MC1317A1 - DERIVATIVES OF UREA - Google Patents

Description

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The present invention relates to novel urea derivatives. It relates particularly to 1-(1-methyl-4-oxo-2-imidazoline-2-yl)-3-thienyl-ureas of general formula i>

CH3

NH—C NHR

N 0

N. n

10 in which R represents a 2-thienyl, 3-thienyl- group

nyle or 5-halogeno-3-thiënyle.

Compounds conforming to formula I above can also exist in the tautomeric form of the general formula

15 <rH3

rN\_ » the

I \=N—C — NHR Ia

H

20 in which R has the meaning indicated above.

The term "halogen" used in this description applies to the four halogens fluorine, chlorine, bromine and iodine, with chlorine and bromine being preferred - chlorine is the most appreciated.

25 The invention relates to urea derivatives of formula I above, their preparation and intermediate products of their preparation, and medicinal products containing a urea derivative of formula I above.

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and the preparation of these drugs as well as the use of a urea derivative of formula I above in the therapeutic and prophylactic use of diseases.

Urea derivatives conforming to formula I above can be prepared according to the invention by reacting creatinine of formula

CH,

I J

10 // ^NH2 11

with an isocyanatothiophene corresponding to the formula

OCN-R m in which R has the meaning indicated above.

15. Creatinine corresponding to formula II

The above is reacted according to known techniques with an isocyanatothiophene of formula III. For this reaction, approximately equimolar amounts of the two starting components are advantageously used. The reaction is preferably carried out in an inert, anhydrous, polar, aprotonic organic solvent. Examples of suitable solvents include ethers such as tetrahydrofuran or dioxane, dimethylformamide, dimethyl tallow oxide, hexamethyl-25-phosphorotriamide, and similar solvents. When the reaction is complete, the product is precipitated by adding cold water to the reaction mixture. The crude product can then be purified by recrystallization in a solvent.

30. The creatinine of formula II above, used as a starting component, is a known compound. Among the compounds corresponding to formula III above, 2-isocyanatothiophene is known, but the other compounds are new and also constitute an object of the present invention. 35. The 3-isocyanatothiophenes,

h

New compounds can be prepared by a procedure analogous to that used for the preparation of the known 2-isocyanatothiophene, advantageously starting from a thiophene-3-carboxylic acid which is converted in a known manner into a reactive derivative, for example, the corresponding acid chloride. This derivative is then converted in a known manner, by reaction with sodium nitrate and subsequent heating, into the desired 3-isocyanatothiophene. The reactive derivatives, for example, the acid chlorides, and the azides obtained as intermediate products do not necessarily need to be isolated. Even 3-isocyanatothiophene does not require isolation before its conversion into the corresponding urea derivative of formula I above. Thiophene-3-carboxylic acids are known compounds.

Urea derivatives corresponding to formula I are valuable drugs and can be used particularly as anxiolytics. The compounds of formula I described above have very low toxicity and have been found to possess highly selective anxiolytic activity, without the muscle-relaxing and sedative properties normally found in anxiolytics. This anxiolytic activity was demonstrated experimentally in an animal study described below.

The test device is a food pill dispenser that activates by pressing on the touch, called "Skinnerbox".

During 3 preliminary 1-hour trials (3 different days), food-deprived female Fullinsdorf rats (SPF, 190-230 g) were trained to press the button on the food pill dispenser to obtain 45 mg food pills (each press of the button caused the dispensing of the food pills).

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of food); in the third preliminary trial, the rats reached a rate of 150 to 200 touch maneuvers per hour.

In a fourth preliminary trial, each of the food deliveries triggered by pressure on the touch was accompanied by a short electric shock to the foot (1.0 mA). Rats confronted with this conflict situation initially manipulated the touch approximately 5 to 10 times, then ceased completely out of fear.

In a fifth preliminary trial, the rats can again press the button on the nutrient pill dispenser without shock to the foot, and they regain the rate of 150 to 200 key presses per hour.

