FI63015B - FREQUENCY REQUIREMENT FOR THERAPEUTIC ACTIVATION OF ACTIVE DI-N-PROPYLMETHYLAMIN DERIVATIVES - Google Patents

Description

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The number of patents and the term of the patent is multiple. -

Patent- och ragistarstyralscn AmMuu * utiafd och utLskriteon published 31.12.82 (32) (33) (31) Pyydutty utuelkni * —Bujird prtorttut 03,06.76

Belgium-Belgien (BE) 8U2528 (71) Sanofi, i + 0, avenue George V, 75008 Paris, France-France (FR) (72) Charles Pigerol, Saint-Ouen, Pierre Eymard, Fontaine, Madeleine Broil, St. Egreve , Jean-Claude Vernieres, Domene, France-France (FR) (7I +) Qy Borenius & Co Ab (5U) Process for the preparation of therapeutically active di-n-propylmethylamine derivatives - For the preparation of therapeutically active di-ci-propylmethylamines .__

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 therapeutically active compounds according to the invention correspond to the general formula: n-C3H7 \ / * 1

R-C-N I

wherein R represents n-propyl, isopropyl, isobutyl or allyl, represents hydrogen, methyl or propargyl and R 2 represents methyl or propargyl or a pharmaceutically acceptable acid addition salt of these compounds, N, N-dimethyl- with the exception of 1,1-di-n-propyl-n-butylamine.

The invention also provides pharmaceutically acceptable acid addition salts of the compounds of formula (I), e.g. , which may optionally 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 by applying, at appropriate stages, methods known in the art.

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 preparation of N, N-dimethyl-1,1-di-n-propyl-n-butylamine is described in Synthesis No. 11, 1972, p. 611. The publication does not disclose the properties of the compound at all, and the method of preparation is not the same as in the present invention.

The four compounds of formula (I) in which and R 2 both represent methyl fall within the very broad general formula of U.S. Patent No. 3,067,011, without being specifically mentioned in this patent.

♦ Accordingly, these four compounds of formula (I) must be regarded as new compounds.

The compounds of formula (I) are prepared according to the invention by heating a compound of general formula 3 63015 n-CO 2

R-C-NHR-II

/ n C3H7 tax its acid addition salt, in which R is as defined above and r3 is hydrogen, methyl or propargyl, in the presence of an alkaline medium with a suitable amount of a halide of the following general formula

R4X III

wherein R 4 represents methyl or propargyl and X represents a chlorine, bromine or iodine atom, this reaction being carried out either with or without a solvent to give the desired methylamine derivative which can then be reacted with an organic or inorganic acid to give a pharmaceutically acceptable acid addition salt of this compound.

By applying chemical methods known in the art and if it is desired to prepare a compound of formula (I) having two identical substituents on the nitrogen atom, a suitable compound of formula (II) is treated, i.e. a compound of formula (II) wherein R represents the desired radical and R3 means a hydrogen atom such that two molar equivalents of a halide of formula (III) react with one molar equivalent of a compound of formula (II).

If it is desired to prepare a compound of formula (I) having a hydrogen atom attached to the nitrogen atom, a suitable compound of formula (II) is treated, i.e. a compound of formula (II) wherein R has the desired meaning and R3 represents a hydrogen atom One molar equivalent of the halide of formula (III) reacts with one molar equivalent of the compound of formula (II).

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It is already known that if it is desired to prepare a compound of formula (I) which is monosubstituted at a nitrogen atom, a mixture is obtained in which, in addition to the desired monosubstituted compound, a certain amount of the corresponding compound of formula (I) is disubstituted at the nitrogen atom. that the above molar equivalents are used.

Likewise, a certain amount of a monosubstituted compound at the nitrogen atom is formed in the case where it is desired to obtain a corresponding compound disubstituted at the nitrogen atom.

Such mixtures of mono- and disubstituted derivatives can be separated into their components by applying methods known in the art, e.g. by fractionally distilling the reaction mixture containing them or by fractionally crystallizing them from their salts.

Those compounds of formula (II) in which R3 represents a hydrogen atom are known compounds which are described by their method of preparation in GB Patent No. 1,467,739.

Other compounds of formula (II), namely those in which R 3 represents methyl or propargyl, are in fact compounds of formula (I), the preparation method of which is described above.

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.

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.

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Furthermore, at doses that completely suppress the catatonia and catalepsy caused by neuroleptic agents, it has been found that the compounds of the invention do not affect the anti-amCetamine 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 British Patent Publication No. 1,467,739.

It has also been found that those compounds in which the methylamine moiety is disubstituted but has no substituent 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.

