DE2322699A1 - MERCURY-FREE DIURETICS - Google Patents

Description

The invention relates to mercury-free diuretics Agents, particularly compositions, to promote urinary excretion without deleterious side effects to evoke.

It is known that 2-phenyl-6-sulphamyl-7-chloro-1,2> 3,4-tetrahydro-4-quinazolinone has a considerable diuretic effect (see essays by Biressi et al. and Barbi et al. On page 199 and 496 in volume 24 (1969) of the magazine "Il Parmaco").

The aforementioned compound was able to promote urine excretion and eliminate sodium and potassium ions under various test conditions. It has also been found that when the dose is increased, the elimination of potassium ions only increased more slowly than that of sodium ions, up to a maximum limit value. From a clinical point of view, this was undoubtedly considered to be

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to be valued as a favorable circumstance. The quinazolines given above also showed the diuretic properties described above Effect although it is completely inactive as an inhibitor of carbonic anhydrase.

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

In the case of the specified dosage units, were found to be Humans have no symptoms of poisoning or intolerance. The diuretic activity shows up both in healthy people with electrolytic balance and in diseases caused by high retention marked on water and electrolytic liquids were not immediately after the administration of the medicine (unlike other diuretics such as furosemides), but started after three to six hours and lasted between 24 and 30 hours or longer after a single one Administration,

However, a process that was difficult to explain emerged i.e. about 20% of the patients, mostly patients in poor general condition, but sometimes also normal Patients did not appear to have been affected by the treatment at all. Even if you are such a patient gradually treated with higher dosage units up to 50 mg, did not respond while sensitivity to other diuretics was readily apparent, e.g. Hydrochlorothiazide, furosemide and ethacrylic acid.

These manifestations of obvious resistance showed a certain number of patients, although one has so far could assume that the clinical response

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on conventional diuretics is constant.

In order to avoid the aforementioned disadvantages of 2-phenyl-6-sulphamyl-7-chloro-1 _# 2> 3,4-tetrahydro-4-quinazolinone when it is used as a diuretic, it has been intended to reduce the acidic behavior of hydrogen to be evaluated both in the sulphamyl group and in the 3-position of the heterocyclic ring.

In the most general case, the invention relates to both the monopotassium and the dipotassium derivatives des 2-phenyl-6-sulphamyl ^ T-chloro-1,2,3,4-tetrahydro-4-quinazolinone as diuretics. These derivatives are obtained by using any hydrogen in the compound of the sulphamyl group is replaced by a potassium atom and, in the latter case, every hydrogen of the sulphamyl group and the hydrogen in the 3-position of the tetrahydroquinazolinone ring is replaced by a potassium atom. Both the monopotassium and the dike.lium derivatives are water soluble. A 1% aqueous solution of the monopotassium derivative has a pH of about 9.9, with excretion observed after a certain period of time which is the initial Sulphonamld, eir. product the hydrolysis, conversely the dipotassium gives a stable one 1% aqueous solution with a pH of about 11.5,

The monopotassium derivative has the following composition

C ₁₄ H ₁₁ Cl KN ₃ O ₃ S

found% K - 10.04% Cl = 9.37% N = 11.04 calculated 10.42 9.44 11.18

The dipotassium derivative has the following composition;

X> JV ⁼ 18th 10 ^C1 K ₂ N ₃ O ₃ S , 17th % N * , 73 found 18th , 85 % Cl = , 50 , 98 calculated , 88 s 9 = 8 9 8th

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

The invention is described below with further features and advantages in connection with the drawings and a number pharmacological and clinical test results explained in more detail.