For a sixth preliminary trial, experimental animals are selected. Half an hour before the start of this preliminary trial, the animals are administered orally 10 mg/kg of chlordiazepoxid; each feeding is again accompanied by a tap on the foot (conflict). Only rats that, in this preliminary trial, achieve a cadence of 20 to 50 tapping maneuvers (compare with 5 to 10 maneuvers in the fourth preliminary trial) are retained as suitable experimental animals for the study of potential anxiolytics. The elimination rate in this preliminary trial is 5%.

In the main trial, for the study of the potential anxiolytic, 30 is generally used

8 rats per substance and per dose. It is not necessary to use a group of untreated control animals since each animal constitutes its own control. The comparator substances are in solution or suspension in a mixture of 10 ml of distilled water and

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Two drops of Tween 80 are administered to the animals via a gastric tube 30 minutes before the main 1-hour trial. During this trial, in which each press of the button causes both the delivery of food and a shock to the foot (conflict), the number of button maneuvers per hour is recorded.

significant is determined by the Wilcoxon test (pair comparison): the number of touch maneuvers in the main test (blow to the foot, after treatment with the substance under test) is directly compared with the number of touch maneuvers in the control test (blow to the foot, after treatment with a sodium chloride solution).

The dose exhibiting significant anxiolytic activity for 1-(5-chloro-3-thienyl)-3-(l-methyl-4-oxo-2-imida-zoline-2-yl)-urea, 1-(l-methyl-4-oxo-2-imidazoline-2-yl)-3-(3-thienyl)-urea and 1-(l-methyl-4-oxo-2-imi-dazoline-2-yl)-3-(2-thienyl)-urea is respectively 3 mg/kg, 10 mg/kg and 30 mg/kg.

killed, in the maximum and minimum electroshock, in the rotating rod test, in the chimney test, in the anti-pentetrazol test and in the 3-mercaptopropionic acid test (all on mice) showed no activity at a dose below 300 mg/kg; the chlorinated compound at position 5- showed activity at the maximum electroshock above 100 mg/kg and in the test at

3-Mercaptopropionic acid has an ED5Q of 76 mg/kg.

whereas this compound, in the rotating rod test, the chimney test, and the anti-pentetrazol test, also shows no activity at doses below 300 mg/kg. The tests mentioned above constitute-

The first dose having an activity

In the essay described above, the first

However, the two non-substitutive compounds

6

10

15

20

25

30

They kill classic and well-known methods for determining sedation and muscle relaxation activity.

Urea derivatives conforming to formula I above can be used as medicinal products, for example in the form of pharmaceutical preparations. These preparations can be administered orally, for example as tablets, coated tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, they can also be administered rectally, for example as suppositories, or parenterally, for example as solutions for injection.

For the preparation of tablets, coated tablets, dragees, and hard gelatin capsules, the urea derivatives of formula I above can be mixed with pharmaceutically inert mineral or organic excipients. Examples of such excipients that can be used for tablets, dragees, and hard gelatin capsules include lactose, corn starch and its derivatives, talc, stearic acid and its salts, etc.

Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, liquid and semi-solid polyols, etc.

Examples of suitable excipients for the preparation of solutions and syrups include polyol water, sucrose, invert sugar, glucose, and similar excipients.

Examples of substances used for injection include water, alcohols, polyols, glycerin, and vegetable oils.

The excipients that are suitable for solutions etc.

Suitable excipients for suppositories include, for example, natural or hydrogenated oils, waxes, fats, liquid or semi-solid polyols and similar excipients.

In addition, pharmaceutical preparations may contain preservatives, solubilizing agents, stabilizers, wetting agents, emulsifying agents, sweeteners, colorings, flavoring agents, salts used to modify osmotic pressure, buffers, coating agents, or antioxidants. They may also contain other substances with therapeutic activity.

A suitable pharmaceutical dosage unit may contain from approximately 0.5 to 50 mg, and preferably from 1 to 30 mg, of a compound of formula I above. The dosage may vary within wide limits and should, of course, be tailored to the specific circumstances of each case. In general, for oral administration, a daily dosage of approximately 0.01 to 2 mg/kg may be considered. These doses should be regarded merely as examples; the specific dosage must be tailored to the particular needs of each case.

