US3870720A - Potassium derivatives of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone - Google Patents

Abstract

Novel, nontoxic, nonmercurial diuretic compounds are disclosed, which are potassium derivatives of 2-phenyl-6-sulphamyl-7-chloro1,2,3,4-tetrahydro-4-quinazolinone. The monopotassium derivative is obtained by replacing either hydrogen of the sulphamyl group of the starting quinazolinone by a potassium atom, whereas the dipotassium derivative is obtained by replacing either hydrogen of the sulphamyl group of the starting quinazolinone and also the hydrogen atom lying in the 3-position of the tetrahydroquinazolinone ring of same starting quinazolinone by a potassium atom each.

Description

United States Patent [1 1 Carissimi et al.

[ POTASSIUM DERIVATIVES OF 2-Pl-lENYL-6-SULPHAMYL-7-CHLORO- l,2,3,4-TETRAHYDRO-4QUINAZOLINONE [76] Inventors: Massimo Carissimi, 3, Via Cesare Cantu; Franco Ravenna, 57/a Via Vincenzo Monti, both of Milan, Italy [22] Filed: May 2, 1973 [21] Appl. No.: 356,403

[30] Foreign Application Priority Data May 5, 1972 Italy 23925/72 [52] US. Cl. 260/2565 R, 424/251 [5 l] Int. Cl C07d 51/48 [58] Field of Search 260/2565 R [56] References Cited UNITED STATES PATENTS 2,952,680 /1960 Novello 260/2565 R Mar. 11, 1975 Primary ExaminerRichard J. Gallagher Attorney, Agent, or Firm-Frank J. Jordan [57] ABSTRACT Novel, nontoxic, nonmercurial diuretic compounds are disclosed, which are potassium derivatives of 2- phenyl-o-sulphamyl-7-chlorol ,2,3,4-tetrahydro-4- quinazolinone. The monopotassium derivative is obtained by replacing either hydrogen of the sulphamyl group of the starting quinazolinone by a potassium atom, whereas the dipotassium derivative is obtained by replacing either hydrogen of the sulphamyl group of the starting quinazolinone and also the hydrogen atom lying in the 3-position of the tetrahydroquinazolinone ring of same starting quinazolinone by a potassium atom each.

2 Claims, 6 Drawing Figures sum 1 or 6 MENTEUHARI 1 i975 8 5 8% 8 mm 95 m 8w m ON \A 2 owe. I.

ow ow k O2 0e mm 9m 7. m

mzomoi POTASSIUM DERIVATIVES OF 2-PHENYL-6-SULPHAMYL-7-CHLORO-l ,2 ,3 ,4- TETRAHYDRO-l-QUINAZOLINONE BACKGROUND OF THE INVENTION This invention relates to non-mercurial diuretics and, more particularly, to compounds capable of enhancing the diuresis without exhibiting obrioxious side effects.

PRIOR ART It is known that 2-phenyl-6-sulphamyl-7-chlorol,2,3,4-tetrahydro-4-quinazolinone has a considerable diuretic activity (Biressi et al.- Il Farmaco Ed.Sc., 24, 199 (1969); Barbi et a1., ibid., 24, 496 (1969)).

The above named compound has proven to be capable, under different experimental conditions, of enhacing the diuresis and also both the elimination of sodium and potassium ions. It has been ascertained, moreover, that the elimination of potassium ions had a slower increase, as the dosage was increased, than that of sodium ions and exhibited a tendency towards a maximum boundary value: this fact wad doubtless a favorable circumstance from the clinical viewpoint. The above identified quinazolinone, in addition, displayed the above described diuretic action while being completely inactive as a carboanhydrase inhibitor.

these properties, along with a virtual nontoxicity, had led to start a considerably wide clinical-test activity, and the compound had been administered in tabloids or gelatlne capsules, at an average dosage unit of to 100 milligrams of active substance.

At the dosages indicated above, no toxic pheno mena were observed in humans, or intolerance of any kind. The diuretic activity, both under normal conditions of hydrosaline balance, and in illnesses which werecharacterized by a high hydrosaline retention rating, did not appear immediately upon the administration of the drug (contrary to what occurs with other diuretics, such as furosemide), but appeared after 3-6 hours and lasted for a period of time ranging from 24 to 30 hours or more after a single administration.

