FI68218C - FREQUENCY REQUIREMENT FOR THERAPEUTIC ACTIVATION OF ACTIVE DI-N-PROPYLMETHYLAMIN - Google Patents

Description

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Process for the preparation of therapeutically active di-n-propylmethylamine derivatives For the preparation of therapeutically active di-n-propylmethylamine derivatives

The invention relates to a process for the preparation of new therapeutically active di-n-propylmethylamine derivatives and their pharmaceutically acceptable acid addition salts.

The general formula of the therapeutically active compounds to be prepared according to the invention is as follows:

"-C3H7X

R-C-NHCH 1 / n-C 3 H 2 in which R represents n-propyl, isopropyl, isobutyl or allyl.

The invention also provides pharmaceutically acceptable acid addition salts of the compounds of formula (I), e.g. acid addition salts with an inorganic acid such as hydrochloric acid, or salts with an organic acid having the free carboxyl of the acid attached to a saturated or unsaturated aralkyl, ariphatic or aliphatic radical. optionally may contain another carboxyl group, e.g. a fumaric acid group.

The compounds of formula (I) have, depending on their chemical structure, one or more isomeric centers, so that they can be prepared as optical isomers or as mixtures of such isomers. Mixtures of these isomers may, if desired, be separated into the corresponding individual isomers 6821 8 by applying, at appropriate stages, methods known in the art.

- I

As will be explained in more detail below, the methylamine derivatives of formula (I) and their pharmaceutically acceptable acid addition salts have been found to have pharmacological properties which make them particularly useful in the treatment of Parkinson's disease and in the treatment of extrapyramidal disorders caused by neuroleptic drugs.

The compounds of formula (I) are prepared according to the invention by reduction with lithium aluminum hydride of an isocyanate of general formula

"-C3H7X

R to C-N = C = O n -c3b / wherein R is as defined above to give the desired methylamine derivative of formula I which may then be reacted with an organic or inorganic acid to give a pharmaceutically acceptable acid addition salt of this derivative.

The reduction can be performed in an inert and anhydrous medium such as ethyl ether.

All compounds of formula (II) are known compounds and their methods of preparation are described in GB Patent No. 1,467,739.

As mentioned above, it has been found that the methylamine derivatives prepared according to the invention have valuable pharmacological properties which allow them to be used in human and veterinary medicine.

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In particular, it has been found that the compounds according to the invention have noradrenergic and essentially dopaminergic properties. These latter properties prove to have an inhibitory effect on catatonia and catalepsy caused by reserpine and neuroleptics.

Furthermore, at doses that completely suppress catatonia and catalepsy caused by neuroleptic agents, it has been found that the compounds of the invention do not affect the anti-amphetamine effects of neuroleptic agents in rats or the anti-apo-morphine effects in dogs. These new compounds also have no antiemetic effect in dogs at any dose and are not cholinolytic agents.

Due to these pharmacological properties, the compounds of formula (I) can be successfully used in the treatment of Parkinson's disease as well as in the treatment of extrapyramidal disorders caused by neuroleptic agents. In this case, the patient is administered an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. When administered to a person weighing 60 kg, the effective dose is suitably about 10 to 60 mg of active ingredient.

It is known that compounds whose methylamine moiety is trisubstituted but unsubstituted at the nitrogen atom have key noradrenergic and key dopaminergic properties that can be used in the treatment of Parkinson's disease and in the treatment of extrapyramidal disorders caused by neuroleptic agents.

These compounds are described in the aforementioned GB Patent No. 1,467,739.

It has also been found that those compounds in which the methylamine moiety is disubstituted but has no substituents on the nitrogen atom, such as 1-n-propyl-n-butylamine, also have the necessary properties for use as a medicine for Parkinson's disease.

Methyl! in in vivo, however, those disubstituted and trisubstituted derivatives which have no substituent on the nitrogen atom have varying degrees of inhibitory effect on monoamine oxidase.

In clinical use, this inhibitory effect is observed in the form of adverse side effects such as heart rate, peroxysmic hypertension and hypertension.

