DE2522218C3 - Composition for human or veterinary medicine, methylamine derivatives and processes for their preparation - Google Patents

Description

R ₁ -H ₂ C

\
R ₂ -C-NH ₂

R ₃ -H ₂ C

wherein Ri and R3 each represent a hydrogen atom or a straight or branched chain alkyl group with about 1 to 6 carbon atoms, alkenyl or alkynyl group with about 2 to 6 carbon atoms and R2 represents a straight or branched chain alkyl, alkenyl or alkynyl group with about 2 to 7 carbon atoms is provided that - when R _{2 is} an alkenyl group of the formula CH = CH-R * or an alkynyl group of the formula C = CR ₄ , where R _{4 is} a hydrogen atom or a straight or branched chain alkyl group having 1 to 5 carbon atoms - Ri and R3 each represent a hydrogen atom or an alkyl group, where Ri, R ₂ and R3 are selected so that the methylamine derivative has no more than about 13 carbon atoms, or a pharmaceutically acceptable acid addition salt of this derivative, optionally in conjunction with a pharmaceutical carrier or Tools for it, includes.

2. Composition for the Ht-man or Veterinary medicine according to claim 1, characterized in that it is an essential active ingredient 1,1-di-n-propyl-n-butylamine or a pharmaceutical contains usable acid addition salt of this.

3. Composition for human or veterinary medicine according to claims 1-2, characterized characterized in that the pharmaceutically acceptable acid addition salt is the hydrochloride or the is acidic fumarate.

4. Methylamine derivative of the general formula:

CH ₃ -CH ₂ -CH ₂

Rj-C-NH ₂

/
Rj

(la)

in which R ' ₂ either denotes the n-propyl group and R'3 denotes the ethyl, isopropyl, isobutyl or tert-butyl group or R'2 denotes the ethyl group! and R'3 stands for the η-butyl or isobutyl group,

or a pharmaceutically acceptable acid addition salt thereof.

5.1-Di-n-propyl-n-butylamine-hydrogen fumarate.

6. Process for the preparation of methylamine derivatives the general formula:

R ₂ -C-NH ₂ (Ia)

Ri

in which R'2 either denotes the n-propyl group and R'3 denotes the ethyl, isopropyl, isobutyl or tert-butyl group, or R ' ₂ denotes the ethyl group and R'3 denotes the η-butyl or Isobutyl group, characterized in that an isocyanate or an N-formylamine of the general formula is used in a manner known per se:

CH ₃ -CH ₂ -CH ₂

R ₂ -CA

Ri

if)

wherein R'2 and R'3 have the above meaning and A stands for the group

N = C = O

or

N-C-H

stands, treated with a strong acid at 15 to 100 ⁰ C in a suitable medium and optionally reacting the acid addition salt of methylamine obtained with a base and converting the free base obtained with an organic or inorganic acid into another pharmaceutically usable acid addition salt.

The present invention relates to pharmacologically active derivatives of methylamine and their pharmaceutically usable acid addition salts as well as pharmaceutical and veterinary Compositions containing these derivatives and salts.

The present invention relates to a composition for human or veterinary medicine, in particular for the treatment of Parkinson's disease and for the elimination of neuroleptics evoked extra-pyramidal disturbances, which is characterized by being essential active ingredient at least one methylamine derivative of the general formula:

R ₁ -H ₂ C

R C-NH ₂

R ₁ -H ₂ C

wherein Ri and Rj each represent a hydrogen atom or a

straight or branched chain alkyl group with about 1 to 6 carbon atoms, alkenyl or alkynyl group with about 2 to 6 carbon atoms and R _{2 represents} a straight or branched chain alkyl, alkenyl or alkynyl group with about 2 to 7 carbon atoms, provided that - when R _{2 represents} an alkenyl group of the formula CH = CH-R ₄ or an alkynyl group of the formula C = CR ₄ , in which R _{4 represents} a hydrogen atom or a straight or branched chain alkyl group with 1 to 5 carbon atoms - Ri and R3 each represent a hydrogen atom or represent an alkyl group, where Ri, R ₂ and R ₃ are selected so that the methylamine derivative has no more than about 13 carbon atoms, or comprises a pharmaceutically acceptable acid addition salt of this derivative, optionally in conjunction with a pharmaceutical carrier or excipient therefor

Another object of the invention is a methylamine derivative of the general formula:

CH ₃ -CH ₅ -CH ₂

R ₂ -C-NH ₂
R3

(Ia)

in which R ' ₂ either denotes the n-propyl group and R-' ₃ denotes the ethyl, isopropyl, isobutyl or tert-butyl group or R ' ₂ denotes the ethyl group and R' ₃ denotes the η-butyl or isobutyl group,
or a pharmaceutically acceptable acid addition salt thereof, as well as the acidic fumarate of 1,1-di-n-propyl-n-butylamine.

The invention also relates to processes for the preparation of the derivatives according to the invention.

It has been found - which will be described in more detail - that the methylamine derivatives Formula I and its pharmaceutically acceptable acid addition salts have pharmacological properties possess which they are particularly useful for the treatment of Parkinson's disease and for the correction of by Neuroleptica-induced extra-pyramidal disorders make valuable.

The daily dose is preferably between about 10 and 60 mg of active ingredient for one People weighing 60 kg.

But there is also a certain number of the compounds used according to the invention that are already are known. In this context, the following compounds can be mentioned, for example will:

1,1-Di (2-propen-1 -yl) -3-buten-1 -ylamine or
Triallylmethylamine,
1,1-diallyl-n-butylamine and
1,1-diallyl-n-pentylamine (described in J.
Amer. Chem. Soc, 65.87; 1943),
1,1,3,3-tetramethyl-n-butylamine (published in J. Amer. Chem. Soc, 70,4048,1948),
1 -methyl-1-ethyl-2-pentyn-1 -ylamine,
1 -Methyl-1 -äthyl-2-heptin-1 -ylamine,
1 -methyl-1 -ethyl-n-pentylamine,
1-methyl-1-ethyl-n-propylamine,
1 -Methyl- i-ethyl-2-propen-l -ylamine (all
described in J. Amer. Chem. Soc, 75, 4297,
1953),

!, l-diethyl-2-propyn-1-ylamine,
1,1-dimethyl-2-propyn-1-ylamine,
1,1-diethyl-n-propylamine
(which are already on the market).
5

However, as far as is known, these known compounds have never been attributed therapeutic activity.
Similarly, tri-n-propylmethylamine or 1,1-din-propyl-n-butylamine and tri-n-butylmethylamine or 1,1-di-n-butyl-n-pentylamine have been reported by Sperber et al. in J. Amer. Chem. Soc, 71, 3352 (1949), where they are presented as "less spasmolytic and more toxic than the corresponding trialkylethylamines".

Here it's more of a musculotropic issue antispasmodic activity than in the cited reference.

Regardless of the fact that the information given in this publication regarding this Both compounds of the formula I are completely lacking in precision, there are in this experiment no clue remotely suggestive of the activities taking place in the face of the present Invention the compounds of formula I in general and the tr-n-propyl- and tri-n-butyl-methylamine in particular are attributed.

The publication relating to the spasmolytic activity of the two methylamine derivatives discussed does not give or give details of the level of activity an indication of the method by which the spasmolytic activity was demonstrated. Furthermore are no information was given on toxicity. The pharmacological information presented by Sperber et al.

published v / urde, is therefore too vague for anyone to deduce that tri-n-propyl- and tri-n-butyl-methylamines possess enough spasmolytic activity at non-toxic doses to be considered therapeutic Funds are used.

In the course of the experiments carried out with the compounds of the formula I, the spasmolytic Activity of tri-n-propylmethylamine or 1,1-di-npropyl-n-bdtylamine investigated in vitro. It was in full agreement with the results of Sperber et al. observed that the spasmolytic Activity of this compound was very weak, d. H. practically nonexistent as it was 20,000 to 25,000 times is weaker than that of atropine. From this it can reliably be concluded that the spasmolytic Activity of tri-n-propylmethylamine in vivo should be applied at doses that are extremely toxic.

