DE1215716B - Process for the preparation of thiobarbituric acid derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Int. CL:

C07d

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12 ρ -7/01

Number: 1215 716

File number: H 46365IV d / 12 ρ

Filing date: July 13, 1962

Opening day: May 5, 1966

The invention relates to a process for the preparation of thiobarbituric acid derivatives of the general formula

11 C -

Il O

C = S

(I)

Ri \ / Rs

OR ₄

(Π)

wherein Ri is an alkyl radical having 11 to 18 carbon atoms and R2 is a saturated or unsaturated, optionally substituted by halogen atoms, means lower aliphatic or cycloaliphatic radical, as well as their alkali and calcium salts.

The radical Ri in the above formula preferably represents a pentadecyl, myristyl, tridecyl or lauryl radical.

The remainder of Ra can be straight or branched lower ones Represent alkyl, alkenyl or alkynyl radicals, e.g. B. the methyl, ethyl, propyl, isopropyl, butyl, Isobutyl or hexyl radical, the vinyl, jS-methylallyl, ^, y-dimethylallyl, propenyl or especially the Allyl radical or the propargyl radical. An example of a halogen-substituted radical R2 is / S-bromoallyl. Examples of saturated and unsaturated lower cycloaliphatic radicals are cyclohexyl and the cyclohexen- (2) -yl radical.

The method is characterized in that in a known manner a compound of general formula

where R3 is a nitrile or carbalkoxy group and R4 is a lower alkyl group and Ri and R2 have the above meaning, condensed with thiourea, and, if one of a compound II started out, in which R3 denotes a nitrile group, the 4-imino-thiobarbituric acid derivative obtained through Treat with mineral acid hydrolyzed.

One embodiment of the condensation according to the invention consists in that the starting components in a suitable organic solvent, for. B. a lower alcohol such as methanol or ethanol, in the presence of an alkaline condensing agent, e.g. B. sodium alcoholate, process for the preparation of
Thiobarbituric acid derivatives

Applicant:

F. Hoffmann-La Roche & Co.

Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr. G. Schmitt, lawyer,

Loerrach (Bad.), Friedrichstr. 3

Named as inventor:

Dr. Peter Fahrni, Binningen;

Dr. Walter Mosimann,

Dr. Otto Schnider, Basel (Switzerland)

Claimed priority:

Switzerland of September 29, 1961 (11 356)

lets react. It is advantageous for increased Temperature worked, e.g. B. at the boiling point of the reaction mixture. However, the reaction works too at lower temperatures in front of you. ' It is appropriate to allow condensation to occur at 50 to 70 ° C. Depending on the temperature and substituents the reaction time varies between ½ to 3 hours or more. The thiobarbituric acid formed becomes after dilution with water or after distilling off the solvent and dissolving the residue in water by adding acid, e.g. B. a mineral acid or acetic acid, in freedom set. It is isolated by filtration or extraction with an organic solvent.

The hydrolysis of any 4-imino-thiobarbituric acid which may be obtained after the condensation takes place z. B. by refluxing the equivalent amount of dilute aqueous hydrochloric acid.

The new thiobarbituric acids of the general formula I can be crystallized from organic solvents Compounds which, due to their acidic character, are able to convert alkali salts, e.g. B. Sodium or calcium salts. The alkali salts are z. B. prepared so that the thiobarbituric acid dissolves in a suitable alcohol and reacts with an alkali alcoholate or with aqueous alkali

609 567/520

tion and brings it to the separation by adding a suitable solvent. The calcium salts can e.g. B. obtained from the sodium salts by double reaction with calcium chloride will.

Some of the starting products (for the manufacture of which protection is not sought) are known Compounds, some of which are compounds made by methods known per se, e.g. B. by alkenylation and / or alkylation of dialkyl malonates or alkyl cyanoacetates can be. A preferred class of starting compounds II, namely the allyl-alkyl-malonic acid diethyl ester, are expediently prepared in such a way that diethyl malonate is first used with an alkyl halide (e.g. an alkyl bromide) in the presence of sodium alcoholate to the alkylmalonic acid diethyl ester, which is then converted into carbonic acid diethyl ester as the sodium salt with allyl bromide is reacted as a solvent.

The products of the process have a valuable therapeutic and prophylactic effect against Viral infections, e.g. B. against influenza viruses, and can therefore be used as a remedy, e.g. B. in the form of pharmaceuticals Preparations, find use.

To prove the superiority of the process products over a 'known reference substance the two compounds 5-allyl-5-myristyl-2-thiobarbituric acid obtained by the process according to the invention (A) and 5 - (/? - bromoallyl) -5-myristyl-2-thiobarbituric acid (B) compared with the known and already used to combat Influenza A, Asia used Nj- [morpholino (iminomethyl)] guanidine hydrochloride (C) tested for virulicidal effect on the mouse using the following method:

There were white inbred mice in groups of ten animals (weight 14 to 17 g) per preparation with 0.05 ml of a suspension of influenza A, Asia virus (dilution 10 ^-4 in Gewebekulturnährmedium) infected intranasally. The infection dose corresponded to about 100 times the DL 50 value.

