DE1645912A1 - 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 for combating Paralysis (Parkinson's disease) are.

The applicant's patent application A 43 991 IVd / 12p describes a process for the preparation of thiobarbituric acid derivatives, according to which thiourea is condensed with a salonic acid ester in the presence of an inert common solvent - and in the presence of a condensing agent at a temperature of up to 30 ° C. condense the reaction components to form a 2-2hiobarbituric acid derivative. The malonic acid ester mentioned has the formula II 000 COO lower alkyl CI (II RCO0 lower alkyl wherein R is: (A) the remainder @wherein R1 and R2 stand for identical or different lower alkyl groups and A r stands for an unsubstituted or methyl-substituted, straight-chain alkylene radical containing 2 or 3 carbon atoms in the chain; or (B) the rest wherein represents a heterocyclic group having at least 5 ring atoms and A has the same meaning as above; or (C) the radical R3 - (CH2) n-, in which n stands for the number 1 or 2 and R3 is a 2-pyridyl or N-methyl-2-piperidinyl radical; and X stands for hydrogen or at least one halogen, a lower alkyl group or a lower alkoxy group, where, however, X should not be hydrogen but at least one halogen, a lower alkyl or a lower alkoxy group when R stands for a dimethylaminoalkyl group which is in the alpha position of the alkyl group is not substituted by methyl.

The terms lower alkyl "and" lower alkoxy "are intended, respectively for the purposes of the present invention alkyl and Denote alkoxy groups, containing 1-4 carbon atoms.

Accordingly, the thiobarbituric acid derivatives obtained by the process described in patent application A 43 991 IVd / 12p can be represented by the following general formula wherein R and X have the same meaning as above, are represented.

According to the present invention, the thiobarbituric acid derivatives of the above formula I into the corresponding 2-oxobarbituric acid derivatives by oxidation transferred, using an acidic oxidizing agent such as dilute aqueous Nitric acid with a normality of 1-10, e.g. B. 2.5 N or 5 N is used.

However, the term acidic oxidizing agent is not intended to be hydrolyzing Agents such as hydrochloric acid or sulfuric acid include, as a result of hydrolysis in the process is not desirable according to the invention.

The process for the preparation of 2-ozobarbituric acid derivatives of the general formula wherein R is: (A) the remainder where R1 and R2 are identical or different lower alkyl groups and A is an unsubstituted or methyl-substituted, straight-chain alkylene radical containing 2 or 3 carbon atoms in the chain; or (B) the rest wherein represents a heterocyclic group having at least 5 ring atoms and A has the same meaning as above; or (c) the radical R3 - (CH2) n-, in which n stands for the number 1 or 2 and R3 is a 2-pyridyl or N-methyl-2-piperidinyl radical; and X stands for hydrogen or at least one halogen, a lower alkyl group or a lower alkoxy group, where, however, X should not be hydrogen but at least one halogen, a lower alkyl or a lower alkoxy group, when R stands for a dimethylaminoalkyl group which is in the alpha position of the alkyl group is not substituted by methyl, and of pharmaceutically acceptable acid addition salts of these derivatives, is characterized according to the invention in that the corresponding 2-thiobarbituric acid derivative is oxidized by reaction with an acidic oxidizing agent to give the desired 2-oxobarbituric acid derivative and the 2-oxobarbituric acid derivative as such or as a pharmaceutically acceptable acid addition salt thereof is isolated after conversion into this.

For example, the 2-thiobarbituric acid derivative of formula I can be mild be heated with 2.5 N nitric acid. The thiobarbituric acid derivative works included in solution and a usually very strong development of nitrous gases occurs. By adding excess ammonia to the filtered and cooled solution the desired 2-oxobarbituric acid derivative can be precipitated.

When working on a larger scale, the thiobarbituric acid derivative becomes expediently slowly boiling 2,5-N-nitric acid (8 mol) in the presence of powdered Glass added.

The object of the present invention comprises the preparation of the pharmaceutically acceptable acid addition salts of the 2-oxobarbituric acid derivatives, the can be prepared according to the process of the present invention. You can prepared by reacting the 2-oxobarbituric acid derivative with a suitable acid will.

According to the present invention, particularly preferred is the compound 5-phenyl-5- (2'-pyridylmethyl) barbituric acid. This connection can after in the patent application no.

(First divisional application filed at the same time as the present application for patent application d 43 991 IVd / 12p) described method in 5-phenyl-5- (2'-piperidinylmethyl) barbituric acid. It was found that this compound in the form of its hydrogen chloride salt is symptomatic Provides relief to patients suffering from paralysis or Parkinson's disease Show symptoms caused by administration of a phenothiazine drug became.

