KR800000039B1 - 4-oxo-2-imida zolidinylidene ureas - Google Patents

Abstract

Title compds. (I; R1, R2 = H, lower alkyl, R3 = H, aryl, R4=H. aryl, arylalkyl, Ar=aryl, but R3=R4≠2, 6-disubstituted aryl) useful as muscle relaxants in mice at 2.5-40 mg/kg, were prepd. by treating 2-aminoimidazolidin-4-on(II) with arylisocyanate in anhydrous and reactive organic solvents as dioxan, hexahydrofuran, 1,2-dimethoxy-ethane, polyether, N,N-dimethylformamide, dimethylsulfoxide, etc.

Description

Method for preparing 4-oxo-2-imidazoridinylidene urea

The present invention relates to a method for producing a novel 4-oxo-2-imidazoridinylidene urea represented by the following general formula.

In the above formula

R ₁ is selected from hydrogen and lower alkyl, in particular hydrogen

R ₂ is selected from hydrogen and lower alkyl and methyl is more suitable

R ₃ is selected from hydrogen and aryl, hydrogen is more suitable

R ₄ is selected from hydrogen, aryl and arylalkyl, with hydrogen being suitable

Ar is aryl under the condition that the R ₃ and R ₄ groups are different from the 2,6-di-substituted aryl

This limitation of the R ₃ and R ₄ is given, so will the production of such compounds is difficult because of steric hindrance to occur Without manil R ₃ and R ₄ have this limitation.

As used herein, "lower alkyl" and "lower alkoxy" are straight or branched chains, e.g., methyl, ethyl, propyl, isopropyl, pentyl, octyl, etc., and 1-8 carbon atoms such as ethoxy, ethoxy. Refers to alkyl and alkoxy having “halo” refers to pullouro, bromo, chromo and iodine. "Aryl" includes phenyl, nitrophenyl, trifluuromethylphenyl, diloweralkylaminophenyl and 1-3 substituted phenyls selected from the group consisting of halo, lower alkyl and lower alkoxy. "Arylalkyl" means benzyl, phenethyl, phenpropyl, and the like and aryl alkyl ground, more suitable arylalkyl is benzyl.

Compounds of general formula (I) in which R ₁ or R ₂ (or both) are hydrogen exist in several isomeric forms other than those represented by general formula (I).

These forms are represented by

In the above formula

R ₁ , R ₂ , R ₃ , R ₄ and Ar are as described above.

Besides the general formula (I), 4-oxo-2-imidazoridinilidene urea is easily obtained by reacting a suitable 2-imino-imidazoridin-4-one (II) with a suitable aryl isocyanate (III). It is preferable to use a slight excess of reactant for complete reaction with aryl isocyanates.

The reaction may be, for example, a polyether solvent such as dioxane, tetrahydrofuran (THF) 1,2-dimethoxy-ethane, dimethyl ether of diethylene glycol, or the like; N, N-dimethylformamide (DMF): Dimethylsulfoxide (DMSO): It is carried out in anhydrous, polar inert organic solvents such as hexamethyl phosphate triamide and other similar organic solvents. After the reaction is completed, a significant amount of 2-amino-1-R-imidazoridin-4-one reactant (II) is filtered off and the desired product is recovered, usually by adding cooling water to the reaction mixture. The crude product is then purified from suitable organic solvents by standard recrystallization methods.

When the purified product is obtained in the form of large crystals, it is pharmacologically advantageous to refine the crystal size by, for example, known standard methods such as milling and reprecipitation. These methods are known to increase the enhanced absorption and physiological availability of a given drug.

Compounds of formula (I) were found to have useful anti-secretory activity by following mouse tests for acute gastric fistulas. The anti-secretory action of the compound to be tested was studied by injecting the compound into the internal duodenum of Dowray female rats at a dosage of 2.5-40 mg / kg body weight. Mice are fasted 24 hours before testing and placed in individual guts and watered only. The mice to be tested are weighed and selected so that each mouse to be tested is within ± 20 g. After anesthesia with ether, remove it with small forceps. Cut the stomach to about 15cm in length and expose the stomach duodenum. Discard the rat if it is filled with gastric food or dung material.

