DE1620556B - 1 Cyclohexylbarbituric acid derivatives - Google Patents

Description

C-N

C = O

(I)

Ο - (CH ₂ ) ₄ - CH

(III)

A '- (CH ₂ ) ₃ - CH

COR ₃

(H)

IO

OC ₆ H ₁₁

in which, R denotes 4-hydroxy-n-butyl-, 3-hydroxyn-butyl-, 3-carboxypropyl or 3-oxobutyl radical means, as well as their alkali and alkaline earth salts. 2. A process for the preparation of the compounds according to claim 1, namely by

a) 5 - (4 - Hydroxy - η - butyl) -1 - cyclohexyl - barbituric acid and their alkali and alkaline earth salts, characterized in that compounds of the general formula III

20th

COR ₃

in which B _{denotes the cyano or COR 3} group and R ₃ denotes an alkoxy, aryloxy or aralkyloxy radical, is reacted with cyclohexylurea in a manner known per se, optionally in the presence of a condensing agent or a solvent, and the reaction product is then hydrolyzed,
b) 5- (3-carboxypropyl) -1 - cyclohexylbarbituric acid and its alkali and alkaline earth metal salts, characterized in that compounds of the general formula II

45 in which A 'is an alkoxy, aryloxy or aralkyloxycarbonyl radical, B is the cyano or COR ₃ group and R _{3 is} an alkoxy, aryloxy or aralkyloxy radical, in a manner known per se, optionally in the presence of a condensing agent and a solvent , reacted with cyclohexylurea and then hydrolyzed the reaction product.

c) 5 - (3 - oxobutyl) -1 - cyclohexyl - barbituric acid and their alkali and alkaline earth salts, characterized in that one in itself as is known, either methyl vinyl ketone and 1-cyclohexylbarbituric acid, optionally reacts in the presence of a condensing agent and a solvent or a Malonic acid derivative of the general formula VII

CH ₂ -CH ₂

O O

C COR ₃

H ₃ C CH ₂ - CH ₂ - CH (VII)

COR ₃

in which R ₃ denotes an alkoxy, aryloxy or aralkyloxy group, optionally in the presence of a condensing agent and a solvent, is reacted with cyclohexylurea and the reaction product is then hydrolyzed.

d) 5 - (3 - Hydroxy - η - butyl) -1 - cyclohexyl - barbituric acid and their alkali and alkaline earth salts, characterized in that 5- (3-oxobutyl) -l-cyclohexylbarbituric acid is in reduced in a manner known per se.

3. A pharmaceutical preparation consisting of a compound according to claim 1 and pharmaceutical harmless auxiliary materials.

The invention relates to substituted 1-cyclohexylbarbituric acids and their alkali or alkaline earth salts, which are not only better anti-inflammatory Effect and a lower toxicity than the previously known 1,5-disubstituted barbituric acids, but also have a uricosuric effect.

1,5-disubstituted ones have already been used by the applicant Barbituric acids including 1-cyclohexyl-5-butylbarbituric acid and their alkali or alkaline earth salts which are not only very high in anti-inflammatory properties Effect, but also have much fewer undesirable side effects than known anti-inflammatory agents such as adrenocorticotrope Hormones such as B. prednisolone or triamcinolone, pyrazolidine derivatives, e.g. B. phenylbutazone, Oxyphenbutazone and 1,4-diphenyl-3,5-dioxopyrazolidine. Further investigations on this series of compounds led to the finding that - cyclohexyl - 5 - (4 - hydroxy - η - butyl) - barbituric acid and 1 - cyclohexyl - 5 - (3 - hydroxy - η - butyl) - barbituric acid Metabolites of l-cyclohexyl-5-n-butylbarbituric acid and that these metabolites and their related compounds, e.g. 1-cyclohexyl- - (3 - oxobutyl) - barbituric acid and 1 - cyclohexyl-5- (3 - carboxy propyl) - barbituric acid, not just one uricosuric effect, but also a strong anti-inflammatory effect and lower toxicity as l-cyclohexyl-5-butylbarbituric acid.

