DE2522218B2 - Composition for human or veterinary medicine, methylamine derivatives and processes for their preparation - Google Patents

Description

R ₁ -H ₃ C

R ₂ -C-NH ₂

R ₃ -H ₂ C

CH ₃ -CH ₂ -CH ₂

\
R ₂ -C-NH ₂

(Ia)

10

15th

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 R ₂ for a straight or branched chain alkyl, alkenyl or alkynyl group with about 2 to 7 carbon atoms, provided that - when R _{2 is} an alkenyl group of the formula CH = CH-Ri or an alkynyl group of the formula CsC-R », where Rt is a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms - Ri and Rj each represent a hydrogen atom or an alkyl group, where R ₁ , R ₂ and R ₃ 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 combination with a pharmaceutical carrier or excipient therefor.

2. Composition for human or Veterinary medicine according to claim!, Characterized in that that they are as an essential active ingredient l, l-di-n-propyl-n-butylamine or a pharmaceutical contains usable acid addition salt of this. 4 y

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. v>

4. Methylamine derivative of the general formula:

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

CH ₃ -CH ₂ -CH ₂

R ₂ -C-NH ₂

Ri

Oa)

in which R ' ₂ either denotes the n-propyl group and R' ₃ denotes the ethyl, isopropyl, isobutyl or tert-butyl group, or RS 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:

CH ₃ -CH ₂ -CH ₂

R ₂ -CA

(Ib)

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 the acid addition salt of methylamine obtained is reacted with a base and the free base obtained is converted into another pharmaceutically usable acid addition salt with an organic or inorganic acid.

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:

in which R> either denotes the n-propyl group and R'i denotes the ethyl, isopropyl, isobutyl or tert-butyl group or R ' ₂ denotes the ethyl group and R' 1 denotes the η-butyl or isobutyl group ,

or a pharmaceutically usable acid addition saline / of that.

5.1-Di η, iropvl n-biitvl.imin hydrogen in: na rat.

K ₁ -II ₂ C

K ₇ -C-NH ₂

/
K, H ₂ C

wherein R; and R, each represents 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 having 1 to 5 carbon atoms. - Ri and R ₃ each represent a hydrogen atom or 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 a pharmaceutically acceptable acid addition salt of this derivative, optionally in conjunction with a pharmaceutical Carriers or auxiliaries therefor

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

CH3-CH ₂ - CH ₂

R ₂ -C-NH ₂

(Ia)

20th

25th

in which R ' ₂ either denotes the n-propyl group and R' ₃ denotes the ethyl, isopropyl, isobutyl or tert-butyl group or R'j 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 umarat 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 rivals of 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 are 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:

l, l-di- (2-propen-l-yl) -3-buten-l-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> o

light in J. Amef. Cheni. SoC, 70, 4048, 1948).

1-methyl-1-methyl-1 -Methyl-

1-methyl-1-methyl-

-ethyl-2-pentyn-i-ylamine,
-ethyl-2-heptin-1-ylamine,
-ethyl-n-pentylamine,
-ethyl-n-propylamine.
-äthyl-2-propen-1 -ylaniin (all

described in |. Amer. Chcm. Soc. 75. 4297,
1953),

t, 1-diethyl-2-propi: nl -ylamine,
1,1-dimethyl-2-projpin-1 -ylamine,
1,1-diethyl-n-propylamine
(which are already on the market).

As far as is known, however, these became known Compounds never ascribed a therapeutic activity.

Similarly, tri-n-propylmethylamine or i, l-din-propyl-n-butylamine and tri-n-butylmethylamine or II-di-n-butyl-n-pentylamine were found by Sperber etaL in]. Amer. Chem. Soc, 71, 3352 (1949), where they are presented as "less spasmolytic and more toxic than the corresponding trialkylethylamines". H ^; it is more a question of musculotropic 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 of the compounds of the formula I in general and the Tir-n-propyl- and tri-n-butyl-methylamine in particular are attributed.

The publication, focusing on the spasmolytic Activity relates to 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 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-butylamine investigated in vitro. It was in full accordance with the results of Sperber et al. observed that the spasmolytic activity of this compound was very weak; H. practically nonexistent, since it is 20,000 to 25,000 times weaker than that of atropine. From this can reliably concluded that the spasmolytic activity of tri-n-propylmethyhmin in vivo in doses, which are extremely toxic should be used.

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.

The compounds of the formula I in which Ri and Rj 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 carbon atoms, another alkenyl group as CH = CH-R4 or another alkynyl group than C = C-R4 can be obtained by treatment in a suitable medium with a strong acid, such as 1. B.

