DE1811767A1 - Pharmaceutically applicable amines - Google Patents

Description

CENTER EUROPEEN DE RECHERGHES MAUVERNAY (GERM), Riom / France

Pharmaceutically applicable amines

Various chemical compounds of a large family have already been described in the literature, represented by the general formula

A - GH - GH ₀ - B I ² OR

can be defined in which

909842/1736

A - an alkyl group

- an aralkyl group, such as

- CHo - 0 - CHo -

CH * O - CH ₂

Bein can, where X »H, Gl ₁ P ,: and η» O ble 3 inclusive ^ -

H - an alkyl group

- an aralkyl group or

- Can represent a heterocyclic group and

B is a group containing etiokitioff, like

a) - HN - R ₁ worti * H ₁ · an alkyl or _o

b) - N ^ n ² ■ where R ₀ and H ₀ ■ are an alkyl · 2 or aralkyl group

- 3 -9Ό9.842 / 17 3 6 ^: "

- 3 - c) - N (CH ₀ ) where m = 4 or 5

d) - N 0 wherein XsH, an alkyl or

I · aralkyl group

3) - N NR ^ ₊ where R ^ = H, an alkyl "or aryl group.

In particular, compounds have been described in which;

- if η * I ₁ A is not the methyl group and B is not

is the morpholine group,

- when R is an alkyl group of the type ^ _n H _{2n + 1} ,

1 is Cn ^ 5 and

- when R is an aralkyl group, this has the formula

has, in the

X · H or Cl and ρ as l _t 2 or 3.

The already known connections of this family

are generally used as analgesics, antihistamines,

de

vasodilator, anti-pressive and vagolytic drugs applicable.

The invention relates to a limited group of compounds of this family, their common pharmacological properties different from those

909842 / 173Ü

of the other compounds of this family differ in type and / or in strength.

This group consists of the N - £ 2-phenyl-2-alkoxf] - ethylpyrrolidines of the general formula:

in which R is an alkyl group, such as the isoamyl or isobutyl group.

These compounds have a number of particularly interesting effects, which are discussed below should be dealt with in detail.

First, the production of two compounds 1 and 2 will be described, for example.

example 1

M - Qi-phenyl-2-isoamyloxy] - ethylpyrrolidine (Comp. No. 1) This compound is obtained from styrene in two stages:

a) Preparation of (2-phenyl-2-isoamyloxy) -äth.yl-bromld A mixture of 130 g of styrene and 300 ml of isoamyl alcohol was added dropwise with stirring with 1.6 mol of terbutyl hypobromite, the temperature being kept at about -10 ° became.

The reaction product was concentrated in vacuo (approximately 15 mm Hg), the water bath having a temperature of approximately 45 ^° C. The residue was

909842/17 36

washed several times with water and dried over anhydrous sodium sulfate. By rectifying the A colorless liquid was obtained in vacuo.

(Kp ₁ = 90 ° - 99 ⁰ U; ng ^{0 >> 4} = 1 _f 5i3O).

This gave 135-3Λ0 g of (2-phenyl-2-isoamyloxy) ethyl bromide.

b) Production of the end product in the form of the chlorohydrate

- 117 g (2-phenyl-2-isoamyloxy) ethyl bromide,

- 6l, 5 g of pyrrolidine and

- 250 ml of toluene

were refluxed for 10 hours with stirring.

After the pyrrolidine bromohydrate had been filtered off, the toluene was evaporated off in vacuo. The residue was taken up with k η HUl. The aqueous solution was washed with ether. It was made alkaline with a 50% JNaOB solution and extracted with ether. The ether phase was dried over anhydrous sodium sulfate and, after evaporation of the solvent, rectified in vacuo.

This gave 90 g of colorless oil with an amine odor.
(Kp ₂ = 121 ⁰ C; njj ¹ ' ⁶ = 1, ^ 970).

The hydrochloride was prepared in the usual manner by dissolving the amine in anhydrous ether and adding it with the required amount of dry, gaseous hydrochloric acid dissolved in absolute alcohol.

A white crystalline powder was obtained which

Melts at 150 ° C and is strong in water and alcohol

9098A2 / 173Ö

and is slightly soluble in ether and ethyl acetate. '*'"" N achieved: 4.70 % Cl "calculated: 11.9Ό " tf? - '■' ■ '■ "· - N found: 4.65 % found: · 11.90 ^ ■ '"■'■"

Example 2 '"

N - ίΖ -Phenyl -2 -iso "butoxy7 -äthylpyrrolidin (Verb. Nr .2)

The procedure was similar to that in Example 1.

a) Preparation of (2-phenyl-2-isobutoxy) ethyl bromide A mixture of 130 g of styrene and 300 ml of isobutanol was added dropwise with stirring with 1.6 mol of terbutyl hypobromite, the temperature being kept at approximately -1O ⁰ G became.