Indeed, pharmacological tests carried out in vivo have shown that at doses at those tri-n-propylmethylamine against Parkinson's disease and as a means of correcting by Neuroleptica-induced extra-pyramidal disorders, d. H. at doses far below the toxic dose, can be used, the spasmolytic activity of this compound is absent.

bo The compounds of the formula I in which Ri and R ₃ each represent a hydrogen atom or an alkyl group with about 1 to 6 carbon atoms, an alkenyl or alkynyl group with about 2 to 6 carbon atoms and R2 represents an alkyl group with about 2 to 7

b> carbon atoms, an alkenyl group other than TH = CH-R4 or an alkynyl group other than c = C —R4, can by treatment in one suitable medium with a strong acid, such as. B.

Hydrochloric or sulfuric acid, an isocyanate or an N-formylamine of the general formula:

Ri-H ₂ C

R ₂ -CA

R ₃ -H ₂ C

(Π)

wherein, _R2 and R3 have the above meaning and A is Ri group dit

NH-C-H

is, are prepared, including the corresponding acid addition salt of the desired compound of Formula I is obtained, optionally with a base, such as. B. sodium hydroxide, is reacted to to obtain the compound of formula I in the form of its free base, which is then with an organic or inorganic acid can be reacted, using another pharmaceutically acceptable acid addition salt receives.

Treatment of the compound of formula 11 mi ι the acid may be performed using the appropriate reagents at a temperature between about 15 and 100 ° C, are preferably carried out between about 50 and 9O ⁰ C.

The compounds of formula I in which R 1 and R 3 each represent an alkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms and R _{2 is} the group CH ₂ -R5, in which R5 is an alkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group with 2 or 3 carbon atoms, where Ri, R3 and R5 are identical, can also be prepared by in anhydrous ether, such as. B. Ethyl ether, a nitrile of the general formula:

R ₅ -CH ₂ -CN

(IU)

wherein R5 has the above meaning with an organomagnesium derivative of the general formula:

R ₅ -CH ₂ MgX

(IV)

wherein R5 has the same meaning as above and X is a chlorine, bromine or iodine atom is heated and the complex thus obtained is hydrolyzed, the desired compound of formula I is obtained, which is then treated with an organic or inorganic acid can be reacted to form a pharmaceutically acceptable acid addition salt of this compound to manufacture.

As hydrolyzing ^o: '<el a saturated solution of ammonium chloride vuii for example, can be used.

The compounds of the formula I in which R 1 and R 3 each represent a water atom or an alkyl group having about 1 to 6 carbon atoms and R _{2 is} an alkynyl group of the formula C = C-R 4, in which R 4 is hydrogen, ie an ethynyl group, can in liquid ammonia by reacting sodium amide and a halide of the general formula:

R ₁ -H ₂ C

HC ^ C-C-HaI

R ₃ -H ₂ C

(V)

wherein R ₁ and R3 have the above meanings and Hai represents a chlorine or bromine atom, the desired compound of formula 1 is obtained, which can then be reacted with an organic or inorganic acid to form a pharmaceutically acceptable acid addition salt of this compound to build.

The compounds of the formula I in which Ri and R3 each represent a hydrogen atom or an alkyl group with about 1 to 6 carbon atoms and R _{2 represents} an alkynyl group of the formula C = C-Ra , in which R _{4 represents} an alkyl group with 1 to 5 carbon atoms, can by reaction of a metal derivative of the general formula:

R ₁ -H ₂ C

Me-C = CC-NH ₂

R ₃ -H ₂ C

(VI)

wherein Me is an alkali metal atom, e.g. B. sodium, and Ri and R3 has the above meaning, with a Halide of the formula:

R ₄ -HaI

(VU)

wherein R _{4 has} the above meaning and Hai has the same

4 (i has the same meaning as in formula V, are produced, wherein the desired compound of formula I is obtained, which is then with an organic or inorganic acid can be reacted to form a pharmaceutically acceptable acid addition salt

4 "to form this connection.

The compounds of the formula I in which R ₁ and R ₃ each represent a hydrogen atom or an alkyl group having about 1 to 6 carbon atoms and R _{2 represents} an alkenyl group of the formula CH = CH-R ₄ , in which R _{4 has the} same meaning as in formula I. can, by hydrogenation in a suitable solvent such as heptane, and in the presence of a Lindlar catalyst, an amine of the general formula:

R ₁ -H ₂ C
R ₄ -C = CC - NH ₂

(VIII)

R ₃ -H ₂ C

wherein Ri, R ₃ and R ₄ are as defined above, are prepared to form the desired compound of formula I, which can then be reacted with an organic or inorganic acid to give a pharmaceutically acceptable acid addition salt of this compound.

The hydrogenation is preferably carried out at a temperature between 30 and 60 ° C and especially at about 50 ⁰ C.

The compounds of formula II can be prepared in different ways, namely:

where Ri, R2 and R3 have the same meaning as in the Have compounds of formula II with an alkali metal cyanide, e.g. B. sodium or potassium cyanide, in Presence of an acid, for example sulfuric acid.

a) if A represents the groups N = C = O:

either by reaction of an acetamide derivative of the general formula:

R ₁ -H ₂ CO

\ Il

R ₂ -CC-NH ₂

/
R ₃ -H ₂ C '

(IX)

wherein Ru R ₂ and R3 have the same meaning as in formula II, with chlorine or bromine in an alkaline medium, e.g. B. in an aqueous solution of sodium or potassium hydroxide,
or by reaction of an acetic acid derivative of the general formula:

R ₁ -H ₂ CO

\ Il

R ₂ - C - C - OH
R ₃ -H ₂ C

wherein Ri, R ₂ and R _{3 have the} same meaning as in the compounds of formula II, with a chlorinating agent, for. B. thionyl or oxalyl chloride. whereby the corresponding acyl chloride is obtained which is then treated with an alkali metal azide, for example sodium azide, to produce the desired compound of formula II, or - by another method - by heating a compound of formula X directly with hydrazoic acid in an acidic medium, z. B. sulfuric acid, whereby the desired compound of formula II is obtained.

In the latter case, the isocyanate thus obtained immediately becomes the corresponding amine by hydrolysis converted to formula I;

M if A is the reason

NH-C-H

represents:

by heating a tertiary alcohol of the general formula:

R ₁ -H ₂ C

R ₂ -C-OH
R ₃ -H ₂ C

The compounds of the formula IX can be obtained by reacting anhydrous ammonia with the corresponding acids of the formula X or, preferably, with the halides of these acids. The acids can be obtained from the alcohols of the formula X! and formic acid in a sulfuric acid medium.
The compounds of formula XI are either known compounds or can be prepared according to known methods, e.g. B. by reaction of an organic lithium compound with a suitable ketone in an anhydrous ether medium, e.g. B. tetrahydrofuran.

The compounds of the formula V are either known products or can be obtained by the process described in J. Org. Chem. 1961, 26, 725, ie by treating 1,1-dialkyl-1-ethinylcarbinol with copper (I) chloride and hydrochloric acid in Presence of a copper bronze powder and calcium chloride. The 1,1-dialkyl-1-äthinyl-carbinole given above are either known products which have been described in Annales de Chimie, 1924, 10 (I), p. 366, or by known methods, the (X) jo for example in Organic Syntheses Collective, Volume III, p. 146. The products of formula VI can be in liquid ammonia by the action of an alkali metal, such as. B. sodium, to the corresponding 1,1-dialkyl-l-äthinylmethylamin, which is a compound falling under the formula I. The compounds of formula VIII are also encompassed by formula I.
It has been found that the methylamine derivatives of the formula I have valuable pharmacological properties. In particular, it has been found that the compounds according to the invention have central noradrenergic and central dopaminergic properties. The latter properties are shown by an inhibitory effect on catatonia and catalepsy induced by reserpine-induced and neuroleptic drugs.

Pharmacological tests carried out with the compounds according to the invention have shown that

so tri-n-propylmethylamine hydrochloride or 1,1-di-npropyl-n-butylamine hydrochloride have extraordinary effectiveness. However, it was surprisingly and quite unexpectedly observed that 1,1-di-n-propyl-n-butylamine hydrogen fumarate has an efficiency level even greater than that of the corresponding hydrochloride. It was observed that 1,1-di-n-propyl-n-butylamic acid fumarate 20 to Is 30% more active than the corresponding hydrochloride in experiments that induced reserpine and neutroleptic

bo ca affect induced catatonia.

