CH624922A5 - Process for the preparation of new methylamine derivatives - Google Patents

Abstract

The methylamine derivatives of general formula: <IMAGE> and their non-toxic addition salts, in which R represents n-propyl, isopropyl, isobutyl or allyl, R1 represents hydrogen, methyl or propargyl and R2 represents methyl or propargyl, are obtained by heating an amine, which is unsubstituted or R1-substituted on the nitrogen, with a methyl or propargyl halide in the presence of an alkaline agent to produce a basic methylamine derivative which is reacted with an acid to produce a non-toxic addition salt. The methylamine derivatives in question are useful in human or veterinary medicine as antiparkinsonian agents or correctors of extrapyramidal disorders due to neuroleptics. They are less inhibiting of monoamine oxidase than the corresponding derivatives which are unsubstituted on the nitrogen and have, for this reason, fewer side effects.

Description

The invention relates both to the racemic mixtures and to the optical isomers of the compounds forming one of the objects of the present invention and in particular to the racemic mixtures and to the optical isomers of the compounds of formula I above.

As will be described in more detail below, it has been found that the N-substituted and N, N-disubstituted derivatives of methylamine of formula I above, as well as their non-toxic addition salts, are endowed with pharmacological properties. likely to make them effective, in particular in the treatment of Parkinson's disease as well as for the correction of extrapyramidal disorders caused by neuroleptics. The daily administration will preferably be from 15 to 60 mg of active principle in a 60 kg human being.

2o The compounds of the invention can be prepared by heating, in the presence of an alkaline agent such as for example sodium bicarbonate, an amine of general formula:

The present invention relates, in general, to the preparation of new methylamine derivatives endowed with pharmacological activities as well as to the preparation of their non-toxic addition salts. The pharmacologically active compounds prepared according to the invention can be represented by the general formula:

n-C, H-

n-C, H,

A:

R-C-N

\

R2

in which R represents n-propyl, isopropyl, isobutyl or allyl, R represents hydrogen, methyl or propargyl.

The invention also relates to the preparation of the non-toxic addition salts of the compounds of formula I above such as the addition salts of an inorganic acid, for example hydrochloric acid. or an organic acid in which the free carboxylic radical is attached to an aliphatic saturated or unsaturated aromatic or aralkyl radical which may optionally include-C3H7N

R-C-NHRj

(II)

n-CJI,

(I)

in which R and Ri have the same meaning as above, with an appropriate amount of a halide of general formula:

30

R2x (III)

wherein R2 has the same meaning as above and X represents a chlorine, bromine or iodine atom, this reaction can be carried out in the presence or not of a solvent such as, for example, ethanol to obtain the desired methylamine derivative of formula I which can subsequently be reacted with an organic or inorganic acid to obtain a non-toxic addition salt of this derivative.

In addition to the compound of formula II in the form of the free base, the appropriate derivative of formula II can also be used in the above process in the form of an addition salt such as, for example, the hydrochloride. In accordance with known chemical techniques, when it is a question of obtaining a compound of formula I as envisaged previously, comprising two identical substituents on the nitrogen atom 45, a compound of formula II will be treated in which R a the intended meaning and R, represents hydrogen so that two molar equivalents of halide of formula III react with one molar equivalent of the compound of formula II.

Similarly, when it is a question of obtaining a compound of formula I such as that envisaged above, comprising an unsubstituted hydrogen atom on the nitrogen atom, a compound of formula II will be treated in which R has the intended meaning and R] represents hydrogen such that a molar equivalent of the halide of formula III reacts with a molar equivalent of the compound of formula II. 55 It is well known however that despite compliance with the molar equivalents mentioned above, the desired compound of formula I when it is monosubstituted on nitrogen, will be found in admixture with a certain proportion of corresponding compound of formula I disubstituted on nitrogen. Likewise, a certain amount of compound 60 of formula I monosubstituted on nitrogen will be formed when it is a question of obtaining the corresponding compound disubstituted on nitrogen.

Such mixtures of mono- and disubstituted derivatives can be separated by known techniques, for example by fractional distillation of the reaction mixture containing them or by fractional crystallization from their salts.

Among the compounds of formula II, those in which Rj represents hydrogen are known products having been described as well as their process of preparation in the Swiss patent.