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

R ₁ -H ₂ C

\
R ₂ -CA

R ₃ -H ₂ C

(TJ)

N = C = O

or

Rs-CH ₂ -CN

(HI)

where Rs has the above meaning, with a Organomagnesium derivative of the general formula:

R ₅ -CH ₂ MgX

(IV)

wherein Rs 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 obtained wild, the can then be reacted with an organic or inorganic acid to produce a pharmaceutical to produce usable acid addition salt of this compound.

As a hydrolyzing agent, for example, a saturated solution of ammonium chloride can be used.

The compounds of the formula I. in which Ri and Ri each represent a hydrogen atom or an alkyl group having about 1 to b carbon atoms and R2 is an alkyne group of the formula C =C-R4. wherein R _{4 represents} hydrogen, ie an ethynyl group. stands.

can in liquid ammonia by reacting sodium amide and a halide of the general Formula;

wherein Ri, R ₂ and R3 have the above meaning and A stands for the group

NH-C-H

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

Treatment of the compound of the formula II with the acid may be performed using the appropriate reagents at a temperature between about 15 and 10O ⁰ C, preferably carried out between about 50 and 9O ⁰ C.

The compounds of the formula I in which Ri and R ₃ each represent an alkyl group with 1 to 3 carbon atoms or an alkenyl or alkynyl group with 2 or 3 carbon atoms and R _{2 represents} the group CH ₂ -R ₅ , in which Rs is an alkyl group with 1 to 3 carbon atoms or an alkenyl or alkynyl group fr't 2 or 3 carbon atoms, where Ri, R ₃ and Rs are identical, can also be prepared by in anhydrous ether, such as. B. Ethyl ether, a nitrile of the general formula:

R ₁ -H ₂ C

HC = C-C-Hal

R ₃ -H ₂ C

(V)

wherein Ri and R _{3 have} the above meanings and Hai represents a chlorine or bromine atom, the desired compound of the formula I being 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 R ₃ each represent a hydrogen atom or an alkyl group having from about} to 6 carbon atoms and R _{2 represents} an alkynyl group of the formula ^ = C-Ri, in which R4 represents an alkyl group having 1 to 5 carbon atoms , can by reaction of a metal derivative of the general formula:

Ri - H ₂ C

Me-C = CC-NH ₂

R ₃ -H ₂ C

(VT)

wherein Me is an alkali metal atom, e.g. B. sodium, and Ri and R _{3 has} the above meaning, with an r> halide of the formula:

R ₄ -HaI

(VII)

where R4 has the above meaning and Hai has the same Meaning as in formula V, are prepared, wherein the desired compound of formula I is obtained, which can then be reacted with an organic or inorganic acid to produce a pharmaceutically usable acid addition salt

4) to form this connection.

The compounds of the formula I in which R ^ 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 R4 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

^fc0 R ₃ -H ₂ C

(VIII)

wherein R 1, Ri and R ₄ are as defined above, are prepared to form the desired compound of formula 1 / u, which can then be reacted with an organic or inorganic acid to give a pharmaceutically acceptable acid addition salt / this compound.

The hydrogenation is preferably carried out at one temperature between 30 and 60 'L and especially at about 50 "C.

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

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

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

where Ri, R? and Rj have the same meaning as in the Have compounds of the formula II with an alkali metal cyanide, for. B. sodium or potassium cyanide, in Presence of an acid, for example sulfur

R ₁ -H ₂ CO

R ₂ -CC-NH;

Rj-H ₂ C

(IX)

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

RH ₂ CO

R ₂ -C -C -OH

/
R ₃ -H ₂ C

wherein Ri. R ₂ and Rj 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. treated \\ ird. to prepare 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, e.g. B. sulfuric acid, the desired compound of the formula II being obtained.

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

b) If A is the group
O

Il

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 formula IX can be prepared by reacting anhydrous ammonia with the corresponding acids of the formula X or preferably

Ki se can be obtained with the halides of these acids. The acids can be prepared from the alcohols of the formula XI and formic acid in a sulfuric acid medium.
The compounds of Formula XI are either

ι; known compounds or can correspond to known methods, e.g. B. united by reaction Lithium-organic compound with a suitable ketone in an anhydrous ether medium, ζ. Β

To * rah «/ *" lr * "> Fnr ·» r »kornoc part t it'ArHon

.'η 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 Opposite wall

r, 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 they can be obtained by known methods which (X) in, for example, Organic Syntheses Collective. Volume III p. 146 described. The products of the formula VI can be in liquid ammonia by the action of an alkali metal, such as ζ. Β Sodium, prepared on the corresponding 1.1 -dialkyl-1-ethinyl methylamine, which is a compound falling under formula 1. 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 own. In particular, it has been found that the compounds according to the invention have central noradrenergic and have central dopaminergic properties. The latter properties show up by an inhibitory effect on reserpine-induced and neuroleptic-induced catatonia and Catalepsy.

