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Publication numberUS3823144 A
Publication typeGrant
Publication dateJul 9, 1974
Filing dateJun 21, 1972
Priority dateJun 23, 1971
Also published asDE2131034A1
Publication numberUS 3823144 A, US 3823144A, US-A-3823144, US3823144 A, US3823144A
InventorsK Schmitt, I Hoffmann
Original AssigneeHoechst Ag
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
N-(benzoyl)-n'-(piperazin-1-yl)alkyl)ureas
US 3823144 A
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Description  (OCR text may contain errors)

United States Patent 3,823,144 N-(BENZOYL)-N'-[(PIPERAZlN-l-YDALKYHUREAS Karl Schmitt, Neuenhain, Taunus, and lrmgard Hoffmanu, Bad Soden, Taunus, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius 8: Bruning, Frankfurt am Main, Germany No Drawing. Filed June 21, 1972, Ser. No. 264,747 Claims priority, application Germany, June 23, 1971, P 21 31 034.9 Int. Cl. C07d 51/70 U.S. Cl. 260-268 PH ABSTRACT OF THE DISCLOSURE Benzoyl ureas of the formula and salts thereof with physiologically acceptable acids, useful as psychopharmacological agents, wherein R is one or more of hydrogen, halogen, alkyl having 1 to 6 carbon atoms, alkyl having 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 4 to 7 carbon atoms, aralkyl having 1 to 4 alkylene carbon atoms, phenyl, hydroxy, acyloxy, alkoxy having 1 to 6 carbon atoms, alkenyloxy having 3 to 6 carbon atoms, aralkoxy having 1 to 4 alkylene carbon atoms, aryloxy, trifluoro, or nitro, in any position, or represents two vicinal substituents which are members of a condensed to 7- membered carbocyclic ring; R is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms; and A is alkylene having 2 to 6 carbon atoms.

8 Claims The present invention relates to benzoyl ureas and to a process for their manufacture.

It is known that acyl ureas (ureides) have sedative or anti-convulsive activities [cf. for example G. Ehrhard and H. Ruschig, Arzneirnittel, pages 287 and 485, Weinheim/Bergstrasse, W. Germany 1968), German Pat. No. 225,710; F. A. Gibbs, G. M. Everett, R. K. Richard,

-Diseases Nerv. System 10, 47 (1949)].

This invention provides novel benzoyl ureas of the formula I as well as the salts thereof with physiologically acceptable acids, in which R stands for hydrogen, halogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 4 to 7 carbon atoms, aralkyl of 1 to 4 alkylene carbon atoms, phenyl, hydroxy, acyloxy, alkyloxy of 1 to 6 carbon atoms, alkenyloxy of 3 to 6 carbon atoms, aralkoxy of 1 to 4 alkylene carbon atoms, aryloxy, trifiuoromethyl or nitro, R being one or more substituents in any position and two vicinal substituents optionally being also members of a condensed 5- to 7-membered carbocyclic ring, R stands for hydrogen, halogen; alkyl of l to 4 carbon atoms or alkoxy of l to 4 carbon atoms, and A stands for alkylene of 2 to 6 carbon atoms.

The benzoyl ureas of the formula I and the cited salts thereof have valuable pharmacological properties and may be used as psycho-pharmacological agents, which especially have a muscle relaxing effect.

Among the compounds of the formula I, those com- 7 pounds are preferred in which R, stands for hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms,

3,823,144 Patented July 9, 1974 cycloalkyl of 5 or 6 carbon atoms, benzyl, phenylethyl, phenyl, alkyloxy of 1 to 4 carbon atoms, phenylalkoxy of 1 or 2 alkylene carbon atoms, phenoxy, methoxyphenoxy, trifluoromethyl, methylene-dioxy, ethylenedioxy or butylene-1,4, and R stands for hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy or ethoxy.