3

624,922

No 605606. The other compounds of formula II, that is to say those in which R! represents methyl or propargyl are in fact compounds of formula I for which several methods of preparation have been described previously.

It has been discovered that the methylamine derivatives according to the invention have remarkable pharmacological properties capable of making them useful in human and veterinary medicine.

In particular, it has been found that the compounds according to the invention have central noradrenergic and central dopaminergic properties, the latter resulting in an activity inhibiting catatonia and neuroleptic and reserpinic catalepsy.

In addition, it has been observed that at the doses where they completely suppress the catatonigenic and cataleptigenic effects of the neuroleptics, the compounds according to the invention do not in any way oppose the antiamphetamine effects of the neuroleptics in the rat and their antiapomorphine effects in the dog. . Furthermore, the compounds according to the invention have no emetic action in dogs regardless of the dose administered and are not cholinolytic.

All of these pharmacological properties are capable of making the compounds of formula I useful in the treatment of Parkinson's disease as well as for the correction of extrapyramidal disorders caused by neuroleptics.

Trisubstituted derivatives of unsubstituted methylamine on the nitrogen atom are already known, possessing central noradrenergic and central dopaminergic properties capable of being used in the treatment of Parkinson's disease and for the correction of extra-pyramidal disorders caused by neuroleptics.

Such compounds have been described in Swiss Patent No. 605606.

Furthermore, it has been found that disubstituted methylamine derivatives having no substitution on the nitrogen atom such as n-propyl 1-n-butylamine also have the qualities required to make them antiparkinsonian agents.

However, the disubstituted and trisubstituted derivatives of methylamine mentioned above possess, in varying degrees, an inhibitory action on monoamine oxidase.

Clinically this inhibitory activity can result in undesirable side effects such as tachycardia, hypotension and paroxysmal hypertension.

Now, it has been surprisingly discovered that at equal concentrations the compounds according to the present invention have a much weaker or even zero monoamine oxidase inhibitory activity than the inhibitory activity exhibited by di- and trisubstituted methylamine derivatives cited above.

This completely unexpected advantage presented by the N-substituted methylamine derivatives according to the invention, compared to the di- and trisubstituted derivatives of methylamine unsubstituted on the nitrogen atom, is capable of rendering the compounds according to the invention more advantageous than unsubstituted derivatives on nitrogen.

The compounds according to the invention are also more advantageous than amantadine or amino-1-adamantane, a product widely used in antiparkinsonian therapy.

Although the pharmacological profile of the compounds according to the invention is very similar to that of amantadine, pharmacological tests carried out with the compounds according to the invention have made it possible to highlight appreciable differences compared to amantadine. For example, by comparing the doses of the compounds according to the invention and of amantadine having a certain activity value, it has been found that the distance between the active dose in question and the toxic dose is always proportionally greater in the case of the compounds according to the invention than in the case of amantadine. In other words, the margin of safety offered by the compounds according to the invention is greater than that of amantadine.

It is indisputable that the search for new antiparkinsonian agents remains of great interest since the treatment of parkinsonism is long and the alternating use of different products is necessary.

In this perspective, the compounds according to the invention constitute a valuable contribution to antiparkinsonian therapy since, at present, no agent represents the treatment of choice for this disease.

The N-substituted and N, N-disubstituted derivatives according to the present invention, which have proved to be particularly advantageous, are:

- N-methyl di-n-propyl-1,1-n-butylamine,

- N, N-dimethyl di-n-propyl-1,1-n-butylamine,

these compounds being used in the form of the free base or of a non-toxic addition salt such as, for example, the hydrochloride or the fumarate.

By way of illustration of the central dopaminergic activity demonstrated in the compounds of the present invention, the results obtained with some of them will be found below, in comparison with amantadine. These compounds are preferably studied in the form of a non-toxic addition salt:

N-methyl di-n-propyl-1,1-n-butylamine (Compound 1),

N, N-dimethyl di-n-propyl-1,1-n-butylamine (Compound 2),

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

I. Inhibiting actions of the reserpinic and neuroleptic catatonìe (dopaminergic properties)

1. Inhibition of reserpinic catatonia

The test performed for this purpose is identical to that described in Swiss Patent No. 605606.

