DE2322699C2 - Mercury-free diuretics - Google Patents

Description

The invention relates to non-mercury diuretics, in particular to compositions that promote urination without causing harmful side effects.

It is known that 2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro Chinazolinon-4 has a considerable diuretic effect (see articles by Biressi et al. And Barbi et al. On page 199 and 496, respectively, in volume 24 [1969] of the magazine »II Farmaco«).

The aforementioned compound was able to increase urinary excretion under various experimental conditions promote with simultaneous excretion of sodium and potassium ions. It has also been established that when the dose was increased, the excretion of potassium ions only increased more slowly than that of the Sodium ions up to a maximum limit. From a clinical point of view, this was without To see doubt as a favorable circumstance. The quinazolinone given above also exhibited that described above diuretic effect, although it is not a carbonic anhydrase inhibitor.

These properties and at the same time non-toxicity led to extensive clinical investigations, wherein the compound is in the form of tablets or gelatin capsules at an average dose of 10 to 100 mg of active substance was administered.

In the case of the indicated dosage sizes, no symptoms of poisoning or intolerance were found in humans. The diuretic activity is evident both in healthy people with normal Electrolyte balance as well as in sick people whose diseases are characterized by high retention of water and Electrolytes were not labeled immediately after administration of the medicine (as opposed to other diuretics, such as furosemide), but started after three to six hours and continued afterwards a single administration between 24 and 30 hours or more.

However, a process that was difficult to explain emerged: around 20% of patients, mostly patients in extremely poor general condition, but sometimes normal patients, did not seem at all to have been affected by the treatment. Even if you get such patients gradually with higher levels Treated doses up to 50 mg did not respond while responding to other diuretics without another ^ was given, e.g. B. on hydrochlorothiazide, furoserriid and etacrynic acid.

These manifestations of obvious resistance showed a certain number of patients, although one so far it could be assumed that the clinical response behavior to conventional diuretics is constant, is.

The invention has for its object to provide a mercury-free, diuretic with a Derivative of 2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro-quinazolinone-4 as an active substance

ίο to improve that it is better at its administration is absorbed by the patient and thereby gains greater reliability.

This object is achieved according to the invention in that the diuretic contains as active substance a potassium derivative of the compound mentioned in which one of the two hydrogen atoms of the sulfamoyl group in the 6-position of the starting molecule is replaced by a potassium atom.
According to a variant, it is proposed that the hydrogen atom on the nitrogen in the 3-position of the starting molecule is also replaced by a potassium atom. In this proposal, the acidic behavior of hydrogen is used both in the sulfamoyl group and in the 3-position of the heterocyclic ring. Both the monopotassium and dipotassium derivatives are water-soluble. A 1% strength aqueous solution of the monopotassium derivative has a pH of about 9.9, after a certain period of time a deposit is observed which forms the initial sulfonamide as a hydrolysis product. Conversely, the dipotassium derivative gives a stable 10% solution with a pH of about 11.5.

The monopotassium derivative has the following composition:

CuH _n ClKN ₃ O ₃ S

found K 10.04, Cl 9.37, N 11.04%;

calculated K 10.42, Cl 9.44, N 11.18%.

The dipotassium derivative has the following composition:

Ci ₄ HiOClK ₂ N ₃ O ₃ S K 18.85, Cl 8.17, N 9.73%; found K 18.88, Cl 8.50, N 9.98%. calculated

However, both derivatives can best be characterized by their IR spectral values, which further are described in more detail below.

The invention is described below with further features and advantages in conjunction with the drawings and a number of pharmacological and clinical trial results. Show it

F i g. 1 and la the spectral analysis of the starting quinazolinone,

2 and 2a the spectral analysis of the monopotassium derivative and

F i g. 3 and 3a the spectral analysis of the dipotassium derivative, the analyzes were carried out with the aid of a Perkin-Elmer spectrometer.

