DE2210503A1 - Pyrimidine derivatives, process for their preparation and their use - Google Patents

Description

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DR.-ING. TH. MEYER DR. FUiS Df FL.-SKStö. Αί £ Κ BY EiF ^ Jl'SiSR DlPL-CHEM. CAROLA KELlEK PlL-UMS, KLÜ ^ SC- 3I? L-iN @. ΙΙ1ϊη? 1 ©

5 COLOGNE!, DHlCi; .ViA; -:>;: - iAUo

To3.11 »asu 2 * 3.1972

Center d 'Etudes pour Jr ^ JTn ^ iisjbrii ^ J ^ ar ^ noetitgj 195, Route d'Espagne, 31 Touloiise (Frankrelah).

Pyrimidlnderlvate, process, for their preparation, and

their use

The invention relates to new Pyrisiiainderivate _s a Ve: drive to their production and their use as active ingredients in pharmaceutical preparations for human and veterinary medicine.

The new compounds according to the invention have the general formula

0
Il

(D

in which R ^ is a hydrogen atom or e.in lower alkyl or an allyl radical ^ R ₀ , and E, each stand for hydrogen atoms or lower alkyl radicals or together an alkylene bridge "^ h ^ n" s ^{in 4s} η an integer of 2 to 6 lot, and R ^ is a V / water atom or a lower alkyl residue.

si Λ

I u

As lower alkyl radicals, radicals with 1 to 4 carbon atoms, in particular methyl radicals or / ithyl radicals, are preferred. The alkylene bridge - (CH ₂ ) _n - is in particular a tetramethylene bridge -

The invention also includes all tautomeric forms of the compounds of the formula (I) and their metal salts.

The process according to the invention for the preparation of the compounds of formula (I) is characterized in that that 2-amino-thiophene-3-carboxylic acid derivatives of the formula

CO-A

(II)

in which A is a group of the formula -NHR.-, in which R ,, the has the above meaning, or a lower alkoxy radical or an allyloxy radical and R2 and R3 are the above Have meanings, reacts with thiourea or ammonium thiocyanate and the compound obtained in this way of formula (I), in which R. is a hydrogen atom, optionally then reacted with an alkylating agent to give the corresponding compound in which R ^ a is lower alkyl.

Pie reaction is preferably carried out in an anhydrous Medium carried out at temperatures between 150 and 200 C. .

The products obtained are preferably obtained by dissolving in a base such as KOH, filtration and acidification with a Acid, e.g. HGl, which causes a new precipitation in crystal form.

Dialkyl sulfates are advantageous as alkylating agents, e.g. dimethyl sulfate, used for the introduction of the methyl radical at R ^. This alkylation is preferably carried out in an alkaline medium at the temperature of the boiling

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Water bath carried out.

The compounds of formula (II) can be prepared by the methods described by K.Gewald (Chem.Ber., 98, .1965, 3571) and K.Gewald, E. Schinke and H.Böttcher (Chem.Ber », 99ι 1966, 94) are described.

The metal salts of the compounds of formula (I) are produced by known methods.

example 1

Production of 2-mercapto-3,4,5,6,7,8-hexahydro - / \ 7-

- ^ - on (derivative no.1)

1000 g of 2-amino-4,5,6,7-tetrahydrobenzo2 ^ 7-thiophene-3-carboxylic acid, prepared according to the method of K.Gewald and coworkers, and 1000 g of thiourea are mixed and ^{heated to 150 to 160 0} O, until darkening occurs with gas formation. The mixture is ^{kept at 160 °} C. for a further hour, whereupon the still hot mixture is poured into an aqueous KOH solution, filtered and acidified with HCl. After washing the precipitation with dioxane, benzene and acetone or after crystallization from dioxane, colorless crystals are obtained which decompose at 240.degree.

Example 2 7

Preparation of 2-mercapto-3, ^, 5,6 ^ 8-hexahydro- / i7-benzothien-Z2,3-d7-pyrimidin-4 ~ un (Derivative no, 1)

5 β 2-Araino- ^z * -, 5,6,7-tetrahydrobenzo / b7-thiophene-3-carboxamide prepared by the method of K.Gewald and employees, and 5 G Aramoniumthiocyanat are heated up to the beginning of a reaction. The mixture is then stirred at a temperature of 190 to 200 ^{° C. for 3 hours.} Ammonia gas is formed during this process. The mixture is poured into dilute sodium hydroxide, filtered and acidified with hydrochloric acid. This gives 2.1 g of crude product. After recrystallization from dioxane in the presence of activated charcoal, colorless blames are obtained,

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which decompose at 240 ° C.

Example 3

Production of 2-mercapto-3-methyl-3,4,5,6,7,8-hexahydro-

(Derivative no.2

1.0 g of 2-AlJiInO - / +, 5.6 »7-tetrahydrobenzo-A7-thiophene-3-carboxylic acid methylamide and 1.0 g of thiourea are mixed and ^{heated to a temperature of 195 to 200 °} C. for 45 minutes. After cooling, the reaction product is treated several times with a sodium hydroxide solution, filtered and then acidified with hydrochloric acid. This gives 0.7 g of crude product. After recrystallization from ethanol in the presence of activated carbon colorless needles melting at 286 to 290 ⁰ C are (determined on Kofler block) obtained.

