts obtained with inorganic 2,61182 acids, e.g. hydrochloric acid, or organic acids in which the free carboxyl is attached to a saturated or unsaturated aliphatic group or to an aromatic or aralkyl group, which acid may optionally contain another carboxylic acid, e.g.

Sperber et al. have described tri-n-propylmethylamine, i.e. 1,1-di-n-propyl-n-butylamine in free base form, in J. Amer-Chem. Soc., 71_, 3 3 52 (1 949), where it is mentioned to be "less convulsive-triggering and more toxic than the corresponding trialkylethylamines". Rather, it is a question of a musculotropic anticonvulsant effect, as emphasized in said publication.

Although the above-mentioned publication on this compound does not specify the data, it does not provide any indication of an effect which, in the light of the present invention, could be considered as a property of the compounds of formula I, nor in particular of tri-n-propyl properties of pharmaceutically acceptable acid addition salts of methylamines.

The publication dealing with the anticonvulsant effect of this methylamine derivative does not contain any details of the degree of effect and does not refer at all to the method by which the anticonvulsant effect would be demonstrated. Also, no data on toxicity are presented, therefore the pharmacological data published by Sperber et al. Are too vague to conclude that tri-n-propylmethylamines have a sufficient anticonvulsant effect when administered in non-toxic amounts to be considered useful drugs.

Pharmacological experiments with the compounds according to the invention also investigated the anticonvulsant effect of tri-n-propylmethylamine, i.e. 1,1-di-n-propyl-n-butylamine, "in vitro". In full agreement with the observations of Sperber et al., It was found that the anticonvulsant (spasmolytic) effect of this compound is very weak, in fact non-existent, as it is 20,000 ...

25,000 times weaker than the effect of atropine. From this 3,61182, it could be concluded that the spasmolytic effect of tri-n-propylmethylamine could be produced "in vivo" at doses which are highly toxic.

In fact, "in vivo" pharmacological experiments have shown that the base form of tri-n-propylmethylamine, as well as the compounds according to the invention, have activity in the treatment of Parkinson's disease and in the correction of extrapyramidal disorders caused by stress-triggering agents. However, it was found that at those doses at which tri-n-propylmethylamine has such activity, i.e. at much lower doses than toxic doses, the spasmolytic effect of this compound is non-existent.

Thus, the use of tri-n-propylmethylamine as a therapeutic agent has not been demonstrated in the prior art.

It has now surprisingly been found that pharmaceutically acceptable acid addition salts of tri-n-propylmethylamine have a very specific effect in the treatment of Parkinson's disease and in the correction of extrapyramidal disorders caused by stress triggers, which is better than the corresponding effect of the tri-n-propylmethylamine base chloride or acid fumarate.

Pharmaceutically acceptable acid addition salts of compounds of formula I may be prepared either by a) reacting ch3-ch2 to ch2 of general formula

R1 - C - N = C = 0 II

isocyanate according to the formula and having the same meaning as above, to react in a suitable medium and at a temperature between 15 and 100 ° C, preferably between 50 and 90 ° C, with a strong acid, such as hydrochloric acid or sulfuric acid, which is capable of To form a pharmaceutically acceptable acid addition salt, to form the corresponding acid addition salt of the desired compound of formula I, or b) by reacting CH 3 of the general formula CH 2

R1 -C-NH-C-H III

N-formylamine according to Rf, wherein and R 2 are as defined above, to react in a suitable medium and at a temperature between 15 ° C and 100 ° C, preferably between 50 ° C and 90 ° C, with a strong acid such as for example with hydrochloric acid or sulfuric acid capable of forming a pharmaceutically acceptable acid addition salt to form the corresponding acid addition salt of the desired compound of formula I, after which the acid addition salt thus obtained is optionally reacted with an alkali metal hydroxide such as sodium hydroxide the base is then reacted with a suitable organic or inorganic acid to form another pharmaceutically acceptable acid addition salt.

The starting materials of the formulas II and III can be prepared in several ways, for example by a) converting the general formula CH3 - CH2 - CH2O

R. - C - C - NH, IV

An acetamide derivative of formula R 2, wherein R 1 and R 2 have the same meaning as above, to react with chlorine or bromine in an alkaline medium such as aqueous sodium or potassium hydroxide solution to give a compound of formula II, or b) by heating the general of the formula ch3 - ch2 - ch2

R. - C - OH V

A tertiary alcohol according to 1 / R 2, wherein and R 2 are as defined above, with an alkali cyanide such as sodium or potassium cyanide in the presence of an acid such as sulfuric acid to give a compound of formula III.

Compounds of formula IV may be obtained by reacting anhydrous ammonia with the corresponding acids or, preferably, with halides of these acids. The acids can be prepared from the corresponding alcohols and formic acid in sulfuric acid solution.