The invention accordingly relates to compounds of the general formula I

R-CH

CO-N

CO-N

CO

QH ₁₁

in which R denotes 4-hydroxy-n-butyl, 3-hydroxy-n-butyl, 3-carboxypropyl or 3-oxobutyl radical means and their alkali or alkaline earth salts. These compounds not only have equally high levels of anti-inflammatory properties Effect like 5-n-butyl-l-cyclohexylbarbituric acid, rather, fewer undesirable side effects (e.g. toxicity) than the latter. Furthermore, they are Valuable agents for the treatment of arthritis due to their uricosuric effect. The invention thus comprises a group of valuable barbituric acid derivatives which are used for the therapy of arthritis and as Non-steroidal anti-inflammatory agents of low toxicity are used in processes for their manufacture and pharmaceutical preparations made from one of the aforementioned new barbituric acid derivatives and pharmaceutically harmless excipients exist.

The compounds of general formula I according to the invention can be prepared in various ways will.

A (a) Of the compounds of the general formula I, that in which R is a 3-carboxypropyl radical can be used means in a manner known per se by reacting malonic acid derivatives of the general Formula II with cyclohexylurea and subsequent hydrolysis of the product thus obtained are produced:. · ■ · ■ · ■■

NH ₂ -

A '- (CH ₂ ) ₃ - CH

Hydrolysis.

COR ₃ QH ₁₁ NH

CO

CO-NH

> HOOC- (CH ₂ ) ₃ -CH CO

CO-N

QH ₁₁

A 'here denotes an alkoxycarbonyl radical, e.g. B. the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl radical, an aryloxycarbonyl radical, e.g. B. the phenyloxycarbonyl radical or the naphthyloxycarbonyl radical, or an aralkyloxycarbonyl radical, e.g. B. the benzyloxycarbonyl radical, B the cyano group or the —COR ₃ group and R ₃ an alkoxy radical, e.g. B. the methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy radical, an Aryloxyrest.z. B. the phenyloxy radical or an aralkyloxy radical, e.g. B. the benzyloxy radical.

(b) The compound of the general formula I in which R is a 4-hydroxy-n-butyl group can in a manner likewise known per se from malonic acid derivatives of the general formula III and cyclohexylurea can be produced by subsequent hydrolysis of the reaction product:

NH,

^) - O- (CH ₂ J ₄ -CH

COR ₃ C ₆ H ₁₁ NH (III)

hydrolysis

CO-NH

HO - (CH ₂ ) ₄ - CH

CO

CO N

QH ₁₁

B and R ₃ have the meaning already mentioned.
In methods A (a) and A (b), compounds of the general formulas II and III are preferably used in which both B and - COR ₃ low molecular weight alkoxycarbonyl radicals,

z. B. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl radicals.

Processes A (a) and A (b) can be carried out at room temperature, however, the Reaction usually accelerated by heating; a low molecular weight solvent is usually used as the solvent aliphatic alcohol, e.g. B. methanol, ethanol, propanol or t-butanol, but can also any other solvents can be used as long as they do not interfere with the reaction process. Of furthermore, the reaction is expediently carried out in the presence of a condensation catalyst. Suitable Condensation catalysts are, for example, alkali metal alcoholates, e.g. B. sodium methylate, potassium methylate, Sodium ethylate, potassium ethylate, alkali metals, e.g. B, sodium or potassium, magnesium, Magnesium alcoholate, e.g. B. magnesium methylate, magnesium ethylate. This creates an intermediate connection. In the case of reaction A (a), an intermediate of the general formula IV

CO-NH

A '- (CH ₂ ) ₃ - CH CO

CO N

I.
QH ₁₁

in the A 'has the same meaning as in the general formula II, while in the Reaction A (b) the intermediate product formed has the formula · ■

, CO-NH

7O - (CH ₂ ) ₄ -CH ... CO

CO -N

QH ₁₁

having.