The 2-amino-4,5,6,7-tetrahydrobenzo-Z ^ Z-thiophenecarboxylic acid methylamide used as the starting material is made as follows:

30 g of N-methyl-cyanoacetamide, 30 g of cyclohexanone and 10 g of sulfur are stirred ^{in a mixture of 30 ml of morpholine and 60 ml of ethanol at 50 to 60 ° C. for 3 hours.} After cooling, a precipitate forms, which is filtered off, washed with ethanol and then dried. A second product fraction can be obtained by adding water to the filtrate. This forms a precipitate which is separated off, washed with ethanol and dried.

A total of 14.1 g of yellow crystals of melting point 192 ⁰ C (determined on Kofler block) obtained.

Example 4

Preparation of 2-mercapto-6-methyl-3 _i 4-dihydro-thien-Z5,3-d7-pyrimidin-4-one (derivative no.3)

114 g of ethyl ester of 2-amino-5-ynethyl-thioρhen-3-caΓboxylic acid, made after the ancestor of K.Gewald μ ^ Coworkers, and 114 g thiourea v / ground at I70 bis

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C slowly mixed. The mixture is then stirred for a further 3% for 5 hours. Gas formation and darkening take place here. After cooling, hot 2N sodium hydroxide solution is added in several portions. Filtered to alkaline liquids with activated charcoal and then acidified with hydrochloric acid. Here, 27 g of the crude product are precipitated. After recrystallization from dioxane and then from dimethylformamide and washing with hot methanol, colorless crystals are obtained, which at 295 to decompose JOO ⁰ C (according to a modification of the crystal structure at about 220 ⁰ C).

example $

Production of 2-mercapto-5,6-dimethyl-3 »4 ~ dihydro-

(Derivative no.4)

200 g ethyl ester of 2-amino-4,5-diinethylthiophene-3-carboxylic acid, prepared according to the method of K.Gewald and coworkers, mixed with 200 g thiourea. The mixture is heated. After the onset of the reaction, the mixture is ^{stirred for 6 hours at 195 to 200 °} C., ammonia gas being released. After adding dilute potassium hydroxide solution, the alkaline liquid is filtered and then acidified with HCl, whereby 70 g of crude product are obtained. After recrystallization from ethanol in the presence of activated charcoal, colorless needles which have a decomposition point of 260 ^° C. are obtained.

The following results of toxicological and pharmacological tests clearly show that advantageous effects of the derivatives according to the invention, in particular the sedative, antitussive and hypocholesterolemic Effects through which these compounds are valuable for therapy.

The invention also includes pharmaceutical preparations, in particular those having a sedative, antitussive and hypocholesterolemic composition Effect which, as the active ingredient, is a derivative of formula (I) or a pharmaceutical

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contain harmless salt of this derivative.

I «Toxicological investigation

This investigation revealed that the toxicity of the derivatives according to the invention is low. For example, is the LDcq / 24 hrs / kc body weight in the mouse intravenous administration 300 mg for derivative No. 2.

The derivatives according to the invention are well tolerated. During all attempts to determine chronic or delayed toxicity, they called to the test animals no local or general reaction and no interference with the regularly performed biology Controls.

II. Pharmacological investigation

1) Hypocholesterolemic effect

This examination shows the strong hypocholesterolemic Effect of the derivatives according to the invention.

a) Test with propylthiouracil (Ranney and colleagues, J. Pharmacol.Exper.Therap. 1963, 142, 132-136): Administration of propylthiouracil to adult rats produces hypercholesterolemia. Here is the cholesterol content in the blood passma by about 15% above the Normal value increased. The comparison animals received only the propylthiouracil, while the treated animals at the same time received the derivative to be examined orally in a dose of 100 mg / kg.

On the 11th day of the experiment, blood samples are taken on which ß-lipoproteins, free cholesterol and total cholesterol can be quantified. These determinations result in 0.18 g of free cholesterol per animal in the comparison animals Liters and 0.834 total cholesterol per liter, while at the animals treated, for example, with derivative no. 2, values of 0.15 g / l or 0.65 c / l are determined.

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b) Triton test

The intravenous administration of the surfactant "Triton W-R 1339" allows for artificial Increasing the amounts of certain lipid fractions of the serum evaluates the hypocholesterolemic effect of the product to be examined. This product is given orally at a dose of 100 mg / kg immediately after intravenous Injection of the surfactant administered ;. After 18 hours the blood is drawn, whereupon ß-lipoproteins, total cholesterol and free cholesterol can be quantified. As with the test described above, there is a large decrease in the salary observed in free cholesterol and total cholesterol. This reduction is, for example, with derivative no. about 3O #.