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

-, o tri-n-propylmethviamine hydrochloride or 1,1-di-npropyl-n-butylamine hydrochloride extraordinary !. Possess effectiveness. However, it was surprising and quite unexpectedly observed that 1,1-di-npropyl-n-butylamine hydrogen fumarate has a level of effectiveness even greater than that of the corresponding hydrochloride. It was observed that 1.1-di-n-propyl-n-butyIamic acid fumarate 20 to Is 30% more active than the corresponding hydrochloride in experiments with reserpine-induced and neutroleptics 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 the Neutroleptica in the Rat and their Antiapomor- (Xi) Do not influence the effects of phin 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 as well as for Correction of extra-pyramidal disturbances caused by Ncnmleptica is valuable.

F'arkinson's disease is chronic and f ■ jgressive impairment, in particular by is characterized by dopamine deficiency in the thalamic and caudatar and lenticular nuclei. being akinesia, rigidity and t; emor visible Symptoms are.

Many effective remedies have been suggested for controlling Parkinson's Syndrome. Most of these products are central anticholinergic agents with peripheral anticholinergic agents Effects. These compounds are of natural origin, such as atropine, or

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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 antiparkinsonian 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

cal disease is therefore of fundamental importance. From this point of view, the connections represent the Formula I valuable additional funds for anti-Parkinsonian therapy because there is currently no ideal remedy for the treatment of this disease, which is explained below in the Detail is described.

The compounds according to the invention therefore provide valuable additional resources to those available to the doctor Therapeutic remedies that are available and are useful in place of any other remedy to be used that for any reason, e.g. B. Change in the condition of the patient or the 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.

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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 made with the most preferred of the invention 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 observed does not have, 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 in order to determine the various properties of the compounds of the invention, which together These compounds are suitable for the treatment of Parkinson's disease and for Correction of di'rch Neuroleptica induced extrapyramidal Disturbances are valuable.

I. Inhibition of those induced with reserpine

and neuroleptic induced catatonia

(dopaminergic properties)

1. Inhibition of reserpine
induced catatonia

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 gibs 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 were considered to have this position held upright for at least 30 seconds. Each animal that held the position thus given received 1 point and those who did not maintain this position were given 0 points. The highest score was therefore 10 per group. An identical experiment was carried out with comparison animals that received reserpine, however received none of the compounds to be tested.

The following compounds of formula I were compared to amantadine according to the above The compounds were examined preferably in the form of a pharmaceutical usable acid addition salt, such as. B. hydrochloride or fumarate

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),

I -π-propyl-1-isobutyl-n-butylamine (compound j), ], 3-dimethyl-ln-piOpyl-n-pentylamine

(Compound 6), ο 1,3-dimethyl-1-ethyl-n-hexylamine

(Compound 7), 1-methyl-1-isobutyl-n-pentylamine (Connection 8),

1-methyl-1-n-propyl-n-hexylamine in (compound 9), 1,1-dimethyl-n-octylamine (Compound 10), 1,1-Di (2-propen-1 -yl) -3-buten-1 -ylamine

(Compound 11), ΙΊ 1,1-di-n-butyl-n-pentylamine (Compound 12), 1,1,3-trimethyl-n-heptylamine (Connection 13),

(Compound 14), 1,1-diethyl-n-propylamine (Compound 15), 1,1-dimethyl-n-propylamine

(Compound 16), 2 ^r > l, l-dimethyl-3-ethyl-n-hexylamine (compound 17), 1,1-diisobutyl-n-butylamine (compound 18), 1-n-propyl-l-isopropyl- n-butylamine (compound 19), in-propyl-l-tert-butyl-n-butylamine (compound 20), l, l-di-n-propyl-2-propyn-l-ylamine (compound 21), l, l -Diethyl-2-pentyn-1-ylamine (compound 22), 1,1 -diethyl-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 abovementioned compounds of the formula I and the results obtained with amatadine are given in Table I below. The results are printed out in the following way:

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

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 70 to 80% inhibition of catatonia compared to the control 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).