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However, those disubstituted and trisubstituted derivatives of methylamine 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 those di- and trisubstituted derivatives of methylamine which are not substituted by a nitrogen atom, these new compounds are more advantageous than those derivatives which do not have a 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 of the invention is very similar to that of amantadine, pharmacological experiments with the new compounds have shown significant differences compared to amantadine. Thus, when comparing the doses of the compounds of the formula I and amantadine, which have a certain effect, it has been found that in the case of the compounds of the formula I, the effective dose required is always relatively further away from the 7 63015 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.

The following N-substituted derivatives and Ν, dis-disubstituted derivatives according to the invention have proven to have the most valuable properties as drugs for Parkinson's disease: N-methyl-1,1-di-n-propyl-n-butylamine in the form of the free base or a pharmaceutically acceptable acid addition salt thereof , such as, for example, as the hydrochloride or fumarate, and N, N-dimethyl-1,1-di-n-propyl-n-butylamine. as a pharmaceutically acceptable acid addition salt, e.g. as the hydrochloride.

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 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, N-dimethyl-1,1-di-n -propyl-n-butylamine (Compound 2) N-methyl-n-propyl-1-isopropyl-n-butylamine (Compound 3) N-methyl-n-propyl-1-isobutyl-n-butylamine (Compound 4) 8 63015 N -methyl-11-propyl-1-allyl-n-butylamine (Compound 5) N-propargyl-1,1-di-n-propyl-n-butylamine (Compound 6) N, N-dimethyl-1-n-propyl -1-isobutyl-n-butylamine (Compound 7)

NrN-dipropargyl 11-1,1-di-n-propyl-n-butylamine (Compound 8) 1 Inhibition of reserpine and neuroleptic drug-induced catatonia (dopaminergic properties) 1. Inhibition of reserpine-induced catatonia The test used for this purpose is similar to that described in the aforementioned British patent publication no. 1467739.

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 British patent publication.

Table I

Compound Dose mg / kg Reserpine-induced catatonia inhibition 16 4 2 6 4 3 6 4 4 6.5 3 5 5 2 6 6 1 7 6.5 3 8 15 2

Amantadine 100 4 9 63015 2. Inhibition of Neuroleptic-Induced Catatonia The assay used for this purpose is similar to that described in British Patent Publication No. 1,467,739.

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

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

With a neuroleptic drug

Compound Dose mg / kg Prevention of induced catatonia 16 3 2 6 4 3 6 3 4 6.5 4 5 5 2 6 6 4 7 6.5 2

Amantadine 100 4 Supplementary experiments have shown that compound 2, at doses as low as 3 mg / kg, has a neuroleptic inhibition index = 2.

Acute toxicity

Acute toxicity The LD50 was determined orally in mice by the administration and application of the method described in the aforementioned British Patent 1,467,739.

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The compounds prepared according to the invention gave the following results, which were compared with the results smoked with amantadine.

Compound ld50 mg / kg 1100 3> 150 5 170 6> 150 7 110 8> 150

Amantadine 1050

The ratio of the corresponding index of the compounds according to the invention to amantadine was compared. LD50 ed20-30 In this quotient, ED20-30 represents the effective dose required to achieve 20-30% inhibition of catatonia, and this value is described in Tables I and II as number 1.

The following results were obtained:

Compound Index 10> 25

Amantadine 21 This result indicates that the compound of the invention is more advantageous than amantadine because a higher safety margin can be used.

Similarly, the LD50 / ED10O index was determined in comparison with amantadine.

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The following results were obtained:

Compound Index 1 16.5 3 25

Amantadine These results again indicate that the compounds of the invention provide a greater 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 polarography.

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

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? 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-butylpropyl-di-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 1,1-di-n-propyl-n- when butylamine hydrochloride is used 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-propargyl-1,1-di-n-propyl-n-butylamine hydrochloride a) N-propargyl-1,1-di-n-propyl-n-butylamine

Boiling under reflux for 48 hours using a sphere containing 11.9 g (0.1 mol) of propargyl bromide, 25 g of sodium bicarbonate, 250 ml of ethanol and 19.7 g (0.1 mol) of 1,1-di-n-propyl butylamine. The insoluble fraction was filtered off and the ethanol was evaporated, after which the residue was treated with dilute sodium hydroxide solution. The organic phase was extracted with ether and distilled on a column.

In this way, 10 g of N-propargyl-1,1-di-n-propyl-n-butylamine were obtained as a pale yellow liquid.