The following examples illustrate the invention.

Example 1: 5- (2'-Diethylaminoethyl) -5-phenylbarbituric acid and its Hydrochloride 5- (2'-diethylaminoethyl) -5-phenyl-2-thiobarbituric acid (4 g) were Warmed gently with 2.5 N nitric acid (50 ccm) until the development of nitrous Gasen stopped. The mixture was filtered hot, cooled and washed with excess Ammonia added.

The precipitate was filtered off and recrystallized from hot water, with crystals of 5- (2'-diethylaminoethyl) -5-phenyl-barbituric acid F. = 193-194 ° C.

The barbituric acid thus obtained was in one equivalent from Dissolved N-hydrochloric acid, evaporated the solution and recrystallized the product from water. There were colorless prisms of the hydrochloride of 5- (2'-Kiäthylaminoäthyl) -5-phenylbarbituric acid M.p. = 2750 C (dec.) Obtained.

Ci 6H22N303Cl found: C 56.60; H 6.64; N 12.40; Cl 10.34% calculated: C 56.56; H 6.53; N 12.37; Cl 10.43% Example 2: 5- (2'-pyridylmethyl) -5-phenyl-barbituric acid The 5- (2 '-pyridylmethyl) -5-phenyl-2-thiobarbituric acid (42 g) was slowly under Stir to a boiling solution of dilute nitric acid (2.5 N; 420 cc) which powdered glass (50 g) was added. After the development of nitrous Gassing stopped, the mixture was filtered, cooled and excess ammonia added, whereupon crystals of 5- (2'-pyridylmethyl) -5-phenylbarbituric acid with the P. = 3200 C (after recrystallization from 2-ethoxyethanol) precipitated.

C16H13N3O3 Found: C, 64.91; H 4.43; N 14.11% calculated: C 65.09; H 4.44; N 14.23% The experiment was carried out using a 5-N-nitric acid '(420 ccm) repeated instead of 2,5-N-nitric acid; there was no significant one Difference in the yield of 2-oxobarbituric acid.

Example 3: 5- (2'-Dimethylaminoethyl) -5-m-methoxyphenylbarbituric acid and its hydrochloride 5- (2'-dimethylaminoethyl) -5- (m-methoxyphenyl) -2-thiobarbituric acid (8 g), was heated with dilute nitric acid (2.5 N; 70 cc) until formation was terminated by nitrous gases. The hot solution was filtered to remove the sulfur remove, and then let stand to cool. Crystals of the nitrate of 5- (2'-dimethylaminoethyl) -5-m-methoxyphenyS-barbituric acid precipitated, mp = 232-233 ° C (dec.). A warm aqueous solution of the nitrate (7.5 g) was treated with ethanolic N-potassium hydroxide (20.4 ccm). After cooling down The free barbituric acid crystallized out at a temperature of 212-213 ° C.

The barbituric acid (3.5 g) was dissolved in N-hydrochloric acid (11.5 cci solved, the solution is evaporated and the product obtained is recrystallized from ethanol / ether, whereupon the hydrochloride of 5- (2t-dimethylaminoethyl) -5-mmethozyphenylbarbituric acid with F = 2360 C (dec.) was obtained.

Example 4t 5- (2'-Dimethylaminopropyl) -5-phenylbarbituric acid and its Hydrochloride 5- (2'-dimethylaminopropyl) -5-phenyl-2-thiobarbituric acid (12 g) heated with 2.5 N nitric acid (100 ccm) until the development of nitrous gases stopped.

The hot solution was filtered to remove the sulfur and left to cool.

The solution was made up by adding dilute sodium hydroxide solution (2.5 N) brought a pH of 8, after which crystals of 5- (2'-dimethylaminopropyl) -5-phenyl-barbituric acid, F = 213-215 ° C, branch out.

The barbituric acid obtained was dissolved in N-hydrochloric acid (20 ccm), the solution evaporates and the residue from ethanol / ether uncrystallized, whereby 5- (2'-Dimethylaminopropyl) -5-phenylbarbituric acid hydrochloride, F = 2850 C (decomp.), was obtained.

C15H20H3O3Cl found: 0 55.47; H 6.18; N 13.39 % Calculated: C, 55.30; H 6.19; N 12.90 s Example 5t 5- (2'-morpholinoethyl) -5-phenylbarbituric acid and its hydrochloride 5- (2'-morpholinoethyl) -5-phenyl-2-thiobarbituric acid (5 g), was heated with dilute nitric acid (2.5 N; 60 ccm) until development was terminated by nitrous gases. The hot solution was filtered to add sulfur remove, then let stand to cool.