1. The starting quinazolinone, ie the 2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro-quinazolinone-4 has a 1R spectrum with two absorption bands at 3420 and 3330 cm- ¹ , the the asymmetrical and symmetrical stretching vibration (NH2-stretching) of the sulphamoyl group, furthermore with a band at 1660 cm- ', which corresponds to the carbonyl group of the quinazolinone ring (CO-stretching), a band at

1620 cm- ', which probably corresponds to the aromatic ring (C = C-stretching), two bands at 1335 and 1160 cm-', which correspond to the asymmetrical and symmetrical stretching vibrations (S = O) of the sulphamoyl group.
For the monopotassium derivative according to FIGS. 2 and 2a, the bands at 3420, 3330, 1335 and 1160 cm- 'disappear, which provides evidence of the substitution that has occurred on the sulfamoyl group. In contrast, the 1655 band remains, corresponding to the absorption of the carbonyl group, and the 1605 cm- 'band, which can be assigned to the aromatic ring. A fairly broad band is observed at the number of rolls of about 1110 cm- ', the assignment or interpretation of which causes difficulties.

example 1

procedure

for the production of the monopotassium derivative of

2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro

Quinazolinone-4

10

15th

For the dipotassium derivative the absorption bands disappear at 3420, 3330, 1335 and 1160cm- ', in addition, the 1655 cm-'band that characterizes the carbonyl group is very weakened, which indicates it indicates that the second potassium atom has replaced the hydrogen atom on the cyclic amide nitrogen and that possibly an equilibrium of the following kind arises:

25th

\ C.
ι C.
I. / \ 1> f C.
Il c— / C ₆ H ₅ 30th N OK -C ₆ H ₅ ^N 1 Il
0 N - K \ / 35

The IR absorption of the aromatic ring at 1610 cm- 'and the width of the band at 1105 cm-' remain strong (see Figs. 3 and 3a).

Examples

for the production of mono- and dipotassium derivatives
from the starting quinazolinone

Below are a few examples of methods for preparing the mono- and dipotassium derivatives of Starting quinazolinones described.

45

■ 50

55

A sufficient amount of 5% aqueous solution of potassium methoxide (or ethoxide) that Contains 11.56 g (0.296 mol) of potassium, is added dropwise with simultaneous cooling of a solution of 100 g of 2-phenyl-6-sulfamoyl-7-chloro-l, 2,3,4-tetrahydro-quinazolinone-4 in 500 ml of dimethylformamide (DMF) admitted.

The monopotassium derivative is precipitated from this solution by adding 5000 ml of ether. That Product is collected on a filter, carefully washed with ether and dried. It turns out to be a white crystalline powder which has the infra spectrum according to FIG. 2 and 2a shows.

Example 2

procedure

to display the monopotassium derivative

2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro

Quinazolinone-4

A suspension of 0.1 mol of 2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro Quinazolinone-4 in 600 ml of anhydrous methanol (or ethanol) that has been cooled to 1 to 2 ° C is added dropwise under Stir 0.1 mol of a 10% solution of potassium methoxide (or ethoxide) in methanol (or Ethanol) added. The potassium alkoxide solution can be replaced by a 10% solution of potassium hydroxide in Methanol to be replaced.

The monopotassium derivative solution thus obtained was filtered off and under reduced pressure evaporated. The product, which is isolated as a white crystalline powder, shows an infrared spectrum according to FIG. 2 and 2a.

Example 3

procedure

for the preparation of the dipotassium derivative of

2- Pheny! -6-SuIf amoyl-7-chloro-1,2,3,4-tetrahydro

Quinazolinone-4

A suitable amount of a 5% solution of potassium methoxide (or ethoxide) in methanol (or Ethanol) with 23.12g (0.592 mol) potassium was added dropwise with simultaneous cooling of a solution of 100 g of 2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro-quinazolinone-4 in 500 ml of DMF was added. The dipotassium derivative was precipitated from this solution by adding 5000 ml of ether. The precipitation was collected on a filter, carefully washed with ether and dried. The end product is a yellow crystalline powder, the infrared spectrum of which corresponds to that of FIG. 3 and 3a are very similar.

Example 4

procedure

to represent the dipotassium derivative of

2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro

Quinazolinone-4

A suspension of 0.1 mol of 2-phenyl-6sulfamoyl-7-chloro-1,2,3,4-tetrahydro Quinazolinon-4 in 600 ml of anhydrous methanol (or ethanol), which is cooled to 1 - 2 ° C, is added dropwise at simultaneous stirring 0.2 mol of a 10% solution of potassium methoxide (or ethoxide) in Methanol (or ethanol) added. The dipotassium derivative solution thus obtained was filtered and evaporated to dryness under reduced pressure. The product shown is a yellow one crystalline powder which is readily soluble in water and an infrared spectrum similar to that of Figures 3 and 3a owns.