Bp 94 ... 96 oc, 5 nun Hg Output: 51 *

Applying the same procedure as above, but using the appropriate starting materials, the following compounds were obtained:

compound K.p. OC

N-methyl-1,1-di-n-propyl-n-butylamine 84 (13 mm Hg) N-methyl-11-propyl-1-isobutyl-n-butylamine 86 (12 mm Hg) N-methyl-1- n-Propyl-1-ipropyl-n-butylamine N-methyl-1n-propyl-1-allyl-n-butylamine N-propargyl-1n-propyl-1-isopropyl-n-butylamine 14 6301 5 N-propargyl- 1-Isobutyl-n-butylamine N-propargyl-1-allyl-n-butylamine N-methyl-N-propargyl-1,1-di-n-propyl-n-butylamine N-methyl-N-propargyl-11-propyl -1-isopropyl-n-butylamine N-methyl-N-propargyl-1n-propyl-1-isobutyl-n-butylamine b) N-propargyl-1,1-di-n-propyl-n-butylamine hydrochloride

By bubbling dry hydrochloric acid gas through an ethereal solution of the amine thus prepared, the desired hydrochloride was mixed, which was then filtered and dried. In this way, N-propargyl-1,1-di-n-propyl-n-butylamine hydrochloride was obtained as crystals.

Melting point: 154 ... 155 oc.

Quantitative output.

By applying the above procedure, but using the appropriate starting compounds, the following compounds were prepared:

Compound Melting point oc N-methyl-1,1-di-n-propyl-n-butylamine hydrochloride 133 ... 134 N-methyl-11-propyl-1-isopropyl-n-butylamine hydrochloride 144 ... 145

Example 2 Preparation of N-methyl-1-n-propyl-1-allyl-n-butylamine fumarate

To a stirred solution of 2.32 g (0.02 mol) of fumaric acid in 400 ml of acetone was added 3.38 g (0.02 mol) of N-methyl-11-propyl-1-allyl-n-butylamine dissolved in to 1 ml of acetone. Stirring was continued for 1 hour, after which the precipitated colorless crystals were separated and washed with acetone and dried. There was thus obtained 5.2 g of N-methyl-1-n-propyl-1-allyl-n-butylamine fumarate.

Mp 149 ° C Yield 91%.

Example 3 Preparation of N-methyl-1-propyl-1-isobutyl-n-butylamine hydrochloride 10.4 g of N-methyl-1-isobutyl-n-butylamine were dissolved in 150 ml of absolute ethanol and 5, 6 ml of concentrated hydrochloric acid, after which the mixture was evaporated to dryness.

The oily product thus obtained was dissolved in 50 ml of hexane and the desired hydrochloride crystallized in the cold. The crystals were separated from the solution and recrystallized from isopropyl ether. There were thus obtained 7.5 g of N-methyl-1-n-propyl-1-isobutyl-n-butylamine hydrochloride.

Mp 139 ° C Yield 61%.

Using the same procedure as above, but using the appropriate starting materials, the following compounds were obtained: N-propargyl-1-propyl-1-isobutyl-n-butylamine hydrochloride N-propargyl-propyl-1'-yl-in-butylamine hydroxy-chloride

Example 4 Preparation of N, N-dipropargyl-1,1-di-n-propyl-n-butylamine hydrochloride a) N, N-Dipropargyl-1,1-di-n-propyl-n-butylamine 16 6301 5

Continuing the distillation described in Example 1a) above to obtain N, N-dipropargyl-1,1-di-n-propyl-n-butylamine, the corresponding N, N-dipropargyl derivative was isolated.

In this way, 3 g of N, N-dipropargyl-1,1-di-n-propyl-n-butylamine were obtained as a colorless liquid.

Bp 120 oc, 5 mm Hg Yield: 13%

Applying the same procedure as above, but using the appropriate starting materials, the following compounds were obtained:

The compound K.p. oc N, N-Dimethyl-1,1-di-n-propyl-n-butylamine 96-97 (15 mm Hg) N, N-dimethyl-11-propyl-1-isobutyl-n-butylamine 106 .. .107 (17 mm Hg) N, N-Dimethyl-11-propyl-1-isopropyl-n-butylamine N, N-dimethyl-1-allyl-11-propyl-n-butylamine N, N-dipropargyl-11 -propyl-1-isopropyl-n-butylamine N, N-dipropargyl-11-propyl-1-allyl-n-butylamine b) N, N-dipropargyl-1,1-di-n-propyl-n-butylamine hydrochloride

By bubbling dry hydrochloric acid gas through an ethereal solution of the amine thus obtained, the desired hydrochloride was precipitated.

In this way, N, N-dipropargyl-1,1-di-n-propyl-n-butylamine hydrochloride was prepared as colorless crystals. Melting point: 177 ° C (decomposed).

By applying the procedure described above, but using the corresponding starting compounds, the following compound was prepared:

Compound Melting point oc N, N-diraethyl-1,1-di-n-propyl-n-butylamine hydrochloride 228-229

Claims (5)

18 6301 5 claims