The compounds of formula V are either known compounds or can be prepared by known methods, e.g. by reacting an organic lithium compound with a suitable ketone in an anhydrous ether medium such as tetrahydrofuran.

It has been found that the pharmaceutically acceptable acid addition salts of the n-butylamine derivatives of the formula I have valuable pharmacological properties which make them useful as medicaments for humans as well as in veterinary medicine.

In particular, the compounds of the invention have been found to have key noradrenergic and key dopaminergic properties. The latter properties are manifested as an inhibitory effect of reserpine and catatonia and catalepsy caused by stress-releasing agents.

Pharmacological experiments with the compounds according to the invention have shown that tri-n-propylmethylamine hydrochloride, i.e. 1,1-di-n-propyl-n-butylamine hydrochloride, has a considerable degree of activity which is stronger than that of the corresponding free base. However, it was quite surprisingly and unexpectedly found that the acid fumarate of 1,1-di- 6,61182 n-propyl-n-butylamine has an effect which is even considerably stronger than that of the corresponding hydrochloride. It was found that 1,1-di-n-propyl-n-butylamino acid fumarate was 20-40% more effective than the corresponding hydrochloride in experiments performed on catatonia induced by reserpine and stress-releasing agents.

Furthermore, at doses that completely inhibit catatonia and catalepsy caused by stress triggers, the compounds of the invention were found to have no effect on the anti-amphetamine effects of stress triggers in rats and their anti-apomorphine effects in dogs. The compounds according to the invention also have no emetic effect in dogs at any dose level and are not cholinolytic agents.

Taken together, these pharmacological properties make the compounds of the invention useful in the treatment of Parkinson's disease as well as in the correction of extra-pyramidal disorders caused by stress-relieving agents.

Parkinson's disease is a chronic and progressive disease, manifested in particular by dopamine deficiency in the thalamus and tail and lens nuclei, as well as inability to exercise, stiffness, and tremor as visible symptoms.

Many effective drugs have already been proposed for the treatment of Parkinson's disease. Most of these products are anticholinergic agents with peripheral anticholinergic activity. These compounds are natural products, such as atropine, or are obtained synthetically, such as dietazine, benzatropine or trihexylphenidyl.

However, these drugs can have adverse side effects, most of which are due to their peripheral anti-cholinergic properties, with side effects manifested as, for example, dry mouth, difficulty with optical accommodation, tachycardia, constipation, and urinary retention. These products therefore cannot be used in the setting of cataracts and prostate hyperplasia.

7 61182 L-dopa, or levodopa, a precursor of dopamine, has also been tried for the treatment of Parkinson's disease. However, because L-dopa is partially degraded in the gastrointestinal tract, it must be administered in very high doses, often with harmful side effects. The most serious of these side effects are cardiovascular in nature and especially manifest as cardiac arrhythmias and low blood pressure in an upright position. Patients treated with L-dopa should therefore have no cardiac symptoms.

Recently, amantadine, i.e., 1-aminoadamantine, has been tried as a drug for Parkinson's disease. This product, which promotes the release of dopamine, is very effective, but causes several harmful side effects and its effectiveness also decreases over time.

For these reasons, it is very difficult to choose an effective and suitable drug for the treatment of Parkinson's disease in each case. Each patient must be considered on a case-by-case basis. All known methods of treating Parkinson's disease are symptomatic, and despite the medicine used, the disease continues to progress. Treatment of Parkinson's disease requires continuous use of one or more drugs and often requires a treatment cycle. Often, two drugs must be given at the same time against Parkinson's disease, with the first drug being considered the parent drug and the second being an adjunct or adjunct drug. Due to the longevity of the treatment, it is still necessary to use different products.

Finding new drugs to treat Parkinson’s disease is therefore very important. In this sense, the compounds according to the invention are valuable additives in the treatment of Parkinson's disease, since there is currently no ideal substance against this disease, as can be seen from the above.

The compounds according to the invention are thus a valuable addition to the medicaments used and can be used to replace various medications which have become ineffective for some reason, such as, for example, a change in the patient's condition or habituation to the medicament.

Although the pharmacological range of action of the novel compounds of the invention is very similar to that of amantadine, pharmacological experiments with pharmaceutically acceptable acid addition salts of the compounds of formula I have shown significant differences from amantadine. For example, when comparing the doses of the compounds of the invention and Amantadine that produce a particular effect, it will be appreciated that the new compounds will always have the effective dose in question relatively further away from the toxic dose than with amantadine. In other words, the reliability of the compounds according to the invention is better than that of amantadine. Other differences have been observed and are particularly evident with the preferred compound of the invention in a pharmaceutically acceptable acid addition salt of 1,1-di-n-propyl-n-butylamine, such as the hydrochloride or acid fumarate.