Example 5

procedure

to represent the dipotassium derivative of

2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro

Quinazolinone-4

A suspension of 0.1 mol of 2-phenyl-6-sulfamovl-7-chloro - !, 2.3.4-tetrahvdro Quinazolinone-4 in

10

_13th

, ₀

680 ml of distilled water, which has cooled to 1-2 ° C, is added dropwise with simultaneous stirring 0.2 mol of KOH was added in aqueous solution. After stirring for 30 minutes, the solution was in filtered through a glass wool filter and frozen dry. It resulted in a very soft yellow powder with high Water solubility and a pH of 11.5.

Results
pharmacological and clinical studies

The above-described two potassium derivatives were noted for their diuretic effects compared to the 2-phenyl-6-sulfamoyl-7-chloro-1,23,4-tetrahydro-quinazolinone-4, which is the abbreviation for the sake of following it is called "starting quinazolinone".

In contrast to the statements made in the introduction, spoke in favor of the starting quinazolinone all patients respond to both the mono- and the dipotassium derivative without exception. The carried out Studies have shown that both potassium derivatives have better and increased diuretic properties than those of the parent quinazolinone. This effect is due to increased absorption of the derivatives traced back through the body system.

This increased absorption can be demonstrated by increased excretion via the urinary tract.

To control the dosage and elimination conditions for the parent quinazolinone and its Potassium derivatives according to the invention, a determination method for the starting quinazolinone was used by the users in urine envisaged to be accurate to 1 microgram per milliliter. For the application This method, it is of fundamental importance that the body from both of the invention Potassium derivatives that regress the original quinazolinone. Carrying out the method of determination is shown below:

The urine is collected at regular intervals, brought to a pH value of 8 and extracted repeatedly with ethyl acetate. This solution, dried with sodium sulfate, is evaporated, the Residue again dissolved in DMF (dimethylformamide) and applied quantitatively to a glass plate, the one 0.25 mm silica gel layer with a fluorescent indicator wearing. Chromatographic analysis is performed using a mixture of 70/30 parts by volume of chloroform and methanol as solvent. The quinazolinone stain comes off easily recognize due to its RF value (about 0.7) and its fluorescence when irradiated with a UV lamp (Wavelength 254 nanometers). The silica gel containing the product is scraped off, several times with DMF extracted, the solution filtered and then the DMF evaporated under reduced pressure. The residue will saponified by boiling it for two hours in 2 ml of a 1N NaOH solution. The resulting solution is acidified with 1N HCl. The resulting 2-amino-4-chloro-5-sulfamoylbenzamide is accordingly the method of Bratton and Marshall (J. Biol. Chem., 128, 537-1939) determined by measuring the color compares the solution with that of a corresponding solution that originally contained a known amount of the Containing starting quinazolinones and has been treated as just described.

A number of parallel studies have been performed on both dogs and humans where, on the one hand, a certain amount of the

_J5

₄₀

₄₅

50

55 starting quinazolinor.5 and, on the other hand, the same amount in the form of the mono- and dipotassium derivatives according to the invention were administered. In all cases, the excreted amount of the starting quinazolinone was measured by the method described above. In this context, it should be remembered once again that both potassium derivatives are converted back into the original quinazolinone in the body.

First investigation group

try
with the starting quinazolinone in dogs

Experiment No. 1

A dog weighing 8.55 kg was given 76.9 mg of the parent quinazolinone. 72 hours after the administration, the total amount of urine excreted was 1145 ml, while the amount of starting quinazolinone excreted in the urine was 13.84 mg; H. 18%. the the corresponding single dose was 9 mg / kg body weight.

Experiment No. 2

A dog weighing 9.2 kg was given 82.8 mg of the parent quinazolinone, corresponding to the dose of 9 mg / kg body weight. That after 72 hours after feeding urine volume excreted was 1600 ml and the total amount of quinazolinone excreted was 13.77 mg, which corresponds to 16.6% of the amount administered.

Experiment No. 3

A dog weighing 10.3 kg was fed 92.7 mg of the starting quinazolinone, corresponding to one Dose of 9 mg / kg body weight. The total amount of urine excreted after 72 hours was 1707 ml, and that of the excreted quinazolinone 14.65 mg, which corresponds to 15.80% of the amount fed.