The preparations to be tested were taken 1 hour before and 1, 5, 24, 30, 48 and 72 hours after infection administered orally. The activity of the preparations was determined on the 10th day by comparing the survival time of the treated animals with that of the untreated control animals on a percentage basis determined. The numerical values obtained are compiled in the following table:

55

60

substance dose
. mg / kg p. 0. Average
"Effectiveness on
10th day (° / o) A. 7-125 51 B. 7 125 23 C. 7-400 2 example 1

agitated solution. Then 80 g of allyl myristyl malonic acid diethyl ester are added. The whole is at a Bädtemperatur of 6O ⁰ C as long allowed to react under stirring, until a sample of the batch clearly dissolved in water, which after about one hour, the should fall. Danach is poured onto ice, adjusted to pH 5 with acetic acid and extracted with ether. After the ethereal layer has been separated off, it is extracted by shaking with sodium bicarbonate solution and then with saturated sodium chloride solution, dried and concentrated. There remains behind a thick oil, which is dissolved in petroleum ether (boiling point 60 to 90 ⁰ C) in the heat. After filtering and cooling the solution, 58 g of 5-allyl-5-myristyl-2-thiobarbituric acid with a melting point of 78 to 79 ^° C. crystallize out.

In an analogous manner, using the corresponding substituted malonic acid esters (cf. Table 2) the compounds listed in Table 1 are established:

Table 1

-2-thiobarbituric acid F. ( ⁰ C) S-allyl-S-undecyl- 84 to 86 S-allyl-S-lauryl- 68 to 69 S-allyl-S-tridecyl- 68 to 70 S-allyl-S-pentadecyl- 74 to 75 5-allyl-S-cetyl- 69 to 71 S-methyl-S-myristyl- 100 to 104 5-n-butyl-5-myristyl 41 to 43 S-n-propyl-S-myristyl- 69 to 71 S-isobutyl-S-myristyl- 75 to 77 S-ß-methylallyl-S-myristyl- 83 to 85 S-propargyl-S-myristyl- 103 to 105 S-Cyclohexyl-S-myristyl- .... 58 to 60 5- (| S-bromoallyl) -5-myristyl- 90 to 91 5-Cyclohexen- (2 ') - yl-5-myristyl- .. 61 to 64 Table 2 -malonic acid diethyl ester Bp ° C / mmHg

23.2 g of thiourea are added to a solution of 16.3 g of sodium in 162 ml of absolute methanol added, and the mixture is

Allyl myristyl

Allyl undecyl

Allyl lauryl

Allyl tridecyl

Allyl pentadecyl

Allyl cetyl

Methyl myristyl

n-butyl myristyl

n-propyl myristyl

Isobutyl myristyl

ß-MethylaUyl-myristyl- ...

Propargyl myristyl

Cyclohexyl myristyl

jS-Bromallyl-myristyl- ....
Cyclohexen- (2) -yl-myristyl-

170 / 0.025

170 / 0.15

157 / 0.15

170 / 0.02

175 / 0.07

190 / 0.2

177 / 0.3

174 / 0.1

155 / 0.07

153 / 0.02

170 / 0.02

186 / 0.25

200 / 0.4

190 / 0.07

195 / 0.04

Example 2

8.4 g of dry thiourea are added to a solution of 4.6 g of sodium in 100 ml of absolute ethanol at a temperature of 40 ° C., and the mixture is stirred until it dissolves. Then is added 32.1 g of a-allyl-a-cyano-myristinsäureäthylester (boiling point 157 ° C / 0, l mm Hg) and stirred for 24 hours at 60 to 8O ⁰ C. internal temperature. It is then poured onto ice, stirred with acetic acid, taken up in ether, the ethereal layer washed with water, dehydrated over sodium sulfate and concentrated. The residue, recrystallized from alcohol, provides 23.5 g of 5-allyl-5-lauryl-2-thio-4-iminobarbituric acid of melting point 228 to 23O ⁰ C (decomposition) represents.

2.35 g of 5-allyl-5-lauryl-2-thio-4-imino-barbituric acid are refluxed in 6.4 ml of water and 7.0 ml of 1N hydrochloric acid for 48 hours. After cooling, it is taken up in ether, the ethereal layer is washed neutral with bicarbonate solution, dried and evaporated. The residue is recrystallized from petroleum ether (boiling range 60 to 9O ⁰ C). In virtually quantitative yield is 5-allyl-5-lauryl-2-thiobarbituric acid of melting point 68-69 ⁰ C obtained which is identical with the compound prepared according to the procedures of Example 1 5-allyl-5-lauryl-2-thiobarbituric acid.

Claims (1)

Claim: Process for the preparation of thiobarbituric acid derivatives of the general formula I. C = S in the Ri an alkyl radical with 11 to 18 carbon atoms and R2 is a saturated or unsaturated one, optionally with halogen atoms substituted, lower aliphatic or cycloaliphatic radical, and their alkali and calcium salts, characterized that in a known manner a compound of the general formula II Rr
R ₂ 'R ₃
COOR ₄ in which R3 denotes a nitrile or carbalkoxy group and R4 denotes a lower alkyl group, with thiourea condensed and, if one started from a compound, in the R3 a nitrile group means the 4-imino-thiobarbituric acid derivative obtained by treatment with mineral acid hydrolyzed and optionally then the compound of formula I obtained in an alkali salt or the calcium salt transferred. (Π) Considered publications:
German interpretative document No. 1 059 464. 609 567/520 4.66 © Bundesdruckerei Berlin