For example, in the cardiovascular region, it has been found that the above-mentioned preferred compound does not cause the adverse effects seen on the electrocardiogram, whereas 5 mg / kg of amantadine when injected into a dog causes cardiac arrhythmias as ventricular extrasystoles.

It has also been found that the preferred compound of the invention does not increase the peripheral effects of norepinephrine and is not a ganglioplegic agent, whereas experiments with amantadine have shown that this compound increases peripheral adrenergic effects and further has a ganglioplegic effect.

Thus, a preferred compound prepared according to the invention which does not have these adverse side effects observed with amantadine does not cause cardiac or hypertensive disorders.

As mentioned above, certain agents used in Parkinson's disease, such as dietazine, benzotropin, etc., often cause adverse anticholinergic side effects (dry mouth, difficulty with optical accommodation, etc.).

The preferred compound prepared according to the invention, which has no anticholinergic effect, does not have these disadvantages.

Likewise, the preferred compound prepared according to the invention, because it does not have emetic properties and no adverse side effects that would appear on the electrocardiogram, does not cause vomiting or cardiac arrhythmias, which are the most common side effects of L-dopa.

9 61182

Pharmacological experiments have been performed to investigate the various properties of the compounds of the invention which together make the compound useful in the treatment of Parkinson's disease and in the correction of extrapyramidal disorders caused by stress-relieving agents.

I. Inhibition of reserpine-induced and stress-induced catatonia (dopaminergic properties) 1. Inhibition of reserpine-induced catatonia

When rats are given adequate doses of reserpine, a number of symptoms occur, more specifically, hanging eyelids, catatonia, and a decrease in temperature. These symptoms cause depletion of intra-granular stores of biogenetic amines at neuronal terminals.

Tricycline-type antidepressants as well as monoamine oxidase inhibitors (I.M.A.O.) are particularly effective against addiction as well as temperature drop. These compounds have some effect on catatonia, but this is much less.

In contrast, synthetic drugs for Parkinson's disease mainly cause catatonia, but their effect on addiction and temperature drop is non-existent or minor.

The test substance was administered orally in aqueous solution to groups of 10 rats that are of the OFA strain and weighed about 150-200 g. Thirty minutes later, a 5 mg / kg dose of reserpine was administered intraperitoneally. Three hours after the reserpine injection, the animals were hung from their four paws on a horizontal, tensioned steel wire clamped to a height of 15 cm. Catatonic animals remained in this position for at least 30 seconds. Each animal that remained in this position was marked 1 and those that did not were marked 0. The maximum mark per group was thus 10. The same experiment was performed on control animals that received reserpine but were not tested for any compounds.

The following pharmaceutically acceptable acid addition salts of the compounds of formula I were tested by comparison with amantadine by the method described above. The compounds were tested in the form of pharmaceutically acceptable acid addition salts such as hydrochloride or fumarate.

The results of the experiment are shown in Table I below. These results are indicated as follows: 0: means 0% inhibition of catatonia compared to control animals (entry 10 for the group studied).

1: means 20 or 30% inhibition of catatonia compared to control animals (labeled 7 or 8 for the group studied).

2: means 50% inhibition of catatonia compared to control animals (entry 5 for the group studied).

3: means 70% or 80% inhibition of catatonia compared to control animals (labeled 2 or 3 for the group studied).

4: means 100% inhibition of catatonia compared to control animals (marking 0 for the group studied).

Table I

Compound, Dose Reserpine-Induced

Well, the salt size of this Katatonian was studied in mg / kg of anti-1 1,1-di-n-propyl-n-butylamine 5 4 2 1-ethyl-1-n-propyl-n-butylamine 5 1 3 1-ethyl-1-isobutyl n-butylamine 20 3 4 1 -ethyl-1-n-butyl-n-butylamine 20 3 5 1 -n-propyl-1-isobutyl-n-butylamine 20 2 6 1-n-propyl-1-isopropyl-n- butylamine 6 3 7 1-n-propyl-1-tert-butyl-n-butylamine 6 2

Amantadine 100 4 These results show that Compound 1, which is the most preferred compound of the invention, is as effective as amantadine, but at a dose of one twentieth of the dose of amantadine.

\ 1 11 61182 2. Prevention of catatonia caused by stress-releasing substances

Blockade of dopaminergic receptors by excitatory agents in the extrapyramidal system causes catatonia in rats. Catatonin is distinguished from its sedative properties by the experiment described above in the study of reserpine-induced catatonia. The same notation was used in this case as well.

