DE1645911A1 - Process for the preparation of derivatives of barbituric acid - Google Patents

Description

Process for the preparation of derivatives of barbituric acid The present Invention relates to the preparation of certain derivatives of barbituric acid, of which has been found to be valuable chemotherapeutic agents in combating the Paralysis (Parkinson's disease) are.

The barbituric acid derivatives produced according to the invention have the following general formula: wherein X is hydrogen or at least one halogen atom, a lower alkyl radical (preferably the methyl radical) or a lower alkoxy radical (preferably the methoxy radical). Preferably 1 is hydrogen.

The terms lower alkyl "and" lower alkoxy "mean In the context of the invention, alkyl or alkoxy groups containing 1-4 carbon atoms contain.

The preparation of the pharmaceutically acceptable acid addition salts of the compounds of general formula I also belong to the subject of the invention. These salts can be obtained from the compounds of the formula I by reaction with a suitable one Acid can be produced.

The compounds of the formula I can be prepared from a barbituric acid derivative of the general formula wherein X has the same meaning as in formula I, can be prepared by catalytic reduction.

The catalytic reduction of the compounds of the formula II can, for example using Adam's platioxide as a catalyst and hydrogen at a pressure of 1-5 Atmospheres and a temperature of 1Q-60 ° C.

The process for the preparation of derivatives of barbituric acid general formula I and onssal zen of pharmaceutically acceptable acid addition salts it is thus characterized according to the invention in that a connection of the general formula II catalytically reduced and the barbiturvic acid derivative formed as such or as a pharmaceutically acceptable acid addition salt formed therefrom is isolated.

The piperidinylmethyl compound of formula I can, if so desired is alkylated on nitrogen by processes known per se, for example on Nitrogen to be methylated. For example, if N-methylation is desired this can be done by heating with formic acid and formaldehyde in aqueous solution, expediently in the presence of a soluble formate, for example an alkali metal formate such as sodium formate.

The preparation of the hydrogen chloride salt is particularly preferred according to the invention of 5-Phent1-5- (2'-piperidinyl-methyl) -bsrbituric acid. It was found that this Compound provides symptomatic relief to patients suffering from paralysis suffer or show Parkinson's symptoms by administering a phenothiazine drug were caused.

It was already pointed out at the beginning that the connections of the general formula I have valuable pharmaceutical properties. It it was found that # they are particularly active in the teet for suppressing eremorin-induced Spasms in mice. This is a recognized screening test for compounds of which it is believed to be used to treat the symptoms of paralysis agitans in animals and - especially useful to people.

The subject of the present invention accordingly also includes pharmaceuticals Preparations which are characterized in that they are an active ingredient or more compounds of the general formula I contain. Such pharmaceutical Preparations for therapeutic use can be prepared according to methods known per se easily made by Pachmann be, at least one of the Compounds according to the invention as an essential active ingredient together with at least one pharmaceutical carrier of the types customarily used for manufacture from drugs used to processed into finished products that are suitable for therapeutic administration.

The carrier may be in the form of a container for the active ingredient to have. For example, this may be an orally ingestible container sgin like hard or soft gelatin capsules that contain the active ingredient per se. It can also be a disposable container, such as an ampoule. However, it usually is more common that the active ingredient, regardless of whether it is in such a container is included in admixture with one or more pharmaceutical diluents and / or excipients of the type customary in the pharmaceutical field are present. Examples for such diluents and excipients are starch, lactose, talc, stearic acid, Ethyl cellulose, theobroma oil, arachis oil, saline solutions and distilled water.

The pharmaceutical preparations can be brought into a form which is suitable for oral, parenteral or rectal use. You can therefore in the form of, for example, tablets, bags, anodizing, suspensions in physiological acceptable media ui-d sterile packed powders for the preparation of injection solutions to be brought.

For clinical use, the composition becomes expedient chosen that it represents a dose unit for the desired application form. This dosage unit is adapted to the desired type of administration. The dose unit can for example be in the form of a tablet, one in a capsule Powder or a suppository.

For the treatment of Parkinson's symptoms, the amount is of the active ingredient in each dose unit generally 1 to 500 mg; the dose for parenteral use is between 1 and 250 mg and that for oral use between 40 and 500 mg. In the case of adult humans, this is preferably applied dose of the active ingredient for oral administration 40 to 120 mg approximately three times a day, with intramuscular use 20 to 60 mg and with intravenous use Use 1 to 30 mg.

A method for the preparation of the compounds of formula II is in the pending parent application A 43 991 IVd / 12p.

The following examples illustrate the invention.

Example 1 A mixture of 5- (2'-pyridylmethyl) -5-phenyl-barbituric acid (10 g), which was obtained according to Example 3 of application A 45 991 IVd / 12p, glacial acetic acid (120 ccm), conc. Hydrochloric acid (5 ccm) and Adams' platinum oxide (0.5 g) was at room temperature and 5 atm. Pressure hydrogenates until the uptake of hydrogen stopped (3 moles). The filtered solution was evaporated to dryness and the residue recrystallized from water to which a few drops of dilute hydrochloric acid were added. The hydrochloride of 5- (2'-piperidinyl-methyl) -5-phenyl barbituric acid crystallized in the form of the hydrate with the F. = 197-199 ° C.