In addition, it has been observed that at doses lower than the catatonia induced by neurolepsy and Completely suppress catalepsy, the compounds according to the invention the antiamphetamine effects of the neutroleptics in the rat and their antiapomorphin effects in the dog. Further the compounds according to the invention do not induce nausea in dogs and at any dose

are not cholinolytic agents.

These pharmacological properties as a whole make the compounds of formula I in the Treatment of Parkinson's disease and the correction of those caused by neuroleptics extra-pyramidal perturbations valuable.

Parkinson's disease is a chronic and progressive impairment that is particularly caused by a dopamine deficiency in the thalamic and caudatar and lenticular nuclei is characterized, with akinesia, rigidity and tremor being visible symptoms.

Many effective remedies have been suggested for controlling Parkinson's Syndrome. Most of these products are central anticholinergic centers! with peripheral antichounergic Effects. These compounds are of natural origin, such as atropine, or are obtained synthetically, e.g. B. Diethazine, Benztropine or Trihexyphenidyl.

However, these remedies can have undesirable side effects, which in most cases occur their peripheral anticholinergic properties are due to these side effects for example in the form of dryness of the mouth, difficulties with optical accommodation, tachycardia, Constipation and retention of urine may occur. These products are therefore used in cases of Contraindicated glaucoma and hypertrophy of the prostate.

L-dopa, or levodopa, a precursor to dopamine, has also been used in the treatment of Parkinson's disease Disease suggested. In view of the partial decomposition in the digestive system, L-Dopa has to be in very high amounts high doses are administered, which very often induces undesirable side effects. The most serious of these side effects are of a cardiovascular nature and are manifested in particular by disorders of the Heart rhythm 'and orthostatic hypotension. Patients treated with L-Dopa are allowed therefore do not have any contraindications in the area of the heart.

Recently, amantadine, i. H. 1-Amino-adamantane has been proposed for the therapy of Parkinson's disease. This product, which stimulates the release of dopamine, is very effective but produces several undesirable side effects and also reduces the effectiveness after a certain period of time.

Because of this, it is very difficult for the doctor to choose among the various remedies for Parkinson's disease Select diseases that are effective in the case to be treated. Every patient must be considered individual case of illness. All known methods of treating Parkinson's disease The disease is symptomatic, and despite the medical treatment applied, the progresses Disease Continues Treatment of Parkinson's disease requires sequential treatment Use of one or more therapeutic substances, and it is often necessary to be therapeutic Cycles are applied. Often two anti-Parkinson’s drugs must be administered at the same time, the first being viewed as a basic remedy and the second being viewed as an auxiliary or adjunct remedy. Furthermore is the alternating use of different products is necessary because the treatment lasts for a long time Duration is

The search for new remedies against Parkinson's disease Illness is therefore of fundamental importance. From this point of view, the connections represent the Formula 1 is a valuable additional resource for anti-Parkinson's therapy as it is currently used to treat this Disease does not give an ideal remedy, which is described in detail below.

The compounds according to the invention therefore provide valuable additional resources to those available to the doctor Available therapeutic remedies

ίο and are suitable in place of any other remedy to be used that for any reason, e.g. B.

Changes in the patient's condition or stay have become ineffective.

Even if the pharmacological spectrum of the compounds according to the invention is that of amantadine is very similar, have pharmacological tests carried out with compounds of the formula I in comparison with amantadine revealed clear differences. For example, if the doses of the invention Compounds are compared with those of amantadine that have a certain degree of effectiveness it should be noted that the effective dose in question for the compounds according to the invention is proportionally further from the toxic dose than amantadine. In other words is the safety margin offered by the compounds according to the invention is that of amantadine think. Other differences, which are particularly evident, were identified with the most preferred inventive

jo contemporary compound observed, namely: tri-n-propylmethylamine or 1,1-di-n-propyl-n-butylamine as Base or in the form of a pharmaceutically acceptable acid addition salt, e.g. B. the hydrochloride or the acidic fumarate (i.e. a fumarate in which only one carboxyl group is involved in the salt formation, hereinafter also Called "hydrogen fumarate").

It has been observed that, for example in the cardiovascular field, the preferred according to the invention Compound has no undesirable effect on the electrocardiogram, whereas 5 mg / kg amantadine, injected into a dog produced cardiac arrhythmias due to ventricular extrasystoles. The compound of the invention has also been found to reduce the peripheral effects of norepinephrine not fortified and not a gangliophlegic agent while performed with amantadine Experiments have shown that this compound enhances the peripheral adrenergic effects and moreover shows a gangliophlegic effect

The investigated compound of the invention that these undesirable side effects associated with amantadine have not been observed, therefore does not induce cardiac or arterial disturbances Blood pressure.

As mentioned above, certain types of anti-Parkinson’s drugs, such as Diethazine and Benztropine, are calling often undesirable side effects of an anticholinergic nature (dryness of the mouth and difficulty with optical accommodation).

The investigated compound according to the invention, which is free from anticholinergic activity, has this Disadvantages do not arise.

The investigated compound according to the invention also proves to be free of emetic properties and undesirable side effects on the electrocardiogram is no vomiting or cardiac arrhythmia, which are two common side effects of L-Dopa.

12th

Pharmacological tests were carried out to determine the various properties of the invention To determine compounds that, taken together, are suitable for those compounds Treatment of Parkinson's disease and for the correction of extrapyramidal induced neuroleptics Disturbances are valuable.

I. Inhibition of those induced with reserpine

and neuroleptic induced catatonia

(dopaminergic properties)

1. Inhibition of reserpine
induced catatonia

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

(Connection 1),

1-ethyl-1-n-propyl-n-butylamine

(Connection 2),

1-ethyl-1-isobutyl-n-butylamine

(Connection 3),

1-ethyl-1-n-propyl-n-pentylamine

(Connection 4),

3 »

After a sufficient dose of reserpine was administered to the rat, a number of symptoms occurred, particularly ptosis, catatonia and a drop in central temperature. These symptoms were by emptying the intragranular supply of biogenetic amines at the synaptic terminals evoked.

The tricyclic antidepressants and the inhibitors of monoamine oxidase (I.M.A.O.) are particularly effective against the occurrence of ptosis and the drop in central temperature. In catatonia it is The effect of such compounds is also present, but considerably less noticeable.

In contrast, the synthetic anti-Parkinson’s drugs influence mainly catatonia, while its effectiveness on ptosis and hypothermia non-existent or weaker.

An oral dose of the test compound in aqueous solution was given to groups of 10 males Administered to rats (OFA strain) weighing about 150 to 200 g. Thirty minutes later it was a dose of 5 mg / kg reserpine administered intraperitoneally. Three hours after the injection with The animals were reserpine with four paws on a horizontally stretched wire, which was 15 cm from the floor was attached away, hanged. The animals with catatonia 4> were considered to be those who held this posture for at least 30 seconds. Any animal that the position given in this way received 1 point and those who did not maintain this position received were given 0 points. The highest score was therefore 10 per group. An identical attempt was made carried out with comparison animals which held reserpine, but none of the compounds to be investigated.

The following connections of the forms! I have been compared to amantadine according to the above specified procedure examined. The compounds were preferably in the form of a pharmaceutical usable acid addition salt, such as. B. hydrochloride or fumarate examined

1-n-propyl-1-isobutyl-n-butylamine (Compound 5), 1,3-dimethyl-1-n-propyl-n-pentylamine (Compound 6), 1,3-dimethyl-1-ethyl-n-hexylamine (Compound 7), 1-methyl-1-isobutyl-n-pentylamine (Compound 8), 1-methyl-1-n-propyl-n-hexylamine (Compound 9), 1,1-dimethyl-n-octylamine (Compound 10), 1,1-Di (2-propen-1 -yl) -3-buten-1 -ylamine (Compound 11), 1,1-di-n-butyl-n-pentylamine (Compound 12), 1,1,3-trimethyl-n-heptylamine (Compound 13), 1,1-diethyl-n-butylamine (Compound 14), 1,1-diethyl-n-propylamine (Compound 15), 1,1-dimethyl-n-propylamine (Compound 16), 1,1-dimethyl-3-ethyl-n-hexylamine (Compound 17), 1,1-Diisobutyl-n-butylamine (Compound 13), 1-n-propyl-1-isopropyl-n-butylamine (Compound 19), 1-n-Propyl-1-tert-butyl-n-butylamine (Compound 20), 1,1-Di-n-propyl-2-propyne-1 -ylamine (Compound 21), 1,1-diethyl-2-penlin-1 -ylamine (Compound 22), 1,1-diet> 1-2-penten-1-ylamine (Compound 23), 1,1-di-n-propyl-2-pentyn-1-ylamine (Compound 24), 1,1-Di-n-propyl-2-penten-1-ylamine (Compound 25), 1,1-Di-n-propyl-3-butyn-1-ylamine (Compound 26).