The test compound was administered orally in aqueous solution to male OFA-derived rats in Group 10 weighing 150-200 g. After 30 minutes, a dose of 12.5 mg / kg of pro-chloroperazine was administered intraperitoneally. Three hours after the injection of the latter substance, Kataton was measured. The same experiment was also performed on control animals receiving prochlorperazine but none of the test compounds.

The results obtained with the compounds according to the invention in comparison with the results obtained with amantadine are shown in Table II. The notations used are the same as in Table I.

Table II

A compound with a dose level of

Well salt was tested in mg / kg inhibition of catatonia caused by rancid substances 1 1,1-di-n-propyl-n-butylamine 5 4 2 1-ethyl-1-n-propyl-n-butylamine 5 1 3 1-ethyl -1-isobutyl-n-butylamine 20 3 4 1-ethyl-1-n-butyl-n-butylamine 20 3 5 1 -n-propyl-1-isobutyl-n-butylamine 20 4

Amantadine 100 4 These results show that compound 1 is again 20 times more potent than amantadine and that compound 5 is five times more potent than amantadine.

In addition, Compound 1 at a dose as low as 1 mg / kg inhibits catatonia caused by stress-triggers by 70%.

12 61182

The results of Tables I and II for compound 1 were obtained with 1,1-di-n-propyl-n-butylamine in the form of its hydrochloride. As the acid fumarate, 1,1-di-n-propyl-n-butylamine is 20-40% more effective than the above form. For example, label 4 was obtained in reserpine-induced and stress-induced catatonia as described above using only 3 mg / kg of 1,1-di-n-propyl-n-butylamino acid fumarate.

II. Acute toxicity

Acute toxicity was determined in mice by the LD50 test by oral administration of compounds by the method of Lichfield and Wilcoxon (J. Pharmacol. 1938), 2, 192-216). The compounds were administered as aqueous solutions and the observation period lasted 10 days after administration of the test compound.

The following results were obtained when compared to amantadine.

No. Compound) the salt of which was examined_50 mg / kg 1 1,1-di-n-propyl-n-butylamine 100 2 1-ethyl-1-n-propyl-n-butylamine 150

Amantadine 1050 These results indicate that the compounds of the invention are generally more toxic than amantadine. However, when comparing the above LDgQ values as well as effective doses for the inhibition of catatonia caused by reserpine or anti-stress agents, it is found that such comparisons are always more advantageous for the compounds of the invention than for amantadine.

LD50 The index -w «- was determined for the salt of compound No. 2,1-ethyl-1-n-U20-30 propyl-n-butylamine.

In this index, ED20 is 30 doses that inhibit catatonia by 20-30%, and this value is denoted by the figure 1 in Tables I and II.

As a result, an index of 30 was obtained for compound # 2.

13 61182

The corresponding index for amantadine is 1 = 21, indicating that the compounds of the invention are more preferred than amantadine.

. 5 o

Similarly, the index ττττ- was determined, where ED1nn means the dose that inhibits Katatonia by 100%.

This value is shown in Tables I and II number 4.

The following results were obtained:

No Compound whose salt was examined_Index 1 1,1-di-n-propyl-n-butylamine 20

Amantadine 10 These figures indicate that Compound 1 has a complete inhibitory effect on the catatonia caused by reserpine and anti-stress agents at a dose relatively twice the toxic dose compared to amantadine. Compound 1 thus has a greater safety margin than amantadine.

When 1,1-di-n-propyl-n-butylamine fumarate is used, the effective dose is even further away from the toxic dose than when compound 1 is used, when the corresponding index is then ~33.

Other experiments were performed on rats using Compound 1 and amantadine. These experiments examined catalepsy that occurred when the equilateral paws of animals were tied together. In these experiments, 5 mg / kg of Compound 1, administered orally 30 minutes before intraperitoneal injection of prochlorperazine, was found to provide complete inhibition of catalepsy 3 hours after injection of the latter.

A dose of 80 mg / kg was required with amantadine to completely prevent catalepsy.

The effect of compound 1 in treatment was also studied.

i ^ 14 61182 a) Stopping Reserpine-Induced Catatonia

Groups of 5 male rats of OFA strains weighing 150-200 g were given 5 mg / kg reserpine intraperitoneally. After one hour and 45 minutes, i.e. in the catatonic state, the test compound was administered orally orally to all animals except the control group.

The progress of catatonia was monitored according to the scale used as well as in the experiments described above.

The maximum mark was then 5 per group, which means that all the animals in the group were still considered to be in a catatonic state.