A phenomenon, which proved to be difficult to explain, had been observed, that is, a certain number of patients, say the percent, for the most part patients whose general conditions were extremely poor, but sometimes also normal patients, did not show to have been influenced in any wise by the treatment. The latter patients, even when treated with gradually higher dosages, up to 50 milligrams, did not respond to the treatment anyhow, whereas they proved to be responsive to other diuretics, such as hydrochlorothiazide, furosemide and ethacrynic acid.

This phenomenon of apparent resistance involved a certain number of patients, whereas it is known that the clinical response of the conventional diuretics is constant.

SUMMARY OF THE INVENTION In order to overcome the above enumerated defects of 2-phenyl-6-sulphamyl-7-chloro-l,2,3,4-tetrahydro- 4-quinazolinone when employed as a diuretic, it has been envisaged to exploit the acidic nature of hydrogen, both in the sulphamyl group and in the 3-position of the heterocyclic ring.

Broadly stated, the invention relates to both the monopotassiumand the dipotassium derivatives of 2- phenyl-6-sulphamyl-7-chloro-l ,2,3,4-tetrahydro-4- quinazolinone, as diuretics. These derivatives are obtained by replacing, for the former, either hydrogen of the sulphamyl group by a potassium atom, and, for the latter, by replacing either hydrogen of the sulphamyl group and the hydrogen lying in the 3-position of the tetrahydroquina-zolinone ring by one potassium atom each, respectively. Both the monoand the dipotassium derivatives are water soluble. A 1 percent aqueous solution of the monopotassium derivative has a pH of about 9.9, and, after a certain period of time a precipitate is observed, which is the starting sulphonamide, a product of hydrolysis. Conversely, the dipotassium derivative yields a stable 1 percent aqueous solution which has a pH of about 11.5.

The analysis of the monopotassium derivative is as follows:

For C,,,H Cl K N O S Found CI 9.37 Calcd. 9 44 The analysis of the dipotassium derivative is as follows: For C|4H10CIK2N3O3S Found 7: K= 18.85 /1Cl=8.l7 "/1 N=9.73 Calcd. 18.88 8.50 9.98

However, both the monoand the dipotassium derivatives are best characterized by their IR spectra, as will be set forth in more detail hereinafter.

The foregoing objects, features and advantages of the invention will become apparent to those skilled in the art from the ensuing detailed description of the spectral characteristics of the novel products as depicted in the accompanying drawings, and from a number of both pharmacological and clinical tests which will be reported hereinafter.

DESCRIPTION OF THE DRAWINGS DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS AND THE SPECTRA l. The starting quinazolinone, i.e. 2-phenyl-6- sulphamyl-7-chloro-l ,2,3,4-tetrahydro-4- quinazolinone has an IR spectrum (FIGS. 1 and la shown for comparison) exhibiting two absorption bands at 3420 and 3330 cm", which correspond to the asymmetrical and symmetrical stretching -NH of the sulphamyl group, respectively, one band at 1660 cm which corresponds to the carbonyl group of the quinazolinone ring (=CO stretching), one band at 1620 cm which presumably corresponds to the aromatic ring (-C=C- stretching), two bands at 1335 and 1160 cm, corresponding to the asymmetrical and symmet- 3 4 rical stretching, S=O, of the sulphamyl group, respec- 1-2C, there was added dropwise, with stirring, 0.1 tively. mol of a 10 percent solution of potassium methoxide 2. For the monopotassium derivative, FIGS. 2 and 2a, (or ethoxide) in methanol (or ethanol). The potassium the bands at 3420, 3330, 1335 and 1160 cm disapalkoxide solution can be conveniently replaced by a l pear, this fact being an evidence of the substitution percent solution of potassium hydroxide in methanol.

which has taken place at the sulphamyl group. con- The thus obtained solution ofthe monopotassium deversely, the 1655 band, corresponding to the absorprivative was filtered and evaporated to dryness under tion of the carbonyl and the 1605 band, which can be reduced pressures. attributed to the aromatic ring, remain, At 1110 The product which has been isolated is a white crys- (approx 3 very wide band is observed, whose inte u IO talline powder exhibiting an IR spectrum such 88 that pretation is difficult. Show" in FIGS- 2 and 3. For the dipotassium derivative, the absorption bands at 3420, 3330, 1335 and 1160 cmare lacking, EXAMPLE 3 and, in addition, the 1655 band, characteristic of carbonyl, is very weakened, thus showing that the second Method for preparing the dipotassium derivative of potassium atoms has replaced thecyclic amide, proba- Z-phenyl-6-sulphamyl-7chloro-l,2,3,4-tetrahydro-4 bly for giving rise to an equilibrium of the kind: quinazolinone l l i l I P c N'K II 0K The absorption of the aromatic ring at 1610 cm, An appropriate volume ofa 5 percent solution of po and the wide one at 1105 (whose origin has not been tassium methoxide (or ethoxide) in methanol (or ethasurely identified) remain strong. (See FIGS. 3 and 3a). 01), C i g 23-12 g of Potassium,