The results obtained with the compounds according to the invention enumerated above, as well as with amantadine, are recorded in Table I below. These results were recorded on the same arbitrary scale ranging from 0 to 4 as that mentioned in the Swiss patent in question.

Table I

Compound

Administered dose

Inhibition of in mg / kg (rat)

reserpinic catatonia

1

6

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

2. Inhibition of neuroleptic catatonia

The test performed for this purpose is identical to that described in Swiss patent No 605606.

The results obtained with compounds listed previously as well as with amantadine are listed in Table II below using the same scale as that used in Table I above.

(Table at the top of the next column)

Additional tests have shown that compound 2 at a dose of 3 mg / kg already has an inhibition index of neuroleptic catatonia equal to 2.

5

10

15

20

25

30

35

40

45

50

55

60

65

624,922

4

Table II

Compound

Dose administered in mg / kg (rat)

Inhibition of neuroleptic catatonia

1

6

3

2

6

4

3

6

3

4

6.5

4

5

5

2

6

6

4

7

6.5

2

Amantadine

100

4

II. Determination of acute toxicity

Acute LD50 toxicity was determined in mice orally in the same way as in Swiss Patent No. 605606.

The following results were recorded with compounds of the present invention in comparison with amantadine:

The ratio of the compounds was compared according to the

DE20-30

present invention with the corresponding ratio of amantadine.

The DE20-30 in question corresponds in Tables I and II above to an inhibition index of reserpinic or neuroleptic catatonia equal to 1.

The following results were obtained:

Compound

Index

6

Amantadine

<25 21

These results show that the compounds according to the present invention are more advantageous than amantadine, since they offer a greater margin of safety.

DL5o

Similarly, a similar report was made,

DE100

in comparison with amantadine.

The following results were obtained:

Compound

Index

1

3

Amantadine

16.5 <25 10

These results show again that the compounds according to the present invention offer a better margin of safety than amantadine.

III. Determination of monoamine oxidase inhibition

To this end, the following test was carried out:

Two rats weighing 190 and 200 g respectively are sacrificed by decapitation. The livers are quickly removed, cut in hypertonic solution and triturated. The homogenate is purified by fractional centrifugation and the mitochon-dries fraction is collected. The inhibition of monoamine oxidase caused by a compound to be studied is then measured by means of a polarograph. In the measuring cell, the following solutions are introduced:

A) 1.1 ml of a 0.1 molar phosphate buffer solution (pH = 7.4) to which a 0.005 molar solution of potassium cyanide is added;

b) 0.01 ml of a 0.5 molar aqueous solution of the compound to be studied. The final concentration of this product in the cell is

0.0333 mole;

c) 0.1 ml of the mitochondria suspension prepared previously, namely 12.5 mg of proteins.

Three minutes after this operation, the reaction is started by adding 0.2 ml of a 0.05 molar solution of serotonin-15 creatine sulfate in phosphate buffer medium, the final concentration of amine being 0.00666 mol.

The mitochondria titer was calculated according to the Biuret method, bovine albumin being taken as the reference protein.

Similar tests were also carried out with 0.02, 0.04.0.06.06.08 and 0.10 ml of the 0.5 molar solution of the test compound.

The above results illustrate the inhibitory activity of the monoamine oxidase of a compound according to the invention in comparison with the inhibitory activity of two derivatives of methylamine unsubstituted on nitrogen, these two derivatives being studied in the same conditions.

Board

These results show that the inhibition of monoamine oxidase is very significant in the case of n-propyl-1 n-45 butylamine hydrochloride, weak in the case of di-n-propyl-1,1 n-butylamine hydrochloride and practically zero in the case of N-methyl di-n-propyl-1,1 n-butylamine hydrochloride.

Therapeutic compositions containing one or more compounds according to the invention can be presented in any form suitable for administration in human or veterinary therapy. As regards the administration units, these can take the form, for example, of a coated or uncoated tablet, a capsule, a suspension or a syrup for oral administration.

The administration unit in this case will comprise, for example, from 5 to 50 mg, preferably from 5 to 20 mg of active principle.

The therapeutic compositions in question can be presented in the form of a suppository containing, for example, from 5 to 100 mg of active principle per unit of administration for rectal administration or in the form of a solution or an injectable suspension containing, for example, from 1 to 20 mg of active principle per administration unit for parenteral administration.