The following results were obtained with compound 1 when compared to amantadine:

Table III

Time since reserpine administration 2h 2h15 2h30 3h 3h30 4h 5h Reference animals 5 5 5 3 3 1 2

Compound 1, 2.5 mg / kg 432,000

Compound 1.5 mg / kg 51,000,000

Amantadine, 80 mg / kg 54321 00 These results indicate that oral administration of Compound 1 at doses of 2.5 mg / kg and 5 mg / kg results in a faster cessation of reserpine-induced Kataton than with 80 mg / kg amantadine under the same conditions.

Compound 1 is thus at least 32-fold more potent than amantadine in the treatment of reserpine-induced catatonia.

b) Stopping catatonia caused by stress-inducing agents Groups of 5 male rats of OFA strain were given 12.5 mg / kg prochlorperazine intraperitoneally. After 25 minutes, all animals were orally administered test compound is 61182 in aqueous solution, except for the control group. The progression of catatonia was studied in the same manner as in the experiments described above.

The following results were obtained with compound 1 and amantadine:

Table IV

Time elapsed since the administration of prochlorperazine_ _1h3Q 2h30 3h 3h30 Uh 5h_

Vertailueläimet_4_4_4_3_1_1_

Compound 1 5 mg / kg_3_0_0_0_0_0__

Amantadine 80 mg / kg_5_2_1_0_0 0_

The results show that during treatment, a dose of 50 mg / kg of Compound 1 acts on catatonia caused by stress-inducing agents more rapidly than a dose of 80 mg / kg of amantadine under the same conditions.

Thus, in this experiment, compound 1 is at least 16-fold more potent than amantadine.

LD50

Here again, the toxicological pharmacological index, ^ -, is more favorable for compound 1 than for amantadine, in particular for compound 1 it is 20 and for amantadine only 13.

An experiment was also performed to determine whether Compound 1 has cholinolytic properties.

For this purpose, the Magnus experiment (Arch. Gen. Physio.

1904, 102). This experiment determines the dose of acetylcholine that, when added to a bath, causes convulsions in the isolated duodenum of a rat. The next step involves determining the dose of test compound that, when added to the bath 30 seconds before acetylcholine, reduces seizures.

The following results were obtained with compound 1 compared to atropine: 16,61182

Table V

Dose in Seizure _bath g / ml_prevention% _

Acetylcholine 0.5 x 10 ~ 3

Atropine 0.1 x 10 ~ 6 45 0.2 x 10-6 100

Compound 1 0.2 x 1 0 ~ 6 0 0.1 x 10 "5 0 0.1 x 10-1 * 0 0.1 x 10" 3 0 0.2 x 10-2 36 0.5 x 10- 2 60

Experiments show that compound 1 is 20,000 to 25,000 times less effective than atrppine.

The "in vitro" cholinolytic activity of Compound 1 must thus be considered to be virtually non-existent compared to atropine.

The very weak cholinolytic effect of Compound 1 occurs only at toxic doses.

The absence of the cholinolytic property of Compound 1 was demonstrated at "in vivo" therapeutic doses.

To this end, the following experiment was performed to determine the tremorine inhibitory properties of Compound 1.

When injected into mice, tremorine causes peripheral effects such as sneezing, sweating, salivation, and diarrhea, as well as central nervous system effects such as tremor and immobility. Such effects are due to an increase in the amount of acetylcholine and serotonin in the brain.

Male mice of the OF ^ strain weighing about 22 g were divided into groups of 10 individuals. Each group was orally administered 50 mg / kg of the test compound in aqueous solution. After 30 minutes, tremorin was injected at a dose of 10 mg / kg intraperitoneally, and at various times after this injection, r · 17 61182 cholinergic effects were observed in each animal using the following scale: 0: no effect 1: slight effect 2: moderate effect 3: strong effect 4 : very strong effect

Compound 1 at 5 mg / kg and amantadine at 40 mg / kg gave the following results:

Taking into account peripheral cholinergic effects, i.e. salivation, sweating and sneezing, label 4 was obtained for control animals 20, 30 and 40 minutes after tremor injection at both 5 mg / kg Compound 1 and 40 mg / kg amantadine. Similar results were obtained when studying cholinergic central nervous system effects, i.e., normal and artificially induced tremor.

These results indicate that Compound 1 and amantadine do not have anti-tremor properties, confirming the lack of cholinolytic properties of Compound 1 when administered at therapeutic doses.

Compound 1 was also tested to investigate the effect of this compound on peripheral noradrenergic phenomena.

The following experiment was performed for this purpose:

A cat anesthetized with pentobromital was given such a high dose of norepinephrine that its blood pressure rose, but the dose was not so high that it caused a contraction of the mucous membrane. Blood pressure was measured in the common carotid artery immediately after norepinephrine administration. Thereafter, increasing doses of Compound 1 were administered as aqueous solutions by intravenous injection every 30 minutes.