It shows

Fig. 1 and la the spectral analysis of the starting quinazolinone, Fig, 2 and 2a the spectral analysis of the monopotassium derivative and 3 and 3a the spectral analysis of the .DikaJHum derivative,

the analyzes using a Perkin-Elmer spectrometer were carried out"

1, The starting quinazolinonf. d _e h «the 2-phenyl-6-sulphamyl-7-chloro-l, 2 _f 3 _? 4 ™ T @ trahydr © -4-Quina52 © linon has an IR spectrum with SWEi Abso ^ ptionshanden "at 3420 and 3330 cm, which the asymmetrical ^" UNAE s ^ ^ ssa ferisehen link -

-NH2 öer Sulpham3fI "= Griag> pe © stsprisclien _s solid with a

Band at ΙββΟ cai """ _? Those of the carbonyl group of the quinasolinone-

ringee CCO ^e Biaduagsgli <sdS © ntspriahtj, a Baad © 'at 1630 em " _e the probability of the aromatic ring (C β C-Verbisdisagsfilied) © ätsprlcht ^ two bands at 1335 and 1160 esa"., äie ä @ n as; pnmetrisehen and a symmetrical connecting member Qgsi ₀ S ^a O ₅ a @ r sulghamyl group.

2. For "das Msaoisaliasft-DQri ^ at sash I ⁵ Ig ₀ 2 and 2a dim ΒαηαΦΆ disappear at 3420 _ff 333O ₀ 1335 and lieOcm" ¹ ^ what the mistake of substitution ^ which has taken the place of the Sulphamyt group @ n « In contrast, the 1655-B & r »de corresponds to the absorption of the carbonyl,

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and the 1605 band assigned to the aromatic ring A fairly broad band is observed at the wave number of about 1110, whose Assignment or interpretation causes difficulties.

For the dipotassium derivative, the absorption bands at 3420, 3330, 1335 and 1160 cm " ^{1. In} addition, the 1655" band _# that characterizes the carbonyl is very weakened, which shows that the second potassium atom has been replaced by the cyclic amide is, so that there is possibly an equilibrium of the following kind »

The absorption of the aromatic ring at 1610 cm and the width of the band at 1105 remains strong (see Figures 3 and 3a).

Examples for the preparation of the mono- and dipotassium derivatives from the starting quinazolinone

Below are some examples of methods for preparing the mono- and dipotassium derivatives of the starting quinazolinone described.

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example 1

Process for the preparation of the MonokaÜum derivative des Z-phenyl-e-sulphamyl - ^ - chloro-, 1,2 , 3, 4-tetrahydro-4-quinazolinone

A sufficient amount of 5% aqueous solution of potassium methoxide (or ethoxide) containing 11.56 g (0.296 molj of potassium is added dropwise with simultaneous cooling of a solution of 100 g of 2-phenyl-6-sulphamyl-7- Added chloro- _{1,2 f} 3,4-tetrahydro-4-quinazylinone in 500 ml of dimethylformamide (DMF).

The monopotassium derivative is excreted from this solution by adding 5000 ml of ether. The product was collected on a filter, carefully with ether washed and dried. It turned out to be white crystalline powder which conforms to the ultra-red spectrum Fig. 2 and 2a shows.

Example 2

Process for the preparation of the monopotassium derivative fcus 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone

A suspension of 0.1 mol of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone in 600 ml of anhydrous methanol (or ethanol1 heated to 1 to 2 ° c Has been cooled, is added dropwise with stirring 0.1 mol of a 10 algae solution of potassium methoxide Coder -EthoxydJ in methanol (or -ethanol) added. Pie potassium alcoatyd solution can be replaced by a 10% solution of potassium hydroxide in methanol.

The monopotassium derivative solution thus obtained was filtered and dehydrated under reduced pressure «That

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Product that isolates as a white crystalline powder shows an ultra-red spectrum corresponding to FIG. 2 and 2a · e

Example 3

Process for the preparation of the dipotassium derivative of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone

Use a suitable amount of a 5% solution of potassium methoxide (or ethoxide) in methanol (or ethanol) with 23.12 g (0.592 mol) of potassium was added dropwise at the same time Cooling of a solution of 100 g of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone in 500 ml DMF added »This solution became the Dipotassium derivative by adding 5000 ml Äthei: filled out. The precipitate was collected on a filter, carefully washed with ether and dried. The end product Is a yellow crystalline powder with an ultra-red spectrum very far from that of Figures 3 u: .id 3a Shaalto