Tabel

ί dragonfly

link Administered dose Inhibition link Administered dose Inhibition of in mg / kg the one with Koserpin in mg / kg by Ncuroleptici incl. Katatnnie in 'u ?. Cytatonia I. 5 4th I. 5 4th 2 5 1 2 5 1 3 20th 3 in 3 20th 3 4th 20th 3 4th 20th 3 5 20th 2 5 20th 4th 6th 20th 6th 20th I. 7th 20th 7th 40 I. 8th 20th '-, 8th 50 4th 9 20th 9 20th I. IO 20th 10 50 1 Il 20th Il 20th I. 1? 20th 12th 20th 1 13th 25th 'o 13 50 I. 14th 50 14th 50 3 15th 50 15th 50 3 16 50 16 10 I. 17th Π 17th Il 2 18th 12th '-, 18 12th 1 19th 6th 19th 6th 3 20th 6th 20th 50 I. 21 30th 21 30th 1 22nd 60 22nd 30th 1 23 60 in 23 30th 1 24 20th 24 20th 2 25th 6th 25th 6th 3 26th 30th \ 26th 30th 4th Amantadine 100 Amantadine 100 4th 2 3 2 2 I. 1 1 3 1 4th

These results indicate that Compound 1 is which is the preferred compound of the present invention. so is as effective as amantadine. but at a dose that is twenty times smaller. than that of Amantadine.

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 applied above for reserpine-induced catatonia. The same point system was also applied in the present case

An oral dose of the test compound in aqueous solution was given to groups of 10 males Rats (OFA strain) weighing about 150 to 200 g were administered thirty minutes later 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 comparison 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 I was found to be twenty! is more active than amantadine 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 I and II above in Compound with compound 1 were given 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, a score of 4 was obtained on attempts using reserpine Induced and neuroleptic-induced catatonia, as described above, only concerned with 3 mg / kg 1,1-di-n-propyl-n-butylamine hydrogen fumarate.

II. Acute toxicity

In the acute toxicity test, the LD 50 value in mice was determined orally using the Method of Lichfield and Wilcoxon (Pharmakol. 1938, 2, 192-216). The compounds were determined administered in aqueous solution and the observation period was 10 days after the administration of the to investigating compound.

The following results were recorded in comparison to amantadine.

link

LD ₅₀ (inmg / kgt

9
12th
Amantadine

100

150

> 500

1750 500

1050

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

The index

ED ₂₀ -. ,,,

was decided.

With this index, ED20-20 represents the effective dose to obtain a 20 to 30% inhibition of catatonia, this value being represented by the number 1 in the Tables I and II is shown.

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

LD ₅₁ ,

ED,

determined, with ED100 being the effective dose to obtain 100% inhibition of catatonia.

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

Link index

1
Amantadine

20th
10

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

At 1,1-di-n-propyl-n-butylamine hydrogen fumarate is the effective dose is even further removed from the toxic dose than for compound 1, since the corresponding 100

index

= 33.

Additional experiments were carried out in rats with compound 1 and amantadine. These experiments concerned catalepsy, which was demonstrated by the crossing of the animals' homolateral paws. It was observed that 5 mg / kg of Compound 1 when administered orally 30 minutes before an intraperitoneal injection of prochlorperazine produced complete inhibition of catalepsy 3 hours after this latter substance was injected. With regard to amantadine, a dose of 80 mg / kg was necessary to effect complete 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) weighing 150-200 g were given 5 mg / kg of reserpine intraperitoneally. ^3/4 hours later, when the animals were in the state of catatonia, an aqueous dose of the test compound was administered orally to all animals except the control group.

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. , ο 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 St. Time after administration of 2h30 Reserpine 3 h 30 4h 5 h 2h 2 h 15 5 3h 3 1 2 S. S. 2 3 0 0 0 Comparison animals 4th 3 0 0 0 0 (I. Compound I
2.5 mg / kg 1 · ' 0 I. (I. 0 Compound I
5 mg / kg 4th 2 Amantiidine
SO nm / kti

030 128/172

These figures show that at doses of 2 ^ 5 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 t 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 sufficient. The progression of the catatonia was correspondingly

were given 12.5 mg / kg prochlorperazine intraperitoneally administered. 55 minutes later, all animals with the exception of the comparison group were given an oral dose of the test compound administered in aqueous solution according to the same as described in the tests above Recorded scale

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

Table IV Time after
Ih30 Administration of
2h30 3h 4th Prochlorperazine
3h30 4 h 5h 4th 4th 0 3 I. 1 Comparison animals 3 0 1 0 0 0 Connection 1
5 mg / kg 5 2 0 0 0 Amantadine
80 mg / kg

These results show that under the conditions

the therapeutic treatment, a dose of 5 mg / kg of 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

40

'5 (1

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

An experiment was also carried out to determine whether Compound I had cholinolytic properties owns.