In addition to the substances cited in the Examples, there are especially mentioned:

N- (4'cyc1ohexyl-benzoyl) -N'- 3- (4-m-tolyl-piperazinl-yl) -propyl] -urea,

N- (4-cyclopentyl-benzoyl) -N'- [3- 4-m-tolyl-piperazinl-yl) -propyl] -ur'ea,

N- (4-n-hexyl-benzoyl) -N'- [3- (4-m-tolylpiperazin- 1-yl)-propyl]-urea,

N- (4-benzyl-benzoyl) -N- [3- (4-m-to1ylpip crazinl-yl) -propyl] -urea,

N- (4-phenylethyl-benzoyl) -N'- 3- (4-m-tolylpiperazin- 1-yl)-propyl]-urea,

N- 2-phenyl-benzoyl) -N'- [3 (4-m-tolylpiperazin- 1-yl)-propyl]-urea,

N-( 3-butoxy-benzoyl) -N'- [3- (4-m-tolylpiperazinlyl) -propyl] -urea,

N- (4-b enzyloxy-b enzoyl) -N'- [3- (4-m-tolylpiperazin- 1-y1)-propyl]-urea,

N- (2-phenoxy-benzoyl) -N- [3- (4-m-tolylpiperazin- 1-yl)-propy1]-urea,

N- (4-p-methoxy-phenoxy-b enzoyl) -N'- [3 (4-m-toly1- piperazin-l -yl -propyl] -urea,

N- (4-methoxy-benzoyl) -N'- 6- (4-m-toly1piperazin- 1-yl -hexyl] -urea,

N- 3 ,4-methylene-dioxy-benzoyl) -N'- [3 (4-phenyl-piperazin-1-y1)-propyl]-urea,

N- (3-methoxy-benzoyl) -N'- [3- (4-m-bromophenyl-piperazinl-yl) -propyl -urea,

N- (3 ,4-dimethoxy-benzoyl -N- 3- (4-m-ethyl-pheny1- piperazin-1-yl)-propyl] -urea,

N- (2, S-dimethyl-b enzoyl) -N'- [3- (4-p-ethoxyphenylpiperazin-l-yl) -propyl] -urea,

N- (3,4, 5-triethoxy-benzoyl) -N'- [3- (4-m-tolylpiperazinl-yl) propyl] -urea,

N- l-naphthoyl) -N'- [3 (4-m-tolylpiperazin-1-yl) propyl] -urea,

N- 5,6,7,8-tetrahydro-1-naphthoyl) -N'- [3- (4-m-tolylpiperazin- 1 -yl) -propyl] -ure a.

This invention also provides a process for the manufacture of benzoyl ureas of the formula I, wherein (a) an R -substituted benzoyl-isocyanate, benzoyl-carbamic acid ester, benzoyl-carbamic acid halide, benzoyl-thiolcarbamic acid ester, benzoyl-urea, benzoylsemicarbazide or benzoyl-semicarbazone, is reacted with an amine of the formula II HzN-A-N N@ in which A and R are defined as above, or with a salt thereof, or a benzamide of the formula III is reacted with an isocyanate, carbamic acid ester, thiolcarbamic acid ester, carbamic acid halide or urea, all substituted by the group (b) a correspondingly substituted benzoyl-isourea ether,

benzoyl-isourea ester, benzoyl-isothiourea ether, ben- 3 zoyl-parabanic acid or benzoyl-halofor ic acid amidine,

' is hydrolyzed, or

(c) a correspondingly substituted benzoyl-thiourea, thiobenzoyl-urea or thio-benzoyl-thiourea, all corresponding to the substituent R is treated with a reagent able to replace the sulfur atom by an oxygen atom, or

(d) water is added on a correspondingly substituted benzoyl-carbodiimide, or

(e) a R -substituted benzoic acid or a halide, ester or anhydride thereof is reacted with a ureasubstituted by the group or a salt thereof, or (f) a compound of the formula IV R: (IV) preferably in the form of a reactive ester, is reacted with a piperazine of the formula V or (g) a compound of the formula VI cm-om-on 2C tH (VI) in which B stands for the radical preferably in the form of a reactive ester, is reacted with an amine of the formula or a compound of the formula VI, in which B stands for the radical preferably in the form of its reactive ester, is reacted with an amine of the formula The compound obtained according to the reactions (a) to (g) is optionally converted with a physiologically acceptable acid into the corresponding salt.