was added dropwise, with cooling, to a solution of 100 Examples of methods for preparing the monoand the grs, of 2 pheny1 6 su1phamyl 7 chlom l .2,34 dipotassium derivatives of the starting quinazolinone. tetrahydm 4 quinazolinone in 5 f The in the following. a few examples of methods for pre- 40 q p f i derivative was p f p from the paring the monoand the dipotassium derivatives ofthe Indicated PY y adding 5,000 of ether starting quinazolinone will be described thereto. The precipitate was collected on a filter, carefully washed with ether and dried. EXAMPLE 1 The final product is a yellow crystalline powder whose IR spectrum is very much the same as that M th df th 0 tas um der'v tive of e 0 or preparing 8 p0 1 a shown in FIGS. 3 and 3a.

2-phcnyl-6-sulphamyl-7-chlorol ,2,3,4-tetrahydro-4- quinazolinone EXAMPLE 4 An appropriate Volume. of a 5 pcrcerit aqueous i Method for preparing the dipotassium derivative of tion ofpotassium methoxlde (or exthoxlde), containing 2 pheny] 6 su]phamy| 7 chloro 1 2 3 4 tetrahydm 4 llr56 grs. (0.296 mol) of potassium was added dropquinazolinone" wise, with cooling, to a solution of 100 grs of Z-phenyl- 6-sulphamyl-7-chloro-l,2,3,4-tetrahydro-4 quinazolinone in 500 mls of dimethylformamide (DMF).

The monopotassium derivative was precipitated from this solution by adding thereto 5,000 mls of ether. The

g gg g ygi gg l 22: 5:22 g gg g zwi (or ethoxide) in methanol (or ethanol). The solution of y p the dipotassium derivative thus obtained was filtered ing the InfraRed Spectrum of FIGS 2 n and evaporated to dryness under reduced pressures.

' 60 EXAMPLE 2 The isolated product is a yellow crystalline powder which is very soluble in water and has an infrared spec- Method for preparing the monopotassium derivative of "um very much the same as Shown in FIGS 3 and 3a.

2-phenyl-6-sulphamyl-7-chloro-l ,2,3,4-tetrahydro-4 quinazolinone EXAMPLE 5 To a suspension of 0.1 mol of 2-phenyl-6-sulphamyl- Method for preparing the dipotassium derivative of 7-chloro-l,2,3,4-tetrahydro-4 quinazolinone in 600 2-phenyl-6-sulphamyl-7-chloro-l ,2,3,4-tetrahydro-4- mls. of anhydrous methanol (or ethanol), cooled at quinazolinone.

To a suspension of 0.1 mol of 2-phenyl-6-sulphamyl- 7-chloro-l,2,3,4-tetrahydro-4 quinazolinone in 600 mls. anhydrous methanol (or ethanol), cooled at 12C, there was added dropwise, with stirring, 0.2 mol of a 10 percent solution of potassium methoxide To a suspension of 0.1 mol of 2-phenyl-6-sulphamyl- 7-chloro-1,2,3,4-tetrahydro-4-quinazolinone in 680 mls. distilled water, cooled at l2C, there are added dropwise, with stirring, 0.2 mol of KOH in an aqueous solution. After a 30-minute stirring, the solution thus obtained was filtered on a glass-wool filter and freezedried. A vey soft yellow powder is obtained, which is readily soluble in water, with a pH of about 11.5.

RESULTS OF THE PHARMACOLOGICAL AND CLINICAL TEST Both the potassium derivatives as described hereinabove have been compared, as to their diuretic activities, with the 2-phenyl-6-sulphamyl-7-ch1oro-l,2,3,4- tetrahydro-4-quinazolinone, hereinafter called the starting quinazolinone for brevity.