C16H20N3O3cl.H2O found: C, 53.96; H 6.08; N 11.9; Cl 9.93% calculated: C 54.0; H 6.22; N 11.8; C1 10.0% Example 2 tablets, each of the following Composition were prepared in the manner described below: 5- (2'-Piperidinylmethyl) -5-phenylbarbituric acid hydrochloride 100 mg Lactose 228 mg Corn starch 70 mg ethyl cellulose N. 100 8 mg talc 20 mg stearic acid 4 mg barbituric acid, Lactose and a portion of the starch (40 mg per tablet) were passed through a 40 mesh sieve (British standard sieve) driven and mixed together. The mixed powder were adjusted with a solution of ethyl cellulose in isopropyl alcohol. These The mass was then granulated through a 12 mesh screen (B.S.S.). The granules were at 400 C dried and then passed through a 16 mesh screen (B.S.S.). Eventually the talc, the stearic acid, and the remaining starch (all became by a 60 B.S.S. mesh sieve driven) mixed with the granules, and the mixture was compressed into tablets, each weighing 430 mg.

Example 3 Capsules each having the following composition were made prepared in the manner described below: 5- (2t-piperidinylmethyl) -5-phenylbarbituric acid hydrochloride 100 mg lactose 25 mg The barbituric acid and the lactose were purified by a 30 (B. S. S.) mesh sieve driven and mixed well together. The mixed powders were then filled into gelatin capsules so that each capsule contained 125 mg of the mixture.

Example 4 suppositories, each having the following composition were prepared in the manner described below: 5- (2'-piperidinylmethyl) -5-phenylbarbituric acid hydrochloride 100 mg Theobroma oil 1 g The barbituric acid was forced through a 60 mesh B.S.S sieve and digested with the melted theobroma oil (cocoa butter) at 450 C to produce a to produce smooth suspension. This was stirred well and put into suppository forms poured, each of which had a nominal capacity of 1 g. It was allowed to cool, making the suppositories.

Example 5 A sterile powder of 5- (2'-piperidinylmethyl) -5-phenylbarbituric acid for the preparation of an injection solution was prepared by the fact that the finely divided solid barbituric acid was sterilized by contact with ethylene oxide.

The sterilized material was then aseptically in 100 mg quantities sterile final containers which were then aseptically sealed.

If this sterile powder is then needed for the application, it can it can be dissolved in 10 ml of sterile common saline solution for injection. The saline solution is suitably placed in the opened container.

EXAMPLE 6 5- (2'-Piperidinylmethyl) -5-phenylbarbituric acid hydrochloride was dissolved in distilled water in an amount of 100 mg / 10 ml. This solution was filtered through a bacteria-proof filter and the filtrate became aseptic transferred in 10 ml portions each into the sterile final container that then freeze-dried under aseptic conditions and aseptically sealed.

This packaged sterile powder can then be used in 10 ml of a sterile usual solution for injection, if it is for therapeutic use is needed.

EXAMPLE 7 tablets, each with the following composition, were prepared as follows: 5- (2'-piperidinylmethyl) -5-phenylbarbituric acid hydrochloride 100 mg lactose 158 mg corn starch, dried 50 mg polyvinylpyrrolidone 8 mg talc 20 mg stearic acid 4 mg The barbituric acid, lactose and corn starch were by a 40 mesh B.S.S. sieve driven and mixed together. The mixed powders were pasted with a solution of polyvinylpyrrolidone in isopropyl alcohol, and the Mass was granulated through a 12 mesh B.S.S. screen. The granules were at 400 C and then forced through a 16 mesh B.S.S. screen. Finally were the talc and stearic acid were added to the granules and the mixture became tablets pressed, each weighing 340 mg.

Patent claims:

Claims (8)

Claims: 1. Process for the preparation of derivatives of barbituric acid of the general formula wherein X stands for hydrogen or at least 1 halogen atom, a lower alkyl or lower alkoxy substituent, and pharmaceutically acceptable acid addition salts of this compound, characterized in that a compound of the general formula wherein 1 has the same meaning as above, catalytically reduced and the barbituric acid derivative formed is isolated as such or as a pharmaceutically usable acid addition salt formed therefrom. 2. The method according to claim 1, characterized in that the catalytic Reduction using idams' platinum oxide as a catalyst and hydrogen carried out at a pressure of 1-5 atmospheres and a temperature of 10-60 ° a will. 3. The method according to claims 1-2, characterized in that as Starting product the compound de @ formula II is used in which X water @@ f means. 4. The method according to claims 1-3, characterized in that the The barbituric acid derivative formed is reacted with hydrochloric acid to form the hydrochloride will. 5 .. Acid addition salts of derivatives of barbituric acid of the general formula wherein 1 represents hydrogen or at least 1 halogen atom, a lower alkyl or lower alkoxy substituent. 6. Acid addition salts of 5- (2 1-piperidinylmethyl) -5-phenyl barbituric acid. 7. 5- (21-piperidinylmethyl) -5-phenyl-barbituric acid hydrochloride. 8. Pharmaceutical preparations containing the compounds of claims 5 to 7 as an active ingredient.