Depending on the route of administration chosen, the therapeutic compositions in question will be prepared by combining at least one of the compounds of formula I above or a non-toxic addition salt of this compound with an appropriate excipient, the latter possibly being consist, for example, of at least one ingredient selected from the following substances: talc, magnesium stearate

Compound

LD50 in mg / kg

1

100

3

<150

5

170

6

<150

7

110

8

<150

Amantadine

1050

30

% inhibition of monoamine oxidase by:

35

Ml of inhibitor

N-propyl-1 n-butylamine hydrochloride

Di-n-propyl-1,1 n-butylamine hydrochloride

Hydrochloride

N-methyl di-n-propyl-1,1 n-butylamine

40

0.01 0.02 0.04 0.06 0.08 0.10

22

25

35.5

44

48

54

1.5 6.0 11.5 11.5 14.5 14.5

3.0

1.5

3.0

0

0

3.0

5

624,922

sium, lactose, sucrose, carboxymethyl cellulose, wheat or corn starch, kaolin, levulite, cocoa butter.

The preparation of the compounds according to the invention as well as a therapeutic composition are illustrated by the following nonlimiting examples:

Example 1:

Preparation of N-propargyl di-n-propyl-1,1 n-butylamine hydrochloride.

A. N-propargyl di-n-propyl-1,1 n-butylamine

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 di-n are brought to reflux for 48 h. -propyl-1,1 n-butylamine. After filtration of the insoluble part and evaporation of the ethanol, the mixture is treated with a dilute solution of sodium hydroxide. The organic part is extracted with ether and distilled on a rotating band column.

In this way, 10 g of N-propargyl di-n-propyl-1,1 n-butylamine are isolated in the form of a light yellow liquid.

M.P .: 94-96 ° C at 5 mm Hg.

Yield: 51%.

In the same manner as that described above, the following compounds were prepared:

Compound

P.E. ° C

N-methyl di-n-propyl-1,1 n-butylamine N-methyl n-propyl-1 isobutyl-1 n-butylamine

84

(13 mm / Hg) 86

(12 mm / Hg)

B. N-propargyl di-n-propyl-1,1 n-butylamine hydrochloride

By bubbling a stream of dry gaseous hydrochloric acid into an ethereal solution of the amine obtained above, the desired hydrochloride is precipitated which is filtered and then dried.

In this way, N-propargyl di-n-propyl-1,1 n-butylamine hydrochloride is obtained in the form of crystals.

M.p .: 154-155 ° C.

Yield: quantitative.

In the same manner as that described above, but starting from the appropriate products, the following compounds were prepared:

Compound

P.E. ° C

N-methyl n-propyl-1 isopropyl-1 n-butylamine hydrochloride N-methyl di-n-propyl-1,1 n-butylamine hydrochloride

144-145 133-134

Example 2:

Preparation of N-methyl n-propyl-1 allyl-1 fumarate

n-butylamine.

A mixture consisting of 9.5 g (0.1 mol) of methyl bromide, 25 g of sodium bicarbonate, 250 ml of ethanol and 15.5 g (0.1 mol) is brought to reflux for 48 h. of n-propyl-1 allyl-1 n-butylamine. After filtration of the insoluble fraction and evaporation of the ethanol, the mixture is treated with a dilute solution of sodium hydroxide. The organic phase is extracted with ether and distilled to obtain N-methyl n-propyl-1 allyl-1 n-butylamine.

To a solution of 2.32 g (0.02 mol) of fumaric acid in 400 ml of acetone is added with stirring 3.38 g (0.02 mol) of the amine prepared above in solution in 30 ml acetone. Stirring of the mixture is continued for one hour and then the colorless crystals which have precipitated are separated. They are washed with acetone and then dried.

In this way, 5.2 g of N-methyl n-propyl-1 allyl-1 n-butylamine fumarate are obtained.

M.p .: 149 ° C.

Yield: 91%.

Example 3:

Preparation of N-methyl n-propyl-1 isobutyl-1 n-butylamine hydrochloride.