However, it has been very surprisingly found that the compounds according to the invention, used in the same concentrations, exhibit a monoamine oxidase inhibitory effect which is much weaker than that of the above-mentioned di- and trisubstituted methylamine derivatives, and in some cases the compounds according to the invention have no inhibitory effect.

Due to this completely surprising advantage of the N-substituted derivatives of methylamine prepared according to the invention, compared to the N-unsubstituted di- and tri-substituted derivatives of methylamine, these new compounds are more advantageous than said derivatives having no substituent at the nitrogen atom.

The compounds of the invention are also more preferred than amantadine, i.e. 1-aminoadamantane, which is widely used in the treatment of Parkinson's disease.

Although the pharmacological spectrum of the compounds according to the invention is very similar to that of amantadine, pharmacological experiments with the new compounds have shown considerable differences compared to amantadine. Thus, when comparing the doses of the compounds of the formula I and 5,682,18 amantadine which have a certain effect, it has been found that the effective dose required for the compounds of the formula I is always relatively further away from the toxic doses than with amantadine. In other words, the compounds of the invention have a wider safety margin than amantadine.

It is very important to try to come up with new drugs for Parkinson’s disease because the treatment is long-term and you have to take different drugs alternately.

Judging from this point of view, the compounds according to the invention constitute valuable additions to the available drugs for Parkinson's disease, since there is currently no ideal drug for the treatment of this disease, as explained above.

N-methyl-1,1-di-n-propyl-n-butylamine has been shown to have one of the most valuable properties as a drug for Parkinson's disease.

The compounds of formula I are used as free bases or pharmaceutically acceptable acid addition salts, e.g. as hydrochlorides or fumarates.

The observed central dopaminergic activity of the compounds of the invention is illustrated below for some compounds and compared to the activity of amantadine. These compounds were suitably tested as pharmaceutically acceptable acid addition salts, and the compounds tested were as follows: N-methyl-1,1-di-n-propyl-n-butylamine (Compound 1) N-methyl-11-propyl-1-isopropyl-n- butylamine (Compound 3) N-methyl-1n-propyl-1-isobutyl-n-butylamine (Compound 4) N-methyl-11n-propyl-1-allyl-n-butylamine (Compound 5) 6,682,188 Reserpine and neuroleptics Inhibition of Drug-Induced Catatonia (Dopaminergic Properties) 1. Inhibition of Reserpine-Induced Catatonia The assay used for this purpose is similar to that described in the aforementioned GB Patent No. 1,467,739.

The following table shows the results obtained with the above-listed preparations according to the invention as well as with amantadine.

These results have been expressed by applying the same grading system, i.e. inhibition indices 0 ... 4, as in the above-mentioned GB patent.

Table I

Compound Dose mg / kg Reserpine-induced catatonia inhibition 16 4 3 6 4 4 6.5 3 5 5 2

Amantadine 100 4 2. Inhibition of Neuroleptic-Induced Catatonia The assay used for this purpose is similar to that described in GB Patent No. 1,467,739.

The following Table II shows the results obtained with the compounds listed above compared to the results obtained with amantadine.

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The same system as in Table I was used for the evaluation. Table II *

With a neuroleptic drug

Compound Dose mg / kg Prevention of induced catatonia I 6 3 3 6 3 4 6.5 4 5 5 2

Aroanthadine 100 4 II Acute toxicity

Acute toxicity The LD50 was determined in mice by oral administration and application of the method described in the aforementioned GB Patent No. 1,467,739.

The compounds obtained according to the invention gave the following results, which were compared with those obtained with amantadine in.

Compound LD50 mg / kg 1100 3> 150 5 170

Amantadine 1050 The LD5Q / EDIOO index was determined for comparison with amantadine.

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The following results were obtained:

Compound Index 1 16.5 3 25

Amantadine These results indicate that the compounds of the invention provide a higher safety margin than amantadine.

III. Monoamine oxidase inhibition The following experiment was used for the assay:

Two rats weighing resp. 190 and 200 g, were killed by cutting off their heads. The livers were rapidly removed, dissected in hypertonic medium, and weighed, and the homogenate was purified by fractional centrifugation, and the mitochondrias fraction was collected.

Inhibition of monoamine oxidase by the test compound was measured by polarograture.