The reaction product was concentrated in vacuo (approximately 15 mm Hg) with the temperature of the water bath being approximately 45 ° C. The residue was washed several times with water and dried over anhydrous sodium sulfate. After rectification in vacuo, a colorless liquid was obtained. (Bp ₁₁ = 128 ° C; Bp ₀ ^ ₅ = 83 ⁰ G; ng ¹ » ⁶ = 1.5190).

This gave 200 to 210 g of (2-phenyl-2-isobutoxy) ethyl bromide.

b) Production of the end product in the form of chlorohydrate

- 257 g (2-phenyl-2-isobutoxy) ethyl bromide,

- 142 g of pyrrolidine and ■ .- ■ -. - ..:.,; . . , ·.

- 600 ml of toluene

were refluxed with stirring for 10 hours.

After filtering the pyrrolidine bromohydrate and ■

- 7 -

• '- ■ ■;,:.,: "\ 909842/1700

Evaporation of the solvent in vacuo, the residue was taken up with 4N HGl. The aqueous solution was washed once with ether and made alkaline with a 50 # NaOH solution. One extracted with ether and dried the ether phase on anhydrous sodium sulfate. After the Solvent was rectified in vacuo.

170-175 g of colorless oil with an amine odor were obtained.

(Bp ₃ = 112-113 ° C; ng ⁵ = 1.4-985).

The hydrochloride was prepared in the usual way by dissolving the amine in ethyl acetate with addition of the required amount of dry, gaseous hydrochloric acid dissolved in absolute alcohol.

This gave a white crystalline powder with a melting point of 165 ° C ₁ which is strongly soluble in water and alcohol and slightly soluble in ethyl acetate and ether.

N calculated: 4.93 % Cl "calculated: 12.49 % N found: 4.95 % Cl" found: 12.40 $>

These compounds are characterized by a number of pharmaceutical W kodynamischer effects in which were tested in the following procedures:

A. Effect on the isolated organs

The test was carried out on the isolated ileum of the guinea pig carried out according to the method of Magnus. The ileum was in Tyrode's solution of constant Temperature kept alive.

9 0 9 8 A 2/1 7 L-

The effect of the product was examined by contracting substances such as acetylcholine, Ba-chloride, Histamine dichlorohydrate, produced spasms.

The ED 50 _1, which was determined by plotting the logarithm of the dose against the effect, is the dose which reduces the spasm produced by the contracting substance by 50%.

B. General effect

The following is recorded on a dog that has been anesthetized with ghloralose of 8 %:

- The blood pressure in a carotid artery

- The changes brought about by the test products at:

Lowering blood pressure as a result of electrical pickling the peripheral end of the vagus, Increase in blood pressure as a result of intravenous Injection of epinephrine and norepinephrine.

- The breathing

- The intestinal motility (connected to a Marey capsule Balloon inside the duodenum) *

In the table below:

X Lowering blood pressure by heating the vagus

Ad increase in blood pressure due to adrenaline

Ka Increase in blood pressure due to noradrenalln

DM intestinal motility

AR breathing rhythm

AB arterial blood pressure

R return to the initial value

The test product was administered i.v. to four animals. administered.

- 9 SÖ9842M736-5'rl

The results are as a percentage of change expressed. -_

ü. Effects on the central nervous system Measurement of the spontaneous motility of the mouse

Groups of ten male mice each weighing i? up to 22 g received the test product by means of esophageal intubation 2 hours after the last feeding.

An hour later the animals were divided into groups of two placed in an annular corridor that was scanned by six 'infra-bot beams.

Each interruption of a light beam due to the passage of an animal has been registered ron a counter. When awake for 10 minutes, the number of interruptions and thus the number of movements of the two animals was noted. The results are expressed as a percentage of the increase or decrease over the comparison animals.

D. Investigation of an antagonism to cholinergic intoxication by oxotremorine in the mouse " "

Groups of ten male mice each, with one Weight of 20 to 22 g received the test product " by means of esophageal intubation "after" 2 hours of me- ternity in increasing doses.