The pH of the solution was increased by the addition of 5-N-ammonium hydroxide brought to 9, after which crystals of 5- (2'-morpholinoethyl) -5-phenylbarbituric acid, F = 260-262 ° C.

The formed barbituric acid (6.6 g) was in a mixture of 5-N-hydrochloric acid (5 ccm), water (20 ccm) and methanol (50 com) dissolved, the solution evaporated and the residue was recrystallized from aqueous alcohol. It became the hydrochloride of the 5- (2'-Morpholinoethyl) -5-phenylbarbituric acid with F = 280-290 ° C (decomp.) Was obtained.

C16H19O4N3.HCl 'found: C, 54.38; H 5.62; N 12.3% calculated: C 54.31; H 5.70; N 11.9% Example 6: 5- (2'-Piperidinoethyl) -5-phenylbarbituric acid and its hydrochloride 5- (2'-piperidinoethyl) -5-phenyl-2-thiobarbituric acid (5 g) was heated with dilute nitric acid (2.5 N; 66 ccm) until development of nitrous gases stopped.

The hot solution was filtered, cooled and then with as much 5-N-ammonium hydroxide added that the pH was increased to 9. Then crystals of 5- (2'-piperidino-ethyl) -5-phenylbarbituric acid separated (F = 230-234 ° C).

A solution of the barbituric acid (14 g) in ethanol (50 ccm) was with N-hydrochloric acid (50 ccm) treated, the solution medium evaporated and the crystalline The residue crystallizes from water, whereby the hydrochloride of 5- (2'-piperidinoethyl) -5-phenylbarbituric acid, Mp = 316-317 ° C (dec).

C17H21N3O3.HCl found: C, 58.35; H 6.57; N 12.25% Calculated: C 58.03; H 6.31; li 11.95% Example 7: 5- (2'-Pyrrolidinoethyl) -5-phenylbarbituric acid and its hydrochloride 5- (2'-pyrrolidinoethyl) -5-phenyl-2-thiobarbituric acid (20 g), was heated with dilute nitric acid (2.5 N; 250 ccm) until development of nitrous gases stopped. The hot solution was filtered, cooled and the pH adjusted the solution adjusted to 9 by adding 5-N-ammonium hydroxide, whereupon crystals of 5- (2 'pyrrolidinoethyl) -5-phenylbarbituric acid, F 3 2450 C (decomp.), precipitated.

The barbituric acid (13.5 g) was added to a mixture of 5N hydrochloric acid (10 ccm) and methyl alcohol (50 ccm) dissolved, the solution evaporated to dryness and the residue is recrystallized from ethanol and then from ethanol / methyl ethyl ketone, whereby the 5- (2'-pyrrolidinoethyl) -5-phenylbarbituric acid hydrochloride, F = 288-293 ° C (decomp.) Was obtained.

C16H19N3O3.HCl found: C, 57.25; H 5.97; N 12.44; Cl 10.52% calculated: C 56.90; H 5.97; N 12.44; Cl 10.50% It has already been introduced pointed out that the veneers of general formula III valuable pharmaceutical Possess properties. They have been found to be particularly active in the test for the suppression of tremorin-induced spasms in mice. This is a recognized one Screening test for compounds believed to be useful for treatment the symptoms of paralysis agitans in animals and especially humans are.

The subject of the present invention accordingly also includes pharmaceuticals Preparations which are characterized in that they are an active ingredient or contain several compounds of the general formula III. Such pharmaceutical Preparations for therapeutic use can be prepared according to methods known per se easily prepared by the person skilled in the art, at least one of the compounds according to of the invention as an essential active ingredient along with at least one pharmaceutical carriers of the types commonly used in the manufacture of medicaments used to be processed into finished products intended for therapeutic Administration are suitable.

The carrier may be in the form of a container for the active ingredient to have. For example, this can be an orally ingestible container such as hard or soft gelatin capsules, ie the active ones. Included in the component per se. It can also be a disposable container, such as an ampoule. However, Bs is usually 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 celulose, 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, sachets, elixirs, suspensions in physiological acceptable media and sterile packaged powders for the preparation of injection solutions to be brought.

For clinical use, the composition becomes appropriate as it is 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 the Porm 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; for intramuscular use 20 to 60 mg and for intravenous use Use 1 to 30 mg.

The following examples illustrate the manufacture of pharmaceutical Preparations according to the present invention.

