DE1909180C - N (3 sulfamyl 4 chlorobenzamido) 2 methylindoline - Google Patents

Description

The invention relates to N- (3-sulfamyl-4-chlorobenzaiiiido) -2-methylindoline of formula I.

The compound of the invention is new and can, starting from N-aminoindoline of the formula II

i N-NH, (! I)

CH ₃

by reaction with 3-sulfanes 1-4-chlorobenzoyl chloride of formula III

Cl-OC-r

Cl

SO ₁ NH,

(III)

hv be rgestelll.

The N-aminoindoline used as the starting product can be prepared according to the method described by J. B. W. RE. VViI Ie tt c in J. Med. And Pharm. Chem. 5, 811 (1962). The process described are prepared by nitrosizing an indoline and reducing the thus formed N-nitrous acid derivative with lithium aluminum hydride.

The new compound according to the invention can in the form of its optically active isomers, both des clockwise as well as counterclockwise. are produced and as such also forms one Subject of the invention.

The following example illustrates the invention. All parts are by weight and melting points were placed on the heated Kofler plate under the microscope (MK) or on the Kofler block (K) definitely.

example

A solution of 8.9 parts of 3-sulfamyl-4-chlorobenzoyl chloride in 50 parts of anhydrous tetrahydro-

Furan is added in portions over the course of 1 hour with stirring to a solution of 5.2 parts of N-amino-2-methylindoline and 3.5 parts of triethylamine in 50 parts of anhydrous tetrahydrofuran.
The reaction mixture is left to stand for 3 hours at ambient temperature. Then the precipitated triethylamine hydrochloride is filtered off. The filtrate is evaporated in vacuo and the residue is recrystallized from a solution of 60 parts of isopropanol with 75 parts of water.

This gives 9 parts of N- (3-sulfamyl-4-chlorobenzamido) -2-methylindoline of melting point (K) 184 to 186 ° C or melting point (MK) 160 to 162 ° C (isopropanol water).

The novel compound of the invention possesses

interesting pharmacological and therapeutic properties, especially diuretic and antihypertensive Effect.

Their toxicity is very low. The LD ₅₀ . determined in the mouse by the method of JT Litchfie I d and JF W i 1 c ο χ ο η (J. Pharmacol. 97.99 [1949]). is> 3 g / kg when administered orally.

In tests on dogs and rats, the compound according to the invention has an important salidiuretic effect Effective wedge, both oral and intravenous administration, shown in a Lasts more than 12 hours. In particular, an increase in the water pressure was observed and the excretion of chlorine and sodium in the urine without any noticeable change in potassium excretion.

For example, in the following table, those in dogs with 300 - // kg perorally due to N- (3-sulfamyl-4-ch! Orbenzamido) -2-methylthylindoline results obtained.

Table I.

Urine volume per animal

(mi / min)

urine pH ...
Na ■ in the urine (mAq / l).
K ⁺ in urine (meq / l) .. Cl "in urine (meq / l). CO ² in urine (meq / 1).

Excretion of

Na ⁺ (μΑς / πΊΐη)

K ⁺ (uAq / min)

Cl "(| iEq / min)

CO ²

comparison

3.18

6.7

5.2

8.1

3.4

11.9

22nd 9 8

Test results:

N - (. 1-.sulfiimyl-4-chlnrhcnzamido (-2-me (hylindolin . '(XI; kg per os

I hour 2 hours

4.94

6.3 15.2

7.9 16.6

3.2

76 39 H3 15

5.12

5.9
22.2

8.2
26.4

1.8

113

42

135

Hours 4 hours 5 hours 6 hours

5.16

6.1
22.9

7.6
26th

2.1

121

38
134

It

5.40

6.1
23.9

7.4
25th

2.5

124

38
134

5.70 5.15 6.2 6.3 21.2 20.4 7.3 6.2 25, f 20.2 2.8 3.4 16 114 37 31 132 107 16 19th

Average of 6 female dog.

The compound according to the invention is the same as known, commercially available and proven drugs Efficacy such as 4-chloro-N- (2-furylmethyl) -5-sulfamoylanthranilic acid superior to that of the following Results of comparative tests, which are carried out according to the methods given above, shown in the table were showing.

Table II

Control of the animals before treatment with

compound according to the invention

4-chloro

N- (2-furvl-

melhyl) -

5-sulfamoyl-

anthranil results of the 1 mg / kg P. O. treated animals

1st day after treatment with
4-chlorine

inventive

according to the compound N- (2-furyl-

methyl)-

5-sulfamoyl-

anthranil

2nd day after treatment with 4-chlorine

appointment

better

connection

N- (2-furyl-

5-sulfamoyl-

anthranil

acid

Urine volume

ml / 24 sid./kü

10.30

2.05 1.98 0.67

12.54

2.18 2.60 0.93

excretion

in mEq / 24 hours kg of

he

Na ⁺

K ⁺

Increase in%, related
on control

URINE VOLITIES

Cr precipitation i ......

Na ⁺ excretion ...
K ⁺ excretion

The examinations were carried out on the dog in the metabolism cage accomplished. The results given were given on test groups of five dogs each receive.

The connection does not noticeably change the arterial pressure of normotonic animals, but does causes a decrease in arterial pressure in hypertensive dogs by 20 to 40 mm / Hg.

If you give the compound in a dose of 40 to 60 mg in humans, you make one Increase in urine volume from 137 to 206%, chlorine excretion from 157 to 284%, sodium excretion from 172 to 252% and the potassium excretion from 39 to 73% within 24 hours after administration of the drug firmly.

The newly found connection can therefore used to treat all affects, 28,87

6.96
6.05
1.75

180
239.5
205
161

19.79

3.65
3.50
1.05

57
67.4
34.6
13th

16.26

2.44 2.35 0.98

57.8 19 18.6 46.2

12.72

1.96

2.32 0.90

1.4

none none none

which are accompanied by hydroelectrolytic retention, especially in cardiac, renal or hepatic insufficiency with edema or ascites, with arterial hypertension and with obesity.

It can be administered orally, rectally or parenterally in the form of tablets, coated tablets, capsules, Suppositories or injectable solutions, together with suitable pharmaceutical carriers, e.g. B. distilled water, glucose, lactose, talc, starch, magnesium stearate, ethyl cellulose, cocoa butter, etc. The doses used can be between 10 and 100 mg.

Claims (1)

Claim: N - (3 - sulfamyl - 4 - chlorobenzamido) - 2 - methylindoline.