- 10 -

8 ^ 2/17

BATH ORIGINAL

- 10 - ■ - ■ .- ·. ■

One hour afterwards, all animals were given Ösötre- * raorin '(Pumarat) in a dose of T, 5 mg / ^{kg by "*' r} " intraperitoneal routes. A group "" ^IV "" of mice was used for comparison. The animals were observed for a quarter of an hour and one hour after the injection of oxotremorine for 15 seconds. The number of animals was recorded at each observation who trembled or whimpered were noted for each dose, and the two numbers obtained for each symptom were added, and this score was then used to calculate the percentage reduction & tremor or whimpering compared to the reference animals.

E. Examination of antagonism to lieserpinptosis in the mouse

Groups of ten male mice each with one Weight from 17 to 22 g received at the same time:

- 3 ^m o / kg reserpine by intraperitoneal route,

- increasing doses of the test product on oral Ways.

The ptosis was assessed 5.6 and 7 hours afterwards using an arbitrarily selected intensity scale (0 = complete opening of the eye, 1 = reduced eyelid slit, 2 = complete closure of the eye) _(the numbers noted for the individual animals in the same group at the different observation times The percentage reduction in ptosis compared to the comparison animals was then calculated from this number of points for each dose.

"The ED 50 in reducing ptosis

- 11 -

'. ... " ^: i \ \: 0 £ C Ö 9 0 9.84 2/1 7. · _:

BATH ORIGINAL

50 % was extrapolated from the straight line of the logarithm of the dose as a function of the effect.

The results are given in the table below.

- 12 -

90 984 2 / 17äH

co O CD CO

ro

Verb.
IMr. Isolated organs histamine
ED 50 g / 1 Ba Cl ₂
ED 50 g / 1 General effects Can
mg / kg
IV X Ad N / A DM AR AWAY R.
min, Acetyl
choline
Eu 50 g / 1 2.3OiO "^ 1, O5.1O " ³ 5 Eliminate
gradually.
recreation ^ 57 io
^ 44 %
fi> 65 ' / 149 5έ
* 80 %
R) 80 » R.A.S, 5i ± J4 %
^ 58 5έ
* l ± 2% > 70 1 6.1O " ⁵ !, 96.10 " ⁴ 2,3.10 " ³ 5 * 88 %
R> 70 * * 44%
R) 40 ' ^ 3 ^ ^
H) 55 ' R.A.S. R.A.S. 2 i ^ .io " ²⁴ "

to

Verb.
Kr. Central
v system Motility OXOTREMORIN Can
mg / kg
per os Tremble whimper RESERPIN , Reduction _kk
the
Ptosis Acute
toxicity i.v. Can
mg / kg
per os * ■ 4 % 15th
25th i'20 %
^ 50 % 0 %
0 % Can
mg / kg
per os V50 % LD 50 (mg) 23.5 1 60 13 (ED 50
50 (ED 50 i'50> ^ 75
(ED 50) ^ 25 % P .0. 24.7 2 30th 30th 540 159

OO

CD

From this it appears that these compounds have strong anti-holinergic properties. The means used to determine the properties can be summarized as follows:

a) in vitro: effect on the isolated organs;

b) in vivo: study of changes in blood

decrease in pressure due to electrical stimulation of the peripheral end of the vagus;

o) in vivo: inhibition of the citing caused by oxotremorine;

d) in vivo: antagonism to reserpine ptosis.

The corresponding properties of these drugs are therefore:

a) spasmolytic

b) vagolytic

c) antiparkinson

d) antidepressant

The drugs can be in the form of tablets, Dragees, injectable ampoules, suppositories with the usual additives in such preparations The following unit doses (in mg) can be administered:

preparation

Verb. No. 1

Connection number 2

Tablets or uragees
Suppositories
Ampoules

10-50 1-5

1-10 10-20

x-5

909842 / 173b

These compounds can be brought into the form of salts, for example chlorine hydrate or quaternary ammonium salts which have practically the same pharmacodynamic properties.

- 15.-

909842 / 173b

Claims (2)

Claims 1. Compounds with spasmolytic, vagolytic, anticholinergic, antidepressant and Antiparkinson effect with the 'general formula -GH - GH ₂ - N
OR in which R is an alkyl group, in particular isobutyl or isoamyl. 2. Compounds according to claim 1 in the form of tablets, Dragees, suppositories or injection ampoules in doses of: preparation Verb. Hr. 1 Verb. Wr. 2 Tablets or coated tablets, suppositories, ampoules 10 - 50 ι - 5 1-10 10-20 1-5 909842/17 j.)