Example 4

Process for the preparation of the Dikaliusa derivative of 2-phenyl-6-sulphamyl-7-chloro-1 _f 2,3,4-tetrahydro-4-quinazolinone

A suspension of 0.1 mol of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone in 600 ml of anhydrous methanol (or ethanol), which is cooled to 1 - 2 ° C, is added dropwise at the same time Stirring 0.2 mol of a 10% solution of potassium methoxide (or ethoxide) in methanol (or ethanol) added »The thus obtained dipotassium derivative solution was filtered and dried under reduced pressure evaporates. The product shown is a yellow one

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crystalline powder which is readily soluble in water and has an ultra-red spectrum similar to that of FIGS. 3 and 3a owns.

Example 5

Process for the preparation of the dipotassium derivative of 2-phenyl-6-sulphamyl-7-chloro-1 , 2 , 3,4-tetrahydro-4-quinazolinone

A suspension of 0.1 mol of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone in 680 ml of distilled water, which has cooled to 1 - 2 ° C, is added dropwise 0.2 mol of KOH in aqueous solution was added with simultaneous stirring. After a stirring time of 30 minutes the solution was filtered through a glass wool filter and frozen dry. It turned out to be very yellow Powder with easy water solubility and a pH value of 11.5.

Results of pharmacological and clinical studies

The above-described two potassium derivatives were compared with that in terms of their diuretic effects 2-phenyl-6-sulphamyl-7-chloro-l, 2,3,4-tetrahydro-4-quinazolinone, which for the sake of abbreviation is hereinafter referred to as "starting quinazolinone" is called.

In contrast to the statements made in the introduction * " for the starting quinazolinone, all patients responded to both the mono- and the dipotassium derivative invariably. The studies carried out have shown that both potassium derivatives are better and increased have diuretic properties than those of the parent quinazolinone. This effect is enhanced on Absorption of the derivatives by the system.

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

According to the invention, a method for metering the starting quinazolinone and the two potassium derivatives is provided proposed according to the invention, the accuracy of which is up to 1 microgram per milliliter. These Dosing method is as follows:

The urine is collected at regular intervals, brought to pH = 8 and repeated extracted with ethyl acetate. The latter, dried over sodium sulphate, is evaporated and the residue again dissolved in DMF (dimethylformamide), whereupon it is applied quantitatively to a glass plate, the one Carrying layer of 0.25 mm silica gel with a fluorescent detector. There will be a chromatographic analysis carried out using a mixture of 70/30 parts by volume of chloroform and methanol as a washout agent. The quinazolinone stain can be easily recognized because of its R value (of about 0.7) and its fluorescence when illuminated with a UV lamp of one wavelength of 254 millimicrons. The silica gel containing the product is scraped out, extracted several times with DMF and filtered and the DMF evaporated under reduced pressure. The residue is then stiffened by making it is boiled for two hours with 2 ml of N / l NaOH. The resulting solution is diluted with N / l HCl acidified, whereupon the resulting 2-amino-4-chloro-5-sulphamyl-benzamide according to the method of Bratton and Marshall (J.Biol.Chem., 128, 537 - 1939) is detected by comparing the color obtained with that of a known amount of the starting quinazolinone, which has been treated as described.

A number of studies have been carried out in both dogs and humans, each in which

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in parallel a certain amount of the starting quinazolinone and on the other hand the same amount in Ebrm of the mono- and Dipotassium derivatives according to the invention were administered. In all cases the excreted amount of the starting quinazolinone was determined by the method described above measured. In this regard, it should be remembered that both potassium derivatives in the body are converted into the starting quinazolinone be transformed back.

First study group

Trial 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, that is, 18%. The equivalent unit dose was 9 mg / kg body weight.

Trial No. 2: A dog with a body weight of 9.2 kg was fed 82.8 mg of starting quinazolinone, corresponding to the equivalent dose of 9 mg / kg body weight. The volume of urine excreted 72 hours after feeding was 1600 ml and the total amount of quinazolinone excreted was 13.77 mg, which is 16.6% of the administered amount.

