DE1468174C - 2 allylsulfamyl 5 chlorine 4 sulfamyl N (3 hydroxy 2 butenylidene) aniline - Google Patents

Description

The present invention relates to I-allylsulfamyl-S-chloro- ^ sulfamyl-N-fS-hydroxy-1-butenylideneJ-aniline formula

SO ₂ - NH - CH ₂ - CH = CH ₂

It is made by adding 2-allylsulfamyl-5-chloro-4-sulfamylaniline with acetylacetaldehyde or its acetal formed from a lower alcohol.

This conversion of the l-allylsulfamyl-S-chloM-suIfamyl-aniline takes place in such a way that the reactants are brought together in a solvent such as alcohol, including methanol and ethanol, dimethylformamide or in an excess of the aldehyde or acetal to be converted. Water can be present in the reaction mixture that is passed through. Accelerating the reaction contains an acidic catalyst such as aqueous hydrochloric acid. Temperatures from room temperature to about 10O ⁰ C lead to satisfactory results. The reaction is generally complete in a period of from about an hour to a day; a few hours is approximately an average response time. When the reaction is over, the solvent is removed by evaporation under reduced pressure

removed and the residue taken up in alcohol and crystallized from aqueous alcohol.

The compound of the formula

NH ₂

SO ₂ NH - CH ₂ - CH = CH ₂

is produced by a 3-keto-7-sulfamyl-2Hrl, 2,4-benzothiadiazine-l-l, dioxide reacted with allyl bromide to form a 2-allyl-3-keto-7-suIfamyll, 2,4-benzothiadiazine-l, l-dioxide to form and this compound with a base to open the ring and forming a 2-Allylsulfamyl-4-sulfamyl-aniline treated. This procedure can be done by the following Equation can be reproduced:

CH ₂ - CH = CH ₂

Cl- f V-NH ₂ .
H ₂ NSO ₂ - Li - 'SO _{2 NH - CH 2} - CH = CH ₂

The preparation of the 3 - keto - 7 - sulfamyl - 2 H -1,2,4 - benzothiadiazine-1,1-dioxide used for this process is in J. Am. Chem. Soc, 82, p. 2042 (1960) and J. Am. Chem. Soc, 82, p. 1132 (1960), described.

• 2-Allylsulfamyl-5-chloro-4-sulfamyl-N- (3-hydroxy-2-butenylidene) aniline, hereinafter referred to as EX 4810, is an effective diuretic, also a Effective means of causing a sodium glut in the urine and means against hypersensitivity for animals and humans. This aniline is therefore applicable to the treatment of rush of blood based on failure of the heart, to combat edema and ascites as well as to treat high blood pressure. EX 4810 is re urine and sodium excretion without a comparable increase in potassium excretion

much more effective than the known compound 6 - chloro - 3,4 - dihydro- 7 - sulfamoyl - 2 H -1,2,4 - benzothiazine-l, l-dioxide, called hydrochlorothiazide. The absence of the simultaneous increase in potassium excretion with the increased urine excretion means an optimal therapeutic effect with a minimum of side effects due to the loss of potassium. .
The effectiveness of EX 4810 as a special

i ^ do i / ^ 3 4

effective diuretic results from the test results given in the following table:

Comparison of the diuretic effect after oral administration of EX 4810 and hydrochlorothiazide

same group of dogs

Total mEq for 6 hours **) ± SE
Na Cl K

EX 4810

Hydrochlorothiazide

33.79 ± 4.52
16.88 ± 2.24

39.77 ± 6.01
17.36 ± 1.78

8.21 ± 1.53
6.45 ± 1.61

*) Average of 0.5 hours% increase over 6 hours.

*) Total mEq for 6 hours S. E. means: Total milliequivalents of sodium, chlorine and potassium that a sample contains, soft was collected over a period of 6 hours taking into account the normal ± error.

Test report
1. Checked connections

EX 1.0-912:

2-dimethylaminomethylene-sulfamyl-4-sulfamyl-5-chloroaniline (according to U.S. Patent 3009910, Example 1).