In the following examples, which illustrate the invention without limiting its scope, all temperature indications are in degrees Celsius.

Example 1

A suspension of 3.20 g (25.6 millimoles) of 2-isocyanatothiophene and 2.90 g (25.6 millimoles) of creatinine in 25 ml of anhydrous dimethylformamide is first shaken for 2 hours at room temperature and then for 1 hour 30 minutes at 55°C. The reaction mixture is then poured into water and the crystals are filtered.

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rates that have formed. Recrystallization of the residue in acetonitrile gives pure l-(l-methyl-4-oxo-2-imida-zoline-2-yl)-3-(2-thienyl)-urea which melts at 191-193°C (dec.).

5 Example 2

A suspension of 2.20 g (17.6 millimoles) of 3-isocyanatothiophene and 2.03 g (17.6 millimoles) of creatinine in 10 20 mL of anhydrous dimethylformamide is first stirred for 2 hours at room temperature and then for 3 hours at 90°C. The reaction mixture is then poured into water and the crystals that have formed are filtered. Recrystallization of the residue in acetone yields pure l-(l-methyl-4-oxo-2-imidazoline-2-yl)-3-(3-thienyl)-urea, which melts at 15 199-201°C and decomposes.

The 3-isocyanatothiophene used as a starting component can be prepared as follows:

21.1 g 2O (165 millimoles) of thiophene-3-carboxylic acid is heated under reflux for 1 hour with 36 ml (495 millimoles) of thionyl chloride. The excess thionyl chloride is then removed using a rotary vacuum evaporator. Distillation of the residue under vacuum using a water aspirator gives thiophene-3-carboxylic acid chloride boiling at 72-74°C/14.3 mbar.

22.56 g (154 millimoles) of thiophene-3-carboxylic acid chloride is dissolved in 400 ml of acetone, cooled to -5°C, and a solution of 11.0 g is added dropwise at a time, at this temperature.

(164 millimoles) of sodium azide in 30 ml of water. The reaction mixture is then stirred for 1 hour at 0°C. Then 1 liter of water is added, the toluene extract is extracted repeatedly, and the toluene extracts are washed with water. The extracts are dried.

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Combined toluenics are added to magnesium sulfate and the solution is heated for 2 hours under reflux. The solvent is evaporated at a maximum temperature of 30°C under a pressure of 19.5 mbar using a rotary evaporator.

5. Distillation of the residue under vacuum in the aspirator

water gives 3-isocyanatothiophene boiling at 45-46°C/ 14.3 mbar.

Example 3

A solution of 15 g (80 millimoles) of 5-chlorothiophene-3-carboxylic acid azide in 155 mL of absolute dioxane is heated under reflux for 3 hours in 10 atmospheres of nitrogen. To the reaction mixture, which contains 5-chloro-3-isocyanatothiophene, 9.33 g (82.5 millimoles) of creatinine is added, and the mixture is stirred in a nitrogen atmosphere for 3 hours at 95°C.

The dioxane is then evaporated to a residual volume of 20 ml, 150 ml of water is added to the residue and the mixture is stirred for 30 minutes at room temperature. The crystallized product is filtered and recrystallized twice in 20 ml of acetone, treating with activated charcoal; the resulting product is l-(5-chloro-3-thienyl)-3-(l-methyl-4-oxo-2-imidazo-line-2-yl)-urea, which melts at 190-191°C.

The azide of 5-chlorothiophene-3-carboxylic acid used as a starting component can be prepared in the following manner:

Dissolve 15 g (92.3 millimoles) of 5-chlorothiophene-3-carboxylic acid in 70 ml of anhydrous acetone, add 9.7 g (95.9 millimoles) of triethylamine, and cool to 0°C. Then add, drop by drop

30 15 g (0.14 mol) of ethyl chloroformate is added and stirred for another 30 minutes at 0°C. Then, also at 0°C, 9.3 g (0.14 mol) of sodium azide in 24 ml of water is added dropwise, and the reaction mixture is stirred for 1 hour at 0°C. 35 The triethylamine hydrochloride precipitate is filtered and...

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Wash with acetone. Concentrate the filtrate until phase separation occurs. Separate the organic phase and extract the aqueous phase three times with 100 mL of methylene chloride each time. Dry the combined organic extracts and evaporate them to dryness at a maximum bath temperature of 30°C. Recrystallization of the residue in n-hexane yields the azide of pure 5-chlorothiophene-3-carboxylic acid, which melts at 54°C.

Example A

Capsule preparation

For one capsule

1-(1-methyl-4-oxo-2-imidazoline-

2-yl)-3-(3-thienyl)-urea 10 mg, lactose 165 mg, corn starch 30 mg, talc 5 mg, total capsule content 210 mg. The active substance, lactose, and corn starch are first passed through a mixer and then a grinding machine. The product is returned to the mixer, the talc is added, and the mixture is thoroughly blended. The mixture is then machine-filled into hard gelatin capsules.

Example B

Tablet preparation

For one tablet

1-(l-methyl-4-oxo-2-imidazoline-

2-yl)-3-(3-thienyl)-urea 10.0 mg, lactose 129.0 mg, corn starch 50.0 mg, gelatinized corn starch 8.0 mg, calcium stearate 3.0 mg, total weight 200.0 mg

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The active ingredient, lactose, corn starch, and gelatinized corn starch are thoroughly mixed. The mixture is then passed through a milling machine and a thick paste is formed by moistening it with water. The moistened mass is then passed through a sieve. The granules are dried at 45°C. The dried granules are thoroughly mixed with calcium stearate. The granules are then machine-formed into 200 mg tablets with a diameter of approximately 8 mm.

Example C: Preparing suppositories

For one suppository l-(l-methyl-4-oxoimidazoline-2-

(yl)-3-(3-thienyl)-urea 0.010 g cocoa butter (p.f.: 36 to 37°C) 1.245 g carnauba wax 0.045 g per 1.3 g suppository. Melt the cocoa butter and carnauba wax in a glass or steel container, mix thoroughly, and cool to 45°C. Then add the finely powdered active ingredient and stir until completely dispersed. Pour the mixture into appropriately sized suppository molds, allow to cool, unmold, and individually wrap in waxed paper or foil.

Example D: Tablet Preparation

For one tablet

l-(5-chloro-3-thienyl)-3-(l-methyl-4-oxo-2-iraidazoline-2-yl)-derived 2.0 mg lactose 100.0 mg corn starch 67.5 mg magnesium stearate 0.5 mg total weight 170.0 mg

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The active substance, lactose, and a portion of corn starch are mixed. This mixture is sieved, combined with a paste made from the remaining corn starch, granulated, dried, and sieved. The granules are then mixed with magnesium stearate and pressed into 170 mg tablets of appropriate size.

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Claims (5)

CLAIMS 1. A process for preparing urea derivatives having the general formula CH3 0 X N' « 1 >— NH— C NHR in which R represents a 2-thienyl, 3-10-thienyl or 5-halogeno-3-thienyl group the process is characterized by the fact that creatinine is reacted according to the formula CH3 I 5 r 15 \ A—NH- H with an isocyanatothiophene corresponding to the general formula OCN-R in which R has the meaning indicated above. 2. A process according to claim 1, characterized in that creatinine is reacted with 2-isocyanatothiophene or 3-isocyanatothiophene. 25 3. A process according to claim 1, characterized in that creatinine is reacted with 5-chloro-3-isocyanatothiophene. 4. Process for preparing medicinal products, usable in particular as anxiolytics, this 30 process characterized in that a urea derivative of formula I according to claim 1 and where appropriate one or more other substances of therapeutic interest are put in a galenic administration form. 35' 14 5. Isocyanatothiophene derivatives corresponding to the general formula H 0 C N H 10 in which R represents hydrogen or a halogen. S 0c\0^\oo? <jorc\pceo<3uiV J^5 Feufîfe^S Without reference of «noV au? «V nf moV o^ooVe