Trial No. 3; A dog weighing 10.3 kg was fed 92.7 mg of the starting quinazolinone, corresponding to an equivalent dose of 9 mg / kg body weight. The total amount of urine excreted after 72 hours was 1707 ml, and the excreted quinazolinone was 14.65 mg, which corresponds to 15.80% of the amount fed.

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Trial No. 4: A dog weighing 7.50 kg was given 67.5 mg of the starting quinazolinone, corresponding to the equivalent 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.

In all experiments the dose was 9 mg / kg body weight. The experiments listed below are given the addition "M ⁿ " after the experiment number as a reference to the monopotassium derivative.

Trial No. IM: A dog weighing 7.5 kg received 74.2 mg of the product (-67.5 mg of the starting quinazolinone). After 72 hours the amount of urine excreted was 2570 ml and the amount of starting quinazolinone 24.5 mg (corresponding to 34.4% of the administered amount).

Trial No. 2M: A dog weighing 8.3 kg received 82 mg of the monosodium derivative, which corresponds to 74.7 mg of starting quinazolinone. The amount of urine excreted after 72 hours was 2830 ml with 27.8 mg of 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 monopotassium derivative, corresponding to 94.5 mg of starting quinazolinone. The amount of urine excreted after 72 hours was 2945 ml and the excreted starting quinazolinone was 38.9 mg = 41.2% of the amount administered.

Trial No. 4M: A dog weighing 7.7 kg received 76.2 mg of monopotassium derivative corresponding to 69.3 mg of starting quinazolinone. After 72 hours, the amount of urine excreted was 2,750 ml

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and the starting quinazolinone 22.6 mg, which corresponds to 32.7% of the amount administered.

The following attempts are next to the serial numbering with the addition "D" to indicate the use of Dicalium derivative. Even when using this Compound only excreted the starting quinazolinone, never the derivative.

Trial No. 5D: A dog weighing 8.7 kg was given 75.7 mg of dipotassium derivative according to the invention. This amount corresponds to 78.3 mg of the starting quinazolinone. The unit dose was 11 mg dipotassium derivative (corresponding to 8 mg / kg body weight) of the starting quinazolinone. After 72 hours, the amount of urine excreted was 2025 ml and the amount of starting quinazolinone excreted therein was 33.91 mg, which corresponds to 43.3% of the amount administered.

Trial No. 6Dt A dog weighing 9.3 kg was given 102.3 mg (corresponding to 83.7 mg of the output quinazolinone) dipotassium derivative according to the invention. After 72 hours the urine excretion was 2080 ml and the excreted amount of initial quinazolinone 37.7 mg, which corresponds to 45.0% of the administered amount. In this case too, the unit dose was 9 mg / kg body weight.

Trial No. 7Ds 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 of starting quinazolinone excreted was 38.83 mg, ie. 34.5% of the administered amount.

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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 72 hours, the amount of urine excreted was 2070 ml and the amount of starting quinazolinone excreted was 31.7 mg, ie. 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 experiments of the first group, the starting quinazolinone and the Mono- and dipotassium derivatives administered to dogs at a unit dose of 1 mg / kg body weight (or the stoichiometric equivalent). The results of the tests are given in the following tables, The consecutive numbers without addition refer to experiments with the starting quinazolinone.

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Experimental Dogs- verabr. lot retired. retired. retired. %-Sentence TJr- weight Output Quinaz. Urine after Starting of the initial 1ΊΧ. kg 72 hours Quinazolinone Quinazolinone 10.4 mg ml mg 9 11.6 10.4 745 1.4 13.6% 10 12.4 11.6 730 1, 7 14.9% 11 12.6 12.4 695 1.5 12.5% 12th dogs
weight 12.6 810 1.7 13.7% Experimental
Mt- administered retired. retired. retired. % Rate i kg Amount of mono- Urine after Starting of the initial 8.7 potassium derivative 72 hours • Quinazolinone Quinazolinone '^; 10.3 mg ml mg % £ 13M 10.9 9.5 850 2.9 I.
33.5% 14M 11.5 11.3 1125 3.6 35.6% 15M dogs
weight 12th 970 3.3 ■ 30.3% 16M 12.6 1305 3.1 27.3% Experimental kg administered retired. retired. retired. %-Sentence No. 9.9 Amount of dipotassium Urine after Starting of the initial 13.6 derivative 72 hours Quinazolinone Quinazolinone 10.6 mg ml mg % 17D 11.4 12.07 773 2.9 30.1% _M. 18 D ■ 16.6 1005 3.1 23.1% C ₀ 19D - 12.9 1060 3.3 31.7% n> 20D 13.9 1175 3.2 28.7% K) CD - - da © = - CO