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

The following results were recorded for Compound I compared to atropine:

Table V Cans
Β, κΙ in µ / ml Inhibition of
Spiisiiuis in% (1.5 X
OI '■ 10
IO '■ ■ 15
100 Acetylcholine
• Mropin

0.2XlO " ⁶ O ₁ IXlO" ⁵ 0.1XIO " 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 activity of compound 1 occurs at most in the case of t-xic doses.

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

To this end, the following experiment was carried out with the aim of determining the antitremorin properties of Compound 1.

When tremorin is injected into mice, it produces peripheral effects, ie, crying, ie, tear formation, sweating, salivation and diarrhea, and central effects, ie, tremor and akinesia. Such effects are due to an increase in the amount of intracerebral acetylcholine and serotonin.

Male mice (OFi strain) weighing about 22 g were divided into two groups of 10 pieces divided, (each group received 50 mg / kg orally of the test compound in aqueous solution. Thirty minutes later, a dose of 10 mg / kg tremorin was applied intraperitoneally

Injected away, and zh 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, d. H. Salivatio, sweating and crying became the most Score 4 for the comparison animals 20, 30 and 40 minutes after the injection of tremorin for both 5 mg / kg of compound 1 and 40 mg / kg of amantadine are registered. Identical results were obtained regarding the central cholinergic effects, d. H. normal and excellent tremor preserved.

These results show that Connection! and Amantadine are devoid of antitremorin properties, indicating the absence of cholinolytic properties confirmed in the case of compound 1 at therapeutic doses

Experiments were also carried out with compound I in order to determine the influence of this compound to investigate 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 Increasing arterial pressure, which was not enough to cause the nictitating membrane to contract. Of the Arterial pressure was measured on the carotid immediately after administration of the narepinphrine dose. Thereafter, increasing doses of compound 1 in aqueous solution were administered intravenously every 30 minutes After each dose of compound 1, another dose of norepinphrine was given, and the The following parameters were recorded: increase in arterial pressure, contractile reaction of the Mick skin due to exogenous norepinphrine as well as contractile reaction from this caused by the release of norepinphrine, that by subnaxinal electrical stimulation of the Cervical Sympaticus' was caused.

The results given below were recorded with Compound 1 and Amantadine:

Table VI 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 0 26th 0 17th Connection 1 0.1 18th 0 15th 1 25th 0 16 3 29 0 17th 5 25th 0 16 10 22nd 0 12th 0 28 0 20th Amantadine 0.1 29 0 20th 1 35 3 20th 3 35 4.4 16 5 59 5.9 10 10 57 7.5 4th

*) The mm express the increase in contraction that was recorded on a curve sheet.

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 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. Amantadin, on the other hand, shows ganglioplegic rigors <> n 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 appropriate dosage form entered, with 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

I ₁ , coated or uncoated tablet, hard or 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.

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

links

Boiling point. C.

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

l-n-l'ropyl-l-isopropyl-n-butyl isocyanate

92 to 93
(0.5 mmHg)

97

(15 mmllg)

b) U-Di-n-propyl-n-biitylamine hydrochloride

In an ore neckN> lbcn. the with a mechanical stirrer, a bowl mixer. a thermometer and a coal burner, 200 ml of water and 90 ml of concentrated hydrochloric acid were added. The acid solution was heated at 3O ⁰ C, and then were dispersed with vigorous stirring 105 g of tl-Di-n-propyl-n-butyl isocyanate, which was prepared as previously described, is added slowly to the addition process took one hour after which the reaction medium further 4 Hours at a temperature between about 95 and 100 ⁰ C was heated. the

ίο mixture was then cooled to about 0 ⁰ C, and the resulting colorless crystals were collected by filtration, with air and then in a desiccator in the presence of potassium hydroxide dried In this manner, 99 g of LL-Di-n-propyl-n-butylamine hydrochloride isolated in the form of a white crystalline powder

The product does not melt but sublimes from 220 ° C.

