NO800720L - UREA DERIVATIVES. - Google Patents

Description

The present invention relates to new urea derivatives, in particular it relates to 1-(1-methyl-4-oxo-2-imidazolin-2-yl)-3-thienyl-urea derivatives with the general formula

where R means 2-thienyl, 3-thienyl or 5-halo-3-thienyl. Compound with the above-mentioned formula I can also exist in tautomeric form with the general formula

where R has the meaning given above.

The term "halogen" used in this description includes the four halogens fluorine, chlorine, bromine and iodine, chlorine and bromine being preferred, and chlorine in particular being preferred.

The subject matter of the present invention is urea derivatives with the above-mentioned formula I, their production and the intermediate product in their production, further drugs containing a urea derivative with the above-mentioned formula I and the production of such drugs as well as the use of a urea derivative with the above-mentioned formula I in combating or preventing diseases.

The urea derivatives with the above-mentioned formula I can be prepared according to the invention by reacting creatinine with the formula • with an isocyanate thiophene with the general formula

wherein R has the meaning given above.

Creatinine with the above-mentioned formula II is reacted according to methods known per se with an isocyanatothiophene with the above-mentioned formula III. In this reaction, one appropriately works with approximately equimolar amounts of both starting materials. The reaction is preferably carried out in an anhydrous inert aprotic polar organic solvent. Examples of suitable solvents are ethers. such as tetrahydrofuran or dioxane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide and the like. After complete reaction, the product is precipitated by adding cold water to the reaction mixture. The crude product can be purified by recrystallization from a solvent.

Creatinine with the above-mentioned formula II which is used as starting material is a known compound.- Of the compounds falling under the above-mentioned formula III, 2-isocyanatothiophene is known, while the other compounds are new and likewise the subject of the present invention. The new 3-isocyanatothiophenes can be prepared in an analogous manner to the preparation of the known 2-isocyanatothiophene, suitably from a thiophene-3-carboxylic acid which is transferred in a known manner in a reactive derivative, e.g. a corresponding acid chloride, which is likewise converted in a known manner by reaction with sodium azide and subsequent heating into the desired 3-isocyanatothiophene, the reactive derivatives acting as intermediates, e.g. the acid chlorides and acid acids must not be isolated. Nor does the 3-isocyanatothiophene need to be isolated before it is transferred into the corresponding urea derivative with the above-mentioned formula I. Thiophene-

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The 3-carboxylic acids are known compounds.

The urea derivatives with the above-mentioned formula I are valuable drugs and can particularly be used as anxiolytics. The compounds of the above-mentioned formula I are very little toxic, and it has been shown that they have a highly selective anxiolytic effect without

- that they have the usual muscle relaxant and sedative properties that are normal with anxiolytics. The anxiolytic effect has been demonstrated experimentally in the animal experiment described below. '

The test equipment is a single-key rail box with a pre-pill sensor.

In 3 one-hour pretrials (on three different days), hungry Fyllinsdorf female rats (SPF, 190-230 g) are trained to press the pill dispenser's key to obtain 45 mg propills (each keypress is rewarded): and in the third pretrial the rats achieved a result of 150-200 key operations per hour.

In a fourth preliminary trial, each pill reward that follows a key press is combined with a short electric foot shock (1.0 mA). The rats who are confronted with this conflict situation operate at the beginning still approx. 5-lo times the push button and then stops

.completeness due to anxiety.

In a fifth preliminary trial, the rats can press the key to the pill dispenser again without further foot shock, whereby a quantity of 150-200 key operations per hour.

In a sixth preliminary trial, a selection of the experimental animals is carried out. The test animals are given 10 mg/kg chlordiazepoxide perorally half an hour before the start of this trial; each pill reward is again combined with a foot shock (conflict). Just root- . ter such as this preliminary attempt reaches a result of 20-50 key operations (compare the 5-10 key operations in the fourth preliminary attempt)

are kept as suitable experimental animals for testing potential

, anxiolytics. The elimination rate in this preliminary trial is 5%.

In the main experiment, as a rule, 8 rats are used to examine the potential anxiolytics per substance and per dosage. An untreated control group is not necessary, as each animal serves as its own control. The test substances which are dissolved or suspended in a mixture of distilled water (10 ml)' and tween 80. (2 drops) are given to the animals by means of a probe for half an hour

■ before the main test of 1 hour. During the main experiment, in which the arrow-leve reward at each key press is combined with a foot shock (conflict), the result of key operations per hour.