The results obtained with the compounds of formula 1 given above and the results obtained with amatadine are given in Table 1 below. The results are expressed in the following way:

0: Represents 0% inhibition of catatonia compared to the animals for comparison (namely a score of 10 per group examined).

1: Represents 20 to 30% inhibition of catatonia compared to the comparison animals (namely a Score from 7 to 8 per examined group).

2: Represents 50% inhibition of catatonia compared to the comparison animals (namely a score of per examined group).

3: Represents -ZO to 80% inhibition of catatonia in comparison to the comparison animals (namely a Score of 2 or 3 per examined group).

4: Represents 100% inhibition of catatonia in comparison to the comparison animals (namely a score of 0 per examined group).

13th 25 22 Inhibition 218 14th Inhibition of the one with reserpine by Neuroleptica Table 1 Administered dose indu. Catatonia ' Table II Administered dose indu. catatonia link in mg / kg 4th link in mg / kg 4th 1 1 5 3 ίο 5 3 1 5 3 1 5 3 2 20th 2 2 20th 4th 3 20th 1 3 20th 1 4th 20th 1 4th 20th 1 5 20th 1 r. 5 20th 4th 6th 20th 1 6th 40 1 7th 20th 1 7th 50 1 8th 20th 1 8th 20th 1 9 20th I. 9 50 1 10 20th 1 20 10 20th 1 11th 20th 3 11th 20th 3 12th 25th 1 12th 50 3 13th 50 1 13th 50 1 14th 50 1 14th 50 2 15th 50 2> 5 15th 10 1 16 11th 3 16 11th 3 17th 12th 2 17th 12th 1 18th 6th 2 18th 6th 1 19th 6th 1 19th 50 1 20th 30th 1 i <> 20th 30th 1 21 60 1 21 30th 2 22nd 60 3 22nd 30th J) 23 20th 1 23 20th 4th 24 6th 4th 24 6th 4th 25th 30th 25th 30th 26th 100 26th 100 Amantadine Amantadine

These results show that Compound 1., which is the preferred compound of the present invention, so is as effective as amantadine, but at a dose that is 4 < > Twenty times smaller than Amantadin's.

2. Inhibition of neuroleptics
induced catatonia

Blocking of dopaminergic receptors by neuroleptics in the extra-pyramidal system induces catatonia in the rat. The catatonia is of sedative properties with the help of the attempt that Above was applied for reserpine-induced catatonia, differed .. That one was rurikisysiem also applied in the present case

An oral dose of the test compound in aqueous solution was given to groups of 10 males Administered to rats (OFA strain) weighing about 150 to 200 g. Thirty minutes later it was a dose of 12.5 mg / kg prochlorperazine intraperitoneally administered Three hours after the injection of this latter compound, the catatonia was measured. An identical experiment was also carried out with reference animals that received prochlorperazine, however none of the compounds to be examined.

The results obtained with the compounds given above are given in Table II below The point system used was the same as stated above.

These results show that compound 1 is twenty times more active than amantadine in this experiment and compound 5 is five times more active than amantadine. while connection 8 is twice more active

Furthermore, compound 1 causes a 70% inhibition of neuroleptics at a dose of only 1 mg / kg induced catatonia.

The results presented in Tables 1 and 11 above in Compound with Compound 1 were given. were with 1,1-di-n-propyl-n-butylamine in the form of his Hydrochloride obtained. In the form of the acidic fumarate, 1,1-di-n-propyl-n-butylamine is about 20 to 40% more active as stated above. For example, one received a. Score of 4 in tests with reserpir-induced and neuroleptic-induced kaiatonia concerned, as described above, inn with 3 mg / kg 1,1-di-n-propyl-n-butylamine hydrogen fumarate

II. Acute toxicity

In the acute toxicity test, the LDso-Wen in mice by the oral route using the method of Lichfield and Wilcoxon (Pharmakol. 1938, 2, 192-216) determined. The compounds were administered in aqueous solution and the observation? - The period was 10 days after the administration of the compound to be tested.

The following results were recorded in comparison to amantadine.

link

LD50 (in mg / kg)

This latter value is represented by the number 4 in Tables I and II.
The following results were recorded:

1
2

9
12th
Amantadine

100

150

> 500

1750

500

1050

Link index

1
Amantadine

20th
10

These results show that the compounds of the invention are generally more toxic than Amantadine. However, if one compares the above given LD50 and the effective dose to inhibit the Obtaining catatonia induced with reserpine or neuroleptics will be seen in such comparisons always better results are obtained for the compounds according to the invention than for amantadine.

These figures show that Compound 1 has a complete inhibitory effect on by reserpine induced and neuroleptic induced catatonia at a dose that is proportional to twice that toxic dose is removed than is the case with amantadine. Compound 1 therefore has one higher margin of safety than amantadine.

When 1,1-di-n-propyI-n-butylamine hydrogen fumarate is the effective dose is even further removed from the toxic dose than for compound 1, since the corresponding

The index

LD ₅ Q
ED

was decided.

index

= 33.

'20 - J (I

In this index, ED20-20 represents the effective dose to inhibit catatonia by 20 to 30% obtained, this value being represented by number 1 in Tables I and II.

The following results were recorded:

link index 2 30th 6th > 25 9 87 12th 25th

The corresponding index for amantadine is 1050

50

= 21,

which shows that the compounds of the invention have greater advantages than amantadine. Similarly, an index

LDs

ED ₁ ,

determined, ED100 is the effective dose to a 100 ⁰ / o to obtain inhibition of the catatonia.

Additional experiments were carried out in rats with compound 1 and amantzdin. These attempts concerned catalepsy, which was shown by the crossing of the homolateral paws of the animals. It was observed that 5 mg / kg of compound 1 when administered orally 30 minutes before intraperitoneal Injection of prochlorperazine complete inhibition

jo of catalepsy 3 hours after injecting it the latter substance evoked. Regarding amantadine, a dose of 80 mg / kg was necessary to complete To effect inhibition of catalepsy.

The effectiveness of compound 1 in a

j5 curative treatment was also shown.

a) Suppression of by reserpine
induced catatonia

Groups of 5 male rats (OFA strain) with <· < > A weight of 150-200 g was given 5 mg / kg of resipin intraperitoneally. IV4 hours later, when the animals were in the state of catatonia, all animals except the control group an aqueous dose of the compound of interest is administered orally.

The progression of catatonia was then determined according to that in the tests described above the scale used.

The highest number of points was therefore 5 per group, ■ which means that all animals in the group are still in the Condition of catatonia.

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

Table 111 Line after administration of 2 h 30 Reserpine 3h30 4h 5h 130 214/153 2h 2 h 15 5 3h 3 1 2 5 5 2 3 0 0 0 Comparison lire 4th ^
j 0 0 0 0 0 Connection 1
2.5 mg / kg 5 1 3 0 1 0 0 Connection 1
5 mg / kg 5 4th 2 Amantadine
80 mg / kg

These figures show that at doses of 23 mg / kg and 5 mg / kg orally Compound 1 suppresses reserpine-induced catatonia faster than a dose of 80 mg / kg amantadine, which is below

given under the same conditions.