Example 8: Tablets, each having the following composition, were prepared in the manner described below: 5- (2'-pyridylmethyl) -5-phenyl - ,,. barbituric acid hydrochlorld 100 mg lactose 228 mg corn starch 70 mg ethyl cellulose N. 100 8 mg talc 20 mg stearic acid 4 mg The barbituric acid, lactose and a portion the starch (40 mg per tablet) was sieved through a 40 mesh sieve (British standard sieve) driven and mixed together. The mixed ones Powder were pasted with a solution of ethyl cellulose in isopropyl alcohol. This mass was then granulated through a 12 mesh (B.S.S.) sieve. The granules were at 400 C dried and then passed through a 16 mesh (B.S.S.) screen. Finally were the talc, stearic acid and residual starch (all were obtained through a 60 B.S.S. mesh sieve driven) mixed with the granules and the mixture became tablets pressed, each weighing 430 mg.

Example 9: An oily suspension for injection is as follows Composition: 5- (2'-Diethylaminoethyl) -5-phenylbarbituric acid hydrochloride 200 mg aluminum monostearate 40 mg Arachis oil to 1 ml This suspension was thereby made that the aluminum monostearate dissolved in the arachis oil by heating became. The resulting solution was then digested with the barbituric acid, and the obtained suspension was passed through a colloid mill. The suspension was then filled into clean and dry glass ampoules, which are then melted shut became. The ampoules with the suspension were finally heated for one hour Sterilized at 1500 C.

Patent claims:

Claims (15)

Patent r 1. Process for the preparation of 2-oxobarbituric acid derivatives of the general formula wherein R is: (A) the remainder where R1 and are for identical or different lower alkyl groups and A for an unsubstituted or methyl-substituted, straight-chain alkylene radical containing 2 or 3 carbon atoms in the chain; or (B) the rest wherein represents a heterocyclic group having at least 5 ring atoms and A has the same meaning as above; or (C) the radical R3 - (CH2) n-, in which n stands for the number 1 or 2 and R3 is a 2-pyridyl or N-methyl-2-piperidinyl radical; and X stands for hydrogen or at least one halogen, a lower alkyl group or a lower alkoxy group, where, however, X should not be hydrogen but at least one halogen, a lower alkyl or a lower alkoxy group when R stands for a dimethylaminoalkyl group which is in the alpha position of the alkyl group is not substituted by methyl, and of pharmaceutically acceptable acid addition salts of these derivatives, characterized in that the corresponding 2-! hiobarbituric acid derivative is oxidized by reaction with an acidic oxidizing agent to give the desired 2-oxobarbituric acid derivative and the 2-oxobarbituric acid derivative is isolated as such or as a pharmaceutically acceptable acid addition salt thereof after conversion into this. 2. The method according to claim 1, characterized in that the acid oxidizing agent aqueous nitric acid with a normality of 1-10 is used. 3. The method according to claims 1-2, characterized in that that the acidic oxidizing agent is aqueous nitric acid with a normality of about 2.5 is used. 4. Process according to Claims 1-3, characterized in that 5- (2'-pyridylmethyl) -5-phenyl-2-thiobarbituric acid is used as the starting product and this is oxidized to pyridylmethyl) -5-phenyl-2-oxobarbituric acid. 5. 2-Oxobarbituric acid derivatives of the general formula wherein R is: (A) the remainder wherein R1 and R2 are identical or different, lower alkyl groups and A is an unsubstituted or methyl-substituted, straight-chain alkylene radical containing 2 or 3 carbon atoms in the chain; or (B) the rest wherein a heterocyclic group with at least Represents 5 ring atoms and A the same Has the same meaning as above; or (C) the radical R3- (CH2) n-, in which n is the number 1 or 2 and R3 is a 2-pyridyl or N-methyl-2-piperidinyl radical; and X for hydrogen or at least one halogen, a lower alkyl group or a lower alkoxy group, but X is not hydrogen, but at least shall be a halogen, a lower alkyl or a lower alkoxy group if R represents a dimethylaminoalkyl group which is in the alpha position of the alkyl group not substituted by methyl, and pharmaceutically acceptable acid addition salts of these derivatives. 6. 5- (2'-Diethylaminoethyl) -5-phenylbarbituric acid. 7. 5- (2'-Pyridylmethyl) -5-phenyl-barbituric acid. 8. 5- (2'-Dimethylaminoethyl) -5-m-methoxyphenylbarbituric acid. 9. 5- (2'-Dimethylaminopropyl) -5-phenylbarbituric acid. 10. 5- (2'-Morpholinoethyl) -5-phenylbarbituric acid. 11. 5- (2'-Piperidinoethyl) -5-phenylbarbituric acid. 12. 5- (2'-Pyrrolidioethyl) -5-phenylbarbituric acid. 13. Acid addition salts of the compounds according to Claims 6 to 12th 14. Hydrochlorides of the compounds according to Claims 6 to 12. 15. Pharmaceutical preparations containing the compounds of claims 5 to 14 as an active ingredient.