The first significant anxiolytic effective dosage is determined with the Wilcoxon test (comparison of pairs) in that the number of tap operations in the main trial (foot shock after pre-treatment with test substance) is directly compared with the number of light tap operations in the control trial (foot shock after pre-treatment with saline solution).

In the experiment described above, the first significant anxiolytic effective dosage for 1-(5-chloro~3-thienyl)-3-(1-methyl-4-oxo-2-imidazolin-2-yl)urea, 1-(l -methyl-4-oxo-2-imidazolin-2-yl)-3-(3-thienyl)urea respectively.1-(1-methyl-4-oxo-2-imidazolin-2-yl)3-( 2-thienylurea 3 mg/kg, 10 mg/kg and 30 mg/kg respectively.

In contrast, the two unsubstituted compounds show in the maximal and minimal electroshock, in the rotary, rod test, in the fireplace test, in the antipentetrazole test and in the 3-mercapto-propionic acid test (all on mice) up to a dosage of 300 mg/kg no activity whatsoever", the 5-chloro compound shows in maximum electroshock an ED^ of > 100 mg/kg and in the 3-mer-^captopropionic acid test an ED^q of 76 mg/kg, while this compound in tests on a rotating rod, in the fireplace test and in the antipentetetrazole test. Similarly, activity is lacking up to a dosage of 300 mg/kg. The above-mentioned tests are common, well-known standard methods for determining sedative and muscle-relaxant effects.

The urea derivatives with the above-mentioned formula I can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be given orally, e.g. in the form of tablets, varnish tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, delivery can also take place rectally, e.g. in the form of suppositories, or

. parenterally, e.g. in the form of injection solutions.

For the production of tablets, varnish tablets, dragées and hard gelatin capsules, the urea derivatives with the above formula can be used. I is treated with pharmaceutically inert, inorganic or organic excipients. As such excipients, one can e.g. for tablets, dragees and hard gelatin capsules use lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof etc.

Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

When preparing solutions and syrups, suitable excipients are e.g. water, polyols, sucrose, invert sugar, glucose and the like.

Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerin, vegetable oils, etc.

Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc...

The pharmaceutical preparations may also contain preservatives, solubility enhancers, stabilizers, wetting agents > emulsifiers, sweeteners, coloring agents, flavoring agents, salts for changing osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable substances.

A suitable pharmaceutical dosage unit can contain approx. 0.5-

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50 mg, preferably 1-30 mg of a compound of the above

formula I. The dosage can vary greatly and must of course be adapted to the individual circumstances in each individual case. In general, with oral administration, a daily dosage of approx. 0.01 mg/kg to 2 mg/kg may be suitable. However, these dosages are only to be taken as examples, and the specific dosages must be adapted to the individual needs of each individual case.

In the following examples which illustrate the present invention, all temperatures are given in degrees Celsius.

Example 1

A suspension of 3.20 g (25.6 mmol) of 2-isocyanatothiophene and 2.90 g (25.6 mmol) of creatinine in 25 ml of anhydrous dimethylformamide is first stirred for 2 hours at room temperature and then for 1.5 hours at 55°C. The reaction mixture is then poured into water and the formed crystals are filtered off. Recrystallization of the residue from acetonitrile in pure 1-(1-methyl-4-oxo-2-imidazolin-2-yl)-3-(2-thienyl)-urea which melts with cleavage at 191-193°.

Example 2

A suspension of 2.20 g (17.6 mmol) of 3-isocyanatothiophene and 203 g (17.6 mmol) of creatinine in 20 ml of anhydrous dimethylformamide is first stirred for 2 hours at room temperature and then for 3 hours at 90°. The reaction mixture is then poured into water and the crystals formed are filtered off. Recrystallization of the residue from acetone gives pure 1-(1-methyl-4-oxo-2-imidazolin-2-yl)-3-(3-thienyl)-urea which melts with cleavage at 199-201°.

The 3-isocyanatothiophene used as starting material can be prepared as follows: 21.1 g (165 mmol) thiophene-3-carboxylic acid is heated with 36 ml (495 mmol) tipnyl chloride for 1 hour at reflux. The excess of thionyl chloride is then removed on a rotary evaporator under reduced pressure. Distillation of the residue in a water jet vacuum gives thiophene-3-carbonic acid chloride, boiling point 72-74°/14.3 mbar.