Use a 4-0 merylene (a trademark of Johnson and Johnson or a Subsidiary company) to make a drawstring on the base, taking care not to penetrate any vessels around it. Make a small gold in the stomach in the center of the drawstring, place a cannula of small vinyl tubes with a rim on the top, and draw a string tightly around the rim. To administer. In general, three rats are used for each dose to be used for each dose to be tested and the comparison rats are usually given only 0.5% liquid methylcellulose as the test solution.

After administration of the test compound, the stomach wall and skin are simultaneously tied with 3-4 18 mm clips and sealed, and the recovery test tube is placed in a cannula. Place each rat in a box that is made horizontally and allows the cannula to hang freely and allow the rat to move freely.

After the rats are allowed to rest for 30 minutes, the collecting tube on the cannula is discarded and replaced with a clean tube to receive gastric juice. After 1 hour of recovery, the cannula is removed and the rats are sacrificed. The collected gastric juice sample is placed in a centrifuge tube, centrifuged to precipitate a precipitate, and the volume is read. 1 ml of the homolog is placed in a beaker containing 10 ml of distilled water and titrated to pH 7 using 0.01 N sodium hydroxide. Results are measured for dose, titrative acid and total acid content, where the total ml-precipitate of gastric juice: the amount of 0.01 N sodium hydroxide required to titrate titrateable acid (pre-equivalent weight / l) acid to pH7 Is titratable acid x capacity. The results were reported as% inhibition. Most of the compounds of the present invention, particularly compounds of formula (I) in which Ar is not three substituted phenyls, exhibit useful anti-secretory activity when measured in this test.

It has also been found that compounds of formula (I) have useful central nerve suppression as shown in the next test on test animals.

Test A: Anti-Anxiety Assay

Anti-anxiety is described in I, Geiler in Psychomatic Medicine, eds J.H. Nadine and J. H. Mayer (Lea and Febiger Phila.) 267 (1962) and Psychopharmacolgoic (Berl.)

13,74-80 (1968) in D.L. Evaluation was as reported by Marcures and L, Spain. The anti-anxiety action of the compound to be tested is usually studied in rats for 5 days after the injection of internal twelve (ip) doses of 5-25 mg / kg (body weight). Observe the animal's bar presing rate. This method consists of the effect of the test compound on the response when not treated and when treated. Hungry rats are trained to push rods to provide food. That is, local milk is given every two minutes to the rat. Under this plan, when the rod is pressed 12 minutes later, a sound for punishment and a punishment will be heard for 3 minutes. (Each time the rod is pressed, it provides local full milk and shocks through the bottom of the grid.) The shock delivered is 0.2 milli-seconds in duration and 0.5-3.5 milli-amps in intensity. Each rat alternates between four and six times the non-penalty given for milk only and the punishment for giving milk and shock. The response of the control group is obtained after each day of 5 days of saline injection for each rat and each rat is evaluated at the same time and in the same test box every day. The reaction is recorded and the feeding (milk) and punishment (shock) is by means of a suitable automatic device. The functionality of the compound to be tested is assessed by comparing the rod pressure number after feeding only the solvent with the rod pressure number after feeding the compound.

Exam B:

Muscle-relaxation is described in M. J. orloff et al, Proc, soc, Exp. Buol, and Med. 70 253 (1049) as modofied by G.chem and B. Bohner, J. Phamlacol Exp.t Terap 117, 142 (1956)

Evaluate the judgment of the effect of the test compound on strikin-induced seizures as described below.

Anti-stricknin action is determined by the effect of the compound in the early stages of seizures-induced seizures following oral administration to mice of 25-5,000 mg / kg body weight.

Test C: Mouse behavior is assessed as described in S. lrwin, Gordon Research Conference on Medical chemistry1959 p.133. In this assessment, a compound tested at a dose of 10-300 mg / kg body weight was administered to 12 internal organs of the mouse and observed for walking impairment, decreased activity, and loss of clove reflection.