After each administration of Compound 1, a further dose of norepinephrine was administered and the following were observed: an increase in arterial pressure, a contractile membrane contraction reaction induced by a given norepinephrine, and a contraction reaction of this membrane caused by the release of norepinephrine 61182

Table VI

Accumulating doses of arterial pressure Elevation of the mucosa ^ contraction mg / kg nm Hg norepinef reaction (nm *) _ rine injection No electrical- Electrical irritation after irritation due to its effect_

Compound 10 26 0 17 0.1 18 0 15 1 25 0 16 3 29 0 17 5 25 0 16 10 22 0 12

Amantadine 0 28 0 20 0.1 29 0 20 1 35 3 20 3 35 4.4 16 5 59 5.9 10 10 57 7.5 4 * mm means the increase in contraction shown in the drawing.

These results indicate that Compound 1 does not potentiate the effects of externally administered or internally generated norepinephrine.

On the other hand, amantadine potentiates the effect of topically administered norepinephrine at a dose of 1 mg / kg because it increases the intensity and duration of the antihypertensive effect of this amine and, after administration, a dose of norepinephrine that would not otherwise affect the membrane causes a partial contraction.

Furthermore, amantadine itself acts as a stimulus for the mucosal contraction reaction, but does not potentiate the effects of electrical irritation. In contrast, amantadine has ganglioplegic properties from a dose of 5 mg / kg.

19 61182

It will be appreciated that the therapeutic use of the compounds of the invention will normally be in a dosage form appropriate for the mode of administration, pharmaceutical or veterinary use used, the active ingredient comprising a compound of the invention in association with a carrier or excipient. For oral administration, the mixture may be, for example, a coated or uncoated tablet, hard or soft gelatin capsule, suspension or syrup. The composition may also be a suppository for rectal administration or as a solution or suspension for parenteral administration.

The dosage unit may contain 5 to 50 mg of active ingredient, preferably 5 to 10 mg for oral administration and 5 to 50 mg for rectal administration or 1 to 10 mg for injection.

Therapeutic compositions are prepared by combining at least one pharmaceutically acceptable acid addition salt of a compound of formula 1 with at least one suitable carrier or excipient. Examples of suitable carriers are talc, magnesium stearate, milk sugar, sucrose, carboxymethylcellulose, starches, kaolin, levilite and cocoa butter.

The following examples illustrate the preparation of pharmaceutically acceptable acid addition salts of compounds of formula I.

Example 1 Preparation of pharmaceutically acceptable acid addition salts of 1,1-di-n-propyl-n-butylamine a) 1,1-di-n-propyl-n-butyl isocyanate in a 2 liter three neck flask fitted with a water condenser, mechanical stirrer, thermometer and a dropping funnel, poured 1 · ι4 g of sodium hydroxide in tablet form and 1200 ml of water. The solution was cooled to 5 ° C and 48 ml of bromine was slowly added with stirring. The addition of bromine lasted for two hours, and then at 0 ° C, 111 g of 2,2-di-n-propylvaleramide was added to the resulting yellow-green solution. Stirring was continued for 4 hours at about 0 ° C. The oily phase was then extracted with three ether fractions, each of 300 ml, and the ether phase was washed twice with 100 ml of water, dried over magnesium sulphate and evaporated in vacuo. The pale yellow oil thus obtained was distilled under reduced pressure (5 mm Hg).

There were thus obtained 105 g of colorless 1,1-di-n-propyl-n-butyl isocyanate.

Boiling point 78 ... 79 ° C at 5 mm Hg.

Yield 95%.

By the method described above, but using the appropriate starting material, the following compound was prepared:

Boiling point ° C

1-n-propyl 1-isopropyl n-butyl isocyanate 97 (15 mm Hg) b) 1,1-di-n-propyl-n-butylamine hydrochloride

200 ml of water and 90 ml of concentrated hydrochloric acid (d = 1.19) were poured into a three-necked flask equipped with a mechanical stirrer, dropping funnel, thermometer and condenser. The acidic solution was heated to 90 ° C and then, with vigorous stirring, 105 g of 1,1-di-n-propyl-n-butyl isocyanate prepared as described above was added thereto. The addition lasted for one hour, after which the reaction mixture was kept at a temperature of 95-100 ° C for a further 4 hours. The mixture was then cooled to about 0 ° C, and the colorless crystals thus obtained were separated by filtration and dried first by allowing air to act and then in a desiccator with potassium hydroxide. There was thus isolated 99 g of 1,1-di-n-propyl-n-butylamine hydrochloride as a white crystalline powder.

The product does not melt, but sublimes at 220 ° C.

