Pharmaceutical composition containing 1,3,5-substituted biuret compound

The present invention relates to a pharmaceutical composition containing a 1,3,5-substituted biuret compound. More particularly, the present invention relates to an analgesic, anti-inflammatory or antipyretic composition containing as the active ingredient 1,3,5-substituted biuret compound of the formula (1), ##STR2## wherein R.sup.1 is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group having chlorine atom(s), cyano group(s), dimethylamino group(s), hydroxy group(s), methoxy group(s) or carboxy group(s) as the substituent(s), a lower alkenyl group, a hydroxy group, a methoxy group, an acetyl group or a phenyl group; R.sup.2 is a hydrogen atom, a lower alkyl group or a phenyl group; R.sup.3 is a phenyl group, a substituted phenyl group having halogen atom(s), trifluoromethyl group(s), methyl group(s), methoxy group(s), methlenedioxy group(s), hydroxy group(s), dimethylamino group(s), carboxyl group(s) or carboxymethyl group(s) as the substituent(s), a benzyl group, a pyridyl group, a substituted pyridyl group having methyl group(s) as the substituent(s), a pyridylmethyl group, a pyrimidinyl group, a thiazolyl group or a thienyl group.
Hitherto, some of 1,3,5-substituted biuret compounds represented by the formula (1) are known. On the other hand, although the definitions of the substituents in the formula (1) are different, other substituted biuret compounds having the basic structure of the formula, ##STR3## which is common to the formula (1) are known.
There have been reported that some of such known substituted biuret compounds, especially the latter compounds having the above-mentioned basic structure, have hypotensive, sedative or anti-convulsive activity. However, the prior art has not been aware that either 1,3,5-substituted biuret compounds represented by the general formula (1) or other known biuret compounds, having the above-mentioned basic structure which is common to the general formula (1), have analgesic, anti-inflammatory or anti-pyretic activity. [cf. British Pat. No. 1,096,006; British Pat. No. 819,853 and J. Amer. Chem. Soc., 62, 1595 (1940)]
The present invention is based on the facts that the 1,3,5-substituted biuret compounds represented by the general formula have analgesic, anti-inflammatory or anti-pyretic activity.
The object of the present invention is to provide novel 1,3,5-substituted biuret compounds.
Another object of the present invention is to provide an analgesic, anti-inflammatory or anti-pyretic composition containing 1,3,5-substituted biuret compound as the active ingredient.
Among the 1,3,5-substituted biuret compounds of the formula (1), the following compounds are novel ones.
1,3-Dimethyl-5-(2-chlorophenyl)biuret
1,3-Dimethyl-5-(2-trifluoromethylphenyl)biuret
1,3-Dimethyl-5-(3,4-methylenedioxyphenyl)biuret
1,3-Dimethyl-5-(2-carboxyphenyl)biuret
1,3-Dimethyl-5-(4-carboxymethylphenyl)biuret
1,3-Dimethyl-5-(2-pyridylmethyl)biuret
1,3-Dimethyl-5-(4-methyl-2-pyridyl)biuret
1,3-Dimethyl-5-(2-pyrimidinyl)biuret
1-Methyl-3-ethyl-5-phenylbiuret
1-Ethyl-5-phenylbiuret
1-Ethyl-5-(2-chlorophenyl)biuret
1-Ethyl-5-(3-chlorophenyl)biuret
1-Ethyl-5-(3,4-dichlorophenyl)biuret
1-Ethyl-5-(4-methoxyphenyl)biuret
1-Ethyl-5-benzylbiuret
1-Ethyl-5-(2-pyridyl)biuret
1-Ethyl-3-methyl-5-phenylbiuret
1-Ethyl-3-methyl-5-(4-fluorophenyl)biuret
1-Ethyl-3-methyl-5-(4-dimethylaminophenyl)biuret
1-Ethyl-3-methyl-5-(4-hydroxyphenyl)biuret
1-Ethyl-3-methyl-5-(4-methoxyphenyl)biuret
1-Ethyl-3-methyl-5-(3,4-dimethoxyphenyl)biuret
1-Ethyl-3-methyl-5-(3,4,5-trimethoxyphenyl)biuret
1-Ethyl-3-methyl-5-(4-methylphenyl)biuret
1-Ethyl-3-methyl-5-(3,4-dimethylphenyl)biuret
1-Ethyl-3-methyl-5-(2-thenyl)biuret
1-n-Propyl-3-methyl-5-phenylbiuret
1-Isopropyl-3-methyl-5-phenylbiuret
1-Propenyl-5-phenylbiuret
1-Propenyl-3-methyl-5-phenylbiuret
1-n-Propyl-5-phenylbiuret
1-n-Propyl-3-methyl-5-phenylbiuret
1-n-Propyl-5-benzylbiuret
1-Isobutyl-3-methyl-5-phenylbiuret
1-(1-Methylpropyl)-3-methyl-5-phenylbiuret
1-tert-Butyl-3-methyl-5-phenylbiuret
1-n-Pentyl-3-methyl-5-phenylbiuret
1-(2-Chloroethyl)-3-methyl-5-phenylbiuret
1-(2-Cyanoethyl)-3-methyl-5-phenylbiuret
1-(2-Dimethylaminoethyl)-3-methyl-5-phenylbiuret
1-(2-Hydroxyethyl)-3-methyl-5-phenylbiuret
1-(2-Methyl-2-hydroxypropyl)-3-methyl-5-phenylbiuret
1-(2,3-Dihydroxypropyl)-3-methyl-5-phenylbiuret
1-(2-Methoxyethyl)-3-methyl-5-phenylbiuret
1-Carboxymethyl-3-methyl-5-phenylbiuret
1-Acetyl-3-methyl-5-phenylbiuret
1-Hydroxy-3-methyl-5-phenylbiuret
1-Methoxy-3-methyl-5-phenylbiuret
The 1,3,5-substituted biuret compound of the formula (1) can be prepared by any processes shown below.