Compound 1 is therefore at least 32 times more effective than amantadine in treating the curative effects of Reserpine induced catatonia.

b) Suppression of neutroleptic induced catatonia

Groups of 5 male rats (OFA strain) io range. The progression of the catatonia was

12.5 mg / kg prochlorperazine were administered intraperitoneally 55 minutes later all animals were given ητ.ά With the exception of the comparison group, administering an oral dose of the compound to be tested in an aqueous solution on the same scale described in the tests above

The following results were registered with both compound 1 and amantadiene:

Table IV Time after Administration of 3h Prochlorperazine 4h 5h lh30 2h30 4th 3h30 1 1 4th 4th 0 3 0 0 Comparison animals 3 0 1 0 0 0 Connection 1
5 mg / kg 5 2 0 Amantadine
80 mg / kg

These results show that under the conditions of curative treatment, a dose of 5 mg / kg of the Compound 1 against induced by neuroleptics

Catatonia acts faster than a dose of 80 mg / kg

Amantadine, which is administered under the same conditions. In this test compound 1 is therefore 16 times more effective than amantadine.

The toxic-pharmacological index,

Doses in g / ml
bath

Inhibition of
Spasm in%

LD ₅ ,
ED

'50

is again cheaper for compound 1 than for amantadine, i.e. H. 20 for compound 1 and only 13 for amantadine.

An attempt was made arch to determine whether compound 1 has cholinolytic properties.

The test by Magnus (Arch. Gen. Physio. 1904, 102) was used for this. This test consists of determining the dose of acetylcholine which, when added to the bath, causes a spasm the isolated duodenum of the rat. In the next stage, the dose is to be examined Compound determines which - if it is added to the bath 30 seconds before the acetylcholine - the Reduced spasm.

The following results were recorded for Compound 1 in comparison to atropine:

Table V Doses in g / ml
bath Inhibition of
Spasm in% 0.5X10 ⁵
0.1 XlO "
0.2X10 " 45
100 Acetylcholine
Atropine

0.2X10 " ⁶
0.1XlO " ⁵
0.1XlO " ⁴
0.1XlO " ³
0.2XlO " ²
0.5XlO " ²

36

60

These results indicate that compound 120,000-bis 25,000 times less effective than atropine.

The cholinolytic activity "in vitro" of the compound 1 can therefore be considered practically non-existent compared to that of atropine.

The extremely weak cholinolytic effectiveness

of compound 1 occurs at most at toxic doses.

The absence of the cholinolytic properties of compound 1 at therapeutic doses was shown in vitro «verified.

To this end, the following experiment was carried out with the aim of defeating the anti-tremorine properties of compound 1 to be determined.

When tremorin is injected into mice it produces peripheral effects; H. Crying, d. H. Tear formation, Sweating, salivation and diarrhea, and central effects, d. H. Tremor and akinesia. Such bo effects are due to an increase in the amount of intracerebral acetylcholine and serotonin.

Male mice (OFi strain) weighing of about 22 g were divided into two groups of 10 pieces bi. Each group received by the oral route 50 mg / kg of the compound to be examined in aqueous solution. Thirty minutes later one came Dose of 10 mg / kg tremorin on intraperitoneal

Injected way, and at different times after this Injection, the cholinergic effects in each animal were determined according to the following scale recorded:

0: No effect
1: Weak effect
2: Medium effect
3: Strong effect
4: Very strong effect

The results obtained with 5 mg / kg of Compound 1 and 40 mg / kg of amantadine were as follows:

Regarding the peripheral cholinergic effects, i.e. salivation, sweating and crying, the Score 4 for the comparison animals 20, 30 and 40 minutes after the injection of tremorin for both 5 mg / kg of compound 1 as well as 40 mg / kg of amantadine. Identical results were obtained regarding the central cholinergic effects, d. H. normal and evoked tremors preserved.

These results show that compound 1 and amantadine are free from antitremorin properties, what the absence of cholinolytic properties in the case of compound 1 at therapeutic Doses confirmed.

Table VI

Experiments were also carried out with compound 1 in order to determine the influence of this compound to study peripheral noradrenergic phenomena

The following experiment was carried out for this purpose:

A cat anesthetized with pentobarbital was given a sufficient dose of norepinphrine to keep the To increase arterial pressure, which was not enough to

ίο induce a contraction of the nictitating membrane. The arterial pressure was measured on the carotid immediately after the administration of the narepinphrine dose. Thereafter, increasing doses of compound 1 in aqueous solution were administered intravenously every 30 minutes this, caused by the release of norepinphrine brought about by submaximal electrical stimulation of the cervical sympaticus.
The results given below were recorded with Compound 1 and Amantadine:

Cumulative doses Increase in Contractile reaction the nictitating membrane in mg / kg Arterial pressure in (in mm *)) mm Hg after injection of norepinphrine without with electrical electrical Stimulation Stimulation

Connection 1

Amantadine

0.1
1
3
5
10

0.1
1
3
5
10

0 0 0 0 0 0

0
0
3

4.4
5.9

7.5

17th
15th
16
17th
16
12th

20th
20th
20th
16
10
4th

*) The mm express the increase in contraction that was registered on a curve blue.

These results show that Compound 1 has neither the effects of exogenous norepinphrine nor des amplify endogenous norepinphrine.

On the other hand, amantadine amplifies exogenous norepinphrine by 1 mg / kg a », as it increases the intensity and The duration of the hypertension effects of this amine is increased and, after it has been administered, calls upon on the other hand, a dose of norepinphrine, which otherwise has no effect on the nictitating membrane, is a contractile reaction from this one out.

Furthermore, Amantadine itself stimulates the contractile reaction of the nictitating membrane, but does not intensify the effects electrical stimulation. In contrast, amantadine shows ganglioplegic properties of 5 mg / kg.

It goes without saying that the compounds according to the invention are used in therapeutic applications usually as a composition for human or veterinary medicine in one for the desired type of Administration entered appropriate dosage form,

bo being the composition as the active ingredient a compound of the invention together with a pharmaceutical carrier or excipient for this includes. For oral administration, for example, the composition can be in the form of a

j, 5 coated or uncoated tablet, Harto (' ι Have soft gelatin capsule, be a suspension or syrup. The composition can also be a Suppository for rectal administration, or a

Solution or suspension for parenteral administration be.

The composition can be in unit dosage form from about 5 to 50 mg, preferably from about 5 to 10 mg, of active ingredient per unit dosage for oral administration, about 5 to 50 mg of the active Ingredient for rectal administration or from about 1 to 10 mg of the active ingredient per unit dose for parenteral administration.

The therapeutic compositions of the invention are prepared by at least one of the compounds of formula 1 or a pharmaceutically acceptable acid addition salt thereof with at least one suitable carrier or auxiliary is combined for it. Suitable carriers are, for example Talc, magnesium stearate, lactose, sucrose, carboxymethyl cellulose, starches, kaolin, levilite and Cocoa butter.

The following examples serve to illustrate the invention.

example 1

Production of

1,1-Di-n-propyl-n-butylamine hydrochloride or
Tri-n-propylmethylamine hydrochloride

a) 1,1-Di-n-propyl-n-butyl isocyanate

In a three-necked flask (21), which is equipped with a water cooler, a mechanical stirrer and a Thermometer and a dropping funnel, 144 g of sodium hydroxide were in tablet form and given 1200 ml of water. The solution was cooled to 5 ° C and 48 ml of bromine were added with stirring slowly admitted. The addition of the bromine took two hours, and then were at one temperature from 0 ° C 111g of 2,2-di-n-propyl-valeramide to the yellowish-green solution given. The mixture was kept stirring at about 0 ° C for 4 hours. The oily phase was then extracted with three ether fractions of 300 ml each and the essential Phase washed twice with 100 ml of water, dried over magnesium sulfate and evaporated in vacuo. The light yellow oil thus obtained was distilled off under a reduced pressure of 5 mmHg.

In this way, 105 g of colorless 1,1-di-n-propyl-n-butyl isocyanate were obtained.
Bp. 78 to 79 ° C below 5 mm Hg.
Yield: 95%.

Following the same procedure described above, but using the appropriate starting materials, the following connections were made:

links

Boiling point. C.