The hydrolysis of these intermediates is carried out in a manner known per se, e.g. B. by Treatment with mineral acids (e.g. hydrochloric acid, sulfuric acid or phosphoric acid) or cation exchange resins.

The starting material of the general formula II for process A (a) can, for example, by Implementation of a malonic acid derivative of the general formula V.

H ₇ C

(V)

COR ₃

X-CH ₂ -CH ₇ -CH ₂ -A '

(VI)

in which B, R ₃ and A 'have the same meaning as in general formula II and X is a halogen atom, e.g. B. means a chlorine, bromine or iodine atom, at an elevated temperature in the presence of a solvent, e.g. B. a low molecular weight aliphatic alcohol such as methanol or ethanol, advantageously using a condensation catalyst, e.g. B. an alkali metal alcoholate, such as sodium methylate, sodium ethylate, potassium methylate or potassium ethylate, can be produced.

The starting material of the general formula III for process A (b) can, for example, by following reactions can be produced:

(1) HO - (CH ₂ ) * - X +

- (CH ₂ J ₄ - X + CH ₂

COR,

HO - (CH ₂ ) ₄ - CH

COR,

(3) HO - (CH ₂ ) ₄ -CH

COR,

(III)

B, R ₃ and X have the same meaning as in the general formulas V and VI. Reactions (1) and (3) are expediently carried out in the presence of a mineral acid, such as hydrochloric acid or sulfuric acid, at room temperature or with heating. The reaction (2) is expediently carried out at room temperature or with heating in the presence of sodium iodide. In carrying out these reactions, a solvent, e.g. B. ether, dioxane, toluene or xylene, are used.

B. The compound of general formula I, in which R is a 3-oxobutyl group, can after a the following two methods known per se:

(a) Conversion between methyl vinyl ketone and 1 -Cy clohexy lbar bituric acid.

and a 4-halobutyric acid derivative of the general Formula VI

CO-NH

H ₇ C

CO + CH, COCH = CH ₂

CO N

QH ₁₁

CH ₃ COCH ₂ CH ₂ - He '

CO-NH

CO N

QH ₁₁

The reaction can be carried out at room temperature, but heating is preferably carried out to about the boiling point of the solvent used or a little below. The solvent used for the reaction is usually a low molecular weight aliphatic alcohol such as methanol, ethanol or t-butanol, but ether, benzene, dioxane, ethyl acetate and other solvents can also be used as long as they do not interfere with the course of the reaction. If appropriate, the reaction can also be carried out without a solvent. In this case, the reaction is accelerated also by heating to about 10O ⁰ C.

The reaction is expediently carried out in the presence of a condensation catalyst. Suitable Condensation catalysts are, for example, alkali metal hydroxides, e.g. B. Sodium Hydroxide or Potassium Hydroxide, Alkali carbonates, ζ. Β. Sodium or potassium carbonate, organic bases, e.g. B. triethylamine or pyridine, alkali metals, e.g. B. sodium or potassium, alkali alcoholates, e.g. sodium methylate, potassium methylate, Sodium ethylate or potassium ethylate.

(b) reaction between a compound of general formula VII and cyclohexylurea and subsequent hydrolysis of the reaction product

CH ₂ -CH ₂

OO COR ₃

CH ₃ -C-CH ₂ -CH ₂ -HC + NH ₂ CONHQH ₁₁

COR ₃

CO-NH

/ \
► CH ₃ COCH ₂ CH ₂ HC CO

CO N

QH11

Here, R _{3 has} the same meaning as in general formula II.

(VII)

The starting material of the general formula VII can, for example, by reacting malonic acid or an ester and methyl vinyl ketone and subsequent reaction of the product obtained be made with ethylene glycol. In this process [B (b)], the reaction is preferably carried out in Carried out in the presence of a condensation catalyst. Suitable condensation catalysts are for example alkali alcoholates, e.g. B. sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, Magnesium alcoholates, e.g. B. magnesium methylate or magnesium ethylate, alkali metals, e.g. B. Sodium or potassium or magnesium sodium amide. The reaction is usually accelerated by heating. It is generally in a low molecular weight aliphatic alcohol such as methanol, Ethanol, propanol, or butanol, but any other solvent can be used as long as they do not interfere with the reaction process. The solvent should be appropriate be as dry as possible. The malonic acid ester derivative is preferably a low molecular weight alkyl ester, z. B. a methyl ester, ethyl ester or propyl ester, so that the reaction proceeds smoothly, but can of course optionally also other esters, e.g. B. phenyl esters, benzyl esters or higher molecular weight alkyl esters, be used.

(c) The compound of the general formula I in which R denotes the 3-hydroxybutyl group can by reduction of 5- (3-oxobutyl) -l-cyclohexylbarbituric acid, which is produced by reaction B (a) or B (b) is obtained, can be produced in a manner known per se:

CH ₃ - CO - CH ₂ - CH ₂ - HC

CO-NH

CO N

CO

OH CO-NH

CH ₃ -CH-CH ₂ -CH ₂ -HC CO

CO N

The reaction can be carried out in the presence or absence of a solvent by a A reducing agent is added to the reaction system or hydrogen gas is added to the reaction medium in the presence a suitable catalyst is initiated. Any suitable reducing agent can be used for example a metal and an alcohol (as metal e.g. sodium, calcium, potassium, lithium, Aluminum amalgam, magnesium, zinc, sodium amalgam, magnesium amalgam or aluminum amalgam and as alcohol z. B. methanol or ethanol) or a metal together with an alkali hydroxide, z. B. the metals aluminum, zinc or aluminum amalgam with sodium or potassium hydroxide, as well Aluminum isopropoxide and isopropyl alcohol, tin (II) chloride, iron (II) chloride, complex metal hydrides, z. B. lithium aluminum hydride, sodium borohydride or potassium borohydride.

Suitable catalysts for the catalytic reduction are, for example, platinum catalysts, e.g. B. Platinum sponge, platinum black, platinum sheet, platinum oxide or colloidal platinum, palladium catalysts, z. B. colloidal palladium, palladium sponge or palladium black, nickel catalysts, e.g. B. reduced Nickel, nickel oxide, Raney nickel or Urushibara nickel, or other metals or compounds of the metals cobalt, copper, iron, molybdenum, tungsten or zinc, catalysts made from two or more of the above metals and / or metal compounds consist (i.e. binary catalysts, multicomponent catalysts, or alloy catalysts). The above-mentioned catalysts are also suitable as supported catalysts, eg. B. on diatomaceous earth, Clay, activated carbon, silicon dioxide, aluminum oxide or asbestos. Theoretically, 1 mole Hydrogen per mole of barbituric acid used of the barbituric acid derivative used during the Reaction started, but the hydrogen in excess can be introduced into the reaction system will.

The solvents used for the reaction are preferably alcohols, e.g. B. methanol or ethanol or Ether, e.g. B. diethyl ether, dioxane or tetrahydrofuran is used, but any others can be used Solvents are used as long as they do not interfere with the reaction. The reaction can be both at Room temperature as well as with heating. You can optionally at normal pressure be performed.

The reaction is expediently carried out under neutral or alkaline conditions.

The barbituric acid derivatives of the general formula I can be in the form of the free acid or in the form of the alkali or alkaline earth metal salts, such as. B. the sodium, potassium, ammonium, calcium or magnesium salt can be isolated. The free acids and their alkali or alkaline earth salts can easily be converted into one another. For example, the free acid can be converted into a salt by adding to the acid an alcoholic or aqueous medium which contains approximately the equivalent amount of the base desired for salt formation, concentrating the mixture and / or cooling it. A salt can be converted to the free acid by neutralization with an acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid, or with cation exchange resins.
The following examples illustrate the invention:

example 1

1.2 parts by weight of metallic sodium were dissolved in 50 parts by volume of absolute methanol, whereupon the methanol was distilled off. 15.8 parts by weight of 4- (2-tetrahydropyranyloxy) butylmalonic acid diethyl ester were added to the residue obtained (Boiling point 121 to 123 ° C / 0.53mmHg), 7.1 parts by weight of cyclohexylurea and 10 parts by volume of benzene.

The mixture was refluxed for 13 hours. After cooling, the reaction mixture was extracted with a small amount of water. the aqueous layer was treated with activated charcoal and then filtered. The filtrate was with Hydrochloric acid acidified, which formed a precipitate, which was separated off and in a mixture of 20 parts by volume Ethanol and 20 parts by volume of sulfuric acid ^ normal) was dissolved. The solution was left to stand for 7 hours

209 529-586

left, with hydrolysis taking place. Ethanol was distilled off under reduced pressure and the The residue was dissolved in 50 parts by volume of water, crystals formed from a mixture of ethanol and water were recrystallized. Here were

7.2 parts by weight of 1 - cyclohexyl - 5 - (4 - hydroxy - η - butyl) barbituric acid obtained as colorless needles with a melting point of 121 ° C.

Elemental analysis: C ₁₄ H ₂₂ O ₄ N ₂ .

Calculated ... C 59.55, H 7.85, N 9.92%;
found .... C 59.63, H 7.78, N 10.1%.

Example 2

In 120 parts by volume of absolute ethanol were

2.3 parts by weight of metallic sodium dissolved. To the solution 24.2 parts by weight of 3-Carbäthoxypropylmalonsäurediäthylester were added (boiling point 150 to 160 ⁰ C / 8 mm Hg) and 14.2 parts by weight of cyclohexylurea. The mixture was refluxed for 8 hours. Ethanol was then distilled off and the residue was dissolved in a small amount of water. The aqueous solution was treated with activated charcoal while cooling and then filtered. The filtrate was acidified with hydrochloric acid, a solid precipitating which was hydrolyzed with 20% hydrochloric acid. Water was added to the hydrolyzate. The mixture was allowed to stand, a solid forming which was recrystallized from a mixture of ethanol and petroleum ether. This gave 18.1 parts by weight of 1 - cyclohexyl - 5 - (3 - carboxypropyl) - barbituric acid as colorless, needle-shaped crystals with a melting point of 148 ° C.

35 Elemental analysis: C ₁₄ H ₂₀ O ₅ N ₂ · H ₂ O.

Calculated ... C 53.49, H 7.05, N 8.91%;
found .... C 54.00, H 6.96, N 8.82%.

Example 3

40

A mixture of 27.2 parts by weight of diethyl 3-ethylenedioxybutylmalonate, 14.2 parts by weight of cyclohexylurea, 5.4 parts by weight of sodium methylate and 10 parts by volume of absolute benzene was refluxed for 15 hours. The reaction mixture was diluted with 30 parts by volume of benzene and extracted with 200 parts by volume of water. The aqueous layer was treated with activated charcoal with cooling and then filtered. The filtrate was acidified with hydrochloric acid, with the formation of a precipitate, which was heated on a water bath with 100 parts by volume of 15% hydrochloric acid for 4 hours. After cooling the solid was filtered off and recrystallized from a mixture of ether and petroleum ether to give 4.5 parts by weight of 1-cyclohexyl-5- (3-oxo-butyl) barbituric acid 103 ⁰ C were obtained with a melting point as colorless prisms.

60 Elemental analysis: C ₁₄ H ₂₀ O ₄ N ₂ .

Calculated ... C 59.98, H 7.19, N 9.99%;
found .... C 59.87, H 7.19, N 9.80%.

B is ρ ie 1 4 ^6s

To a suspension of 1 part by weight of powdery Lithium aluminum hydride in 10 parts by volume of diethyl ether gradually became a solution of 1.3 parts by weight of the 1 - cyclohexyl - 5 - (3 - oxobutyl) - barbituric acid in 100 parts by volume of diethyl ether. The mixture was stirred for 6 hours and left to stand overnight. 5 parts by volume of ethyl acetate were added to the reduction product thus obtained. To 10 parts by volume of a saturated aqueous sodium sulfate solution were added for 1 hour and the mixture was filtered. The solid thus obtained was gradually dissolved in dilute hydrochloric acid with cooling and with Chloroform extracted. The chloroform was distilled off, the residue by column chromatography Purified on silica gel using chloroform as the eluant and from a mixture recrystallized from ether and petroleum ether, 0.7 parts by weight of 1 - cyclohexyl - 5 - (3 - hydroxy - η - butyl) barbituric acid with a melting point of 131 ° C.

Elemental analysis: C ₁₄ H ₂₂ O ₄ N ₂ .

Calculated ... C 59.55, H 7.85, N 9.92%;
found .... C 59.30, H 7.73, N 9.79%.

Example 5

A mixture of 48.2 parts by weight of 1-cyclohexylbarbituric acid, 64 parts by weight of potassium carbonate, 350 parts by volume of ethyl acetate and 17.5 parts by volume of methyl vinyl ketone was refluxed for 6 hours, during which time precipitation occurred. It was filtered and the residue was dissolved in 300 parts by volume of water. The aqueous solution was treated with activated charcoal while cooling and filtered. The filtrate was made slightly acidic with hydrochloric acid, whereby a precipitate was formed, which was filtered off and recrystallized from a mixture of ether and petroleum ether, 35 parts by weight of l-cyclohexyl-5- (3-oxobutyl) -barbituric acid as colorless prisms with a melting point of 103 ⁰ C.

Elemental analysis: C ₁₄ H ₂₀ O ₄ N ₂ ;

Calculated ... C 59.98, H 7.19, N 9.99%;
found .... C 59.87, H 7.19, N 9.80%.

Pharmacological examination

The barbituric acid derivatives of the invention have some interesting features, in particular with regard to the physiological effects and their chemico-physical properties.

1. One of the characteristic properties of the compounds of the invention is their low level Toxicity, as can be seen from the following experiments.

A tragacanth emulsion of each test compound was given intraperitoneally or orally to mice (dd strain) weighing 14 to 15 g. The LD ₅₀ and 95% safety limits were calculated by the Litchfield-Wilcoxon method from the number of mice that died within 24 hours of the ingestion.

The results are shown in Table 1. It can be concluded from this that the compounds according to the invention are considerably less toxic than not only phenylbutazone or aminophenazone, but also as l-cyclohexyl-S-in-butyO-barbituric acid.

Table 1

Test connection

LD ₅₀ (95% SG) mg / 10 g in mice

intraperitoneally

orally

1-Cyclohexyl-S - '^ - hydroxy-n-butyl-barbituric acid

l-Cyclohexyl-5- (3-oxobutyl) barbituric acid

1 -Cyclohexy 1- 5- (3-hydroxy-n-butyl) barbituric acid

l-Cyclohexyl-5- (n-butyl) barbituric acid

Phenylbutazone (4-butyl-1,2-diphenylpyrazolidine-3,5-dione)

Aminophenazon (2,3-dimethyl-4-dimethylaminol-phenyl-3-pyrazolin-5-one)

8.10 (7.94 to 8.27)

9.6 (8.60 to 10.70)

9.1 (7.90 to 10.40)

3.31 (2.88 to 3.81)

2.20 (1.94 to 2.49)

2.69 (2.50 to 2.82)

32.3 (25.8 'to 40.4)

6.45 (5.56 to 7.49)

3.90 (3.34 to 4.57)
4.38 (4.14 to 4.64)

2. The invention was also found to be injected subcutaneously. The percentage of maximum connections an excellent inflammatory inhibition of the edema compared to the have an anti-manure effect. In each case 50 or 100 mg of 20 control animals were given for each test compound Test compounds per kilogram were intrameasured. The results are shown in Table 2, peritoneal male rats (Wister strain), which can be seen from the that the Ver-130 weighed up to 180 g, injected. 30 minutes after the bond and l-cyclohexyl-5- (n-butyl) barbitur injection Acid in these rats as well as control animals had a stronger anti-inflammatory effect through the hind paw 0.05 ml of a 1% aqueous 25 show as phenylbutazone. Carrageenin solution that causes inflammatory udema

Table 2

Test connection inhibition the swelling + 3 l-cyclohexyl-5- (4-hy- + 2 droxy-n-butyl) -bar- bituric acid + 3 *) + 3 l-cyclohexyl-5- (3-oxo- butyl) barbituric acid + 4 *) +4 +3 l-cyclohexyl-5- (3-hy- droxy-n-butyl) - barbituric acid + 4 *) +4 +3 l-Cyclohexyl-5- (n-butyl) - barbituric acid + 3 *) + 3 *) +3 +4 Phenylbutazone + 2 *) Aminophenazone + 1 *)

Remarks

+ 1 = 15 to 25% inhibition.
+ 2 = 26 to 50% inhibition.
+ 3 = 51 to 65% inhibition.
+ 4 = inhibition more than 65%.
*) = injected amount 50 mg, otherwise 100 mg.

3. Finally, it was found that the compounds according to the invention have excellent uricosuric properties Have an effect. As in the report by Br ο d i e s (cf. Soc.Exp.Biol. Medi., Vol. 86, p. 884 [1954]), described, the uricosuric effect is comparable to the ability to retain phenolsulfophthalein in the circulation. The uricosuric effect of the compounds according to the invention was thus determined by their ability to retain phenolsulfophthalein in rabbits' circulatory systems a method by Kreppel (see Med.exp., Vol. 1, P. 285 [1958]), was measured as follows:

Groups of three adult rabbits (1.9 to 2.4 kg, male) received the test compound intraperitoneally in the amount of 100 mg / kg. Received 15 minutes after injection of test compound each rabbit intravenously phenolsulfophthalein (75 mg / kg, 1.5% solution in 0.9% saline). Blood samples were cardicentesis for 30 minutes, 1 hour, 2 hours and 3 hours, respectively Taken after the injection of the phenolsulfophthalein. The concentration of phenolsulfophthalein in the blood was πΐμ at 560 in a Hitachi spectrophotometer (Hitachi Ltd., Tokyo, Japan) and calculated as y / ml blood. The results are listed in Table 3, from which it can be seen that the compounds according to the invention are excellent have uricosuric effects.

. Table 3

Test connection 30 min. Reluctance to
(y / ral
IStd. 'henolsulfophthalein
Blood)
2 hours. 3 hours. l-Cyclohexyl-5- (4-hydroxy-n-butyl) -
barbituric acid
l-Cyclohexyl-5- (3-hydroxy-n-butyl) -
barbituric acid
l-Cyclohexyl-5- (3-oxobutyl) -
barbituric acid
control 97.5 ± 21.5
116.0 ± 12.3
136.5 ± 30.0
67.5 + 6.3 37.7 ± 13.8
46.0 ± 7.8
58.0 ± 8.5
27.0 ± 5.4 30.0 ± 15.5
25.5 ± 16.5
24.5 ± 8.5
7.0 ± 2.7 ¹ 12.5 ± 7.5
14.0 ± 5.8
13.0 ± 8.0
1.5 ± 1.0

The compounds according to the invention can be used alone or in combination with pharmaceutically acceptable ones Adjuvants are administered.

Claims (1)

Patent claims: 1. 1-Cyclohexylbarbituric acid derivatives of the general Formula I. O H R-CH C-N