Contrary to what has been said above in the introductory part of this specification for the starting quinazolinone, the diuretic response of the patients to both the monoand the dipotassium derivatives was intense and no exception was detected.

The tests which have been carried out have shown that both the potassium derivatives of this invention exhibit an increased diuretic activity over that of the starting quinazolinone. This action is due to a more intensive absorption of the derivatives in question by the system. This exalted absorption is evidenced by a more pronounced elimination through the urinary tract.

A method for dosing in the urines both the starting quinazolinone and the two potassium derivatives of this invention has been envisaged by the applicants and has an. accuracy as high as l microgram per milliliter.

The outline of the dosage method indicated above is as follows:

The urines are collected at regular intervals and brought to a pH of 8, and repeatedly extracted with ethyl acetate. The latter, dried upon sodium sulphate, is evaporated to dryness and the residue, redissolved in DMF (dimethylformamide), is quantitatively placed on a glass plate carrying a layer of 0.25 mms. of silica gel containing a fluorescent detector. Chromatographic analysis has been carried out by using a 70/30 (by vol.) mixture ofchloroform and methanol as the eluant. The quinazolinone spot (this is valid in any case. since in the body both the potassium derivatives restore the starting quinazolinone) can easily be recognized for its R (0.7 approx.) and its fluorescence when lighted by a lamp emitting a UV light with a wavelength of 254 millimicrons. The silica gel which contains the product is scraped out, extracted many times with DMF and filtered and the DMF is evaporated under reduced pressures. The residue is then saponified by boiling it during 2 hours with 2 mls. of N/l NaOH, the resultant solution is acidified with N/l NCl and the as formed 2-amino-4- chloro-S-sulphamyl-benzamide is evaluated according to the method of Bratton and Marshall (l.Biol.Chem., 128, 537 (1939), by comparing the color obtained with that of a known amount of the starting quinazolinone which has undergone the same treatment as described just now.

A number of tests have been carried out, both on dogs and humans, in each of which there was administered, in parallel, a certain amount of the starting quinazolinone and, on the other sides, the same amount in the form of the monoand the dipotassium derivatives of this invention. In all cases. the excreted amount of the starting quinazolinone (in the body. as recalled above, both the potassium derivatives are reconverted to the starting quinazolinone), was measured with the method which has been outlined herein above.

FIRST SET OF TESTS Tests with the starting quinazolinone, on dogs Test No. 1

To a dog having a body weight of 8.55 kgs. there were administered 76.9 mgms. of the starting quinazolinone. 72 hours after the administration, the total amount of excreted urine was 1.145 mls. and the amount of starting quinazolinone eliminated with the urines was 13.84 mgms., that is, about the 18 percent. The equivalent unitary dosage was 9 mgms. per kilogram of body weight. Test No. 2

To a dog having a body weight of 9.2 kgs. there were administered 82.8 mgms. of the starting quinazolinone, that which was equivalent to 9 mgms/kgbw. The volume of urines as excreted after 72 hours from the administration was 1,600 mls. and the total excreted quinazolinone was 13.77 mgms., equivalent to 16.6 percent of the administered amount. Test No. 3

To a dog weighing 10.3 kgs. there were administered 92.7 mgms. of the starting quinazolinone, equivalent to 9 mgms/kg b.w. The total excreted urine after 72 hours was 1,707 mls, and the excreted quinazolinone was 14.65 mgms., equivalent to the 15.80 percent of the administered amount. Test No. 4

To a dog weighing 7.50 kgs. there were administered 67.5 mgms. of the starting quinazolinone, that which is equivalent to 9 mgms. per kg. b.w. After 72 hours, the total excreted urine was 1,874 mls., containing 15.15 mgms. of the starting quinazolinone, equivalent to the 22.4 percent of the administered amount.

TESTS WITH THE MONOPOTASSIUM DERIVATIVE, ON DOGS In all of these tests, the dosage was 9 mgms. per kg.b.w. The tests have been numbered with an M added to the figure, to recall the monopotassium derivative of this invention.

45 TSt NO.

A dog weighing 7.5 kgs. received 74.2 mgms. of the product (=67.5 mgms. of starting quinazolinone). After 72 hours, the excreted urine was 2,570 mls, and the starting quinazolinone-which had been excreted was 24.5 mgms. (=34.4 percent of the administered amount.