By the method described above, but using the appropriate compounds as starting materials, the following compounds were prepared: 21,61182

Sp. 0

1-ethyl-1-propyl-n-butylamine hydrochloride 180 ° C

(Yield: 64%) (sublimes)

1-ethyl-1-isobutyl-n-butylamine hydrochloride 230 ° C

(Yield: 55%) (sublimes)

1-n-propyl-1-isobutyl-n-butylamine hydrochloride 260 ° C

(Yield: 60%)

1-ethyl-1-n-butyl-n-butylamine hydrochloride 230 ° C

(Yield: 59%) (decomposes) 1-n-propyl-1-isopropyl-n-butylamine hydrochloride 260 ° C (Yield: 75%) (decomposes)

Other pharmaceutically acceptable acid addition salts were prepared by reacting the above hydrochloride with an alkali hydroxide followed by the desired acid.

A. 1,1-Di-n-propyl-n-butylamino acid fumarate

To a solution of 1.16 g (0.01 mol) of fumaric acid in 20 ml of acetone was slowly added 1.57 g (0.01 mol) of 1,1-di-n-propyl-21n-butylamine (n = 1.4349) dissolved in 10 ml of acetone, the amine prepared from its hydrochloride obtained as described above and 30% aqueous sodium hydroxide solution. After stirring for 1 hour, the crystals formed were filtered off with suction, washed with acetone and dried in vacuo.

There was thus obtained 1,1-di-n-propyl-n-butylamino acid fumarate as a white powder. Sp. 216 ° C, sublimes.

Yield 100%.

In the same manner as described above, but stirring the reaction mixture for 3 hours, 1-n-propyl-1-tert-butyl-n-butylaminic acid fumarate with a melting point of 180 ° C (sublimes) was obtained. Yield 98%.

B. 1-Ethyl-1-n-butyl-n-butylamine tartrate 1-Ethyl-1-n-butyl-n-butylamine hydrochloride was reacted in acetone with a 30% aqueous solution of sodium hydroxide in 1-ethyl-1-n-butyl-n- to give butylamine in the form of the free base. The amine thus obtained was extracted with ether.

22 61 1 82

To a solution of 1 mole of L - (+) - tartaric acid in isopropanol was added 1 mole of 1-ethyl-1-n-butyl-n-butylamine base. The reaction mixture was refluxed for 5 minutes, cooled, after which the formed crystals were filtered.

In this way, the salt of 1-ethyl-1-n-butyl-n-butylamine and L - (+) - tartaric acid was obtained as colorless crystals which, when recrystallized from isopropanol, melted at 180 ° C with sublimation.

In a similar manner to the above, a salt of 1-ethyl-1-n-butyl-n-butylamine and D - (-) - tartaric acid was obtained. Mp 87.7 ° C recrystallized from water.

Example 2 Preparation of 1-n-propyl-1-isobutyl-n-butylamine hydrochloride a) 1-n-propyl-1-isobutyl-n-butanol in a 250 ml three-necked flask equipped with a mechanical stirrer, a nitrogen line, a dropping funnel and a thermometer , 2.8 g (0.2 mol) of lithium and 100 ml of anhydrous and purified tetrahydrofuran were poured under nitrogen. A suspension of lithium in tetrahydrofuran was cooled to -20 ° C and then a mixture of 22.8 g (0.2 moles) of di-n-propyl ketone and 30 g (0.2 moles) of 10% excess) iso-butyl bromide. The addition took about 3 hours during which time the temperature was maintained at about -20 ° C. The solution was allowed to stand for about 12 hours at room temperature and then concentrated. The oil thus obtained was dissolved in water, extracted with ether and distilled under reduced pressure.

There was thus obtained 21 g of 1-n-propyl-1-isobutyl-n-butanol as a clear liquid which was slightly yellowish.

Kp. 74 ... 76 ° C at 5 mm Hg.

Yield about 60%.

By the method described above, using the appropriate starting materials, the following compounds were prepared: 23 61 1 82

Compound Boiling point ° C

1-ethyl-1-isobutyl-n-butanol 78, 79 (yield 40%) (15 mm Hg) 1-ethyl-1-n-propyl-n-butanol 17 8 ... 17 9 (yield 35%) ) (760 mm Hg) 1,1-di-n-propyl-n-butanol 78-80 (60% yield) (0.15 mm Hg) 1-n-propyl-1-isopropyl-n-butanol 81 (15 mm Hg) 1-n-propyl-1-tert-butyl-n-butanol 90-92 (14 mm Hg) 1-ethyl-1-n-propyl-n-pentanol 87 (yield 35%) (11 mm Hg) b) 1-n-Propyl-1-isobutyl-n-butylamine hydrochloride 6.5 g (0.1 mol) were poured into a 250 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, condenser and thermometer. ) dry potassium cyanide in powder form, 14.4 g (0.083 mol) of 1-n-propyl-1-isobutyl-n-butanol and 12 ml of acetic acid. A mixture of 25 g of concentrated sulfuric acid (d = 1.83) and 12 ml of acetic acid was added slowly with stirring. The addition took about 2 hours during which time the temperature was maintained at about 50 ° C. The reaction mixture was heated to 70 ° C for two hours and then slowly poured into 100 ml of ice water. It was then neutralized with 20% aqueous sodium hydroxide solution and extracted with ether. The ether was evaporated off and the oil, 1-n-propyl-1-isobutyl-n-butylamine in N-form, was collected.