R₄=수소 R₂는 메틸이며 Ar가As a result of this test, the amount of an effective central nervous inhibitor of the compound of formula (I) mixed with a pharmaceutically acceptable carrier may be administered to warm-blooded animals, including humans, to induce central nervous suppression. For this purpose, the amount of active ingredient when used in the above-mentioned unit dosage form is used in a single unit dose of 15-500 mg, in particular 15-250 mg. Suitable compounds of the invention are wherein R ₁ = R

R ₄ = hydrogen R ₂ is methyl and Ar

(Where X is selected from hydrogen, halo, methyl methoxy, ethoxy, and tripulouro-methyl) and the most suitable compound is R ₁ = R ₃ = R ₄ = hydrogen R ₂ is methyl and Ar is

Where X is selected from hydrogen, methyl, methoxy, chloro, bromo and tripulomethyl. These are particularly useful as anti-anxiety agents. The present invention is suitable for reducing the anti-anxiety of the above-mentioned compounds, which are effective as active ingredients, for example, in people whose anxiety has impaired their ability to cope with the various requirements of everyday life or who have anxiety adversely affect physical well-being. It provides a method of reducing anxiety by administering at a concentration.

15-500 mg of the active ingredient of the present invention is used in unit dosage form for anti-anxiety purposes, and the most suitable amount for human use of the most suitable compound described above is administered orally or orally 3-4 times a day. Administered 15-500 mg.

Suitable compounds of formula (I) for the purpose of relaxing skeletal muscle are those in which R ₁ = R ₃ = R ₄ = hydrogen R ₂ is methyl and Ar is selected from the following general formula.

In the above formula

A is selected from halo and lower alkyl

B is selected from halo lower alkyl

C is selected from halo, lower alkyl lower alkoxycripulomethyl and dimethylamino, D is halo, E is lower alkyl and F is lower alkyl

The present invention is an active ingredient for a person suffering from muscle spasms or chronic lower keel rods, for example.

Provided are methods for attenuating muscle pain, including administering the above-described compounds at an appropriate concentration to depart effective skeletal muscle relaxation response.

A unit dosage form containing 15-500 mg of active ingredient is used for muscle relaxation purposes and the appropriate amount for administering such a suitable compound to humans is 15-500 mg orally or parenterally administered 3-4 times a day.

The following examples are not intended to suggest the scope of the present invention but are intended to be illustrative and all parts are to be understood.

Example 1

1.68 g to a suspension of creatinine (5.66 g, 0.05 mole) in 150 ml of 1-m-chlorophenyl-3- (1-methyl-4-oxo-2-imida cookedinylidene urea in dry dimethylformamide (DMF) (0.05 mole) of m-chlorophenylisocyanate is added and the mixture is stirred for 2 hours and then heated in a steam bath for 30 minutes to clarify the solution (yellow). Water is added to the filtrate.

When a light yellow solid precipitates, it is filtered and recrystallized from acetone-methanol and tetrahydrofuran-ether to give pure product 1-m-chlorophenyl-3- (1-methyl-4-oxo-2- with a melting point of 180-180.5 ° C. Imidasoriridinylidene) urea.

Assay: for C ₁₁ H ₁₁ CIN ₄ O ₂

Calculated: C, 49.54; H, 4.16%

Found: C, 49.45; H, 4.19%

Example 2

1-m-chlorophenyl-3- (1-methyl-4-oxo-2-imida cookinylidene) urea hydrate

120 g of pure 1-m-chlorophenyl 3- (1-methyl-4-oxo-2-imidazoridinylidene) urea obtained in Example 1 was dissolved in 400 ml of dimethylformamide and 3.5 L of Pour in water.

The resulting 1-m-chlorophenyl-3- (1-methyl-4-oxo-2-imidazoridinylidene) ureahydride high temperature crystals were recovered by filtration, washed with water and dried at room temperature for 4 hours. Drying in a vacuum of 5.0 mm (room temperature) for 8 hours yields about 120 g of product having a melting point of 180.5-181.5 ° C.

Assay: for C ₁₁ H ₁₁ ClN ₄ O ₂ H ₂ O

Calculated Value: C, 46.41; H, 4.60; H ₂ O, 6.33, N, 18.64%

Found: C, 46.43: H, 4.62; N, 19.83, H ₂ O 6.37, 6.41%

Example 3

1- (2,6-dichlorophenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea

Substitute an equivalent of 2,6-dichlorophenyl isocyanate in place of the m-chlorophenyl isocyanate used and according to the process of Example I 1- (2,6-dichloro with a melting point of 211-212 ° C. (decomposition) Phenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea.

Analysis of C ₁₁ H ₁₀ Cl ₂ N ₄ O ₂

Calculated: C, 53.8 H; 3.35%

Found: C, 43.55 H; 3.31%

Example 4

1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-P-methoxyphenylurea

P-methoxy phenylisocyanate (14.91 g, 0.100 mol) is added dropwise over 15 minutes while cooling to a stirred suspension of creatinine (11.88 g, 0.105 mol) in 100 ml of dry DMF.

After stirring for 8 hours, the mixture was poured into 500 ml of ice water to give a white crystalline product which was filtered, washed with water and purified by recrystallization (twice) from tetrahydrofuran-methanol. The crystal product is microcrystallized by adding the solution of the product dissolved in the minimum DMF to the stirred water (about 1.1 L) and leaving the resulting crystal for 24 hours under vacuum at room temperature after filtration.

Melting Point: 193.5 ℃ (Decomposition)

Example 5

Subsequent to the process of Example 4, equivalents of the appropriate imidazoridin-4-one and the appropriate aryl isocyanate are obtained to yield the following respective products.

1- (1-methyl-4-oxo-2-imidazoridinylidene) -3- (3.4-dichlorophenyl (urea hemihydrate: melting point 199-202 ° C (decomposition): 1- (1-methyl 4-ozo-2-imidazoridinylidene) -3-P-methoxyphenylurea hydrate melting point 144 DEG C and 1-m-chlorophenyl-3- (4-oxo-2-imidazoridinyl) Den)

Urea: Melting Point 225-227 ℃ (Decomposition)

Example 6

1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-P-chlorophenylurea

To a stirred suspension of creatinine (11.88 g, 0.105 mole) in 100 ml of dry DMF was added dropwise cooling P-chlorophenylisocyanate (15.36 g, 0.100).

The mixture was stirred for 16 hours, then poured into 500 ml of ice water, the resulting crystals were filtered off, washed with water, recrystallized from tetrahydrofuran (THF) twice from acetone-methanol and from methanol and dried for 24 hours in vacuo. Pure 1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-P-chlorophenylurea having a melting point of 190-2 ° C. (decomposition) is obtained.

Example 7

1- (1-Methyl-4-oxo-2-imidazoridinylidene) -3-P-torylurea

To a stirred suspension of creatinine (11.88 g, 0.105 mol) in 100 ml of dry DMF was added dropwise over 15 minutes with cooling of P-tolyl isocyanate (13.31 g, 0.100 mol). After stirring for 3.5 hours, the mixture was poured into 500 ml of ice water. The crystal product is filtered off and washed with water.

With acetone-methanol, then recrystallization from THF-methanol gives pure 1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-Ptolylurea.

The crystal grains are made into finer particles by adding the obtained product solution dissolved in minimal DMF to 1.1 L of finely stirred water, filtering and then drying the resulting fine crystals in vacuo for 24 hours.

Melting Point 198-200 ℃ (Decomposition)

Example 8

1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-m-tolylurea

Prepared by repeating the process of Example VII by substituting the equivalent of m-tolyl isocyanate in place of the P- toryl isocyanate used. Reaction time is 6 hours and twice with THF-methanol

Recrystallization: Melting Point 183-185 ℃ (Decomposition)

Example 9

1- (1-Methyl-4-oxo-2-imidazoridinylidene) -3-trifluorofluoromethyl-phenylurea

Prepared by repeating the process of Example V with an equivalent of m-tripulofluorophenylisocyanate in place of the used P-phoryl isocyanate, with a reaction time of 6 hours and recrystallized from acetone-methanol

Melting Point 197-8 ℃ (Decomposition)

Example 10

1- (1-methyl-4-oxoimidazoridinylidene) -3- (2,6-cysyl) urea

A suspension of 5.66 g (0.05 mole) of creatinine and 7.36 g (0.05 mole) of 2.6-cycylyl isocyanate was heated under reflux overnight (about 15 hours) in 200 ml of dry THF, then the hot solution was filtered Dilute with ether to a total volume of 400 ml to form a crude product.

Recrystallization with methanol yields pure 1- (1-methyl-4-oxoimidazoridinylidene) -3- (2.6-cyrylyl) urea with a melting point of at least 190 ° C (decomposition).

Analysis of C ₁₃ H ₁₆ N ₄ O ₂

Calculated: C, 59.98; H, 6.20%

Found: C, 60.17; H, 6.24%

Example 11

1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-phenylurea

Except for substituting the equivalent of phenylisocyanate in place of the P-methoxyphenyl-isocyanate used, the process of Example VI was repeated, yielding 1- (1-methyl-4) having a melting point of (185 ° C) 187-9 ° C as the final product. Oxo-2-imidazoridinylidene) -3-phenylurea is obtained.

Example 12

Each of the following products is obtained by repeating the process of Example VI except that the equivalent of 2-amino-1-lower alkylimidazoridin-4-one and the appropriate aryl isocyanate are used as reactants.

1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-phenylurea

3-m-bromophenyl-1- (1-methyl-4-oxo-2-imidazoridinylidene) urea: melting point-183-184 ° C. (decomposition)

3-m-ethoxyphenyl-1- (1-n-octyl-4-oxo-2-imidazoridinylidene) urea

3-m-ethylphenyl-1- (1-ethyl-4-oxo-2-imidazoridinylidene) urea

1- (3.4-dimethylphenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea melting point 219-221 ° C (decomposition)

1- (P-trifluorofluoromethylphenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea: melting point 197-200 ° C (decomposition)

1- (P-Tbutylphenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea: melting point 188-189 ° C

1- (3-n--propylphenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea: Melting point 167-168 ° C

Example 13

1- (3-chlorophenyl) -3- (1,3-dimethyl-4-oxo-2-imidazolinylidene) urea

6.35 g (0.050 mole) of 1,3-dimethyl-2-iminoimidazoridin-4-one, 7.85 g (0.050 mole) of 3-chlorophenylisocyanate and 75 ml of dry tetrahydrofuran at room temperature After stirring for 4 hours, the solution is evaporated in vacuo and the residue is crystallized from acetonitrile. Pure 1- (3-chlorophenyl) -3- (1,3-dimethyl-4-oxo-2-imidazoridinylidene) urea having a melting point of 134-137 ° C when determined twice from acetonitrile-ether Get

Example 14

1- (3-Chloro-2,6-dimethylphenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea

To a stirred suspension of 7.92 g (0.07 mole) of creatinine in 50 ml of dry DMF was added 9.08 g (0.05 mole) of 3-chloro-2,6-dimethylphenylisocyanate and stirred for 4 hours before the reaction mixture was unreacted creatinine. Filtration through diatomaceous earth pad to remove and adding excess ice water precipitates a semisolid mass like gum. The product is blown for 18 hours to dry and then recrystallized from acetone-ether.

The final product is placed in dichloromethane and the resulting solution is filtered through diatomaceous earth.

Concentration and dilution with ether gives 1- (3-chloro-2,6-dimethylphenyl-3- (1-methyl-4-oxo-2-imidazolidinide) as a pure product with a melting point of 140-141.5 ° C. Get urea.

Example 15

1- (2,6-dimethylphenyl) -3- (5,5-diphenyl-4-oxo-2-imidazoridinylidene) urea

Treatment of a suspension of 6.95 g (0.0306 moles) of 5,5-dimethyl-2-amino-2-imidazolyl-4-one in 300 ml of dry DMF with 4.5 g (0.0306 moles) of 2,6-dimethylphenyl isocyanate do. The reaction mixture is stirred at 40 ° C. for 2 hours, then poured into cooled water and the solid obtained is filtered.

Add 30 ml of water while heating the crude product and add acetone (1.5 L) to the heated slurry until all solids are in solution. The solution was evaporated to a volume of 300 ml and the solid formed by cooling was filtered and pure 1- (2,6-dimethylphenyl) -3- (5,5-diphenyl-4-oxo-2 without melting point up to 350 ° C. was obtained. -Imidazodininiden) urea is obtained.

Analysis of C ₂₄ H ₂₂ N ₄ O ₂

Calculated: C, 72.32; H, 5.56%

Found: H, C, 72.00; 5.68%

Example 16

1- (1,3-dimethyl-4-oxo-2-imidazoridinylidene) -3- (2,6-dimethylphenyl) urea

A mixture of 6.35 g (0.050 moles) of 1,3-dimethyl-2-iminoamazoridin-4-one and 7.25 g (10,050 moles) of 2,6-dimethylphenylisocyanate in 75 ml of dry tetrahydrofuran was prepared at room temperature. After stirring for 2 hours at reflux for 30 minutes.

The reaction mixture is evaporated in vacuo and the remaining solid is crystallized with tetrahydrofuran-ether.

Two more recrystallizations from the same solvent mixture give pure product 1- (1,3-dimethyl-4-oxo-2-imidazoridinylidene) -3- (2,6-dimethyl with a melting point of 115.5-188.5 ° C. Phenyl) urea is obtained.

Example 17

The process of Example 16 by substituting the equivalent imidazoridin-4-one and the appropriate aryl isocyanate in place of 1,3-dimethyl-2-iminoimidazoridin-4-one and 2,6-dimethylphenylisocyanate. According to the following products are obtained.

1- (3-chlorophenyl) -3- (1-octyl-4-oxo-2-imidazoridinylidene) urea, melting point 98-100 ° C

1- (1-octyl-4-oxo-2-imidazoridinylidene) -3-phenylurea, melting point 109.5 -110 ° C

1- (3-chlorophenyl) -3- (1-methyl-4-oxo-5-benzyl-2-imidazoridinylidene) urea, melting point 167-168 ° C.

1- (1-methyl-4-oxo-5-benzyl-2-imidazoridinylidene) -3-phenylurea, melting point 158-160 ° C

Example 18

1- (1-Methyl-4-oxo-2-imidizoridinylidene) -3-m-nitrophenylurea

To a stirred slurry of 12.45 g of creatinine in 100 ml of dry DMF was added 16.41 g (0.1 mol) of m-nitrophenylisocyanate (precrystallized from benzene-pentane) and after 9 hours the ice water gradually became crystallized until crystallization occurred. Is added. The addition of excess ice water precipitates crystals such as chewing gum.

THF-water then recrystallized from THF pure product 1- (1-methyl-4-oxo-2-imidazoridinylidene) -3-m-nitrophenylurea with melting point 182-188 ° C (decomposition) Get

Example 19

Subsequent replacement of 2,6-dimethylphenylisocyanate with an equivalent amount of arylisocyanate, which was followed and used according to the process of Example XIII, gave the following product.

1- (1-methyl-4-oxo-2-imidazoridinylidene) -3- (P-nitrophenyl) urea, melting point 220-223 ° C (decomposition)

1- (P-dimethylaminophenyl) -3- (1-methyl-4-oxo-2-imidazoridinylidene) urea: Melting point 210-216 ° C (decomposition)

Example 20

Following the process of Example X and substituting the used creadinine and 2,6-cycylyl isocyanate with an equivalent of suitable imidazoridin-4-one and the appropriate aryl isocyanate, each of the following products is obtained.

1- (3-chlorophenyl) -3- (3-methyl-4-oxo-2-imidazoridinylidene) urea melting point 169-171 ° C

Claims (1)

4-oxo-2-imidazoridinylidene urea having the following general formula (I) characterized by reacting a compound of the general formula (II) with a compound of the general formula (III) in a non-aqueous organic solvent Manufacturing Method

In the above formula R ₁ is hydrogen or lower alkyl R ₂ is hydrogen or lower alkyl R ₃ is hydrogen or aryl R ₄ is hydrogen, aryl or aryl alkyl Ar is aryl. Provided that R ₃ and R ₄ are other than 2,6 di-substituted.