Test No. 2M

To a dog weighting 8.3 kgs. there were administered 82 mgms. of the monopotassium derivative, as defined above. This was equivalent to 74.7 mgms. of the starting quinazolinone. The urine excreted after 72 hours was 2,830 mls, and the starting quinazolinone which had been excreted was 27.8 mgms, equivalent to 37.2 percent of the administered amount.

Test No. 3M

To a dog weighing 10.5 kgs. there were administered 103.9 mgms. of the monopotassium derivative, equivalent to 94.5 mgms. of starting quinazolinone. the urine excreted after 72 hours was 2,945 mls., the starting quinazolinone excreted was 38.9 mgms., that is, the 41.2 percent of the administered amount.

Test No. 4M

to a dog weighting 7.7 kgs. there were administered 76.2 mgms. of monopotassium derivative, as defined above. This was equivalent to 69.3 mgms. of starting quinazolinone. After 72 hours, the excreted urine was 2,750 mls., and the starting quinazolinone excreted was 22.6 mgms., equivalent to the 32.7 percent of the administered amount.

TESTS WITH THE DIPOTASSIUM DERIVATIVE,

ON DOGS Also in this case, the compound which is excreted is the starting quinazolinone: its derivative is never excreted as such. Test No. D

To a dog weighing 8.7 kgs. there were administered 95.7 mgms. of the dipotassium derivative, as defined above, according to the invention. The quantity was equivalent to 78.3 mgms. of the starting quinazolinone. The unitary dose was 1 1 mgms. of the dipotassium derivative (equivalent to 8 mgms./kg b.w.) of the starting quinazolinone, per kg.b.w.) After 72 hours, the ex creted urine had a volume of 2,025 mls and the excreted starting quinazolinone was 33.91 mgms., equivalent to the 43.3 percent of the administered amount.

of the starting quinazolinone which has been excreted was 38.83 mgms., that is to say, the 34.5 percent of the administered amount. Test No. 8D

A dog weighing 8.9 kgs. was treated with 97.9 mgms. of the dipotassium derivative, as defined above. This dose is equivalent to 9 mgms./kg.b.w. of the starting quinazolinone. After 72 hours, the excreted urine vol ume was 2,070 mls., the excreted starting quinazolinone 31.7 mgms., that is, the 39.66 percent of the amount as administered originally.

SECOND SET OF TESTS, ON DOGS, WITH THE STARTING QUINAZOLINONE AND THE TWO POTASSIUM DERIVATIVES THEREOF Under the same conditions as in the tests of the first set, the starting quinazolinone and the mono-, and the dipotassium derivatives were administered to dogs, the unitary dosage (or its stoichiometrical equivalent for each of the potassium derivatives) being 1 mgm./kg.b.w. The results are tabulated below: in the Tables, the tests having no character after their numbers relate to the starting quinazolinone, those having an M after the number relate to the monopotassium derivative, and those having a D after the number relate to the dipotassium derivative.

Test Dog Administered Urine Starting Excreted percentage No. wt. amount of start. excreted quinazolinone of the starting quinazolinone after 72 hrs. excreted quinazolinone kgs. milligrams milliliters milligrams Test Dog Administered Urine Starting Excreted percentage No. wt. amount of excreted quinazolinone of the starting monopotassium after 72 hrs. excreted quinazolinone derivative kgs. milligrams milliliters milligrams "/1 13M 8.7 9.5 850 2.9 33.5% 14M 10.3 11.3 1.125 3.6 35.6% 15M 10.9 12 970 3.3 30.3% 16M 11.5 12.6 1,305 3.1 27.3%

Test Dog Administered Urine Starting Excreted percentage No. wt. amount of excreted quinazolinone of the starting dipotassium after 72 hrs. excreted quinazolinone derivative kgs. milligrams milliliters milligrams "/t 17D 9.9 12.07 773 2.9 30.1% 18D 13.6 16.6 1,005 3.1 23,192 19D 10.6 12.9 1,060 3.3 31.7% 20D 11.4 13.9 1,175 3.2 28.7%

Test No. 6D

To a dog weighing 9.3 kgs. there were administered 102.3 mgms.(equiv.to 83.7 mgms of the starting quinazolinone) of the dipotassium derivative of the invention. The total excreted urine after 72 hours was 2,080 mls., and the excreted starting quinazolinone was 37.7 mgms., equivalent to the 45.0 percent of the administered amount. Also in this case the unitary dose was 9 mgms of the starting quinazolinone per kilogram of body weight. Test No. 7D

To a dog weighing 12.5 kgs. there were administered 137.5 mgms. of the dipotassium derivative, as defined above. This amount is equivalent to 9 mgms. per kg.b.w. of the starting quinazolinone. The The urine excreted after 72 hours was 1,945 mls. and the quantity Also the second set of tests shows, beyond any doubt, the advantages achieved with the use of the potassium derivatives prepared according to the invention over the starting quinazolinone.