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The second experimental group also shows, without any doubts, the results obtained by using the potassium derivatives according to the invention achievable advantages over the starting quinazolinone.

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

The third experimental group was carried out on human test subjects. It should be noted here that it is a repeat experiment in which the same subjects administered the parent quinazolinone and the two potassium derivatives. The unit reference dose of the starting quinazolinone is about 0.4 mg / kg body weight for all experiments in this group. The results are shown in the table below.

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TRY the parent quinazolinone on humans

Trial Kr,

Surname

body weight

kg

verabr. Amount of output quinaz,

mg

excreted urine after 72 hours

ml

retired.
Output quinazolines

mg

retired. % Of the starting quinazolinone

22 23 24

F.P. 75 R.F. 82 CG. 73 P.G. 68

30 30 30 30

2060 1150 1995 1835

6.1
5.9
5.6
6.3

20.4% 19.9% 18.7% 21.1%

TRY the monopotassium derivative on humans

Surname

Trial no.

body weight

kg

verabr. Amount of monopotassium derivative

mg

passed, urine after 72 hours

ml

retired.

Starting

Quinazolinone

mg

retired. &% Rate of the starting quinazolinone

© 3

2IM 22M ■ 23M 2 4M

F.P. 75 R.F. 82 CG. 73 P.G. 68

33 33 33 33

2350 2120 2420 2080

9.9

8.2

10.6

7.8

33.2% 27.5% 35.4%

26.3%

TRY the dipotassium derivative on humans

Trial name

body weight

kg

verabr. Amount of dipotassium derivative

mg

passed, urine after 72 hours

ml

retired.

Starting

Quinazolinone

mg

retired

% Of the starting quinazolinone

21D 22D 23D 24D

P.P · '

RF CG. P ₉ G.

75 82 73 68

36.7 36.7 36.7 36.7

2450 2600 2255 2695

10.4
9.9
7.6

11.4

34.8%

33.2% 25.4%

38.3%

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The above results of the clinical examinations were made on the same persons for the purpose of comparison and show that the amount of urine excreted and also the amount of excreted starting quinazolinone is always greater if the potassium derivatives according to the invention are administered instead of starting quinazolinone.

Results have been confirmed in clinical practice determined that the smallest still diuretic dose in humans for both the monopotassium derivative as also for the dipotassium derivative close to 0.1 mg / kg Body weight and that the average therapeutic dose is between 0.3-1.0 mg / kg body weight.

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Claims (4)

Claims 1. Mercury-free, non-toxic diuretic, characterized from the derivative of 2 ~ phenyl-6-sulphamyl-7-chloro-l, 2,3,, 4-tetrahydro-4-quinazolinoh, in which each hydrogen of the sulphamyl group of the starting quinazolinone is replaced by a potassium atom. 2. Mercury-free, non-toxic diuretic compound, characterized by a derivative of 2-phenyl-6-sulphamyl-7-chloro-l, 2,3,4-tetrahydro-4-quinazolinone, in which each hydrogen of the sulphamyl group of the starting quinazolinone and the hydrogen in the 3-position of the tetrahydro-quinazolinone ring of the same starting quinazolinone is replaced by a potassium atom. 3. Pharmaceutical composition to promote urinary excretion in humans, characterized in that it uses one of the compounds according to Claim 1 as the active substance or contains 2, 4. A pharmaceutical composition according to claim 3, characterized in that a certain amount of dil ^ administration active substance in at least 0.1 mg / kg body weight. 309302/1366 Empty be ie