Experiment No. 4

A dog weighing 7.50 kg was given 67.5 mg of the parent quinazolinone, accordingly the dose of 9 mg / kg body weight. The total amount of urine excreted after 72 hours was 1874 ml with 15.5 mg of the starting quinazolinone, which corresponds to 22.4% of the amount administered.

Tried the monopotassium derivative in dogs

In all experiments, the comparable dose was 9 mg starting quinazolinone / kg body weight. The tests listed below are given the suffix "M" after the test number as Reference to the monopotassium derivative.

Try no. IM

A dog weighing 7.5 kg received 74.2 mg of the product (a67.5 mg of the starting quinazolinone). After 72 hours, the amount of urine excreted was 2570 ml and the amount excreted of starting quinazolinone 24.5 mg (corresponding to 34.4% of the administered amount).

Trial number 2M

A dog weighing 8.3 kg received 82 mg of monopotassium derivative, which corresponds to 74.7 mg of starting quinazoli

non corresponds. The amount of urine excreted after 72 hours was 2830 ml with 27.8 mg starting quinazolinone, which corresponds to 37.2% of the amount administered.

Trial No. 3M

A dog weighing 10.5 kg was fed 103.9 mg of the monopotassium derivative, accordingly 94.5 mg starting quinazolinone. The amount of urine excreted after 72 hours was 2945 ml and that Excreted starting quinazolinone 38.9 mg = 41.2% of the administered amount.

Trial No. 4M

A dog weighing 7.7 kg received 76.2 mg of the monopotassium derivative corresponding to 69.3 mg of starting quinazolinone. After 72 hours the amount of urine excreted was 2,750 ml and the starting quinazolinone 22.6 mg, which corresponds to 32.7% of the amount administered.

Trial with dipotassium derivative in dogs

In addition to the serial number, the following tests are marked with the suffix "D" as a reference to the use of dipotassium derivative. Even when using this connection, only the starting quinazolinone, never excreted the derivative.

Trial No. 5D

A dog weighing 8.7 kg was given 95.7 mg of dipotassium derivative (as indicated above, corresponding to of the invention) administered. This amount corresponds to 78.3 mg of the starting quinazolinone. The single dose was 11 mg / kg dipotassium derivative (corresponding to 9 mg / kg body weight of the starting quinazolinone). After 72 hours, the amount of urine excreted was 2025 ml and the amount excreted therein was Starting quinazolinone 33.91 mg, which is 43.3% of the administered amount.

Experiment No. 6D

A dog weighing 9.3 kg was given 102.3 mg (corresponding to 83.7 mg of the starting quinazolinone) of the invention Dipotassium derivative entered. After 72 hours the urine excretion was 2080 ml and the Excreted amount of starting quinazolinone 37.7 mg, which corresponds to 45.0% of the amount administered. In this case too, the single dose was 9 mg / kg body weight.

Experiment No. 7D

A dog weighing 12.5 kg was given 137.5 mg dipotassium derivative (9 mg / kg body weight starting quinazolinone). The amount of urine excreted in 72 hours was 1945 ml and the amount excreted with it Amount of starting quinazolinone 38.83 mg, i.e. H. 34.5% of the administered amount.

Experiment No. 8D

A dog weighing 8.9 kg received 97.9 mg of the dipotassium derivative, this dose corresponding to 9 mg / kg body weight with respect to the starting quinazolinone. Within After 72 hours, the amount of urine excreted was 2070 ml and the amount excreted with it Amount of starting quinazolinone 31.7 mg, i.e. H. 39.66% of the administered amount.

Second experimental group

in dogs, with the starting quinazolinone

and the two potassium derivatives

Under the same conditions as in the first group trials, dogs did Starting quinazolinone administered in a single dose of 1 mg / kg, the mono- and dipotassium derivative in single doses which are stoichiometrically equivalent to the above single dose. The results of the Experiments are given in the following tables, the consecutive numbers without Addition refer to experiments with the starting quinazolinone.