REACTION PROCESS--A
Reaction of an urea compound of the formula (2) or (4) with an isocyanate of the formula (3) or (5) to obtain the 1,3,5-substituted biuret compound of the formula (1) is shown as follows: ##STR4##
In this reaction process A, the reaction of the urea with the isocyanate may be carried out in the presence or absence of a solvent. The solvent used in this reaction is not subjected to any specific restriction and any known inert type which gives no adverse effect to the reaction can be used. Among the examples of the solvents are ethers such as ether, dioxane, tetrahydrofuran and the like; halogenated lower alkanes such as methylene chloride, chloroform, carbon tetrachloride and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like. The ratio of amount of the urea and the isocyanate in this reaction is not subjected to any specific restriction and may be suitably selected from a wide range, and usually, it is desirable that they are used in equimolar quantity respectively. The reaction temperature is also not subjected to any particular restriction and may be suitably selected from a wide range, and usually the reaction can advantageously be carried out at a room temperature to the boiling point of the solvent used generally within the range of 20.degree. to 200.degree. C. The obtained 1,3,5-substituted biuret compound of the formula (1) can be isolated by usual separation means.
REACTION PROCESS--B
Reaction of an allophanoyl chloride of the formula (6) or (8) with an amine of the formula (7) or (9) to obtain 1,3,5-substituted biuret compound of the formula (1) is shown as follows: ##STR5##
In this reaction process B, the reaction of the allophanoyl chloride with the amine may be carried out in a solvent. The solvent used in this reaction is not subjected to any specific restriction and any known inert type which gives no adverse effect to the reaction can be used. Among the examples of the solvents are halogenated lower alkanes such as methylene chloride, chloroform, carbon tetrachloride and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like. If necessary, basic compounds such as trialkylamine, pyridine and the like may be used as suitable condensation agent. The ratio of amount of the allophanoyl chloride and the amine in this reaction is not subjected to any specific restriction and may be suitably selected from a wide range, and usually it is desirable that the amine (7) or (9) is used in equimolar to 2 times the molar quantity of the allophanoyl chloride (6) or (8). The reaction temperature is also not subjected to any particular restriction, and the reaction can advantageously be carried out at -20.degree. to +50.degree. C. Thus formed 1,3,5-substituted biuret compound of the formula (1) can be isolated by usual separation means.
The allophanoyl chloride of the formula (6) or (8) used as the starting material in the reaction process-B is usually known compound and if necessary, it can be prepared by reacting the urea compound of the formula (2) or (4) used in the reaction process-A with phosgene according to known method [e.g. J. Org. Chem., vol. 29, pp. 2401 (1964)].
REACTION PROCESS--C
Reaction of a 1,3-diazetidine-2,4-dione of the formula (10) or (11) with an amine of the formula (7) or (9) to obtain 1,3,5-substituted biuret compound of the formula (1) is shown as follows: ##STR6##
In this reaction process-C, the reaction of the 1,3-diazetidine-2,4-dione with the amine may usually be carried out in a solvent. The solvent used in this reaction is not subjected to any specific restriction and any known inert type which gives no adverse effect to the reaction can be used. Generally, water, acetone, acetonitrile and the like may be used as the solvent. The ratio of amount of the 1,3-diazetidine-2,4-dione and the amine in this reaction is not subjected to any specific restriction and may be suitably selected from a wide range, and usually, it is desirable that the amine (7) or (9) is used in equimolar to 2 times the molar quantity of the 1,3-diazetidine-2,4-dione (10) or (11). The reaction temperature is also not subjected to any particular restriction, and the reaction can advantageously be carried out at a room temperature to about 100.degree. C. The thus formed 1,3,5-substituted biuret compound of the formula (1) can be isolated by usual separation means. The 1,3-diazetidine-2,4-dione of the formula (10) or (11) used as the starting material in the reaction process-C is usually known compound and if necessary, it can be prepared by reacting the allophanoyl chloride compound of the formula (6) or (8) in the reaction process-B with boron trichloride according to known method [e.g. Angew. Chem. International Edition, vol. 9, pp. 373 (1970)].
REACTION PROCESS--D
When preparing 1,3,5-substituted biuret compound of the formula (1), wherein R.sup.1 =R.sup.2 or R.sup.2 =R.sup.3, it is prepared by reacting a 1,3,5-oxadiazine-2,4,6-trione of the formula (12) or (13) with an amine of the formula (7) or (9) as follows: ##STR7##
In this reaction process-D, the reaction of the 1,3,5-oxadiazine-2,4,6-trione with the amine may usually be carried out in a solvent. The solvent used in this reaction is not subjected to any specific restriction and any known inert type which gives no adverse effect to the reaction can be used. Generally, acetonitrile, tetrahydrofuran and the like may be used as the solvent. The ratio of amount of the 1,3,5-oxadiazine-2,4,6-trione and the amine in this reaction is not subjected to any specific restriction and may be suitably selected from a wide range, and usually, it is desirable that the amine (7) or (9) is used in equimolar to 2 times the molar quantity of the 1,3,5-oxadiazine-2,4,6-trione (12) or (13). The reaction temperature is also not subjected to any particular restriction, and the reaction can advantageously be carried out at a room temperature to about 100.degree. C. The thus formed 1,3,5-oxadiazine-2,4,6-trione of the formula (1) can be isolated by usual separation means.
The 1,3,5-oxadiazine-2,4,6-trione of the formula (12) or (13) used as the starting material in this reaction process-D is usually known compound and if necessary, it can easily be prepared by reacting the isocyanate of the formula (3) or (5) used in the reaction process-A with carbon dioxide according to known method [e.g. Bull. Soc. Chim. Fr., 1974, 1497].
Most of the 1,3,5-substituted biuret compounds of the formula (1) of the present invention [that is, all compounds, except those of formula (1') below] are useful as analgesic agents, anti-inflammatory agents or anti-pyretic agents. However, among of those compounds, 1,3,5-substituted biuret compounds of the formula (1') ##STR8## wherein R.sup.1' is a lower alkyl group, a substituted lower alkyl group having chlorine atoms(s), cyano group(s), dimethylamino group(s) or hydroxyl group(s) as the substituent(s), a lower alkenyl group or a methoxy group; R.sup.2 is a hydrogen atom, a lower alkyl group, or a phenyl group; R.sup.3' is a phenyl group, a substituted phenyl group having halogen atom(s), trifluoromethyl group(s), methoxy group(s), methylenedioxy group(s), dimethylamino group(s) or hydroxy group(s) as the substituent(s), a benzyl group, a pyridyl group, a substituted pyridyl group having methyl group(s) as the substituent(s), a thiazolyl group or a thienyl group, are useful only as anti-inflammatory agents.