THIRD SET OF TESTS. ON HUMANS, WITH THE STARTING QUINAZOLINONE AND THE TWO POTASSIUM DERIVATIVES THEREOF The results are tabulated hereinafter, and the test number code is the same as above.

TESTS WITH THE STARTING QUINAZOLINONE, HUMANS.

Test Name Wt. Administered rme Starting Percentage No. (init.) amount of excreted quinazol. of excreted starting after 72 hrs. excreted quinazolinone quinazolinone kgs. milligrams milliliters milligrams 21 Mr.F.P. 75 2,060 6.1 20.4% 22 Mr.R.F. 82 30 1,150 5.9 19.9% 23 Mr.C.G. 73 30 1,995 5.6 18.7% 24 Mr.F.G. 68 30 1,835 6.3 21.1%

TESTS WITH THE MONOPOTASSIUM DERIVATIVE, ON HUMANS.

Test Name Wt. Administered Urine Starting Percentage No. (init.) amount of excreted quinazol. of excreted monopotassium after 72 hrs. excreted quinazolinone derivative kgs. milligrams milliliters milligrams 21M Mr.F.P. 75 33 2,350 9.9 33.2% 22M Mr.R.F. 82 33 2,120 8.2 27.5% 23M Mr.C.G. 73 33 2,420 10.6 35.4% 24M MR.P.G 68 .33 2,080 7.8 26.3%

TESTS WITH THE DIPOTASSIUM DERIVATIVE, ON HUMANS.

Test Name Wt. Administered Urine Starting Percentage No. (initi.) amount of excreted quinazolinone of excreted dipotassium after 72 hrs. excreted quinazolinone derivative kgs. milligrams milliliters milligrams "/0 21D Mr.F.P. 75 36.7 2,450 10.4 34.8% 22D Mr.R.F. 82 36.7 2,600 9.9 33.2% 23D Mr.C.G. 73 36.7 2,255 7.6 25.4% 24D Mr.P.G. 68 36.7 2,695 11.4 38.3%

The above reported clinical tests, made for comparison on the same persons, show that the amount of the diuresis, as well as the excreted quantity of the starting quinazolinone is always greater, whenever the potassium derivatives are administered rather than the starting quinazolinone as such.

In the clinical practice, it has been ascertained that the minimum diuresis-promoting unit dose for humans is, for both the monopotassium and the dipotassium derivatives as hereinbefore defined, in the vicinity of 0.1 milligrams per kilogram of body weight, and that the average therapeutic dose is 0.3 1 milligram per kilogram of body weight.

While the invention has been described in connection with a few preferred embodiments thereof, it will

Claims (3)

1. AS A NOVEL, NONTOXIC, NONMERCURIAL DIURETIC COMPOUND, THE DERIVATIVE OF 2-PHENYL-6-SULPHAMYL-7-CHLORO-1,2,3,4TETRAHYDRO-4-QUINAZOLINONE, WHEREIN EITHER HYDROGEN OF THE SULPHAMYL GROUP OF THE STARTING QUINAZOLINONE IS REPLACED BY A POTASSIUM ATOM.

1. As a novel, nontoxic, nonmercurial diuretic compound, the derivative of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone, wherein either hydrogen of the sulphamyl group of the starting quinazolinone is replaced by a potassium atom.

2. AS A NOVEL, NONTOXIC, NONMERCURIAL DIURETIC COMPOUND, THE DERIVATIVE OF 2-PHENYL-6-SULPHAMYL-7-CHLORO-1,2,3,4TETRAHYDRO-4-QUINAZOLINONE, WHEREIN EITHER HYDROGEN OF THE SULPHAMYL GROUP OF THE STARTING QUINAZOLINONE AND THE HYDROGEN IN THE 3-POSITION OF THE TETRAHYDROQUINAZOLINE RING OF SAME STARTING QUINAZOLINONE ARE REPLACED BY A POTASSIUM ATOM EACH.

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