Attempt no. Dog weight Verabr. lot
Initial
Quinazolinone Eliminated.
Urine after
72 hours Eliminated.
Initial
Quinazolinone Eliminated.
% Rate of
Initial
Quinazolinone kg mg ml mg % 9 10.4 10.4 745 1.4 13.6 10 11.6 11.6 730 1.7 14.9 11th 12.4 12.4 695 1.5 12.5 12th 12.6 12.6 810 IJ 13.7 Attempt no. Dog weight Verabr. lot
Monopotassium
derivative Eliminated.
Urine after
72 hours Eliminated.
Initial
Quinazolinone Eliminated.
% Rate of
Initial
Quinazolinone kg mg ml mg % 13M 8.7 9.5 850 2.9 33.5 14M i0.3 11.3 1125 3.6 35.6 15M 10.9 12.0 970 3.3 30.3 16M 11.5 12.6 1305 3.1 27.3

9 23 22 699 10 Eliminated. llundeweight Eliminated. % Rate of Attempt no. Vcrabr. lot Eliminated. Initial Initial Dipotassium Urine after Quinazolinone Quinazolinone Deri \ at 72 hours 0 / kg mg 30.1 9.9 mg ml 2.9 23.1 17 D 13.6 12.07 773 3.1 31.7 18D 10.6 16.6 1005 3.3 28.7 19D 11.4 12.9 1060 3.2 2OD 13.9 1175

The second test group also shows, beyond any doubt, the effects of the use of the potassium derivatives according to FIG

Invention achievable advantages over the starting quinazolinone.

Third experimental group with the starting quinazoinone and the two potassium derivatives in humans

The third experimental group was carried out on human test subjects. It should be noted that that it is a repetition of the same test subjects Administrations of the parent quinazolinone and the

received both potassium derivatives. The single reference dose of the starting quinazolinone is approximately 0.4 mg / kg Body weight for all attempts in this group. The results are shown in the following Tabel.

Try the parent quinazolinone on humans

Trial no. Surname body weight Verabr. lot
Initial
Quinazolinone body weight Verabr. lot
Monopotassium
derivative body weight Verabr. lot
Dipotassium
derivative Eliminated.
Urine after
72 hours Eliminated.
Initial
Quinazolinone Eliminated.
% Rate of
Initial
Quinazolinone kg mg kg mg kg mg ml mg % 21 F. P. 72 30th 75 33 75 36.7 2060 6.1 20.4 22nd R. F. 82 30th 82 33 82 36.7 1150 5.9 19.9 23 CG. 73 30th 73 33 73 36.7 1995 5.6 18.7 24 P. G. 68 30th 68 YY 68 36.7 1835 6.3 21.1 Try with the monopotassium derivative in humans the dipotassium derivative in humans Trial no. Surname Surname Eliminated.
Urine after
72 hours Eliminated.
Initial
Quinazolinone Eliminated.
% Rate of
Initial
Quinazolinone ml mg % 21 M. F. P. F. P. 2350 9.9 33.2 22 M. R. F. R. F. 2120 8.2 27.5 23 M. CG. CG. 2420 10.6 35.4 24 M. D η
1 . VY. P. G. 2080 7.8 26.3 Try with Trial no. Eliminated.
Urine after
72 hours Eliminated.
Initial
Quinazolinone Eliminated.
% Rate of
Initial
Quinazolinone ml mg % 21D 2450 10.4 34.8 22 D 2600 9.9 33.2 23 D 2255 7.6 25.4 24 D 2695 11.4 38.3

11 12

The above results of the clinical investigations have been confirmed in clinical practice For the purposes of comparison, the results were determined on the basis that the smallest was still diuretic Individuals made and show that the amount of the dose in humans for both the monopotassium deri urine excretion and also the amount of excreted as well as for the dipotassium derivative close to those starting quinazolinones is always greater when 5 0.1 mg / kg body weight and that the substitute of Aiisgangs-quinazolinone the inventive therapeutic dose between measured potassium derivatives are administered. 0.3 - 1.0 mg / kg body weight.

Claims (2)

Patent claims: 1. Mercury-free diuretic with a derivative of 2-phenyl-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro Quinazolinon-4 as an active substance, characterized in that it is as active substance contains a potassium derivative of said compound, in which one of the two Hydrogen atoms of the sulfamoyl group in the 6-position of the starting molecule through a potassium atom is replaced. 2. A diuretic according to claim 1, characterized in that in addition also the The hydrogen atom on the nitrogen in the 3-position of the starting molecule is replaced by a potassium atom.