1,1-di-n-butyl-n-pentyl isocyanate
(Yield: 80%)

1-n-propyl-1-isopropy '
butyl isocyanate

92 to 93
(0.5 mmHg)

97

(15 mmHg)

b) 1.l-di-n-propyl-n-butylamine hydrochloride

To a three-necked flask equipped with a mechanical stirrer, dropping funnel, thermometer and condenser were added 200 ml of water and 90 ml of concentrated hydrochloric acid (W = 1.19). The acid solution was heated to 90 ° C, and then were dispersed with vigorous stirring, 105 g of ^1, l-di-n-propyl-n-butyl-isocyanate, which was prepared as described above, is slowly added. The addition process lasted one hour, after which the reaction medium was heated for a further 4 hours at a temperature between about 95 and 100 ° C. The mixture was then cooled to about 0 ⁰ C, and the resulting colorless crystals were abfiiuiert. mn air and then dried in a desiccator in the presence of potassium hydroxide. In this way, 99 g of 1,1-di-n-propyl-n-butylamine hydrochloride were isolated in the form of a white crystalline powder

The product does not melt but sublimates from 220 ⁰ C.

Yield: 90%.

Using the same process as described above, but using the appropriate starting materials, the following compounds were obtained:

link

!, l-di-n-butyl-n-pentylamine- F.p. 68.1 C

hydrochloride

(Yield: 63%)

l-ethyl-l-n-propyl-n-bulylamine- 180 C "

hydrochloride (sublimation)

1-ethyl-1-isobutyl-n-butylumine-230C

hydrochloride (sublimation)

1-n-propyl-1-isobutyl-n-butyl- m.p. 260 C

amine hydrochloride

1-ethyl-1-propyl-n-pentylamine- F.p. 230 C

hydrochloride (decomposition)

1-n-Propyl-1-isopropyl-n-butylamine- m.p. 260C
hydrochloride (decomposition)

Example 2

Production of
1,1-Di-n-propyl-n-butylamine hydrogen fumarate

To a solution of 1.16 g (0.01 mol) of fumaric acid in 20 ml of acetone, 1.57 g (0.01 mol) of 1,1-di-n-propyln-butylamine (n ',! = 1.4349 ), which was dissolved in 10 ml of acetone, was slowly added, this amine having been prepared from its hydrochloride and a 30% strength aqueous solution of sodium hydroxide. The mixture was stirred for one hour, and then the resulting crystals were filtered off with the suction filter, washed with acetone and dried under vacuum.

In this way, 1,1-di-n-propyl-n-butylamine hydrogen fumarate was obtained in the form of a white powder.
Mp. 216 ° C with sublimation
Yield: 100%

Example 3

Production of 1-n-propyl-l-isobutyln-butylamine hydrochloride

a) l-n-propyl-1-isobutyl-n-butanol

To a three-necked flask (250 ml) fitted with a mechanical stirrer, nitrogen inlet, one

Adding funnel and thermometer were added under a nitrogen atmosphere 2.8 g (0.2 Mol) lithium given in small portions and 100 ml of anhydrous and purified tetrahydrofuran. The suspension of lithium in tetrahydrofuran was cooled to -20 ° C. and a mixture was stirred of 22.8 g (0.2 mol) of di-n-propyl ketone and 30 g (0.2 mol plus 10% excess) isobutyl bromide slowly added. The addition process took about 3 hours, during which a temperature of about -20 ° C was maintained. The solution became about 12 Allowed to stand for hours at room temperature and then concentrated. The oil thus obtained was dissolved in water taken up, extracted with ether and distilled under reduced pressure.

In this way, 21 g of 1-n-propyl-1-isobutyl-n-butanol were obtained in the form of a clear liquid that was pale yellow.

Bp. 74 to 76 ⁰ C below 5 mm Hg Yield: about 60%

Using the same process as described above, but using the appropriate starting materials, the connections listed below were established:

link

Boiling point, t "

1,1-diethyl-n-butanol 62

(Yield: 50%) (15 mmHg)

1-ethyl-1-n-propyl-n-bulanol 178 to 179

(Yield: 35%) (760 mmHg)

1-ethyl-1-isobutyl-n-butanol 78 to 79

(Yield: 40%) (15 mmHg)

1,1-di-n-propyl-n-butanol 70 to 80

(Yield: 60%) (0.15mmHg)

1 -n-propyl-1-isopropyl-n-butanol 81

(15 mmHg)

l-n-Propyl-l-tert-butyl-n-butanoI 90 to 92

(14 mmHg)

1,1-dimethyl-n-octanol 93 to 95

(Yield: 45%) (13 mmHg)

1,1,3-trimethyl-n-heptano! decomposition (Yield: 60%)

1,1-dimethyl-3-ethyi-n-hexano! decomposition

(Yield. 30%)

1,3-Dimethy 1-1 -ethyl-n-hexanol decomposition (Yield: 35%)

1,3-Dimethyl-1-n-propyl-n-pentanol decomposition (Yield: 46%)

1-methyl-1-isobutyl-n-pentanol decomposition (Yield: 33%)

1 -Methyl-1-n-propyl-n-hexanol decomposition (Yield: 30%)

1,1-diisobutyl-n-butanol 75 to 76

(Yield: 60%) (4 mmHg)

1-ethyl-1-n-propyl-n-pentanol 87

(Yield: 35%) (11 mmHg)

b) l-n-propyl-l-isobutyl-n-butylamine hydrochloride

To a three-necked flask (250 ml) equipped with a mechanical stirrer, dropping funnel, condenser and immersion thermometer, 6.5 g (0.1 mol) of dry powdered potassium cyanide, 14.4 g (0.083 mol) of 1-n Propyl-l-isobutyl-n-butanol and 12 ml acetic acid. While stirring, a mixture of 25 g of concentrated sulfuric acid (d = 1.83)

ίο and 12 ml of acetic acid slowly added. The addition process took about 2 hours, during which time a temperature of about 50 ⁰ C maintained. The reaction mixture was ^{heated to 70 °} C. for 2 hours and then slowly poured into 100 ml of ice water. It was then neutralized with a 20% strength aqueous solution of sodium hydroxide and extracted with ether. The ether was evaporated and an oil comprising N-formylated 1-n-propyl-1-isobutyl-n-butylamine collected.

The N-formylated amine thus obtained was 2 Heated for hours in the presence of 20 ml of concentrated hydrochloric acid and reflux. At the Upon cooling, the hydrochloride of this amine crystallized. It was then filtered off and washed with acetone.

In this way, there was 11 g of 1-n-propyl-1-isobutyl-n-butylamine hydrochloride collected in the form of a white powder.

The melting point was> 260 ° C with decomposition without melting at about 28O ⁰ C

i »Yield: 64%

In the case of thin layer chromatography on silica gel plates using a solvent system, which comprises 79 parts of benzene, 14 parts of methanol and 7 parts of acetic acid, and iodine as a test reagent, an Rf value of 0.6 was recorded.

Using the same process as described above, but using the appropriate starting materials, the compounds listed below were made. The one for each of these connections

■ to given Rf value was obtained on thin layer chromatography using the same carrier, the same solvent system and the same test reagent, as described in the example above, determines:

link

1,1-diethyl-n-propylamine-hydro-210 C

Chloride (sublimation)

(Yield: 40%)
Rf - 0.49

1,1-di-n-propyl-n-butylamine-hydro-220 C
chloride (sublimation)

1,1-diethyl-n-butylamine-hydro- F.p. > 300 C

chloride

(Yield: 60%)
Rf = 0.59

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

hydrochloride (sublimation)

(Yield: 25%)
Rf = 0.64

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

hydrochloride (sublimation)

(Yield: 30%)
Rf = 0.60

link

1,1-dimethyl-n-octylamine-hydro- m.p. 111.8 C
chloride

(Yield: 45%)
Rf = 0.65

1,3-dimethyl-1-ethyl-n-hexylamine- F.p. 133.3 C

hydrochloride

Rf = 0.56

1-methyl-in-propyl-n-hexylamine- M.p. 174.7 C
hydrochloride
(Yield: 60%)
Rf = 0.60

In-propyl-1-isopropyl-n-butylamine- m.p. 260C
hydrochloride (decomposition)

1-ethyl-in-propyl-n-pentylamine- m.p. 230 ° C
hydrochloride (decomposition)

(Yield: 30%)
Rf = 0.60

Example! 4th

Production of 1,1-dimethyl-3-ethyl-n-hexylamine hydrogen fumarate

a) l, l-dimethyl-3-ethyl-n-hexylamine

1, l-Dimethy! -3-ethyl-n-hexylamine in the form of its free base was initially a reaction 30% solution of sodium hydroxide with 1,1-dimethyl-3-ethyl-n-hexylamine hydrochloride manufactured. The free base thus obtained was then extracted with ether.

b) 1,1-dimethyl-3-ethyl-n-hexylamine hydrogen fumarate

To a solution of 1.74 g (0.015 mol) of fumaric acid in 300 ml of acetone were 2.3 g (0.015 mol) of l, l-dimethyl-3-ethyl-n-hexylamine, which, as already described, was prepared in 40 ml of acetone, slowly added. The mixture was stirred for 3 hours and the fumarate which crystallized, filtered off with Acetone washed and dried.