The 1,3,5-substituted biuret compound of the formula (1) of the present invention can be administered in the range of from 10 to 2,000 mg per day, preferably from 50 to 1,000 mg per day, for an adult, as a analgesic, anti-inflammatory or anti-pyretic agent. The administration of the compound is carried out by dividing the above-mentioned daily dosage into 2 or 3 portions. Said dosage of the compound may be adjusted in consideration of the clinical conditions and age of the patient.
The administration may be carried out in the form of peroral preparations, injection preparations, suppository preparations for rectal use, topical preparations and the like.
An analgesic, anti-inflammatory or anti-pyretic composition containing the present 1,3,5-substituted biuret compound of the formula (1) is prepared and administered by formulating with conventional pharmaceutically acceptable carriers or excipients through a common method.
Peroral preparations such as tablets, capsules, granules, powders, etc. may contain excipients used generally in the art. Said excipients are exemplified such as calcium carbonate, calcium phasphates, starch, sucrose, lactose, talc, magnesium stearate, gelatine, polyvinylpyrrolidone, gum arabic, sarbitol, microcrystalline cellulose, polyethyleneglycol, carboxymethylcellulose, silica polyvinylacetal diethylamino acetate, hydroxypropyl methylcellulose, shellac, etc. Further, the tablets may be coated with a suitable coating by a common method known in the arts. Peroral liquid form preparations may be of aqueous or oily suspensions, syrups, elixiers and the like and are prepared by common methods. Injection preparations may be of aqueous or oily suspensions, powdery or lyophilyzed preparations which is dissolved upon use. These preparations may be prepared by a common method.
The present substituted biuret compound may be administered as a suppository composition for rectal use, which may be contain pharmaceutically acceptable carriers, known in the art, such as polyethylene glycols, lanoline, cacao butter, fatty acid triglycerides, and the like.
As to preparations for topical use, the substituted biuret compound of the formula (1) of the present invention may be administered in the form of an ointment or cream which is prepared by formulating with a suitable ointment base and other additives by common method.

EXAMPLES OF THE INVENTION
The present invention is further explained in detail by illustrating examples of synthesis of the substituted biuret compounds in Table 1; and pharmacological tests including analgesic activity test, anti-inflammatory activity test and anti-pyretic activity test in Table 2 together with examples of pharmaceutical preparations.
EXAMPLE 1
Synthesis of 1-ethyl-5-phenylbiuret (Compound No. 23 in Table 1) by reaction process--A
In 50 ml of anhydrous dioxane, 3.5 g (0.04 mol) of ethyl urea was dissolved, and under stirring 4.8 g (0.04 mol) of phenylisocyanate was added thereinto. The reaction was carried out at a room temperature for 15 hours, then the solvent was removed by distillation under a reduced pressure. The residue thus obtained was recrystallized from ethanol-water to obtain 4.6 g (yield 55%) of 1-ethyl-5-phenylbiuret having a melting point of 80.degree.-81.5.degree. C.
EXAMPLE 2
Synthesis of 1,3-dimethyl-5-phenylbiuret (Compound No. 3 in Table 1) by reaction process--A
In 50 ml of anhydrous dioxane, 3.5 g (0.04 mol) of 1,3-dimethyl urea was dissolved, and under stirring 4.8 g (0.04 mol) of phenylisocyanate was added thereinto. The reaction was carried out at a room temperature for 15 hours, then the reaction mixture was treated a procedure same as in Example 1. The residue thus obtained was recrystallized from ethanol-petroleum ether to obtain 5.0 g (yield 60%) of 1,3-dimethyl-5-phenylbiuret having a melting point of 93.degree.-95.degree. C.
EXAMPLE 3
Synthesis of 1-ethyl-3-methyl-5-phenylbiuret (Compound No. 31 in Table 1) by reaction process--B
In 50 ml of anhydrous tetrahydrofuran, 9.0 g (0.2 mol) of ethylamine was dissolved, and under cooling below 0.degree. C. with stirring, a solution prepared by dissolving 21.3 g (0.1 mol) of 2-methyl-4-phenylallophanoyl chloride into 50 ml of anhydrous tetrahydrofuran was added by drop-wise. The reaction was continued at a room temperature for 1 hour, the solvent was then removed by distillation under a reduced pressure. To the residue thus obtained was added water and the precipitate thus formed was separated by filtration and dried, and recrystallized from ether-petroleum ether to obtain 17.7 g (yield 80%) of 1-ethyl-3-methyl-5-phenylbiuret having a melting point of 80.5.degree.-81.5.degree. C.
EXAMPLE 4
Synthesis of 1-phenyl-3,5-diphenylbiuret (Compound No. 22 in Table 1) by reaction process--C
In 30 ml of acetonitrile, 6.0 g (0.025 mol) of 1,3-diphenyl-1,3-diazetidine-2,4-dione was added. Then 3.9 ml (0.05 mol) of aqueous solution (40%) of methylamine was added dropwise thereinto with stirring. The reaction was continued at 50.degree. C. for 0.5 hours, then the solvent was removed by distillation under a reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain 5.1 g (yield 76%) of 1-methyl-3,5-diphenylbiuret having a melting point of 145.degree.-147.degree. C.
EXAMPLE 5
Synthesis of 1,3-dimethyl-5-(2-pyridyl)biuret (Compound No. 14 in Table 1) by reaction process--D
In 50 ml of acetonitrile, 5.0 g (0.0316 mol) of 3,5-dimethyl-2,4,6-trioxohydro-1,3,5-oxadiazine and 3.0 g (0.0319 mol) of 2-aminopyridine were added. The reaction was continued under refluxing condition for 7 hours. After the reaction was completed, water was added to the reaction mixture and was filtered. The filtrate thus obtained was extracted with chloroform, and the extracted liquid was dried with anhydrous sodium sulfate and the chloroform was removed by distillation. The residue thus obtained was recrystallized from benzene to obtain 3.0 g (yield 46%) of 1,3-dimethyl-5-(2-pyridyl)biuret having a melting point of 112.degree.-115.degree. C.