EX 4810:

2 - Ally lsulfamy 1 - 5 - chlorine - 4 - sulfamy 1 - N - (3 - hydroxy-2-butenylidene) -aniline

Urea-driving effect
a) Experimental set-up

Only one group of four dogs was used for the entire study. This group of four dogs was given a preparation every week, so there was enough time for the dogs to fully recover from the effects of the respective preparation. Feeding was discontinued 19 hours before each experiment. Water could be ingested ad libitum up to about X ¹ I ₂ hours before a test. Urine samples were taken every 30 minutes from the standing, lightly restrained, catheterized bitches: four control samples and eight samples after ingestion of the preparation. However, urine tests were collected prior to each test run and destroyed along with the first two control samples. This means that the results listed below consist of two control samples and eight samples taken after the preparation has been administered. In all samples, the amount of urine and electrolytes (Na, K, Cl) were determined and calculated as a unit per kilogram and minute. The lower doses were administered orally via gastric tube as a 0.002% suspension in 5% acacia gum. The higher dose was given as a 0.2% suspension in 5% acacia gum. This was designed so that each animal received 0.5 cc / kg followed by approximately 10 cc of water. EX 4810 was given in a dose of 0.1 mg / kg, while EX 10-912 was given in two doses, one 0.1 mg / kg and the other 1.0 mg / kg. ■

b) Result and comment

The results obtained with EX 4810 and EX 10-912 are summarized in the table and graphs 1, 2 and 3. From this it can be clearly seen recognize that EX 4810 as an oral dose of 0.1 mg / kg is a very effective and powerful diuretic

was. ,.

In contrast, EX 10-912 was essentially ineffective at both 0.1 and 1.0 mg / kg; it produced only a minimal and temporary effect. From this it can be concluded that EX 4810 is highly effective as a diuretic when administered orally in non-anesthetized dogs, ten times more effective than EX 10-912.

". Average 60-30 30-0 Urine and electrolyte excretion control 60-90 90-120 120-150 After administration
of the preparations 180-210 210-240 Min. Min. 30-60 Min. Min. Min. 150-180 Min. Min. 0-30 Min !. Min. 0.016 0.014 Min. 0.043. 0.028 0.032 0.019 0.018 EX 4810 (0.1 mg / kg) 0.037 0.023 Urine / vol. 2.524 2.663 0.030 9,954 5,942 5.834 3.853 3.340 cc / kg / min 9.032 4.184 N / A 1,231 1.138 6.574 1.628 1.024 1.218 1.007 0.965 μΕς / kg / min 1.019 1,000 1,814 9.264 6.232 6.475 1.097 4,299 3.720 K. 2.354 6.680 4,868 Cl 3.481 | iEq / kg / min 0.008 0.008 0.008 0.008 0.007 0.006 0.006 EX 10-912 (0.1 mg / kg) 0.008 0.006 Urine / vol. 0.011 cc / kg / min

1 <4-ÜO i /

Continuation

60-30
Min. 30-0
Min. 0-30
Min. control 60-90
Min. 90-120
Min. 120-150
Min. After administration
of the preparations 180-210
Min. 210-240
Min. 1.208 1,226 1,840 30-60
Mini 0.803 0.558 0.370 150-180
Min. 0.388 0.466 N / A
[iEq / kg / min
, K
| xEq / kg / min
Cl
uEq / kg / min 0.783 0.906 1,233 1.086 0.642 0.528 0.438 0.382 0.362 0.332 I Ti CT
EX 10-192 (1.0 mg / kg)
Urine / vol.
cc / kg / min
Well ■ ■
wEd / ke / min 0.310 0.253 0.526 0.679 0.352 0; 231 0.177 0.389 0.217 0.222 f ^ "^ ™ * ^^ u cy ******
K
μEq / kg / min
Cl
μΕς ^^ ηιϊη 0.007
1.219 0.007
1.369 0.009 '
1.530 0.290 0.008
0.985 0.009
0.914 0.006
0.698 0.194 0.005
0.592 0.006
0.672 0.715
0.619 0.926
0.586 1.070
0.670 0.012
1.351 0.856
0.411 0.938
0.384 0.634
0.308 (
0.006
0.585 0.599
0.225 0.550
0.239 1.325
0.525 0.579
0.238