22.56 g (154 mmol) of thiophene-3-carboxylic acid chloride are dissolved in .400 ml of acetone, cooled to -5° and mixed at that temperature dropwise with a solution of 11.0 g (164 mmol) of sodium azide in .30 ml of water. The reaction mixture is then stirred for 1 hour at 0°. The reaction mixture is then mixed with 1 liter of water, extracted several times with toluene and the combined toluene extracts are washed with water. The combined toluene extracts are then dried over magnesium sulphate and thus heated to dryness.

' bored solution 2 hours at reflux. Then evaporates; loose-

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ning agent with a maximum of 30 and a pressure of 19.5 mbar on a rotary evaporator. Distillation of the residue in a water jet vacuum gives 3-isocyanatothiophene boiling point 45-46°/14.3 mbar.

Example 3

A solution of 15 g (80 mmol) of 5-chlorothiophene-3-carboxylic acid azide

-.in 155 ml abs. dioxane is heated under a nitrogen atmosphere for 3 hours under reflux. 9.33 g (82.5 mmol) of creatinine is then added to the reaction mixture containing 5-chloro-3-isocyanatothiophene and stirred for 3 hours at 95° under a nitrogen atmosphere. The dioxane is then evaporated to 2.0 ml, and the remainder is mixed with. 150 ml water and stir for 30 min. at room temperature. It precipitated. crystalline product is then filtered off and recrystallized 2 times from acetone with the addition of active carbon, whereby pure is obtained. 1-(5-chloro-3-thienyl)-3(1-methyl-4-oxo-2-imidazo-lin-2-yl)urea melting at 190-191°. 5-Chlorothiophene-3-carboxylic acid azide, which is used as starting material, can be prepared as follows: 15 g (92.3 mmol) of 5-chlorothiophene-3-carboxylic acid are dissolved in 70 ml of acetone, mixed with 9.7 g (95m9 mmol) of triethylamine, cooled to 0°. Then 15 g (0.14 mol) ethyl chloroformate is added dropwise and the mixture is stirred for 1/2 hour at 0°. Then, likewise at 0°, 9.3 g (0.14 mol) of sodium azide in 24 ml of water are added dropwise, and the reaction mixture is stirred for a further 1 hour at 0°. The precipitated triethylamine hydrochloride is filtered off and washed with acetone. The filtrate is evaporated for phase separation. The organic phase is then separated and the aqueous phase is extracted a further 3 times with 100 ml portions of methylene chloride. The combined organic extracts are dried and evaporated with a maximum bath temperature of 30° to dryness. Recrystallization of the residue from n-hexane gives pure 5-chlorothiophene-3-carboxylic acid azide melting at 54°. Example A

The active ingredient, milk sugar and corn starch are mixed together

first in a mixer and then in a mincing machine. The mixture is returned to the mixer, talc is added and mixed thoroughly. The mixture is filled mechanically into hard gelatin capsules.

Example B

The active substance, the milk sugar, the cornstarch and the gelatinized cornstarch are mixed well with each other. The mixture passes through a shredding machine and is then moistened with water to form a thick paste. The moist mass passes through a sieve. The moist granulate is dried at 45°. The dry granulate is thoroughly mixed with calcium stearate. The granulate is now pressed

tablets with a weight of 200 mg and a diameter of approx. 8 mm.

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Example C

Melt coconut butter and Carnauba wax in a glass or steel container, mix well and cool to 45°. Then you add

finely powdered active ingredient and stirs until it is completely dispersed. The mixture is poured into suitable suppository forms

size, allow to cool, then take the suppositories out of the molds and wrap them individually in wax paper or metal foil.

Example D

The active ingredient, the milk sugar and part of the cornstarch. mixed, sifted, treated with cornstarch - water paste. granulated, dried and sieved. The granulate is mixed with magnesium stearate and pressed into tablets of 170 mg and a suitable size. 1 in-

Claims (5)

1. Procedure for the production of urea derivatives with the general formula wherein R means 3-thienyl, 3-thienyl or 5-halo-3-thienyl, characterized by converting creatinine with formula with an isocyanatothiophene of the general formula wherein R has the meaning given above. 2. Method according to claim 1, characterized in that creatinine is reacted with 2-isocyanatothiophene or 3-isocyanatothiophene.. 3. Method according to claim 1, characterized in that creatinine is reacted with 5-chloro-3-isocyanatothiophene. 4. Process for the manufacture of pharmaceuticals, especially for use as anxiolytics, characterized in that one brings a urea derivative with the formula I specified in claim 1 and possibly one or more other therapeutically valuable substances in a galenic administration form. 5. Isocyanatothiophene derivatives of the general formula wherein is hydrogen or halogen.