The benzoyl radical of the formula may be varied within wide limits by substitution without substantially affecting the pharmacological activity of the products. The Examples hereinafter indicated refer to this fact; the process of the invention is, however, not limited to the use of the acyl radicals indicated therein; substances containing the indicated acyl radicals as well as other acyl radicals may be prepared according to the process and used as psychopharmacological agents.

The phenyl radical may also carry a variety of substituents. As substituted phenyl radicals, there may be mentioned ortho-, meta and para-tolyl, ortho-, metaand parachlorophenyl, ortho-, metaand para-methoxy-phenyl, 2-chloro-4-methylphenyl and other radicals. The m-tolyl radical is preferred.

The alkylene radical A having 2 to 6 carbon atoms may especially be an ethylene, 1,2-propylene, 1,3- or 2,4butylene, tetraor penta-methylene, preferably a trimethylene radical.

The preferred method (a) for the manufacture of the compounds of the invention from benzoyl isocyanate and an amine of the formula II may be carried out without using a solvent; it is, however, advantageous to use an inert solvent, such as ether, methylene chloride, dichloro-ethane, benzene, chlorobenzene, nitrobenzene, toluene or dimethylformamide. The reaction temperature may generally be between room temperature and the boiling temperature of the solvent used. For example, the reaction may be started at about 20 C. by adding a solution of the amine in toluene dropwise to a solution of benzoyl isocyanate in toluene, whereupon an increase in temperature is generally observed. The reaction temperature is advantageously between 30 and C.; lower and higher temperature only influence the reaction rate.

The benzoyl-isocyanates to be used as starting material may be prepared in known manner, for example by reacting corresponding benzoyl-halides with metal salts of cyanic acid or from the corresponding acid amides.

According to method (a), the chlorides are preferably used as benzoyl-carbamic acid halides.

Moreover, according to method (a), a benzoyl-carbamic acid ester, benzoyl-thiocarbamic acid ester, benzoyl-urea, benzoyl-semicarbazide or benzoyl-semiearbazone is reacted with an amine of the formula II. Alternatively, the functional groups in the reaction components may also be exchanged so that an aromatic carboxylic acid amide of the formula III is reacted with an aryl-piperazino-alkylisocyanate, aryl-piperazino-alkyl-carbamic acid ester, arylpiperazino-alkyl-thiolcarbamic acid ester, aryl-piperazinoalkyl-carbamic acid halide or aryl-piperazino-alkyl-urea. The reaction generally requires elevated temperatures, preferably between 80 and C.

Benzoyl-carbamic acid esters and benzoyl-ureas to be used as starting material according to method (a) may be obtained from benzoyl-isocyanates and alcohols or amines or by acylation of urethanes and ureas, for example by a gcaction with the corresponding carboxylic acid chlo- 1! es.

The benzoyl-carbamic acid esters or benzoyl-thiolcarbamic acid esters may contain, in the alcohol component, an alkyl radical or an aryl radical or even a heterocyclic radical. Since this radical is split off during the reaction, its chemical constitution has no influence on the nature of the end product and can therefore be varied within wide limits. The same applies to the carbamic acid esters substituted by the group wide limits. In addition to benzoyl-ureas containing alkyl,

aryl, acyl or heterocyclic groups, bis-acyl-ureas which may carry a further substituent at one of the nitrogen atoms, for example methyl, may also be used. For example, such bis-acyl-ureas or N-benzoyl-N'-benzoyl-ureas may be treated with amines of the formula R2 HzN-A- N Q by heating them to elevated temperatures, especially above 100 C.

It is furthermore possible to start from ureas of the or from ureas which carry one or two substituents at the free nitrogen atom, and to react them with amides of the formula Q-CO-Nfia.

As such starting materials, there are mentioned, for example:

N- [3- 4-m-tolyl-piperazinl-yl) -propyl] -uera,

N- [4-(4-m-tolylpiperazinl-yl -butyl] -urea,

N- [5- (4-m-tolylpiperazin-1-yl)-pentyl] -urea,

N- [3 (4-m-tolylpiperazin-1-yl) -buty1] -urca,

N- [2-methyl-3- (4-m-tolylpiperazin-1-yl) -propyl] -urea, N- [4- 4-m-tolylpiperazin- 1-yl) -butyl- (2) J-urea,

N- [3 4-p-fluorophenylpiperazin-l-yl) -propyl] -urea, N- 3- (4-m-chlorophenylpip erazin-l-yl) -propyl] -urea, N- 3- 4-phenylpip erazinl-yl) -propyl] -urea,

N- [3- (4-p-methoxyphenyl-pip erazinl-yl) -propyl] -ure a, 1\ [3- (4-m-ethylphenyl-piperazinl-yl) -propyl] -urea,

the corresponding N'-acetyl-, N'-nitro-, -aryl-piperazino-alkyl-, N',N'-diphenyl- (the two phenyl radicals may also be substituted or linked to each other directly or 'via a bridge member, such as CH,, NH, -O- orS), N-methyl-N'-phenyland N,N'-dicyclohexylureas.

According to method (b), the hydrolysis of the cited starting substances is advantageously carried out in an alkaline medium. The cited isourea ethers and isourea esters may also be hydrolized in an acid medium.

According to method (c), the replacement of the sulfur atom by the oxygen atom in the cited starting substances is performed, for example, with the aid of heavy metal oxides, such as lead oxide or mercury oxide, or heavy metal salts, such as lead nitrate, or by means of oxidizing agents such as hydrogen peroxide, sodium peroxide, or nitrous acid.

The benzoyl-carbodiimides to be used according to method (d) may be obtained as intermediate products in the desulfuration of benzoyl-thioureas according to method (c). They may also be prepared by reacting benzoyl-thioureas with acylating agents such as phosgene, or with phosphorus pentachloride. By an addition reaction with water they are converted into acylureas.

Method (e) is carried out in the presence or absence of basic condensation agents, such as tertiary organic bases, alkali metal or alkaline earth metal carbonates, hydroxdies, hydrides, amides or the metals themselves, advantageously in inert solvents. As acid anhydrides which react in a manner similar to that of acid chlorides, mixed anhydrides may also be used. The reaction of the acid anhydrides may also be promoted by means of acid catalysts, such as sulfuric acid, perchloric acid, aluminum chloride or ion(III) chloride, instead of the basic condensation agents.

In method (e), esters of low molecular weight alcohols, of benzyl alcohols or of phenols are especially used as carboxylic acid esters. The reaction of these starting materials with the substituted ureas may advantageously be performed with the aid of alkali metals, alkali metal hydrides or amides in inert solvents, such as benzene,

toluene, dioxane, glycol ether, dimethyl-formamide, and sometimes also in liquid ammonia.

According to method (f), there may be used as reactive esters, for example, esters of hydrohalic acids, especially of hydriodic, hydrobromic and hydrochloric acids, and esters of sulfuric acid or of sulfonic acids, for example benzeneor toluene-sulfonic acid.

The reactive esters to be used according to method (g) are the same as mentioned for the afore-mentioned method (f).

The benzoyl-ureas of the invention may be employed in the form of the free bases and of the salts of physiologically acceptable acids. Suitable acids for salt formation are, for example, hydrochloric acid, hydrobromic acid and hydriodic acid, phosphoric acid, sulfuric acid, amidosulfonic acid, methyl-sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, succinic acid, tartaric acid, lactic acid, malonic acid, fumaric acid, citric acid, malic acid, mucic acid, benzoic acid, salicylic acid, aceturic acid, embonic acid, naphthalene-1,5-disulfonic acid, ascorbic acid, hydroxy-ethanesulfonic acid, benzene-sulfonic acid, or also synthetic resins containing acid groups.

The benzoyl-ureas of the invention have valuable pharmacodynamic properties. Especailly on various kinds of animals they produce effects which mark them as psychopharmacological agents having a tranquilizing activity.

For example, N-(4-methoxybenzoyl) N-[3-(4-n1- tolylpiperazin-l-yl)-propyl]urea hydrochloride or N-(S- chloro-2-methoxybenzoyl)-N'-[3-(4 m tolylpiperazin- 1-yl)propyl]-urea dihydrochloride shows a muscle-relaxing elfect which is several times stronger than that of merprobamate. The period of action is also substantially longer than that of the known compound.

Moreover, in a test on animals, the benzoyl-ureas of the invention exhibit a protection elfect against lethal nicotine dosages and prolong an anaesthesia initiated by barbiturates or alcohol. In the pentetrazol test, the novel benzoyl-ureas bring about intensification of a spasm similar to the accumulative effect of the psychopharmacological agents of the amitriptyline type.

Within the group of the benzoyl-ureas of the invention, there are distinct differences in the activity of individual substances in the somnolence test. In contrast to other compounds of the invention, N-(S-chloro-Z-methoxy-benzoyl)-N'[3-(4 m-tolylpiperazin-1-yl)propyl]- urea dihydrochloride causes practicaly no somnolence in a test on animals. Thus, it is possible to select from the group of benzoyl-ureas those compounds which meet various requirements according to each individual case.

The toxicity of the acyl-ureas of the invention is very low. For example, the lethal dose LD of the two abovementioned hydrochlorides, administered to mice per os, i.e. the dose that kills 50 percent of the test animals, is about twice as high as that of meprobamate.

For the treatment of psychic diseases, the novel benzoylureas may be administered parenteraly, preferably orally, for example in the form of tablets or dragees. For the manufacture of the compositions, the usual carriers and adjuvants, such as lactose, starch, tragacanth, magnesium stearate, are used.

The following Examples serve to illustrate the invention.

EXAMPLES l. A solution of g. of 3-(4-m-tolylpiperazin-1-yl)-propylamine in 200 ml. of toluene was added dropwise, while stirring, to a solution of 79.6 g. of 4-methoxybenzoyl-isocyanate in 400 ml. of toluene, While the internal temperature rose above 50 C. Stirring Was then continued for about 3 hours. The reaction solution was evaporated and the residue was converted into the hydrochloride by means of methanolic hydrochloric acid. g. of N (4-methoxy-benzoyl)-N'-[3-(4-m-tolylin 100 ml. of methanol, the solution was acidified with alcoholic hydrogen chloride and ether was added. 2.8 g. of N-(5-chloro-2-methoxy-benzoyl)-N'-[3-(4-m-tolylpiperazin-1-yl)propy1]-urea dihydrochloride were obtained, m.p. 185-190 C. By recrystallization from aqueous methanol, the monohydrochloride was obtained, m.p. 189-19l C.

52. 6.05 g. of benzamide and 2.4 g. of a 50% suspension of sodium hydride in oil were heated for some hours at 80-90" C. in 100 ml. of xylene. The reaction mixture was combined, while stirring, at 60 C. with 17.7 g. of N-[(3 (4-m-tolylpiperazin-1-yl)-propyl]-carbamic acid phenyl ester (m.p. of the hydrochloride: 159-161 C.) in 60 ml. of xylene. Heating was continued for 15 minutes at 80 C., the reaction mixture was allowed to cool, 250 ml. of methylene chloride were added and the solution was washed with water. The organic solution was dried with potassium carbonate and evaporated. 18 g. of N-benzoyl-N'-[3-(4-m-tolylpiperazin-1- yl)-propyl]-urea were obtained, which was recrystallized from methanol, m.p. 142-144 C.

53. The base prepared from 1.73 g. of N-benzyl-N'-[3- (4 m-tolylpiperazin-l-yl)-propyl]-thiourea hydrochloride, m.p. 207-209 C., by means of aqueous sodium carbonate solution was heated, while vigorously stirring, for 1 hour at 65-70 C., with 1.2 g. of yellow mercury oxide in 50 ml. of ethanol. The reaction mixture was filtered by means of charcoal and the filtrate was neutralized with methanolic hydrochloric acid. 1.2 g. of N- benzoyl-N'-[3 (4-m-tolylpiperazin-1-yl)-propyl]-urea dihydrochloride-were obtained, which was recrystallized from methanol, m.p. 215-217 C.

54. 1.1 g. of S-chloro-2-methoxy-benzoyl chloride were introduced slowly while stirring at 10 C. into a solution of 1.38 g. of N-[3-(4-m-tolylpiperazin-1-yl)-propyl]-urea, m.p. 138-139 C., in 50 ml. of pyridine. The mixture was heated for 2 hours on a steam bath and the pyridine was separated by distillation. The residue was taken up in methylene chloride, the solution was washed with an'aqueous sodium carbonate solution and water, dried with sodium sulfate and evaporated. The product was subjected to a fractionated elution through a silica gel column. 0.7 g. of N(5-chloro-2-rnethoxy-benzoyl)- N-[3-(4-m-tolylpiperazin 1 yl)-propyl]-urea was obtained, the dihydrochloride thereof had a melting point of 189-190 C. after recrystallization from methanol.

55. 1.64 g. of benzoyl-urea and 2.33 g. of 3-(4-m-tolylpiperazin-l-yl)-propyl-amine were heated at the boil in 50 ml. of xylene for hours. After cooling, the reaction product was suction-filtered and recrystallized from methanol. 2.5 g. of N-benzoy1-N'-[3-(4-m-tolylpiperazin-1-yl)-propyl]-urea were obtained, m.p. 142-144 C.

56. 5.1 g. of 4-benzoyl-l-phenyl-semicarbazide (m.p. 212- 214 C. prepared by reacting benzoyl-isoeyanate with phenyl-hydrazine) and 5 g. of 3-(4-m-tolylpiperazin-1- yl)-propylamine were heated at the boil for 10 hours in 100 ml. of xylene. After cooling, the product was suction-filtered and recrystallized from methanol. 3.5 g. of N-benzoyl-N-[3-(4-m-tolylpiperazin-1-yl)propyl]- urea were obtained, m.p. 142-144" C.

57. 10 g. of N-benzoyl-carbamic acid ethyl ester and 11.7 g. of 3-(4-m-tolylpiperazin 1 yl)-propylamine were heated at 80 C. for 5 hours in 100 ml. of xylene in the presence of 0.5 g. of sodium methylate. The product obtained after distillation of the solvent was recrystallized from methanol. 5 g. of N-'benzoyl-N'-[3-(4-m-tolylpiperazin-1-yl)propyl]-urea were obtained, m.p. 142- 144 C.

58. 14.4 g. of 5-chloro-2-methoxy-benzamide and 2.5 g. of sodium hydride were heated at the boil for 2 hours in 100 ml. of benzene. After cooling, 100 ml. of dimethylformamide were added. A solution of 33 g. of N-[3- (4-m-tolylpiperazin-1-yl)-propyl]-carbamic acid phenyl ester in 50 ml. of benzene was added at about 40 C.

to this mixture, and stirring was continued for 2 hours at 45 C. The reaction solution was evaporated and the residue was recrystallized from methanol. 20 g. of N- (5-chloro 2-methoxy-benzoyl)-N'-[3-(4-m-tolylpiperazin-1-yl)-propyl]-urea were obtained, m.p. 118-120 C.

When dimethylformamide or dioxan was used as a solvent instead of benzene, the same product was obtained.

59. 3 g. of l-benzoyl-1-[3-4-m-tolylpiperazin-l-yl)-propyl]-parabanic acid (m.p. 136-140" C., prepared by benzoylation of 1-[3-(4-m-tolylpiperazin-1-yl)propyl]- parabanic acid, the hydrochloride thereof melted at 245- 250 C. with decomposition) were heated for 30 minutes in 50 ml. of boiling 1N sodium hydroxide solution. After cooling, the reaction product was suction-filtered and recrystallized from methanol. 1 g. of N-benzoyl- N'-[3 (4-m-tolylpiperazin-1-yl)-propyl]-urea was obtained, m.p. 142-l44 C.

60. 10 ml. of thionyl chloride were added at about 10 C. to 4.4 g. of N-benzoyl-N'-(3 hydroxy-propyl)-urea, m.p. -122 C., in 20 ml. of chloroform. The temperature was gradually raised to 30 C., stirring was continued for some time and the solution was evaporated under reduced pressure. The residue was taken up in 50 ml. of ethanol and, after addition of 16 g. of N-m-tolylpiperazine, the mixture was heated at the boiling point for about 15 hours. The reaction product was purified by fractionated elution from a silica gel column by means of a mixture of chloroform and methanol. 0.9 g. of N-benzoyl-N'[3-(4-m-tolylpiperazin-1-yl)-propyl]-urea was obtained, m.p. 142-l44 C.

61. 15 ml. of thionyl chloride were added at 5-l0 C. to 3.5 g. of 1-benzoy1-3-(S-diethanol-aminopropyl)-urea hydrochloride, m.p. 112-115" C., in 20 ml. of chloroform. The temperature was slowly raised to 30 C. and the reaction mixture was evaporated under reduced pressure. The residue was taken up in 40 ml. of methanol and, after addition of 2.3 g. of m-toluidine, the solution was heated at the boiling point for 15 hours. The reaction mixture was then evaporated and the residue was treated with dilute sodium hydroxide solution and ether. The product obtained from the ether was purified by fractionated elution from a silica gel column by means of a mixture of methanol and carbon tetrachloride. 0.6 g. of N-benzoyl-N-[3-(4-m-tolylpiperazin-1- yl)-propyl]-urea was obtained, m.p. 142-144 C.

What we claim is: 1. A benzoyl-urea of the formula 0 0 @ii -NH-h-NH-A-N NQ R1 L/ and salts thereof with physiologically acceptable acids, wherein R is one to three substituents, in any position, selected from the group consisting of hydrogen, halogen, alkyl having 1 to 6 carbon atoms, alkenyl having 3 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 4 to 7 carbon atoms, phenalkyl having 1 to 4 alkylene carbon atoms, phenyl, hydroxy, alkoxy having 1 to 6 carbon atoms, alkenoxy having 3 to 6 carbon atoms, phenalkoxy having 1 to 4 alkylene carbon atoms, phenoxy, methoxy-substituted phenoxy, trifiuoromethyl, and nitro, or R represents two vicinal substituents forming a condensed 6-membered carbocyclic or methylenedioxy ring with the phenyl group to which they are attached; R is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms; and A is alkylene having 2 to 6 carbon atoms.

2. N-(4-methoxy-benzyl) N' [3-(4-m-tolyl-piperazin- 1-yl)-propyl]-urea hydrochloride.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4355178 *Oct 17, 1980Oct 19, 1982Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T.By acylation of the corresponding urea
US4529819 *Jun 21, 1984Jul 16, 1985The Dow Chemical CompanyMethod for making benzoylphenylureas
US6677365Mar 25, 2002Jan 13, 2004Telik, Inc.Antagonists of MCP-1 function and methods of use thereof
US6809113Feb 27, 2002Oct 26, 2004Telik, Inc.For therapy of arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis transplant rejection
US6962926Aug 8, 2003Nov 8, 2005Telik, Inc.monocyte chemoattractant protein-1 (MCP-1); 1-{1,3-dimethyl-6-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-5-carbonyl}-3-(3-isopropoxyphenyl)urea; inflammatory/autoimmune diseases (multiple sclerosis), and allergic hypersensitivity
US6992086Nov 17, 2003Jan 31, 2006Telik, Inc.Antagonists of MCP-1 function and methods of use thereof
US6998407Nov 18, 2003Feb 14, 2006Telik, Inc.For prophylaxis and therapy of chronic or acute inflammatory or autoimmune diseases, those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease
US7297696Oct 19, 2004Nov 20, 2007Telik, Inc.Antiarthritic agents; antihistamines; atherosclerosis; multiple sclerosis; Crohn's disease; nephritis; pancreastitis; skin disorders; restenosis; prevent leukocyte migration
EP0187700A1 *Jan 6, 1986Jul 16, 1986H. Lundbeck A/SNovel aminoalkyl substituted urea derivatives, acid addition salts thereof and enatiomers
WO2002081463A1 *Mar 28, 2002Oct 17, 2002Sanwa Kaguku Kenkyusho Co LtdAntagonists of mcp-1 function and methods of use thereof
Classifications
U.S. Classification544/377, 564/44, 544/393, 514/906
International ClassificationC07D295/13
Cooperative ClassificationY10S514/906, C07D295/13
European ClassificationC07D295/13