A mixture consisting of 9.5 g of methyl bromide, 25 g of sodium bicarbonate, 250 ml of ethanol and 17.1 g (0.1 mol) of n-propyl-1 is brought to reflux for 48 h. isobutyl-1 n-butylamine. After filtration of the insoluble fraction and evaporation of the ethanol, the mixture is treated with a dilute solution of sodium hydroxide.

The organic phase is extracted with ether and distilled to obtain N-methyl n-propyl-1 isobutyl-1 n-butylamine (m.p .: 86 ° C under 12mm / Hg).

10.4 g of the amine prepared above are dissolved in 150 ml of absolute ethanol. The solution is treated with 5.6 ml of concentrated hydrochloric acid and then evaporated to dryness. The oil thus obtained is taken up in 50 ml of hexane and the desired hydrochloride crystallizes when cold. It is separated and then recrystallized from isopropyl ether.

In this way, 7.5 g of N-methyl n-propyl-1 isobutyl-1 n-butylamine hydrochloride are obtained.

M.p .: 139 'C.

Yield: 61%.

Example 4:

Preparation of N, N-dipropargyl di-n-propyl-1,1 n-butylamine hydrochloride.

A. N, N-dipropargyl di-n-propyl-1,1 n-butylamine

Continuing the distillation undertaken in Example 1A above in order to obtain N-propargyl di-n-propyl-1,1 n-butylamine, the corresponding N, N-dipropargylated derivative is isolated.

In this way, 3 g of N, N-dipropargyl-1,1 n-butylamine are obtained in the form of a colorless liquid.

M.p .: 120 ° C at 5 mm / Hg.

Yield: 13%.

In the same manner as that described above, but starting from the appropriate products, the following compounds were prepared:

Compound

P.E. C

N, N-dimethyl di-n-propyl-1,1 n-butylamine

N, N-dimethyl n-propyl-1 isobutyl-1 n-butylamine

96-97 (15 mm / Hg)

106-107 (17 mm / Hg)

B. N, N-dipropargyl di-n-propyl-1,1 n-butylamine hydrochloride

By bubbling a stream of gaseous and dry hydrochloric acid into an ethereal solution of the amine obtained previously, the desired hydrochloride is precipitated.

In this way, N, N-dipropargyl di-n-propyl-1,1 n-butylamine hydrochloride is obtained in the form of colorless crystals.

M.p .: 177 ° C (decomposition).

In the same manner as that described above, but starting from the appropriate products, the following compound was prepared:

Compound

P.F. C

N, N-dimethyl di-n-propyl-1,1 n-butylamine hydrochloride

228-229

5

10

15

20

25

30

35

40

45

50

55

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65

R

Claims (6)

624,922 i CLAIMS 1. Process for the preparation of new methylamine derivatives corresponding to the general formula: n-C3H7 as well as their non-toxic addition salts, in which R represents n-propyl, isopropyl, isobutyl or allyl, R] represents hydrogen, methyl or propargyl and R2 represents methyl or propargyl, characterized in that a compound of general formula or an addition salt of this compound is heated, in the presence of an alkaline agent: n-C3H7> R-C-NHR, n-C.H, in which R and R] have the same meaning as above, with an appropriate amount of a halide of general formula: R2X in which R2 has the same meaning as above and X represents a chlorine, bromine or iodine atom to obtain the desired methylamine derivative which can subsequently be reacted with an organic or inorganic acid to obtain a non-toxic addition salt of this derivative. 2. Method according to claim 1, characterized in that the alkaline agent is sodium bicarbonate. 3. Method according to claim 1, characterized in that the solvent is ethanol. 4. Method according to claim 1, characterized in that the organic acid is fumaric acid and the inorganic acid is hydrochloric acid. 5. Method according to claims 1 to 4 for the preparation of N-methyl di-n-propyI-l, ln-butylamine and its non-toxic addition salts, characterized in that the di- n-propyl-1,1-n-butylamine with a methyl halide. 6. Method according to claims 1 to 4 for the preparation of N, N-dimethyl di-n-propyl-1,1-n-butylamine and its non-toxic addition salts, characterized in that one makes react di-n-propyl-1,1 -n-butylamine with a methyl halide. dre a second carboxylic group such as, for example, fumaric acid. The compounds of the present invention can have, depending on their chemical configuration, one or more centers of easy-5 metry and can therefore be in the form of racemic mixtures or of individual optical isomers.