In the following Table 1, there are mentioned the physico-chemical properties of 1,3,5-substituted biuret compounds of the formula (1) including the compounds prepared in Examples 1-5.
TABLE 1__________________________________________________________________________ poundCom- ##STR9## tionReac- Mp, UV.lambda..sub.max.sup.Cyclohexane Molecular (Found)CalculatedElem ental analysis (%)No. R.sup.1 R.sup.2 R.sup.3 process (.degree.C.) m.mu. (.epsilon.) formula C H N__________________________________________________________________________1* H CH.sub.3 ##STR10## B 188- 190 243.5 (17700) C.sub.9 H.sub.11 N.sub.3 55.95 (55.62) 5.74 (5.57) 21.75 (21.61)2* CH.sub.3 H ##STR11## A 121- 122 240 (19600) C.sub.9 H.sub.11 N.sub.3 55.95 (55.91) 5.74 (5.59) 21.75 (21.77)3* CH.sub.3 CH.sub.3 ##STR12## A 93-95 244 (17900) C.sub.10 H.sub.13 N.sub.3 O.sub.2 57.96 (58.09) 6.32 (6.39) 20.28 (20.18)4* CH.sub.3 CH.sub.3 ##STR13## B 148- 150 240.5 (25800) C.sub.10 H.sub.12 FN.sub.3 O.sub.2 53.33 (53.22) 5.37 (5.30) 18.66 (18.32)5 CH.sub.3 CH.sub.3 ##STR14## A 168.5- 170.5 247.5 (20700) C.sub.10 H.sub.12 ClN.sub.3 O.sub.2 49.70 (49.99) 5.00 (4.96) 17.39 (17.32)6* CH.sub.3 CH.sub.3 ##STR15## A 143- 145 250.5 (25000) C.sub.10 H.sub.12 ClN.sub.3 O.sub.2 49.70 (49.70) 5.00 (5.09) 17.39 (17.18)7 CH.sub.3 CH.sub.3 ##STR16## B 115- 117 243 (17200) C.sub.11 H.sub.12 F.sub.3 N.sub.3 O.sub.2 48.00 (48.30) 4.39 (4.43) 15.27 (15.38)8* CH.sub.3 CH.sub.3 ##STR17## B 110- 111 249 (20300) C.sub.11 H.sub.15 N.sub.3 O.sub.3 55.69 (55.66) 6.37 (6.63) 17.71 (17.50)9 CH.sub.3 CH.sub.3 ##STR18## B 176- 178 256 (13500) C.sub.11 H.sub.13 N.sub.3 O.sub.4 52.59 (52.61) 5.22 (5.19) 16.72 (16.43)10 CH.sub.3 CH.sub.3 ##STR19## B 178- 179 250 (16400) C.sub.11 H.sub.13 N.sub.3 O.sub.4 52.59 (52.58) 5.22 (5.12) 16.72 (16.70)11 CH.sub.3 CH.sub.3 ##STR20## D 195- 196 248.5 (21600) C.sub.12 H.sub.15 N.sub.3 54.33 (54.29) 5.70 (5.95) 15.84 (15.79)12* CH.sub.3 CH.sub.3 ##STR21## B 118- 119 C.sub.11 H.sub.15 N.sub.3 59.71 (59.70) 6.83 (7.01) 18.99 (18.97)13 CH.sub.3 CH.sub.3 ##STR22## D 101.5- 102.5 262 (2700) C.sub.10 H.sub.14 N.sub.4 54.04 (54.14) 6.35 (6.26) 25.21 (25.41)14* CH.sub.3 CH.sub.3 ##STR23## D 112- 115 238 (19400) C.sub.9 H.sub.12 N.sub.4 51.92 (51.88) 5.81 (5.93) 26.91 (27.04)15* CH.sub.3 CH.sub.3 ##STR24## D 149- 150 242 (15400) C.sub.9 H.sub.12 N.sub.4 O.sub.2 51.92 (52.01) 5.81 (5.74) 26.91 (26.95)16* CH.sub.3 CH.sub.3 ##STR25## D 177- 178 C.sub.9 H.sub.12 N.sub.4 O.sub.2 51.92 (51.80) 5.81 (5.88) 26.91 (27.00)17* CH.sub.3 CH.sub.3 ##STR26## D 146- 147 239 (19200) C.sub.10 H.sub.14 N.sub.4 54.04 (53.86) 6.35 (6.38) 25.21 (25.20)18 CH.sub.3 CH.sub.3 ##STR27## D 120- 121.5 240 (20300) C.sub.10 H.sub.14 N.sub.4 54.04 6.35 (6.42) 25.21 (25.16)19 CH.sub.3 CH.sub.3 ##STR28## D 229- 231 (de- com- posed) 272 (3100) C.sub.8 H.sub.11 N.sub.5 O.sub.2 . HCl 39.13 (38.92) 4.93 (5.03) 28.52 (28.67)20* CH.sub.3 CH.sub.3 ##STR29## D 166- 167 263 (11500) C.sub.7 H.sub.10 N.sub.4 O.sub.2 S 39.24 (39.26) 4.70 (4.81) 26.15 (26.03)21 CH.sub.3 C.sub.2 H.sub.5 ##STR30## B 84-86 244 (19700) C.sub.11 H.sub.15 N.sub.3 59.71 (60.06) 6.83 (7.05) 18.99 (19.13)22* CH.sub.3 ##STR31## ##STR32## C 145- 147 C.sub.15 H.sub.15 N.sub.3 66.90 (66.70) 5.61 (5.54) 15.60 (15.53)23 C.sub.2 H.sub.5 H ##STR33## A 80-81.5 242 (21700) C.sub.10 H.sub.13 N.sub.3 57.96 (58.05) 6.32 (6.48) 20.28 (20.25)24 C.sub.2 H.sub.5 H ##STR34## A 152- 154 245.5 (20300) C.sub.10 H.sub.12 ClN.sub.3 O.sub.2 49.70 (49.95) 5.00 (4.86) 17.39 (17.08)25 C.sub.2 H.sub.5 H ##STR35## A 120- 122 244.5 (22300) C.sub.10 H.sub.12 ClN.sub.3 O.sub.2 49.70 (49.98) 5.00 (4.82) 17.39 (17.25)26* C.sub.2 H.sub.5 H ##STR36## A 175- 177 248 (25900) C.sub.10 H.sub.12 ClN.sub.3 O.sub.2 49.70 (49.97) 5.00 (5.13) 17.39 (17.24)27 C.sub.2 H.sub.5 H ##STR37## A 184.5- 185.5 250.5 (26600) C.sub.10 H.sub.11 Cl.sub.2 N.sub.3 O.sub.2 43.50 (43.30) 4.02 (4.01) 15.22 (15.22)28 C.sub.2 H.sub.5 H ##STR38## A 141- 142 248 (21400) C.sub.11 H.sub.17 N.sub.3 55.69 (55.60) 6.37 (6.13) 17.71 (17.41)29 C.sub.2 H.sub.5 H ##STR39## A 108- 110 C.sub.11 H.sub.15 N.sub.3 59.71 (59.85) 6.83 (6.89) 18.88 (19.14)30 C.sub.2 H.sub.5 H ##STR40## A 125- 126 240 (19800) C.sub.9 H.sub.12 N.sub.4 O.sub.2 51.92 (51.83) 5.81 (5.94) 26.91 (26.80)31 C.sub.2 H.sub.5 CH.sub.3 ##STR41## B 80.5- 81.5 244 (19900) C.sub.11 H.sub.15 N.sub.3 59.71 (59.78) 6.83 (7.03) 18.99 (18.69)32 C.sub.2 H.sub.5 CH.sub.3 ##STR42## B 112- 114 241 (20000) C.sub.11 H.sub.14 FN.sub.3 O.sub.2 55.22 (55.08) 5.90 (6.04) 17.56 (17.24)33 C.sub.2 H.sub.5 CH.sub.3 ##STR43## B 116- 118 263 (22300) C.sub.13 H.sub.20 N.sub.4 59.07 (58.93) 7.63 (7.61) 21.20 (21.20)34 C.sub.2 H.sub.5 CH.sub.3 ##STR44## B 151- 153 248 (15100) C.sub.11 H.sub.15 N.sub.3 55.69 (55.60) 6.37 (6.29) 17.71 (17.80)35 C.sub.2 H.sub.5 CH.sub.3 ##STR45## B 58-59 249 (22000) C.sub.12 H.sub.17 N.sub.3 57.36 (57.13) 6.82 (6.96) 16.72 (16.41)36 C.sub.2 H.sub.5 CH.sub.3 ##STR46## B 98-100 252 (14700) C.sub.13 H.sub.19 N.sub.3 55.51 (55.63) 6.81 (6.87) 14.94 (14.54)37 C.sub.2 H.sub.5 CH.sub.3 ##STR47## B 104- 106 256 (15400) C.sub.14 H.sub.19 N.sub.3 54.01 (53.94) 6.80 (6.79) 13.50 (13.74)38 C.sub.2 H.sub.5 CH.sub.3 ##STR48## B 88-90 246 (20100) C.sub.12 H.sub.17 N.sub.3 61.26 (61.23) 7.28 (7.46) 17.86 (17.61)39 C.sub.2 H.sub.5 CH.sub.3 ##STR49## B 66-68 247 (18800) C.sub.13 H.sub.19 N.sub.3 O.sub.2 . 1/2 H.sub.2 O 60.45 (60.07) 7.80 (7.71) 16.27 (16.09)40 C.sub.2 H.sub.5 CH.sub.3 ##STR50## B 112- 114 271 (11400) 267 (11600) C.sub.9 H.sub.13 N.sub.3 O.sub.2 S 47.56 (47.78) 5.77 (5.77) 18.49 (18.38)41 (CH.sub.2).sub.2 CH.sub.3 CH.sub.3 ##STR51## B 74-76 244 (20800) C.sub.12 H.sub.17 N.sub.3 61.26 (61.22) 7.28 (7.52) 17.86 (17.47)42* (CH.sub.2).sub.2 CH.sub.3 H ##STR52## A 85.5-88 not available C.sub. 12 H.sub.17 N.sub.3 O.sub.2 61.26 (61.33) 7.28 (7.20) 17.86 (17.68)43 CH(CH.sub.3).sub.2 CH.sub.3 ##STR53## B 92-93.5 243 (20500) C.sub.12 H.sub.17 N.sub.3 61.26 (61.67) 7.28 (7.49) 17.86 (17.83)44 CH.sub.2 CHCH.sub.2 H ##STR54## A 75-78 253 (20500) C.sub.11 H.sub.13 N.sub.3 60.26 (59.95) 5.98 (6.06) 19.17 (19.10)45 CH.sub.2 CHCH.sub.2 CH.sub.3 ##STR55## B 79-80 243 (19900) C.sub.12 H.sub.15 N.sub.3 61.79 (61.75) 6.48 (6.71) 18.01 (18.15)46 (CH.sub.2).sub.3 CH.sub.3 H ##STR56## A 106.5- 108.5 241.5 (22400) C.sub.12 H.sub.17 N.sub.3 61.26 (61.03) 7.28 (7.19) 17.86 (17.92)47 (CH.sub.2).sub.3 CH.sub.3 CH.sub. 3 ##STR57## B Oily pro- duct C.sub.13 H.sub.19 N.sub.3 (a)ub.248 (CH.sub.2).sub.3 CH.sub.3 H ##STR58## A 95-96.5 C.sub.13 H.sub.19 N.sub.3 62.63 (62.66) 7.68 (7.77) 16.85 (16.55)49 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 ##STR59## B 56-57 243.5 (20800) C.sub.13 H.sub.19 N.sub.3 62.63 (62.75) 7.68 (7.96) 16.85 (16.82)50 ##STR60## CH.sub.3 ##STR61## B 98-100 253 (19900) C.sub.13 H.sub.19 N.sub.3 62.63 (62.78) 7.68 (7.96) 16.85 (16.77)51 C(CH.sub.3).sub.3 CH.sub.3 ##STR62## B 94-95 243 (20100) C.sub.13 H.sub.19 N.sub.3 62.63 (62.57) 7.68 (7.84) 16.85 (16.91)52 (CH.sub.2).sub.4 CH.sub.3 CH.sub.3 ##STR63## B Oily pro- duct C.sub.14 H.sub.21 N.sub.3 (b)ub.253 CH.sub.2 CH.sub.2 Cl CH.sub.3 ##STR64## B 117- 118 244 (19200) C.sub.11 H.sub.14 ClN.sub.3 O.sub.2 51.67 (51.66) 5.52 (5.53) 16.43 (16.23)54 CH.sub.2 CH.sub.2 CN CH.sub.3 ##STR65## B 116- 118 245 (18800) C.sub.12 H.sub.14 N.sub.4 58.53 (58.38) 5.73 (5.59) 22.75 (22.93)55 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 CH.sub.3 ##STR66## B 179- 181 245 (19500) C.sub.13 H.sub.21 ClN.sub.4 O.sub.2 51.91 (51.98) 7.04 (7.14) 18.63 (18.46)56 CH.sub.2 CH.sub.2 OH CH.sub.3 ##STR67## B 105- 106 244 (19600) C.sub. 11 H.sub.15 N.sub.3 O.sub.3 55.69 (55.68) 6.37 (6.56) 17.71 (17.85)57 ##STR68## CH.sub.3 ##STR69## B 117.5- 119 241 (17300) C.sub.13 H.sub.19 N.sub.3 58.85 (58.94) 7.22 (7.39) 15.84 (15.66)58 ##STR70## CH.sub.3 ##STR71## B 96-97 244 (19700) C.sub.12 H.sub.17 N.sub.3 53.92 (53.86) 6.41 (6.66) 15.72 (15.65)59 CH.sub.2 CH.sub.2 OCH.sub.3 CH.sub.3 ##STR72## B 52-53 243 (16600) C.sub.12 H.sub.17 N.sub.3 57.36 (57.36) 6.82 (6.84) 16.72 (16.71)60 CH.sub.2 COOH CH.sub.3 ##STR73## B 80-82 243 (20900) C.sub.11 H.sub.13 N.sub.3 O.sub.4 . H.sub.2 O 49.07 (48.70) 5.62 (5.63) 15.61 (15.48)61 ##STR74## CH.sub.3 ##STR75## A 118- 120 274 (12300) C.sub.11 H.sub.13 N.sub.3 56.16 (56.19) 5.57 (5.58) 17.86 (18.04)62 OH CH.sub.3 ##STR76## B 128- 129 245 (18200) C.sub.9 H.sub.11 N.sub.3 O.sub.3 51.67 (51.53) 5.49 (5.30) 20.09 (19.81)63 OCH.sub.3 CH.sub.3 ##STR77## B 155- 157 243 (17800) C.sub.10 H.sub.13 N.sub.3 53.81 (53.76) 5.87 (5.81) 18.82 (18.57)64* ##STR78## CH.sub.3 ##STR79## B 106- 106.5 C.sub.15 H.sub.15 N.sub.3 66.90 (67.06) 5.61 (5.58) 15.60 (15.67)__________________________________________________________________________
In Table 1, the compounds with * marks are known compounds and thus the remaining compounds are novel ones. Further (a) in the Compound No. 47 and (b) in Compound 52 indicate the following data obtained by NMR and mass-spectrography methods in place of data obtained by elemental analysis.
.sup.(a) NMR(CDCl.sub.3).delta.: 0.88 (3H, m, N.sub.1 --CH.sub.2 CH.sub.2 CH.sub.2 --CH.sub.3), 1.00-1.68 (4H, m, N.sub.1 --CH.sub.2 --CH.sub.2 CH.sub.2 --CH.sub.3), 3.18 (2H, m, N.sub.1 --CH.sub.2 --CH.sub.2 CH.sub.2 CH.sub.3), 3.18 (3H, s, N.sub.3 --CH.sub.3), 6.00 (1H, broad, N.sub.1 --H), 6.88-7.49 (5H, m, Ar--H), 10.62 (1H, broad s, N.sub.5 --H), MS m/e: 249 (M.sup.+).
.sup.(b) NMR(CDCl.sub.3).delta.: 0.88 (3H, broad t, J=6 Hz, N.sub.1 --CH.sub.2 --CH.sub.2 CH.sub.2 CH.sub.2 --CH.sub.3), 1.07-1.92 (6H, m, N.sub.1 --CH.sub.2 --CH.sub.2 CH.sub.2 CH.sub.2 --CH.sub.3), 2.99-3.27 (2H, m, N.sub.1 --CH.sub.2 --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3), 3.12 (3H, s, N.sub.3 --CH.sub.3), 5.89 (1H, broad t, N.sub.1 --H), 6.80-7.43 (5H, m, Ar--H), 10.44 (1H, broad s, N.sub.5 --H). MS m/e: 263 (M.sup.+).
Next, several tests for determining the pharmacological properties, in that acute toxicity, anti-pyretic activity, analgesic activity and anti-inflammatory activity of the present 1,3,5-substituted biuret compounds of the formula (1) were conducted and the test results are shown in Table (2). In the tests, each compounds to be tested was used as a suspension in 0.25% carboxymethylcellulose solution. Methods for testing are explained as follows:
1. Acute toxicity
The ddy strain of male mice (body weight, 20-25 g) were used as test animals. The mice were fasted overnight and the compound to be tested was administered orally. General symptom of the mouse after the administration was observed for 7 days. The lethal dose (mg/kg, body weight) of the test compound was determined in connection with the death number of mice/the number of mice tested. In Table 2, the values indicated with .DELTA. marks are 50% lethal dose, LD.sub.50 (mg/kg, body weight).
2. Anti-pyretic activity
According to the method reported by Tanabe [Folia Pharmacologia Japonica, Vol. 73, pp. 803 (1977)], the Wistar strain of male rats (150-180 g body weight) were used as test animals. The rats were fasted overnight, and 1 ml/100 g (body weight) of 10% dry-yeast suspension were subcutaneously injected on the back of the rats. Five hours after the injection, the test compound was administered orally, then the body temperature of the rat was measured time sequences. Anti-pyretic activity of the test compound was determined as the FI (febril index) by integrating pyrogenetic curve up to 4 hours after the administration of the test compound with time, and indicated as inhibitory ratio (%) shown by the following formula, ##EQU1##
3. Analgesic activity
(1) Acetic acid-induced stretching method
According to the method reported by Koster et.al., [Fed. Proc., Vol. 18, pp. 412 (1959)], the ddy strain of male mice (body weight, 20-25 g) were used as test animals. The mice were fasted overnight, 100 mg/kg body weight of the test compound was administered orally, then 1 hour after the administration, 0.2 ml of 0.7% acetic acid solution was injected intraperitoneally. The acetic acid-induced stretching symptom of mouse was observed. Analgesic activity of the test compound was calculated as the inhibitory ratio (%). In Table 2, the values in parentheses show the data obtained from the test by using the dosage other than 100 mg/kg body weight. Further, the values indicated with .DELTA. marks show 50% effective dose, ED.sub.50 (mg/kg body weight).
(2) Haffner method
According to the modified method reported by Fujimura et.al., [Bulletin of the Institute for Chemical Research, Kyoto University, No. 25, pp. 36 (1951)], the ddy strain of male mice (body weight, 20-25 g) were used as test animals. The mice were fasted overnight, 100 mg/kg body weight of the test compound was administered orally, then 45 minutes after the administration, the threshhold amount (1.5-2.5 mg/kg body weight) of morphine hydrochloride was injected subcutaneously. Then 1-hour pain reaction of the mouse caused by a clamp was observed. Analgesic activity of the test compound was calculated as the inhibitory ratio (%). In Table 2, the values in parentheses show the data obtained from the test by using the dosage other than 100 mg/kg body weight. Further, the values indicated with .DELTA. marks show 50% effective dose, ED.sub.50 (mg/kg body weight).
4. Anti-inflammatory activity
According to the method of acute carrageenin-induced inflammatory test [Folia Pharmacologia Japonica, Vol. 56, pp. 575 (1960)], the Wistar strain of male rats (body weight, 150-180 g) were used as test animals. The rats were fasted overnight, 100 mg/kg body weight of the test compound was administered orally, then 1 hour after the administration, 0.1 ml of 1% carrageenin solution, as the inflammation inducing agent, was injected subcutaneously to the hindpaw of the rat and the volume of the hindpaw was measured at time sequences. Anti-inflammatory activity of the test compound was calculated as inflammation inhibitory ratio (%) at 3 hours after the injection of inflammation inducing agent.
TABLE 2______________________________________ Analgesic activity (%) Anti- Acetic acid- Anti- inflam-Com- Acute induced pyretic matorypound toxicity stretching Haffner activity activityNo. (mg/kg) method method (%) (%)______________________________________ 1* 2000-2/4 37.5 2* 500-0/4 75 50 28 1000-4/4 3* .DELTA.1448 .DELTA.35(16-77) .DELTA.111(66-188) 145 88 4* 2000-0/4 37.5 25 79 41 5 2000-0/4 37.5 37.5 28 53 (200 mg/kg) (200 mg/kg) (200 mg/kg) 6* .DELTA.1239 .DELTA.40(21-76) 50 72 43 7 1000-0/4 62.5 12.5 121 60 2000-3/4 (200 hours value) 8* .DELTA.1445 87.5 50 110 40 9 .DELTA.1084 87.5 25 38 4610 1000-1/4 12.5 2000-4/411 2000-0/4 25 37.5 712* 500-0/4 100 50 47 1000-4/413 1000-0/4 25 37.5 2000-2/414* .DELTA.656 62.5 .DELTA.145(76-276) 5415* .DELTA.1100 .DELTA.44(21-94) 62.5 94 3716* .DELTA.1100 62.5 25 3417* 1000-0/4 25 25 55 33 2000-3/418 .DELTA.1500 75 25 60 2019 .DELTA.1400 50 37.5 620* 1000-3/4 25 25 112 4621 1000-1/4 50 37.5 56 2000-3/422* 2000-0/4 37.5 50 35 (200 mg/kg)23 2000-0/4 62.5 60 49 (200 mg/kg)24 2000-0/4 25 37.5 77 (200 mg/kg) (200 mg/kg) (200 mg/kg)25 2000-0/4 25 37.5 86 (200 mg/kg) (200 mg/kg) (200 mg/kg)26* 2000-0/4 12.5 25 76 (200 mg/kg) (200 mg/kg) (200 mg/kg)27 1000-0/4 12.5 12.5 44 2000-1/4 (200 mg/kg) (200 mg/kg) (200 mg/kg)28 .DELTA.1600 37.5 37.5 75 (200 mg/kg) (200 mg/kg) (200 mg/kg)29 1000-0/4 12.5 25 31 2000-1/430 1000-0/4 37.5 30 2000-3/431 .DELTA.1594 .DELTA.70(44-112) .DELTA.105(69-159) 149 6332 1000-2/4 100 37.5 63 2000-4/433 1000-0/4 62.5 25 87 30 2000-4/434 2000-0/4 25 12.5 1935 1000-0/4 87.5 62.5 112 19 2000-4/436 .DELTA.833 50 62.5 43 2337 .DELTA.749 75 .DELTA.46(31-69) 9738 1000-0/4 87.5 25 80 2000-3/439 2000-0/4 50 37.5 840 .DELTA.559 75 37.5 42 2441 2000-0/4 62.5 37.5 65 6742* 2000-0/4 82.5 50 31 (200 mg/kg) (200 mg/kg) (200 mg/kg)43 2000-0/4 50 25 38 5144 .DELTA.1400 62.5 50 3345 1000-2/4 50 12.5 125 59 2000-4/446 2000-0/4 25 84 (200 mg/kg) (200 mg/kg)47 2000-0/4 75 62.5 19 2748 2000-0/4 .DELTA.111(87-141) .DELTA.110(75-162) 46 (200 mg/kg)49 2000-0/4 50 .DELTA.50(29-83) 55 57 (40 mg/kg)50 2000-0/4 62.5 25 27 4751 2000-0/4 50 37.5 83 3452 2000-0/4 62.5 37.5 3853 2000-0/4 12.5 25 4054 1000-0/4 50 12.5 39 2000-3/455 500-2/4 12.5 12.5 22 1000-3/456 2000-0/4 62.5 37.5 4257 1000-0/4 100 50 2000-2/458 2000-0/4 37.5 37.559 1000-1/4 25 25 2000-4/460 2000-0/4 25 2561 2000-0/4 50 12.562 1000-0/4 25 2000-1/463 1000-0/4 50 25 50 2000-4/464* 2000-0/4 37.5 12.5 (200 mg/kg)______________________________________
The followings are examples of preparation for analgesic, anti-pyretic or anti-inflammatory composition containing 1,3,5-substituted biuret compound of the formula (1) as the active ingredient.
PREPARATION 1
______________________________________Ingredients Amount (mg)______________________________________1,3-Dimethyl-5-phenylbiuret(Compound No. 3) 200Lactose 500Corn Starch 280Hydroxypropylcellulose 20 To make one package contains 1,000______________________________________
By using the ingredients in the above-mentioned formulation, granular preparation is prepared by conventional methods.
PREPARATION 2
______________________________________Ingredients Amount (mg)______________________________________1,3-Dimethyl-5-(4-methoxyphenyl)-biuret (compound No. 8) 100Lactose 85Crystalline cellulose 50Hydroxypropylstarch 30Talc 4Magnesium stearate 1 To make one tablet cntains 270______________________________________
By using the ingredients in the above-mentioned formulation, tablet preparation is prepared by conventional methods.
PREPARATION 3
______________________________________Ingredients Amount (mg)______________________________________1,3-Dimethyl-5-(3-pyridyl)-biuret (Compound No. 15) 100Lactose 50Potate starch 50Crystalline cellulose 109Magnesium stearate 1 To make one capsule contains 310______________________________________
By using the ingredients in the above-mentioned formulation, a capsule preparation is prepared by conventional methods.
PREPARATION 4
______________________________________Ingredients Amounts (mg)______________________________________1-Ethyl-3-methyl-5-phenylbiuret(Compound No. 31) 200Lactose 100Crystalline cellulose 98Magnesium stearate 2To make one capsule contains 400______________________________________
By using the ingredients in the above-mentioned formulation, a capsule preparation is prepared by conventional methods.
PREPARATION 5
______________________________________Ingredients Amounts (mg)______________________________________1-Ethyl-3-methyl-5(3,4,5-trimethoxyphenyl)biuret(Compound No. 37)Witepzol W-35(A trade name for a suppositorybase material manufactured by 750and sold from Dynamite NobelCompany.)To make one suppository contains 1,000______________________________________
By using the ingredients in the above-mentioned formulation, a suppository preparation is prepared by conventional methods.
PREPARATION 6
______________________________________Ingredients Amounts (mg)______________________________________1-(2-Methyl-2-hydroxypropyl)-3-methyl-5-phenylbiuret 100(Compound No. 57)Sodium chloride 16Distilled water for injection q.s.To make one ampule contains 2 ml______________________________________
By using the ingredients in the above-mentioned formulation, an injection preparation (ampule) is prepared by conventional methods.
PREPARATION 7
______________________________________Ingredients Amount (g)______________________________________1-Ethyl-3-methyl-5-phenylbiuret(Compound No. 31) 2.0White vaserine 23.0Stearyl alcohol 22.0Propylene glycol 12.0Sodium laurylsulfate 1.5Ethyl p-oxybenzoate 0.025Propyl p-oxybenzoate 0.015Purified water q.s.To make the whole 100______________________________________
By using the ingredients in the above-mentioned formulation, an ointment preparation is prepared by conventional methods.
PREPARATION 8
______________________________________Ingredients Amount (mg)______________________________________1-Methyl-3-ethyl-5-phenylbiuret 100(Compound No. 21)Lactose 85Crystalline cellulose 50Hydroxypropylstarch 30Talc 4Magnesium stearate 1To make one tablet contains 270______________________________________
By using the ingredients in the above-mentioned formulation, tablet preparation is prepared by conventional methods.
PREPARATION 9
______________________________________Ingredients Amount (mg)______________________________________1-Ethyl-3-methyl-5-phenylbiuret 100(Compound No. 31)Lactose 50Potate starch 50Crystalline cellulose 109Magnesium stearate 1To make one capsule contains 310______________________________________
By using the ingredients in the above-mentioned formulation, a capsule preparation is prepared by conventional methods.
PREPARATION 10
______________________________________Ingredients Amounts (mg)______________________________________1-n-Propyl-3-methyl-5-phenylbiuret 200(Compound No. 41)Lactose 100Crystalline cellulose 98Magnesium stearate 2To make one capsule contains 400______________________________________
By using the ingredients in the above-mentioned formulation, a capsule preparation is prepared by conventional method.
PREPARATION 11
______________________________________Ingredients Amounts (mg)______________________________________1-Isopropyl-3-methyl-5-phenylbiuret 250(Compound No. 43)Witepzol W-35(A trade name for suppository basematerial manufactured by and sold from 750Dynamite Nobel Company)To make one suppository contains 1000______________________________________
By using the ingredients in the above-mentioned formulation, a suppository preparation is prepared by conventional methods.
PREPARATION 12
______________________________________Ingredients Amounts (mg)______________________________________1-Propenyl-3-methyl-5-phenylbiuret(Compound No. 45) 100Sodium chloride 16Distilled water for injection q.s.To make one ampule contains 2 ml______________________________________
By using the ingredients in the above-mentioned formulation, an injection preparation (ampule) is prepared by conventional methods.
PREPARATION 13
______________________________________Ingredient Amount (g)______________________________________1-Isobutyl-3-methyl-5-phenylbiuret 2.0(Compound No. 49)White vaserine 23.0Stearyl alcohol 22.0Propylene glycol 12.0Sodium laurylsulfate 1.5Ethyl p-oxybenzoate 0.025Propyl p-oxybenzoate 0.015Purified water q.s.To make the whole 100______________________________________
By using the ingredients in the above-mentioned formulation, an ointment preparation is prepared by conventional methods.

Number	Date	Country	Kind
54/38791	Mar 1979	JPX
54/38793	Mar 1979	JPX

Number	Date	Country
819853	Sep 1959	GBX
1096006	Dec 1967	GBX

Pharmaceutical composition containing 1,3,5-substituted biuret compound

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