example

14.8 g (0.0475 mol) of 6 _: chloro-3,4-dihydro-3-keto-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide were dissolved in 50 ml of dimethylformamide and 2 , 1 g of 56.3% NaH in oil (0.0475 mol) was added with stirring at room temperature. After stirring for a further 0.5 hours, 6.05 g (0.0475 mol) of allyl bromide were added and the reaction mixture was kept at 60 to 70 ° C. for 3 hours. After cooling, the reaction mixture was poured into 1.5 liters of water. Cooling overnight gave a solid which was taken up, washed with water, dissolved in dilute NaOH and then reprecipitated with dilute acetic acid. The solid material obtained was taken up, washed with water and dried was 13.4 g (81%) of 2-allyl-6-chloro-3,4-dihydro-3-keto-7-sulfamyl-1,2,4-bezothiadiazine -1,1-dioxide obtained; F. = 285 to 289 ° C.

Analysis: C ₁₀ H ₁₀ ClN ₃ O ₅ S ₂ :

Theoretically ... S 18.21, Cl 10.07;
found S 18.97, Cl 10.25.

There were 26.0 g (0.075 mol) of the 2-AHyl-6-chloro-3,4-dihydro-3-keto-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide obtained dissolved in 300 ml of 15% NaOH and the solution at 90 to 100 ° C. for 7 hours held. Cool and add excess hydrochloric acid yielded a solid that was taken up, washed with water and made from dilute ethanol was recrystallized; 11.1 g (45%) of 2-allylsulfamyl-5-chloro-4-sulfamylaniline were obtained obtained as a monohydrate; F. = 76 to 78 ° C.

Analysis: C ₉ H ₁₄ ClN ₃ O ₅ S ₂ .

Theoretically ... p 18.70;
found ..: .. S 18.71.

Long drying at 100 ° C gave the product as an amorphous solid.

Analysis: C ₉ H ₁₂ ClN ₃ O ₄ S ₂ .

Theoretically ... S 19.72, Cl 10.89;
found ..... S 19.48, Cl 10.98.

6.9 g (0.020 mol) of 2-allylsulfamyl-5-chloro-4-sulfamylaniline monohydrate were dissolved in 14 ml of acetylacetaldehyde dimethylacetal at room temperature and the viscous solution was filtered. Adding 6 drops of 10: 1 H ₂ O / conc. HCl and stirring for 20 hours resulted in a heavy suspension. Dilution with 150 ml of ethanol, taking up the solid, washing twice with 40 ml of ethanol each time and drying gave 6.2 g (78%) 2-allylsulfamyl-4-sulfamyl - 5 - chloro - N - (3 - hydroxy - 2 - buteny liden) - aniline

with a melting point of 204 to 206 ° C.

Analysis: C ₁₃ H ₁₆ ClN ₃ O ₅ S ₂ .
Theoretically ... Cl 9.00, N 10.67, S 16.27;
found Cl 9.05, N 10.79, S 16.32 ..

/ _mflX 343 ΐημ (f 32900).

Claims (2)

'. Patent claims: 1. 2-AHylsulfarnyl-5-chloro-4-sulfamyl-N- (3-hydroxy-2-butenylidene) aniline of the formula '- SO ₂ - NH - CH ₂ - CH = CH ₂ 2. Process for the preparation of 2-allylsulfamyl-5-chloro-4-sulfamyl-N- (3-hydroxy-2-butenylidene) aniline according to claim 1, characterized in that 2-allylsulfamyl-5-chloro-4-sulfamyl - N - (3 - hydroxy - 2 - butenylidene) - aniline with acetylacetaldehyde or its with a lower one Alcohol formed converts acetal.