Yield: 90%.
Following the same procedure as described above, but using the appropriate starting materials, the joints were obtained:

25th

144 g of sodium hydroxide in tablet form and 1200 ml of water were placed in a three-necked flask (21) equipped with a water cooler, a mechanical stirrer, a thermometer and a dropping funnel. The solution was cooled to 5 ° C, and 48 ml of bromine was y with stirring, slowly added. The addition of the bromine lasted two hours, and then 111 g of 2,2-di-n-propyl-vaIeramid were added to the yellowish green solution at a temperature of 0 ⁰ C. The mixture was kept stirring at about ⁰ ° C. for 4 hours. The oily phase was then extracted with three fractions of 300 ml of ether each and the ethereal phase was 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 mmHj.

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%.

Using the same method as described above, but using the appropriate starting materials, the following connections were made:

60 connection

1,1-di-n-butyl-n-pentylamine- m.p. 68.1 C

hydrochloride

(Yield: 63%)

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

hydrochloride (sublimation)

1-Ethyl-I-isobutyl-n-butylamine-230C

hydrochloride (sublimation)

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

amine hydrochloride

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

hydrochloride (decomposition)

In-propyl-1-isopropyl-n-butylamine- m.p. 260 ° C
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 (η ^? Ό = 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 a 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 ^J Γ with sublimation
Yield: 100%

Example 3

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

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

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

Tropftrichtc'- and an I liermomcicr equipped was. were under a nitrogen atmosphere 2.8 g (0.2 mol) of lithium in small portions and 100 ml given anhydrous and purified tetrahydrofuran. The suspension of lithium in tetrahydrofuran was cooled to -20 C and a mixture of 22.8 g (0.2 mol) of di-npropylkemon and 30 g (0.2 mol plus 10% excess) isobiityl bromide slowly added. The addition process lasted about 3 hours, during which a temperature of about -20C was maintained. The solution was allowed to stand at room temperature for about 12 hours and then focused. The oil thus obtained was taken up in water, extracted with ether and reduced under reduced pressure Distilled 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. H up to 76 ° C below 5 mm Hg yield: approx. 60%

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

link

Boiling point, (

l-diethyl-n-butanol 62

(Yield: 50%) (15 millimeters)

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.l-di-n-propyl-n-butanol 70 to 80

(Yield: 60%) (0.15 mmHg)

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

(15 mmHg)

1-n-propyl-1-tert-butyl-n-butanol 90 to 92

(14 mmHg)

1.l-dimethyl-n-octanol 93 to 95

(Yield: 45%) (13 mmHg)

1.1.3-Trimethyl-n-heptanol decomposition (Yield: 60%)

I. I -Dimethyl-3-ethyl-n-hexanol decomposition (Yield: 307ο)

1.3-Dimethyl-1-ethyl-n-hexanol decomposition (Yield: 35%)

I, 3-dimethyl -] - n-propyl-n-pentanol decomposition (yield: 46%)

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

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

I.I-diisobutyl-n-butanol 75 to 76

(Yield: 60%) (4 mmHg)

1-Ethyl-1-n-propyl-n-pentanol 87

(Yield: 35%) (Il mmHg)

b) 1-n-Propy I-1-isobii ty I-η-butylamine hydrochloride

In a three-necked flask (250 ml) fitted with a mechanical stirrer, a dropping funnel. The cooler and ί immersion thermometer were fitted with 6.5 g (0.1 mol) of dry potassium cyanide in powder form. 14.4 g (0.083 mol) of in-propyl-1-isobutyl-n-butanol and 12 ml of acetic acid were added. 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 ° C was maintained. The reaction mixture was heated for 2 hours at 7O ⁰ C and then slowly in 100 ml

ij poured ice water. Thereafter, it was treated with a 20% aqueous solution of sodium hydroxide neutralized and extracted with ether. The ether was evaporated and an oil. the N-shaped 1-n-propyl-I -isobutyl-n-butylamine was collected.

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

In this way, Il g of 1-n-propyl-1-isobutyl-n-butylamine hydrochloride were obtained collected in the form of a white powder.