The following solutions were added to the measuring cell: a) 1.1 ml of 0.1 molar phosphate buffer solution (pH * 7.4) supplemented with 0.005 molar potassium cyanide solution.

b) 0.01 ml of a 0.5 molar aqueous solution of the test compound. The final concentration of this product in the cell was 0.00333 moles.

c) 0.1 ml of the mitochondrial suspension prepared above, i.e. 12.5 mg of protein.

Three minutes later, the reaction was started by adding 0.2 ml of a 0.05 molar phosphate buffer solution of aerotomine creatine sulfate to give a final amine concentration in the cell of 0.00666 mol.

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The mitochondrial titer was calculated using the method presented by Biuret using bovine albumin as a reference protein.

Similar experiments were also performed using 0.02 of test compounds; 0.04; 0.06; 0.08 and 0.10 0.5 molar solutions.

The following results describe the percentage inhibition of monoamine oxidase by the compound of the invention compared to the inhibitory effects obtained with two methylamine derivatives having no substituent on the nitrogen atom when the two derivatives were studied under the same conditions.

Table ml ml of esto-1-n-propyl-1,1-di-n-N-methyl-1,1-compound n-butylpropyldi-n-propylamine hydro-n-butyl-n-butylamine chloride amine hydrochloride chloride 0.01 22 1.5 3 0.02 25 6 1.5 0.04 33.5 11.5 3 0.06 44 11.5 0 0.08 48 14.5 0 0.10 54 14.5 3 These results show that the inhibitory effect of monoamine oxidase is very pronounced when 1-n-propyl-n-butylamine hydrochloride is used, the weak 1,1-di-n-propyl-n-butylamine -hydrochloride and practically non-existent in the case of N-methyl-1,1-di-n-propyl-n-butylamine hydrochloride.

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The following examples illustrate the preparation of the compounds of the invention.

Example 1 Preparation of N-methyl-1,1-di-n-propyl-n-butylamine hydrochloride a) N-methyl-1,1-di-n-propyl-n-butylamine

To a suspension of 1.9 g (0.05 mol) of lithium aluminum hydride in 60 ml of anhydrous ethereal sulfuric acid was added 3.66 g (0.02 mol) of 1,1-di-n-propyl-n-butyl isocyanate in 20 ml of dry ether.

The addition was performed over 30 minutes at room temperature, after which the reaction mixture was heated to reflux for 3 hours. The hydrolysis was performed first with ether saturated with water and then with water, after which the organic phase was separated. The organic phase was dried over magnesium sulfate and distilled under reduced pressure.

In this way, 3.2 g of N-methyl-1,1-di-n-propyl-n-butylamine were obtained as a colorless solution.

Bp t 84 oC 13 mm Hg Yield: 94% b) N-methyl-1,1-di-n-propyl-n-butylamine hydrochloride

By bubbling dry hydrochloric acid gas through an ethereal solution of the amine thus prepared, N-methyl-1,1-di-n-propyl-n-butylamine hydrochloride was mixed as colorless crystals. Melting point: 133 ... 134 OC.

Yield: 90%.

Applying the above procedure, but using the appropriate starting materials, the following compounds were prepared: 11 6821 8

Compound Melting point oc N-methyl-1-n-propyl-1-isopropyl-n-butylamine hydrochloride (Yield: 80%) 144-145 N-methyl-11-propyl-1-isobutyl-n -butylamine hydrochloride 139 N-methyl-11-propyl-1-allyl-n-butylamine hydrochloride.

Claims (3)

12 6821 8 A process for the preparation of therapeutically active di-n-propylmethylamine derivatives of the general formula "-SH7X RC-NHCH / 311" -sv and their pharmaceutically acceptable acid addition salts, wherein R represents n-propyl, isopropyl, isobutyl or allyl, characterized in that lithium aluminum hydride is reduced with an isocyanate of the general formula n which can then be reacted with an organic or inorganic acid to give a pharmaceutically acceptable acid addition salt of this derivative. Process according to Claim 1, characterized in that the inert solution is ethyl ether. Process according to Claim 1 or 2, characterized in that N-methyl-1,1-di-n-propyl-n-butylamine and a pharmaceutically acceptable acid addition salt thereof are prepared. tl