The N-form amine thus obtained was boiled under reflux for 2 hours in the presence of 20 ml of concentrated hydrochloric acid. On cooling, the hydrochloride of this amine crystallized. It was separated by filtration and washed with acetone.

There was thus obtained 11 g of 1-n-propyl-1-isobutyl-n-butylamine hydrochloride as a white powder.

Sp. > 260 ° C and decomposes without melting at about 280 ° C.

Yield: 64%.

2.1 61182

Thin layer chromatography on silica gel plates (Merck HF 254) using solvents containing 79 parts of benzene, 14 parts of netanol and 7 parts of acetic acid and iodine gave an Rf of 0.6.

By the same procedure as above, but using the appropriate starting materials, the following compounds were prepared. The Rf values reported for these compounds were determined by thin layer chromatography using the same medium and solvent system as above.

Compound

1,1-di-n-propyl-n-butylamine hydrochloride 220 ° C

(Sublimes)

1-ethyl-1-n-propyl-n-butylamine hydrochloride 180 ° C

(yield 25%); Rf = 0.64 (sublimes)

1-ethyl-1-isobutyl-n-butylamine hydrochloride 230 ° C

(yield 30%); Rf = 0.60 (sublimes)

1-n-propyl-1-isopropyl-n-butylamine hydrochloride M.p. 260 ° C

(Dec)

1-ethyl-1-n-propyl-n-pentylamine hydrochloride M.p. 230 ° C

(yield 30%); Rf = 0.60 (decomposes)

Claims (1)

An analogous process for the preparation of pharmaceutically acceptable acid addition salts of n-butylamine derivatives of the general formula ch3 to ch2 to ch2 R- to NH0 (I) 1/2 R2, in which formula represents an ethyl or n-propyl group and Rj represents i) ethyl -, n-propyl, isopropyl, isobutyl or tert-butyl when R 1 is n-propyl, or ii) an n-butyl or isobutyl group when R 2 is ethyl, characterized in that a) CH, - CH „- CH0 o 1 vz R„ - C - N = C = O (II) V Isocyanate according to R2, in which formula and R2 have the same meaning as above, to react in a suitable medium and at a temperature of 15 ° C and 100 ° C preferably between 50 ° C and 90 ° C, with a strong acid such as hydrochloric acid or sulfuric acid capable of forming a pharmaceutically acceptable acid addition salt to form the corresponding desired acid addition salt of the compound of formula I, or b) N-formylamine of the formula CH3 - CH2 - CH2O - C-NH-CH (III) in which R1 and R2 have the same meaning as above, to react in a suitable medium at a temperature of 15 ° C and 100 ° C preferably between 50 ° C and 90 ° C, with a strong acid such as hydrochloric acid or sulfuric acid 26 61 1 82 which is capable of forming a pharmaceutically acceptable acid addition salt to form the corresponding desired acid addition salt of the compound of formula I which the acid addition salt thus obtained, if desired, is reacted with an alkali metal hydroxide, such as sodium hydroxide, to give a compound of formula I in the form of a free base, which base is then reacted with a suitable organic or inorganic acid to form another pharmaceutically acceptable acid addition salt. Analogs of the pharmaceutical form of a pharmaceutically acceptable syrup addition of n-butylamines with the formula ch3 - ch2 - ch2 R- '-'C-NH9 (I) V R2 are betecyl and ethyl- or n-propyl group o R2 R2 is i) en ethyl, n-propyl, isopropyl, isobutyl or tert-butyl, then R, n-propyl n-propyl, or ii) en n-butyl or isobutyl, then R, ethyl, ethyl and isocyanate with all of the formulas CH2-CH0 - CH0 3 2 R1 - * C - N = C = O (II) R2 is R1 and R2 is taken as such, reacting with a heated medium at a temperature of 15 and 100 ° C, warm to 50 ° C to 90 ° C, with stark syrup, säsom t.ex. salt or syrup, in the case of a pharmacologically acceptable formulation of salt, for the manufacture of self-propelled liquids under the formulation of formula I, or