The melting point was> 260 ^r C with decomposition without melting at about 280 ° C

w yield: 64%

With a thin-layer chromatography on silica gel plates using a solvent system containing 79 parts of benzene, 14 parts of methanol and 7 parts Includes 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 given Rf value was determined by thin layer chromatography using the same support, the same solvent system and the same test reagent, as described in the example above, determines:

link

1.l-diethyl-n-propylamine-hydro- 210 C "

chloride (sublimation *

(Yield: 40%)
Rf = 0.49

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

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

chloride

(Yield: 60%)
Rf = 0.59

1-Ethyl- 1-n-propyl-n-butylamine- 180 C

hydroehlorid (sublimation)

(Yield: 25%)
Rf = 0.64

b>! -Ethyl -] - isobutyl-n-butylamine-230 C

hydroehlorid (sublimation)

(Yield: 30%)
Rf = 0.60

link

1.l-Dimethyl-n-octyliimine-hydro- l'.p. 111.8 C

chloricl

(Yield: 45%)
Rf = 0.65

1.3-Diniethyl-l-iithyl-n-hexylaniine-l'.p. 133.3 C
'<chlorochloride
Rl = 0.56

l-methyl-ln-propyl-n-hexyhimin-l'.p. 174.7 C
hydrochloride
(Yield: 60%)
Rr = 0.60

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

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

(Yield: 30%)
Rf = 0.60

Example 4

Production of I, l-dimethyl-3-ethyl-n-hexylaniine hydrogen fumarate

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

!, l-Dimethyl-3-ethyl-n-hexylamine in the form of his The free base was first obtained by reacting a 30% strength 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 1,1-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.

M.p. 160.6 ° C
Yield: 50%

In thin layer chromatography on silica gel plates using an oil 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 process as described above, but using the appropriate starting materials, the compounds listed below were made

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 = Q54

1-n-Propyl-1-tert-butyl-n-butylamine-hydrogenfumardt

F.p. 140 C

1,3-dimethyl-1-n-propyl-n-pentyl-m.p. 114.4 C

; imine hydrogen lumarate

Rf 0.56

1,1-diisohutyl-n-butylaniine-hydro- F.p. 179 C

gene fumarate

Rl '- 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-isobutyl-n-pentylamine in the form of its free base was first obtained by reacting a 30% strength aqueous solution of sodium hydroxide with I-methyl-

180 C
(Sublimation) ■! 5cbü ** '! ~ Iv ^ srit ^ lsrriiri'fVdrocriloriii her ^ esieü *

The free base thus obtained was then extracted with ether.

b) I-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 ⁰ 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
1-ethyl-1-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 been cooled to 5 ° C, and 4 ml of formic acid given. While the mixture was kept at a temperature of 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 mixture was at room temperature over 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 ye Sodium salt was prepared with a 20% aqueous solution of sodium hydroxide. 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 ⁰ 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 mmllg)

b)! - Ethyl-t-n-propyl-n-pentylamine

A three-necked flask equipped with a mechanical stirrer and a condenser was filled with? 0 m! Chloroform,! 8 m! concentrated sulfuric acid Cc / = 1.83) and II g (0.06 mol) of 2-ethyl-2-n-propyl-caproic acid, which was prepared as described above, was added. The mixture was ^{heated to 50 °} C. and, while stirring, 7.5 g of sodium azide in powder form were added. The addition took 90 minutes, after which the reaction mixture was heated to 50 ° C for 2 hours. The mixture was then neutralized with a 40% strength aqueous solution of sodium hydroxide which had previously been ^{cooled to 0 ° C.} The amine was extracted with ether and the ethereal phase washed with water and dried over magnesium sulfate. The ether was evaporated off in vacuo and the oil thus obtained was taken up in dry ether, 1-ethyl-1-n-propyl-n-pentylamine being obtained in the form of its free base.

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

link

K.p.

, l-di-n-propyl-n-butylamine

190.5 to 195 C (742 mmHg)

c) 1-ethyl- l-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 way, 1-ethyl-1-n-propyl-npentylamine hydrochloride was obtained in the form of colorless crystals that sublimed from 200 ° C. Yield: 45%

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

link

1,1-di-n-propyI-n-butylamine-

hydrochloride

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

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

20O ⁰ C (sublimation)

180 ⁰ C (sublimation)

230 ⁰ C (sublimation)

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

amine hydrochloride

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

amine-hydrochloHd

1,1-Di-n-propyl 3-bi! In-1 -ylamine hydrochloride

M.p. 260 ^° C

M.p. 260 ^° C
(Decomposition)

262 ° C

(Sublimation and decomposition)

Example 7

Production of l, l-di- (2-propen-l-yl) -i-, 3-buten-l-ylamine oxalate

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

Under a nitrogen atmosphere, 13.4 g (0.2 mol) of allyl cyanide in 20 ml of dry ether became a Solution of 0.4 mol of allyl magnesium bromide in 350 ml of ether. The addition process took a long time Hour while the ether was gently refluxed. Thereafter, the reaction medium heated to boiling point for 4 hours. After cooling, the mixture was poured into 200 ml of a poured saturated solution of ammonium chloride. The ethereal phase was separated with water washed 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-1-yl) -3-buten-1-ylamine were obtained in the form of a pale yellow liquid.