In this way, 2 g of 1,1-dimethyl-3-ethyln-hexylamine hydrogen fumarate were obtained in the form of colorless crystals.

Mp. 160.6 ⁰ C
Yield: 50%

In thin layer chromatography on silica gel plates using a solvent system, which comprises 79 parts of benzene, 14 parts of methanol and 7 parts of acetic acid and with iodine as the test reagent an Rf value of 0.56 was recorded.

Using the same procedure as described above was, but using the appropriate starting materials, the compounds given below manufactured.

The Rf value given for each of these compounds was obtained by thin layer chromatography using the same carrier, solvent system and assay reagent as above has been described, determines:

link

1,1,3-trimethyl-n-heptylamine-

hydrogen fumarate

Rf = 054

1-n-Propyl-1-tert-butyl-n-butylamine hydrogen fumarate

F.p. 140 C

180 C
(Sublimation) 1,3-dimethyl-in-propyl-n-pentyl- m.p. 114.4 ° C

amine hydrogen fumarate

Rf = 0.56

1,1-diisobutyl-n-butylamine-hydro- F.p. 179 C

gene fumarate

Rf = 0.66

Example 5

Production of

1 -Methyl-1 -isobutyl-n-pentylamine fumarate
(neutral fumarate)

a) 1-methyl-1-isobutyl-n-pentylamine

1-methyl-l-isobutyi-n-pentylamine in the form of its free base was first obtained by reacting a 30% aqueous solution of sodium hydroxide with 1-methyl-1 -isobutyl-n-pentylamine hydrochloride produced.

The free base thus obtained was then extracted with ether

b) 1-methyl-1-isobutyl-n-pentylamine fumarate

With stirring, the amine thus obtained slowly became a solution of 2.32 g in the form of its free base (0.02 mol) of fumaric acid in 300 ml of acetone. The fumarate slowly crystallized. The stirring became one maintained for another hour, and the resulting crystals were filtered off, washed with acetone and dried.

In this way, 3.1 g of 1-methyl-1-isobutyl-n-pentylamine fumarate were obtained in the form of colorless crystals.

Mp 198.4 ° C
Yield: 70%

Rf = 0.58 (The Rf value was determined by thin layer chromatography using the same solvent and test reagent as in the examples 2 and 3 obtained above)

Example 6

Production of

l-ethyl-l-n-propyl-n-pentylamine hydrochloride

a) 2-ethyl-2-n-propyl-caproic acid

In a three-necked flask fitted with a mechanical stirrer, thermometer and two dropping funnels was equipped, 204 g of 96% sulfuric acid, which had cooled to 5 ° C, and added 4 ml of formic acid. While the mixture is at a temperature

was kept at about 10 ° C, 23 g (0.5 mol) Formic acid and 15.8 g (0.1 mol) 1-ethyl-1-n-propyln-pentanol in 100 ml of pentane added at the same time. The addition process took 40 minutes, after which the Mix at room temperature for 2 hours

was allowed to come back. The mixture was poured onto 100 g of crushed ice and the acid with Ether extracted The acid was purified by adding its sodium salt with a 20% aqueous solution of Sodium hydroxide was produced. The aqueous phase was acidified with 50% hydrochloric acid and extracted with ether

The organic fraction was then poured over magnesium sulfate dried and concentrated under vacuum

In this way, 2-ethyl-2-n-propyl-caproic acid was obtained in the form of a colorless liquid. Bp. 130 to 132 ° C below 20 mm Hg Yield: about 20%

Using the same procedure as described above, the following compound was made manufactured:

link

K.P.

2-ethyl-2-n-propyl-caproic acid

122 C

(12 mmHg)

b) 1-ethyl-1-n-propyl-n-pentylamine

70 ml of chloroform, 18 ml of concentrated sulfuric acid (tf = 1.83) and 11 g (0.06 mol) of 2-ethyl-2-n-propyl-caproic acid were placed in a three-necked flask equipped with a mechanical stirrer and a condenser , which was prepared as described above, given. The mixture was heated to 5O ⁰ C and while stirring, 7.5 g of sodium azide were added in powder form. The process of addition took 90 minutes after which the reaction mixture heated to 50 "C for 2 hours. The mixture was then triumhydroxyd Ni with a 40% aqueous solution of which had been previously cooled to 0 ⁰ C, neutralized. The amine was extracted with ether and the ethereal phase washed with water and dried over magnesium sulfate, the ether was evaporated in vacuo and the oil thus obtained was taken up in dry ether, 1-ethyl-1-n-propyl-n-pentylamine in the form of its free base received.

Using the same procedure as described above, the following compound was made manufactured:

link

K.p.

1,1-di-n-propyl-n-butylamine

190.5 to 195 C (742 mmHg)

c) 1-ethyl-1-n-propyl-n-pentylamine hydrochloride

The hydrochloride of the amine obtained above was precipitated by drying gaseous hydrochloric acid was bubbled through the solution of this amine.

In this manner, there was obtained 1-ethyl-1-n-propyl-n-pentylamine-hydrnchlorid in the form of colorless crystals which sublime from 200 ⁰ C to. Yield: 45%

Using the same procedure as described above, the following compounds were made:

link

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

1-ethyl-1-n-propyl-n-butylamine hydrochloride

1-ethyl-1-isobutyl-n-butylamine hydrochloride

200 ⁰ C (sublimation)

180 ⁰ C (sublimation)

230 ° C (sublimation)

1 -n-propyl-l -isobutyl-n-butyl-

amine hydrochloride

1 -n-propyl-1-isopropyl-n-butyl-

amine hydrochloride

1,1-Di-n-propyl-3-butyn-1-ylamine hydrochloride

Mp. 260 ° C

Mp. 260 ° C
(Decomposition)

262 ° C

(Sublimation and decomposition)

Example 7

Preparation of 1,1-Di (2-propen-1-yl) -3-buten-1-ylamine oxalate

a) 1,1-Di (2-propen-1-yl) -3-buten-1-ylamine
(or triallylmethylamine)

Under a nitrogen atmosphere, 13.4 g (0.2

Mol) allyl cyanide in 20 ml of dry ether to a solution of 0.4 mol of allyl magnesium bromide in 350 ml Ether given. The addition process took an hour while the ether was gently refluxing was heated. Thereafter, the reaction medium was heated to the boiling point for 4 hours. To After cooling, the mixture was poured into 200 ml of a saturated solution of ammonium chloride. The ethereal phase was separated, washed with water and dried over magnesium sulfate and

evaporated under vacuum. The oil thus obtained was distilled under reduced pressure.

In this way, 14 g of 1,1-di- (2-propen-lyl) -3-buten-1-ylamine were obtained in the form of a pale yellow liquid.

Bp. 79 to 80 ° C (below 15 mm Hg)

Yield: 46%

Following the same procedure as described above, the following compound was made.

link

1,1-di-n-propyl-n-butylamine

η '"' = 1.4349

b) 1,1-di- (2-propen-1-yl) -3-buten-1-ylamine oxalate

3 g (about 0.02 mol) of l, l-di- (2-propen-l-yl) -3-buten-1-ylamine, which was prepared as described above, added in 20 ml of ether to 2.5 g (about 0.02 mol) of oxalic acid hydrate (2 molecules of water of hydration) in 300 ml of ether.

Stirring was maintained for 30 minutes and then the colorless crystals that precipitated became filtered off. The crystals were washed with ether and recrystallized from ethyl acetate.

In this way, 4 gl, l-di- (2-propen-lyl) -3-buten-1-ylamine oxalate were obtained
Mp 96.2 ° C
Yield: 70%

bo Following the same procedure as described above but using hydrochloric acid instead of oxalic acid became the following Connected:

link

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

220 ° C
(Sublimation)

Example 8

Production of
1,1-Di-n-propyl-2-propyne-1 -ylamine hydrochloride

a) 1.l-Di-n-propyl-2-propyn-1-ol

A three-necked flask (21) fitted with a mechanical stirrer, condenser, submerged tube and a dropping funnel was placed in a hood. In the flask that was previously in a bath had been cooled by dry ice in acetone, 1 liter of liquid ammonia was added. Acetylene that before was cleaned by passing it through a trap containing dry ice, and into a sulfuric acid solution was blown and dried over caustic potash, was then blown through the reaction medium.

23 g of finely divided sodium were added to the acetylene solution in ammonia. Blowing in the acetylene was maintained for 1 hour after the addition of the sodium. Then 114 g (1 mol) Di-n-propyl ketone was added and the flow of acetylene was continued for 1 hour, after which time 500 ml of ether were added and the mixture was allowed to stand at room temperature for 12 hours. She then became hydrolyzed by moist ether and subsequently with crushed ice. After acidification with 10% Sulfuric acid, the ethereal phase was separated, dried over magnesium sulfate and reduced under reduced Focused pressure.

In this way, 45 g of 1,1-di-n-propyl-2-propyne-1-oil were collected after distillation, which is a yield of 32%.
Bp 68 to 70 ° C

b) 1,1-Di-n-propyl-1-chloro-2-propyne

To a three-necked flask equipped with a magnetic stirrer, thermometer, and dropping funnel were placed 6.5 g of freshly made copper (I) chloride, 9.1 g of calcium chloride, 0.020 g of copper bronze powder, and 71 ml of concentrated and iced hydrochloric acid ( d = 1.19). While stirring, 23 g of 1,1-di-n-propyl-2-propyl-1-oil prepared as described above was added to the mixture kept at 10 ° C.

The addition of the alcohol took 30 minutes and then the reaction mixture took 2 hours Left to stand at room temperature. The supernatant portion of the mixture was placed in a dropping funnel decanted and twice with 15 ml of concentrated and iced hydrochloric acid and then three times with Washed 20 ml of distilled water. After drying over potassium carbonate, the mixture was distilled, whereby the desired product was obtained.

In this way, 17 g of 1,1-di-n-propyl-1-chloro-2-propyne were obtained in the form of a transparent, colorless liquid, which represents a yield of 65%.
Bp. 63 to 65 ° C below 14 mm Hg.

c) 1,1-di-n-propyl-2-propyn-1-ylamine

To a suspension of sodium amide in liquid ammonia, consisting of 6.9 g of sodium and 250 ml of liquid Ammonia was produced, 17 g of 1,1-di-n-propyl-1-chloro-2-propyne given in 50 ml of anhydrous ethyl ether. The process of adding the chlorinated derivative lasted an hour. Stirring the mixture was maintained for 2 hours, and then added 300 ml anhydrous ethyl ether added.

The reaction medium was left to stand for 12 hours, after which the ammonia was evaporated and 100 g of crushed ice was added. The ethereal phase was separated and the basic Phase extracted with 300 ml of a 10% aqueous solution of hydrochloric acid. The amine was by adding concentrated and iced caustic soda and re-extraction with ether won.

ίο In this way one obtained l, l-di-n-propyl-2-propyne-1 -ylamine in the form of its free base.

Following the same procedure as described above, the compounds given below were prepared manufactured:

link

1,1-Dimethyl-2-propyne- m.p. 18 ° C
1-ylamine

U-Diethyl ^ -propin- Kp. 71-72 ⁰ C

1-ylamin (90 mm Hg)

d) l, l-di-n-propyl-2-propyne- ,. 1-ylamine hydrochloride

The ethereal solution of the previously obtained amine was dried over magnesium sulfate and the The hydrochloride of this amine is then precipitated by bubbling in dry gaseous hydrochloric acid.

The crystals thus obtained were separated and dried in a desiccator in the presence of caustic potash.

In this way, 12 g of l, 1-di-n-propyl-2-

propin-1-ylamine hydrochloride, which represents a yield of 68%.

r. Fp.200 ⁰ C (with decomposition).

Example 9

Production of II-diethyl-2-pentyn- _{4 (|} 1-ylamine hydrochloride

a) 1,1-Diethyl-2-pentin-1-ylamine

In a three-necked flask with a mechanical Stirrer, a vertical condenser and a dropping funnel. became a suspension of sodium amide from 150 ml of liquid ammonia, 2.4 g of sodium and a few crystals of ferrous nitrate manufactured. A solution of 11 g of l, l-diethy! -2-propyn-1-ylamine was added to this suspension in 30 minutes. there < as previously described, and 20 m ". given anhydrous ethyl ether. When the addition process was completed, the stirring of the mixture became 30% Maintain minutes and a solution of 15 g of dry ethyl bromide in 30 ml of anhydrous ethyl ether added dropwise to the reaction mixture. The addition of the ethyl bromide took one time Hour after which the mixture was kept stirring for 4 hours. The reaction medium was then left to stand for 12 hours to allow the ammonia to evaporate and 50 g of crushed ice became added. The ethereal phase was separated, dried over magnesium sulfate and then under evaporated under reduced pressure

In this way, 8 g of 1,1-diethyl-2-pentyne were obtained 1-ylamine after distillation in the form of a colorless liquid.

Bp. 62 to 63 ° C below 15 mm Hg.

Yield: 57%.

Using the same process as described above, but using the appropriate starting materials, the following connection was established:

link

K.p.

1,1-di-n-propyl-2-pentyn-1-ylamine 92-94 C
(Yield: 55%) (15 mmHg)

b) l, l-diethyI-2-pentine-l-yiamine hydrochloride

The hydrochloride of the amine obtained previously was prepared by anhydrous ethereal solution of this amine was treated with dry gaseous hydrochloric acid. By Evaporation of the ether and drying of the crystals thus obtained in a desiccator and in the presence of Caustic potash obtained U-diethyl-2-pentyn-1-ylamine hydrochloride in the form of a white powder.

Mp. 85 ° C,

Yield: 100%.

Using the same procedure as described above, the following connection was made:

tors (catalyst made from palladium, sodium carbonate and lead oxide) hydrogenated. The addition of the hydrogen at the triple bond was facilitated by keeping the mixture stirring and heating it to a temperature of about 50 ° C. The absorption of 560 cm ^{3 of} hydrogen was achieved in 90 minutes. After evaporation of the solvent, the desired hydrochloride was separated off by adding dry gaseous hydrochloric acid. The crystals thus obtained were dried in a desiccator in the presence of caustic potash

In this way, 1,1-diethyl-2-pentene-lylamine hydrochloride was obtained in the form of a white powder.

Mp. 200 ° C with sublimation.
Yield: 100%.

Using the same procedure as described above, the following connection was made:

link

!, l-di-n-propyW-penten-l-ylamine-

hydrochloride

(Yield: 100%)

200 C
(Sublimation)

link

F.p.

!, l-di-n-propyl-1-pentin-1-ylamine-118 C

hydrochloride

(Yield: 100%)

Example 10

Production of
l, l-ethyl-2-penten-l-ylamine hydrochloride

In 40 ml of heptane there were 3.5 g of U-diethyl-2-pentynylamine in the presence of 50 mg of a Lindlar catalyst Example 11

A hard gelatin capsule that contains the following ingredients was produced according to known pharmaceutical processes:

Ingredients mg

!, l-di-n-propyl-n-butylamine hydrochloride
Lactose

130 214/153

Claims (1)

Patent claims: 1. Composition for human or veterinary medicine, especially for the treatment of Parkinson's disease and to remedy extra-pyramidal disorders caused by neuroleptics, characterized in that it is an essential active ingredient at least one methylamine derivative of the formula: