DE1237577B - Process for the production of barbituric acid derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Int. Cl .:

C07d

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 ρ -7/01

Number: 1237 577

File number: S71389IVd / 12p

Filing date: November 23, 1960

Open date: March 30, 1967

The invention relates to a process for the preparation of therapeutically useful barbituric acid derivatives.

It is known that many derivatives of barbituric acid, commonly referred to as barbiturates, have a sedative and narcotic effect. However, the toxicity of these compounds is in many Cases quite high, i.e. that is, that large doses cannot be given with certainty, or that undesirable side effects can occur during administration. Ideally it should be a sedative or sleeping pills as high a therapeutic index as possible (ratio of therapeutic Toxicity activity) so that large doses can be safely given if necessary can, with no noticeable side effects occurring even with moderate doses.

It has now been found that barbituric acid derivatives of the general formula I listed below in generally have a considerably higher therapeutic index than known barbiturates, e.g. B. 5-phenyl-5-ethylbarbituric acid, as it has a high therapeutic activity, e.g. B. as an anticonvulsant, however, have very low toxicity. The new compounds can be used in medicine for those Purposes are used for which the barbiturates were previously used; therefore they are excellent Sedatives and sedatives and generally have anticonvulsant effects, which makes them suitable for use in the treatment of epilepsy.

The process according to the invention for the preparation of barbituric acid derivatives of the general formula I CH ₂ - R ₁

IOR ₄ CH - R ₂ 1 I.

Process for the production of
Barbituric acid derivatives

Applicant:

Sapos SA, Geneva (Switzerland)
Representative:

Dr. F. Zumstein, Dr. E. Assmann

and Dr. R. Koenigsberger, patent attorneys,

Munich 2, Bräuhausstr. 4th

Named as inventor:

Philippe Gold Aubert, Geneva (Switzerland)

Claimed priority:

Great Britain 23 November 1959 (39 718)

CH ₂

-N

Y
O

—N
H

R ₃
O

wherein Ri represents a halogen atom or a group - OZ, where Z is optionally replaced by a Alkoxy group substituted saturated or an unsubstituted unsaturated aliphatic radical or an aryl or aralkyl group or a group

-CO-N (Yi) Y ²

in which Y ¹ and Y ² symbolize hydrogen atoms or alkyl groups, R ₂ a hydroxyl group or the group defined above - OZ, R4 and Rs mean aliphatic, saturated or olefinically unsaturated radicals or aryl or aralkyl groups, consists in that in per se known manner a compound of the general formula

Ri-CH ₂ -CH (R ₂ ) -CH ₂ -Hal II

wherein Hal represents a halogen atom, with a compound of the general formula

Rix / CO n {

V \ Vo ΠΙ

Ra ^xx CO-HN ⁷
wherein M is a metal atom, reacted and optionally a hydroxyl group present by treatment with a carbonyl halide and subsequent treatment with a compound of the formula HN (Yi) Y ²
in the group

- O - CO - N (Y ¹ ) Y ²

is convicted.

Preferably this reaction is carried out by simply heating the barbiturate salt and of the halohydrin derivative with one another, optionally in the presence of an inert solvent. the Purification of the reaction product is generally not easy; however, it was found to be less difficult to perform if the reaction is carried out in the absence of a solvent and treating the product with water first to remove the metal halide salt, and then

709 547/411

after with an organic solvent, preferably ether, in which the desired process product is soluble. The solution in the organic The solvent is then dehydrated, the solvent is evaporated and the excess of the starting compound of the general formula II is distilled off. If the remaining process product at very low pressure and at a Temperature below the decomposition temperature of the desired product of the fractional distillation is subjected, it is found that a separation of the desired product from the unreacted barbiturate is easily achievable.

Compounds of the above general formula I, specifically due to their favorable activity and of the therapeutic index are preferred are those in which Ra is a hydroxyl group or preferably represents a carbamyloxy group.

Alkoxy groups for Ri, preferably with 1 to 10 carbon atoms, are e.g. B. a methoxy, ethoxy, n- or iso-propyloxy, butyloxy, amyloxy or hexyloxy group. As an alkenyloxy group z. B. an allyloxy group, as an alkynyloxy group z. B. a propargyloxy group and as a halogen atom, for example, a chlorine or bromine atom for Ri; Examples of one or both radicals Y ¹ and Y ² are, in addition to the hydrogen atom, the methyl, ethyl, n-propyl and isopropyl groups. The group Ri can also be a benzyloxy group or a group

-O (CH ₂ ) _n OX

where η is an integer from 1 to 6 and X is a lower alkyl group.

R4 and Rs are preferably alkyl groups having 1 to 6 carbon atoms, e.g. B. methyl, ethyl, η-propyl or isopropyl groups; the allyl group may be mentioned as the alkenyl group and the phenyl group as the aryl group. Particularly preferred compounds are those in which both radicals R4 and R5 are ethyl groups or allyl groups or in which R4 is a phenyl group and R _{0 is} an ethyl group.

The preferred compound obtained according to the invention is 5-phenyl-5-ethyl-3 - (/ S-carbamyloxyy-butoxypropyl) -barbituric acid.

It has been found that a suitable daily dose of the process products is between 50 and 500 mg and is preferably between 100 and 200 mg.

The superiority of the process products over the well-known 5-phenyl-5-ethylbarbituric acid, which, among other things, is also known under the abbreviation »Phenobarbital«, is used in the following Comparative tests proven in both animal and clinical trials.

I. Animal experiments

The compounds obtainable according to the invention , 5-phenyl-5-ethyl-3-(β -hydroxy- γ- propargyloxy-propyl) -barbituric acid, designated "S 1067" in the table, were 5-phenyl-5-ethyl-3 - (/ S-carbamyloxy-y-chloropropyl) -barbituric acid, referred to in the following table as "S 762", 5-phenyl-5-ethyl- (ß - carbamyloxy - γ - bromopropyl) - barbituric acid, in the table as "S 765" labeled, and 5-phenyl-5-ethyl-3 - (^ - carbamyloxy-y-butoxypropyl) -barbituric acid, labeled "S 560" in the table, compared with phenylethylbarbituric acid (phenobarbital). The determinations of the tranquilizer effect were carried out according to the following methods:

1. Groups of five to ten guinea pigs were administered orally increasing doses of the comparison substances and the behavior of the Animals observed. It was considered sleep if the animal spontaneously assumed the lateral position or if it remained in the supine position, if the experimenter artificially found this position brought about. The spontaneous standing on the paws was accepted as an awakening.

2. To determine the potentiation of sleep induced by phenobarbital were orally 30 mg / kg phenobarbital to groups of five to ten guinea pigs and simultaneously administered increasing doses of the reference substances. It became the length of sleep between the Test animals and the animals that had received only phenobarbital, compared with the Total sleep duration in percent, based on 100 minutes of sleep, caused by phenobarbital, is specified.

3. The lethal dose LD50 was determined by oral administration of the test substances to the mouse.

The results are given in Table I below.

Table I.

Ver
same dose
mg / kg
per os attempt S 1067 S 762 Results
S 765 S 560 Phenolic barbital 1 10 Simple sleep (sea piggy) 0 minutes 9 minutes 20 minutes 0 minutes 30 minutes 20th the same 15 minutes 15 minutes 27 minutes 0 minutes 55 minutes 50 the same 15 minutes 50 minutes 5 minutes 185 minutes 2 Potentiation of the phenobar bital sleep (100 minutes Sleep at 30 mg / kg per os Phenobarbital) (sea piggy) duration duration duration duration duration 10 the same 51% 20th the same 106% 226% 150% 153% 50 the same 154% 287% 3 DLöo (oral in the mouse), mg / kg 750 600 250 1065 168

The results leave the surprising advantages of the process products both as a tranquilizer as also recognize as synergistic sleeping pills compared to the known phenobarbital: the one according to the invention The compounds produced have a significantly lower sleep-inducing effect than Phenobarbital, which is a particularly important feature for use as a tranquilizer, while, on the other hand, they greatly potentiate the sleep induced by phenobarbital, what is a decisive advantage because of its significantly lower toxicity. So has z. Legs Combination of 30 mg / kg phenobarbital and 30 mg / kg process product »S 560« at lower Toxicity same effect as more than 90 mg / kg phenobarbital, taking such high doses of phenobarbital rarely used because of their high toxicity and the risk of undesirable side effects could. The exceptionally low toxicity of the process products also opens them up also in other areas of therapy much greater application possibilities.

II. Clinical Trials

In clinical trials, the clear superiority of the process product designated as "S 560" 5-Phenyl-5-ethyl-3 - (/? - carbamyloxyy-butoxypropyl) -barbituric acid compared to the known Phenylethylbarbituric acid can be shown as an anti-titremor agent.

A total of 26 patients between the ages of 24 and 86 years with senile or drug-related disease Tremors were treated with the test substances (1 tablet three times a day) and the anti-tremor effect assessed according to clinical criteria ("good, low, none, bad").

The test subjects were eleven patients with predominantly senile tremors, fourteen Patients with drug-induced tremor and one patient with alcoholic tremor.

The results are summarized in Table II.

The results show that the well-known 5-phenyl-5-ethylbarbituric acid (1 tablet »0.015« noon, medication for 14 days), apart from the expected additional sedation, the tremor in no way affected.

The 5-phenyl-5-ethyl- 3- (ß- carbamyloxy- γ-butoxypropyl) -barbituric acid ("S 560") produced according to the invention, on the other hand, has a good and reliable effect on both senile and drug-induced tremors, some of them chronically ill patients showed a sudden improvement. In some cases, however, a psychotropic effect that was not yet clearly perceptible was found, such as loosening, improved attention and a slight, desired increase in drive.

The * combination of 5-phenyl-5-ethylbarbituric acid (»0.015«) + »S 560« (two times 1 tablet) shows apart of additional sedation, only the effect of the process product.

Table II

Attempt
person
No. tremor "S 560" Effect of
"S 560"
-t- 5-phenyl-5-ethyl-
barbituric acid 5-phenyl-5-ethyl
barbituric acid 3 senile Well Well no 4th senile Well 7th senile Well Well no 8th senile Well 10 senile canceled 11 senile small amount 18th senile Well 19th senile small amount 22nd senile Well 24 ' senile Well 25th senile no 9 alcohol-related Well Well no 1 drug-related small amount small amount no 2 drug-related small amount 5 drug-related 'Well Well no 6th drug-related Well Well no 12th drug-related Well no 13th drug-related Well 14th drug-related Well no 15th drug-related Well no I 16 drug-related Well 17th drug-related Well Well no 20th drug-related small amount 21 drug-related small amount 23 drug-related small amount 26th drug-related small amount

1 23

The following examples illustrate the invention. For the production of the starting materials, im Protection not sought within the scope of the present invention.

example 1

a) 5-phenyl-5-ethyl-3 - (/ ?, y-dihydroxypropyl) -

barbituric acid

25.4 g of sodium 5-phenyl-5-ethyl barbiturate (phenobarbitone sodium) are mixed with Ilg glycerol chlorohydrin heated in 100 ml of ethyl alcohol. After a while, some sodium chloride separates out, which after completion of the reaction, which requires 4 to 6 hours, is recovered quantitatively. To After filtering off the sodium chloride, concentrate by evaporating off the alcohol. You get a brown mass that is very sticky and rubbery and easily melts on a water bath.

Crystallization of the mass thus obtained is difficult, but the following procedure was found as suitable.

After the reaction product had been heated in vacuo to 150 ° C. for one hour in order to remove remaining traces of the chlorohydrin, the gummy residue was dissolved in 25 cm ^{3 of} boiling benzene. The solution is placed in the refrigerator for about 24 hours, after which a mass is obtained which is digested three times with cold benzene. The digested mass is dried in vacuo and the resinous material is taken up in 20 cm ^{3 of} ethyl alcohol and precipitated with dry ether. The precipitate is digested again with absolute ether in quantities of 3.5 cm ³ , taken up in ether and precipitated with water. At this stage a thick, colorless oil separates, which gives the following analysis:

Ci ₅ Hi ₇ NoO ₅ ; Molecular weight 305:
Calculated ... N 9.50%;
found ... N 10.01%.

Distillation under usually reduced pressure is impossible because the compound ^{decomposes at 230 °} C, so the oil is distilled using a diffusion pump at a vacuum of 0.05 mm. The compound distills slightly at 200 ° C without decomposition in the form of a colorless oil. When poured into a mortar, it results in a breakable glass-like mass which, when crushed, gives a powder with a melting point of 98 ° C. The yield is about 95%.

Analysis: C15H17N2O5; Molecular Weight305:
Calculated ... N 9.50%;
found ... N 9.46%.

The same procedure was applied to all compounds, their preparation in the following Examples are described with generally good results. The yields were found to be excellent. However, the distillation sometimes had to be repeated up to four or five times under high vacuum to obtain a product with a constant analysis.

b) 5-phenyl-5-ethyl-3 - (/ ?, y-dihydroxypropyl) -

barbituric acid dicarbamate

With the successive action of gaseous phosgene and gaseous ammonia on

7 577

an ethereal solution of the compound prepared according to a) gives a well crystallized, white powder, which can be recrystallized from acetone, with a melting point of 80 ° C

Analysis: C17H21N4O7; Molecular weight 393:

Calculated ... N 14.3%;
found ... N 14.37%.

B e i s ρ i e 1 2

5-phenyl-5-ethyl-3 - (/ miydroxy-y-methoxy-propyl) -barbituric acid

This connection can be produced as in Example 1, a). The connection has the same sticky properties like the compound produced in Example 1, a). By distillation under high vacuum a resin with a melting point of 37 ° C. and a boiling point of 205 is obtained up to 210 ° C (0.04 mm). The yield is 93%.

Analysis: C16H20N2O.5 ; Molecular Weight 312:

Calculated ... N 9.0%;
found ... N 9.24%.

Example 3

5-phenyl-5-ethyl-3 - (/ i-hydroxy-y-ethoxypropyl) barbituric acid

This connection can be produced as in Example 1, a). That by distillation under high vacuum product obtained is a cake-like material. It boils at 196 to 202 ° C (0.04 mm). It is obtained in a yield of 72%.

Analysis: C17H22N2O0; Molecular weight 334:

Calculated ... N 8.4%;
found ... N 8.48%.

Example 4

S-phenyl-S-ethyW-tjtf-hydroxy-y-n-propyloxypropyl) barbituric acid

This substance, prepared as in Example 1, a), is a rubber-like, colorless resin, which in Boils 198 to 200 ° C under 0.03 mm pressure. The yield is 60%.

Analysis: CigHoaNiO ₅ ; Molecular weight 348:

Calculated ... N 8.05%;
found ... N 8.07%.

Example 5

5-phenyl-5-ethyl-3 - (/ i-hydroxy-y-isopropyloxypropyl) barbituric acid

This compound has the same appearance as the compound according to Example 4 and distills at 190 ° C at a pressure of 0.03 mm. Obtained yield: 60%.

Analysis: C18H24N2O5; Molecular weight 348:

Calculated ... N 8.05%;
found ... N 8.06%.

ίο

Example 6

5-phenyl-5-ethyl-3 - (/ miydroxy-y-n-butyloxypropyl) barbituric acid

This substance has a boiling point of 203 ^° C. (0.05 mm) and is present as a transparent, sticky resin. They are obtained in a yield of 84%.

Analysis: Q9H26N2O5; Molecular weight 362:

Calculated ... N7.4%; found ... N 7.75%.

Example 7

5-phenyl-5-ethyl-3 - (/? - hydroxy-y-propargyloxy-

propyl) barbituric acid

This substance distills at 208 ° C. at 0.05 mm pressure and is obtained in a yield of 65%. It has the same rubbery properties as the previous compounds.

Analysis: C18H20N2O5; Molecular weight 344:

Calculated ... N 8.15%;
found ... N 7.98%.

25th

Example 8

5-phenyl-5-ethyl-3 - (/? - hydroxy-y-ethoxyethyloxypropyl) -barbituric acid

This substance has the same appearance as the previous compounds. She distills at 210 ° C (0.1 mm). They are obtained in a yield of 70%.

Analysis: C19H26N2O6; Molecular Weight 378: _J5 Calculated ... N 7.4%;
found ... N 7.01%.

Example 9

S-phenyl-S-ethyl-S-OS-hydroxy-y-benzyloxy) barbituric acid

The obtained substance is very sensitive to high temperature heating. During the distillation in vacuo, part of the product passes over between 220 and 225 ^° C. at a pressure of 0.05 mm. At 225 ^° C. the substance decomposes. The result is a brown, solid, brittle residue that is strongly piezoelectric. The yield of pure substance is no more than 17%.

Analysis: C22H24N2O5; Molecular weight 396:

Calculated ... N 7.06%;
found ... N6.40%.

55

Example 10

5-phenyl-5-ethyl-3 - (/? - hydroxy-y-phenoxypropyl) -barbituric acid

The substance is obtained in the form of a clear, yellow oil which is distilled in vacuo. The product obtained gives a white mass on cooling, which can easily be recrystallized from dilute alcohol after comminution. The powder obtained is piezoelectric and, when left in a flask, quickly forms a single mass like transparent glass. Yield: 75%; M.p. 63 ^° C

Analysis: C21H22N2O5; Molecular weight 382:

Calculated ... N 7.53%;
found ... N 7.53%.

Example 11
5-phenyl-5-ethyl-3 - (/ i-carbamyloxy -} '- butoxypropyl) barbituric acid

A. Preparation of the starting compound

a) Preparation of the acid chloride

150 g of i-hydroxy-a-butoxy- 7- chloropropane are mixed with 170 g of antipyrine base and 400 cm ^{3 of} chloroform at room temperature with thorough stirring. 560 ml of an approximately 20% solution of phosgene in toluene are added to the solution obtained, with constant stirring. The addition time should be about 8 hours and the internal temperature should be between 45 and 50 ° C. After this time the chloroform is driven off and the antipyrine hydrochloride that has formed is removed by filtration. By removing the toluene, the crude acid chloride (about 200 g) is then obtained, which is required for the next stage of production.

b) Carbamate of / ί-hydroxy-a-butoxy-7-chloropropane

About 200 g. Of added crude acid chloride and 800 ml of benzene. The mixture is then refluxed for 12 hours heated while a vigorous stream of ammonia gas is passed through the mixture. It part ammonium chloride is removed.

Then a lemon yellow color appears, which indicates the end of the reaction. The ammonium chloride is filtered off and the benzene is distilled off. The desired carbamate is obtained, which is obtained by distillation at reduced pressure at 160 ° C. under a pressure of 6 mm. It is a thick liquid that turns into an odorless and colorless oil, which has a melting point of 36.5 ° C after crystallization.

B. Production of the process product

100 ml of absolute alcohol is poured into a 500 ml flask and, with stirring, 16 g of sodium phenobarbitone admitted. The homogeneous suspension is heated to reflux and 12 g of the carbamate, that was prepared in A, b) are added drop by drop together with 100 ml of absolute alcohol admitted. The sodium chloride separates out when the addition is complete. The precipitation will washed with alcohol, evaporated the alcoholic fractions and proceeded with heating the oil, to complete the reaction. 300 ml of distilled water are then added, to wash off the excess sodium phenobarbitone, whereupon the product is then followed by Precipitation from the system dioxane-water is purified.

Analysis: C20H27N3O6; Molecular weight 405:

Calculated ... N 10.33%;
found ... N 10.33%.

709 547/411

Claims (1)

1 23 Example 12 Preparation of 5-phenyl-5-ethyl-3 - (/? - N-diethylcarbamyloxy-j'-methoxypropyl) barbituric acid A. Preparation of starting compound a) N-diethylchlorformamide This compound is prepared by at low temperature 50 g of diethylamine in 200 ml of toluene in 250 ml of a 20% solution of phosgene in toluene. After removing the hydrochloride formed from the amine, the toluene is distilled, a product being obtained which distills between 186 and 190 "C (20 Torr). 7 Example 14 5-Phenyl-5-ethyl-3 - (/ tf-diisopropylcarbamyloxyy- isobutyloxy-propyl) barbituric acid The analogously prepared N-diisopropyl carbamate of α-chloro-γ-isobutyloxy-propanol- (2) (bp 102 to 104 ° C. / 0.2 Torr) is condensed with sodium phenobarbitone as in the previous examples. The desired substance is obtained, which consists of a ίο thick, colorless, odorless oil that has no sticky properties. Analysis: C26H39N3O6; molecular weight 489: calculated ... N 8.59%; found ... N 8.50% b) N-diethyl carbamate of α-chloromethoxy-propanol- (2) 20 13.5 g of N-diethylchlorformamide are mixed with 12.5 g of (i-chloro-v-methoxypropanol- (2)) in the presence of a hydrogen chloride acceptor. By distilling the substance obtained in vacuo, an oil is obtained which distills between 99 and 104 ° C. (ITorr) iert. B. Preparation of the end product The substance prepared according to A, b) is condensed with sodium phenobarbitone as in the previous examples, for which purpose it is refluxed in an ethanol medium for 6 hours. After cleaning, a solid, white, crystalline substance is obtained that is about oily. is. It melts at 168 ° C. Analysis: C21H29N3O6; Molecular Weight 419: Calculated ... N 10.01%; found ... N 10.10%). Example 13 5-Phenyl-5-ethyl-3 - (// - carbamyloxy-y-chloropropyl) -barbituric acid To the melt of the carbamate of /? - hydroxy - «, y-dichloropropane (white powder , which melts slightly on the water bath) the required amount of sodium phenobarbitone is added and the mixture is heated on an oil bath to a temperature of 150 ° C. for about 8 hours until the reaction has ended. At this moment, three times the amount of distilled water is added with stirring, as is necessary to bring about the complete extraction of the excess of sodium phenobarbitone. The water is then removed and the mixture is distilled under very reduced pressure to obtain the compound which distills at 225 ° C. under a pressure of 0.03 torr. The substance obtained crystallizes into a brittle mass that melts at 80 ° C. Analysis: Ci6Hi8ClN3O5; Molecular Weight 367.5: Calculated ... N 11.42%; found ... N 11.05%. Patent claims: 1. Process for the preparation of barbituric acid derivatives of the general formula CH ₂ - Ri I OR ₄ wherein Ri is a halogen atom or a group - OZ represents, where Z is a saturated or optionally substituted by an alkoxy group an unsubstituted unsaturated aliphatic radical or an aryl or aralkyl group or a group - CO - N (Y ¹ ) Y ² in which Y ¹ and Y ² symbolize hydrogen atoms or alkyl groups, R2 is a hydroxyl group or the group defined above - OZ, R4 and Rs aliphatic, saturated or olefinically unsaturated radicals or aryl or Aralkyl groups, characterized in that in a known manner a compound of the general formula R ₁ -CH ₂ -CH (R ₂ ) -CH ₂ -Hal H wherein Hal represents a halogen atom, with a compound of the general formula / M R4 \ / CO n { / C \ / CO III Rs ^xx CO - hw wherein M is a metal atom, reacted and optionally a hydroxyl group present by treatment with a carbonyl halide and subsequent treatment with a compound the formula HN (Yi) Y ² in the group - O - CO - N (Y ¹ ) Y ²
is convicted.