_J5 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, l-di-n-propyl-n-butylamine

η '"' = 1.4349

b) 1,1-Di (2-propen-1 -yl) -3-buten- ⁴⁾ 1-ylamine oxalate

3 g (about 0.02 mol) of 1,1-di- (2-propen-l-yl) -3-buten-l-y! Amine, which was prepared as described above, in 20 ml of ether at 2.5 g (about 0.02 Mol) oxalic acid hydrate (2 molecules of hydration water) added to 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, 1-di- (2-propen-1-yl) -3-buten-1-ylamine oxalate were obtained.
Mp 96.2 ° C
Yield: 70%

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

link

1,1-di-n-propylene-n-butylamine hydrochloride

220 ⁰ C
(Sublimation)

Example 8

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

a) 1.1-Di-n-propyl-2-propyne-1-oil

A three-necked flask (2 L). the one with a mechanical stirrer, a condenser, a submerged tube and was equipped with a dropping funnel. was put in a fume cupboard. In the flask that was previously in a bath had been cooled by dry ice in acetone. 1 l of liquid ammonia were added. Acetylene that before was cleaned by removing it through a dry ice? Trap passed, 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 v 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 II-di-n-propyl-2-propyn-1-ol 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

Into a three-necked flask equipped with a magnetic stirrer, thermometer and dropping funnel. 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 = \, \ 9) were added. While stirring, 23g of 1,1-di-n-propyl-2-propyne-1-oil, which was prepared as described above, was added to the mixture, which was 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.

r>

5 (i

c) 1,1-Di-n-propyl-2-propyne-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

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

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

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

link

U-Dimethyl-2-propyne- mp 18 ° C

1-ylamine

ll-Uiäthyi - ^ - propin- Kp.7i to 72 ^C C

1-ylamin (90 mm Hg)

d) i.l-Di-n-propyl-2-propynyl-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, l-di-n-propyl-2-propyn-l-ylamine hydrochloride were obtained, which represents a yield of 68%.

Mp 200 ° C (with decomposition).

Example 9

Production of 1,1-diethyl-2-pentinl-ylamine hydrochloride

a) l, l-diethyl-2-pentyn-l-ylamine

In a three-necked flask with a mechanical A stirrer, a vertical condenser and a dropping funnel became a suspension of sodium amide from 150 ml of liquid ammonia. 2.4 g sodium and some ferric nitral crystals manufactured. A solution of 11 g of l, l-diethyl-2-propyn-l-ylamin.dp '· as previously described, was prepared, and added 20 ml of anhydrous ethyl ether. As the adding process When the mixture was stopped, stirring was maintained for 30 minutes and a solution of 15 g dry ethyl bromide in 30 ml of anhydrous ethyl ether introduced dropwise into the reaction mixture. The addition of the ethyl bromide took one hour, followed by stirring the mixture for 4 hours was maintained. The reaction medium was then left to stand for 12 hours so that the ammonia was allowed to evaporate, and 50 g of crushed ice was added. The ethereal phase has been separated dried over magnesium sulfate and then evaporated under reduced pressure.

In this way, 8 g of 1,1-diethyl-2-pentin-1-ylamine were obtained 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

ICp.

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

b) 1,1-diethyl-2-pentyn-1-ylamine hydrochloride

The amine hydrochloride obtained previously was prepared by treating an anhydrous ethereal solution of this amine with dry hydrochloric acid gas. Evaporation of the ether and drying of the crystals thus obtained in a desiccator and in the presence of caustic potash gave 1,1-diethyl-2-pentynylamine 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 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 9 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-penten-l ylamine 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 compound was made:

link

Ll-di-n-propyl-2-penten-1-ylamine hydrochloride

(Yield: 100%)

200 C (sublimation)

link

F.p.

1.l-Di-n-propyl-2-pentyn-1-ylamine-118C

hydrochloride

(Yield: 100%)

Example 10

Production of
1,1-Diethyl-2-penteri-1 -ylamine hydrochloride

In 40 ml of heptane there were 3.5 g of l, l-diethyI-2-pentynylamine in the presence of 50 mg of a Lindlar catalyst

Example 11

A hard gelatin capsule that contains the following loading contained ingredients, was manufactured according to known pharmaceutical processes:

Components

U-di-n-propyl-n-butylamine hydrochloride Milk sugar

030 178 / U

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: