US3823144A - N-(benzoyl)-n'-(piperazin-1-yl)alkyl)ureas - Google Patents

N-(benzoyl)-n'-(piperazin-1-yl)alkyl)ureas Download PDF

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Publication number
US3823144A
US3823144A US00264747A US26474772A US3823144A US 3823144 A US3823144 A US 3823144A US 00264747 A US00264747 A US 00264747A US 26474772 A US26474772 A US 26474772A US 3823144 A US3823144 A US 3823144A
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Prior art keywords
benzoyl
carbon atoms
acid
urea
propyl
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Expired - Lifetime
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US00264747A
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English (en)
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K Schmitt
I Hoffmann
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Hoechst AG
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • 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 atom
  • the present invention relates to benzoyl ureas and to a process for their manufacture.
  • acyl ureas 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,
  • 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
  • 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.
  • R stands for hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms
  • 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,
  • 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.
  • 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.
  • the chlorides are preferably used as benzoyl-carbamic acid halides.
  • 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.
  • 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.
  • 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.
  • benzoyl-ureas containing alkyl In addition to benzoyl-ureas containing alkyl,
  • bis-acyl-ureas which may carry a further substituent at one of the nitrogen atoms, for example methyl, may also be used.
  • 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.
  • 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.
  • 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.
  • 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.
  • heavy metal oxides such as lead oxide or mercury oxide
  • heavy metal salts such as lead nitrate
  • 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.
  • 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.
  • 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.
  • 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,
  • esters of hydrohalic acids especially of hydriodic, hydrobromic and hydrochloric acids
  • 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.
  • 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.
  • the benzoyl-ureas of the invention exhibit a protection elfect against lethal nicotine dosages and prolong an anaesthesia initiated by barbiturates or alcohol.
  • the novel benzoyl-ureas bring about intensification of a spasm similar to the accumulative effect of the psychopharmacological agents of the amitriptyline type.
  • the toxicity of the acyl-ureas of the invention is very low.
  • 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.
  • the novel benzoylureas may be administered parenteraly, preferably orally, for example in the form of tablets or dragees.
  • the usual carriers and adjuvants such as lactose, starch, tragacanth, magnesium stearate, are used.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00264747A 1971-06-23 1972-06-21 N-(benzoyl)-n'-(piperazin-1-yl)alkyl)ureas Expired - Lifetime US3823144A (en)

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DE19712131034 DE2131034A1 (de) 1971-06-23 1971-06-23 Acylharnstoffe und verfahren zu ihrer herstellung

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US (1) US3823144A (cs)
AR (2) AR194692A1 (cs)
AU (1) AU461846B2 (cs)
BE (1) BE785378A (cs)
DD (1) DD101401A5 (cs)
DE (1) DE2131034A1 (cs)
FR (1) FR2143361B1 (cs)
GB (1) GB1368699A (cs)
HU (1) HU165554B (cs)
IL (1) IL39727A0 (cs)
NL (1) NL7208259A (cs)
ZA (1) ZA724294B (cs)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4355178A (en) * 1979-10-19 1982-10-19 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. Process for the preparation of substituted acyl ureas
US4529819A (en) * 1982-08-02 1985-07-16 The Dow Chemical Company Method for making benzoylphenylureas
EP0187700A1 (en) * 1985-01-10 1986-07-16 H. Lundbeck A/S Novel aminoalkyl substituted urea derivatives, acid addition salts thereof and enatiomers
WO2002081463A1 (en) * 2001-04-03 2002-10-17 Telik, Inc. Antagonists of mcp-1 function and methods of use thereof
US20030105085A1 (en) * 2001-03-01 2003-06-05 Edgardo Laborde Antagonists of MCP-1 function and methods of use thereof
US20040077680A1 (en) * 2001-01-31 2004-04-22 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US20040198719A1 (en) * 2001-01-31 2004-10-07 Edgardo Laborde Antagonist of MCP-1 function, and compositions and methods of use thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES472295A1 (es) * 1978-08-02 1979-02-16 Invest Tecnica Aplicada Procedimiento de obtencion de nuevas acilureas con actividadfarmacologica
US4666911A (en) * 1981-07-14 1987-05-19 Taiho Pharmaceutical Company Limited Allophanoylpiperazine compound and analgesic composition containing same as active ingredient
HUT48093A (en) * 1986-08-04 1989-05-29 Sandoz Ag Herbicides comprising benzohydroxamic acid or benzoic acid hydrazide derivatives as active ingredient and process for producing benzohydroxamic acid or benzoic acid hydrazide derivatives

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4355178A (en) * 1979-10-19 1982-10-19 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. Process for the preparation of substituted acyl ureas
US4529819A (en) * 1982-08-02 1985-07-16 The Dow Chemical Company Method for making benzoylphenylureas
EP0187700A1 (en) * 1985-01-10 1986-07-16 H. Lundbeck A/S Novel aminoalkyl substituted urea derivatives, acid addition salts thereof and enatiomers
US20040198719A1 (en) * 2001-01-31 2004-10-07 Edgardo Laborde Antagonist of MCP-1 function, and compositions and methods of use thereof
US6992086B2 (en) 2001-01-31 2006-01-31 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US6962926B2 (en) 2001-01-31 2005-11-08 Telik, Inc. Antagonist of MCP-1 function, and compositions and methods of use thereof
US20040077680A1 (en) * 2001-01-31 2004-04-22 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US6809113B2 (en) 2001-03-01 2004-10-26 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US20030105085A1 (en) * 2001-03-01 2003-06-05 Edgardo Laborde Antagonists of MCP-1 function and methods of use thereof
US7297696B2 (en) 2001-03-01 2007-11-20 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US20040127513A1 (en) * 2001-04-03 2004-07-01 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
US6677365B2 (en) 2001-04-03 2004-01-13 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
WO2002081463A1 (en) * 2001-04-03 2002-10-17 Telik, Inc. Antagonists of mcp-1 function and methods of use thereof
US6998407B2 (en) 2001-04-03 2006-02-14 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof

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NL7208259A (cs) 1972-12-28
AU4366072A (en) 1974-01-03
DE2131034A1 (de) 1973-01-11
FR2143361B1 (cs) 1975-06-20
AR194692A1 (es) 1973-07-31
AU461846B2 (en) 1975-06-05
IL39727A0 (en) 1972-08-30
AR194693A1 (es) 1973-07-31
ZA724294B (en) 1973-03-28
HU165554B (cs) 1974-09-28
BE785378A (fr) 1972-12-27
GB1368699A (en) 1974-10-02
FR2143361A1 (cs) 1973-02-02
DD101401A5 (cs) 1973-11-05

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