2) Sedative effect

The derivatives according to the invention have a strong sedative effect. This effect is different according to Methods proven.

a) Observation of the behavior, showing a significant reduction in motor activity in mice shows who received the derivative to be investigated in a dose of 100 mg / kg,

b) Effect against Hypnotic? , they have a considerable effect increase, recognizable by the increase in the number of sleepers and the shortening of the time it takes to fall asleep.

c) Effect on chloral, whose hypnogenic effect it extend.

3) Antitussive action

Experiments on male h'eerschv / singles according to the method by Ealle-Brunoud (Arch.Int.Pharmacodyn.1-2, '120-126, 1960) have shown that the derivatives according to the invention to a very large extent those caused by ammonia aerosol Reduce skin activity.

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The results of the studies described above show that the compounds according to the invention sedating, antitussive and hypocholesterolemic effects to have.

The pharmaceutical preparations according to the invention for oral administration may be in the form of tablets, sugar-coated tablets, capsules or syrups. she can for rectal administration in the form of suppositories and prepared for parenteral administration in the form of injection solutions. Each dosage unit advantageously contains 100 to 500 mg of the active Ingredients. The doses to be administered in 24 hours can vary between 100 mg and 1 g.

The following is an example of the composition of some called pharmaceutical preparations which contain the derivatives according to the invention.

1) tablets :

Derivative No. 2 0.200 g

Starch 0.020 g

Dextrin 0.010 g

Magnesium stearate 0.010 g

Glucose 0.005 g

2) Draped tablets 0.150 ε traces ε a) Core: 0.010 G 0.005 Derivative No. 3 0.015 e Potato starch 0.005 ε Lactose Magnesium stearate 0.010 6th b) Ceiling: 0.015 e talc Gum arabic Purified
Rubber lacquer Titanium dioxide

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White wax traces Cornstarch 0.010 g White sugar required amount for 1 coated tablet 5) capsules Derivative No. 1 0.250 s Magnesium stearate Oj020 s 4) syrup Derivative No. 2 2 ε Excipient ad 100 ml

*>) Suppositories derivative no.4

Semi-synthetic triglycerides

6) Injection solution derivative no.2

Isotonic saline solution

0.200 6

required amount for 1 soup,

0.150 g to 5 ml

The derivatives according to the invention are found to be effective Means in therapy · Because of their sedation They are effective in nervous syndromes, insomnia, Teething difficulties and spasmodic conditions and anxiety.

Because of their effect as antitussives and sedatives they effectively remedy all types of coughs.

Since they also attributed the hyperlipemia and hypercholesterolemia to normal values _t they allow an effective treatment of atherosclerosis and of dyslipemias.

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Claims (10)

Claims Pyrimidine derivatives of the formula (D R ₃ ^ \ _S ' ^ N ^ ^ SR ₄ in which R ^ is a hydrogen atom or a lower alkyl radical or an allyl radical, Ro and R each represent hydrogen atoms or lower alkyl radicals or together form an alkylene bridge - (CHp) _n - in which η is an integer from 2 to 6 and R ^ is a hydrogen atom or a lower alkyl radical, as well as the tautomeric forms and metal salts of the pyrimidine derivatives. 2. Derivatives according to claim 1, characterized in that the lower alkyl radicals are methyl radicals or ethyl radicals. 3. Derivatives according to claim 1 or 2, characterized in that that the alkylene bridge is a tetramethylene bridge. 4. 2-Mercapto-3, ^, 5,6,7 »8-hexahydro- / 17-benzothien-Z ^, 3-d7-pyrimidin-4-one. 5 · 2-mercapto-3-methyl- 3,4.5% 6,7,8-hexahydro-Z ³ ! 7-benzothien-Z?, 3- ^ 7-pyrimidin-4-one. 6. 2-i "ercapto-6-methyl-3,4-dihydro-thien-Z5,3-d7-pyrimidin-4-one. 7. 2-Mercapto-5,6-dimethyl-3,4-dihydro-thien- _< / 2,3-d7-pyrimidin-4 · - one. 8 Pharmaceutical preparations, especially those with sedating, cough suppressant and hypocholterine. y / effect, characterized by a content of one Pyrimidine derivative according to claim 1 to 7 or one 209839/1230 pharmaceutically acceptable salt of these derivatives as an active ingredient. 9. A process for the preparation of derivatives according to claim 7 »characterized in that 2-aminothiophene-3-carboxylic acid derivatives the formula (II) in which A is a group of the formula -NHR ₁ , in which R _{1 has} the meaning given above, or is a lower alkoxy radical or an allyloxy radical and R2 and R, which have the meanings given above, reacts with thiourea or ammonium thiocyanate and the compound obtained in this way of formula (I), in which R ^ is a hydrogen atom, optionally subsequently reacted with an alkylating agent to give the corresponding compound in which R _{z is} a lower alkyl radical. 10. The method according to claim 8, characterized in that the reaction of the derivative of formula (II) with Thiourea or thiocyanate is carried out at elevated temperature under anhydrous conditions. 209839/1230