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GB2113684A - Antiatherosclerotic substituted ureas and thioureas - Google Patents

Antiatherosclerotic substituted ureas and thioureas Download PDF

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GB2113684A
GB2113684A GB08301863A GB8301863A GB2113684A GB 2113684 A GB2113684 A GB 2113684A GB 08301863 A GB08301863 A GB 08301863A GB 8301863 A GB8301863 A GB 8301863A GB 2113684 A GB2113684 A GB 2113684A
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urea
benzyl
butyl
phenyl
dimethylphenyl
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GB8301863D0 (en
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Vern Gordon Devries
Elwood Eugene Largis
Ransom Brown Conrow
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority claimed from US06/342,698 external-priority patent/US4387105A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
    • C07C273/1827—X being H
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine

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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Furan Compounds (AREA)

Abstract

Substituted ureas and thioureas of the formula below are disclosed which are useful as antiatherosclerotic agents <IMAGE> wherein X represents at least one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1-C4 alkoxy, phenoxy, mercapto, C1-C4 alkylthio, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group: <IMAGE> wherein Y is selected from the group consisting of oxygen and sulfur; R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, furyl and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, phenoxy, benzyloxy, methylenedioxy, C1- C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro; and R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl, and phenyl bearing at least one substituent Z, Z being selected independently of X from the group consisting of those from which X is selected.

Description

SPECIFICATION Antiatherosclerotic substituted ureas and thioureas Background of the invention This invention relates to substituted urea and thiourea compounds useful as pharmaceutical agents, some of which are novel compounds. The compounds of the present invention are antiatherosclerotic agents capable of ameliorating atherosclerosis by counteracting the formation or development of atheromatous lesions in the arterial wall of mammals. The invention also relates to the chemical synthesis of the compounds disclosed herein. In addition, the invention pertains to pharmaceutical compositions for the utilization of these compounds in the treatment of disease in mammals. Further, the invention contemplates methods for treating atherosclerosis in a manner designed to prevent, arrest, or reverse the course of the disease.
A variety of urea and thiourea compounds can be found in the literature, for example, in J. Med. Chem. 18, 1024 (1975); ChemAbsts. 95: 6758m (1981) and 91: 746319 (1979): U.S. Patent Nos. 2,688,039; 3,335,142; 2,856,952; 3,903,130; and in West German Offenlegungschrift 2829485. The compounds found in the literature are disclosed as being useful herbicides, plant growth regulators, bactericides, pesticides, fungicides, algacides, photographic sensitizers, antihelmintics, sympatholytics, and antivirals. Those urea compounds found in Offenlegungschrift 29 28485 are disclosed as useful in inhibiting lipid absorption.
There are, however, no literature references disclosing thetetrasubstituted urea and thiourea compounds of the present invention or their use in the treatment of atherosclerosis or-hyperlipidemia.
Atherosclerosis is a form of arteriosclerosis characterized by lipid accumulation in and thickening of the arterial walls of both medium- and large-sized arteries. Arterial walls are thereby weakened and the elasticity and effective internal size of the artery is decreased. Atherosclerosis is the most common cause of ischemic heart disease and is of great medical importance since the occlusion of medium- and large-sized arteries diminishes the supply of blood to vital organs such as the heart muscles and the brain. The sequelae to atherosclerosis include ischemic heart disease, heart failure, life-threatening arrythmias, senility, and stroke.
The fact that cholesterol is a major component of atherosclerotic lesions or plaques has been known for more than 100 years. Various researchers have studied the role of cholesterol in lesion formation and development and also, more importantly, whether lesion formation can be prevented or lesion development arrested or reversed. Atheromatous lesions have now been shown [Adams, etal., Atherosclerosis, 18429 (1974)] to contain a greater quantity of esterified as opposed to unesterified cholesterol than the surrounding undiseased arterial wall.The intracellular esterification of cholesterol with fatty acids is catalyzed by the enzyme Fatty acyl CoA:cholesterol acyl transferase or ACAT and the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of this enzyme [Hashimoto and Dayton, Atherosclerosis, 28,447 (1977)]. In addition, cholesteryl esters are removed from cells at a slower rate than unesterified cholesterol [Bondjers and Bjorkerud,Atherosclerosis, 15,273(1972) and 22,379(1975)]. Thus, inhibition of the ACAT enzyme would diminish the rate of cholesterol esterification, decrease the accumulation and storage of cholesteryl esters in the arterial wall, and prevent or inhibit the formation and development of atheromatous lesions.The compounds of the present invention are very potent inhibitors of the ACAT enzyme. Thus, these compounds are useful for controlling and reducing the cholesteryl ester content of mammalian arterial walls, and decreasing the accumulation and storage of cholesterol in the arterial walls of mammals. Further, the compounds of this invention inhibit the formation or development of artherosclerotic lesions in mammals.
The evidence that hyperlipidemia is one of the factors involved in coronary heart disease is very impressive. A most important study carried out in Framing ham, Massachusetts (Gordon and Verter, 1969) in over 5,000 persons for more than 12 years established a correlation between high concentrations of blood cholesterol and increased risk of heart attack. Although the causes of coronary artery disease are multiple, one of the most constant factors has been the eievated concentration of lipids in the blood plasma. A combined elevation of cholesterol and triglycerides has been shown (Carlson and Bottiger, 1972) to carry the highest risk of coronary heart disease.The majority of patients with ischemic heart disease or peripheral vascular disease were found to have hyperlipoproteinemia, involving very low-density and/or low-density lipoproteins (lewis, metal., 1974).
We have now found that certain members of this class of compounds can safely and effectively lower both serum lipids in warm-blooded animals. Such action on serum lipids is considered to be very useful in the treatment of atherosclerosis. For some time, it has been considered desirable to lower serum-lipid levels and to correct lipoprotein imbalance in mammals as a preventive measure against atherosclerosis.The compounds of the present invention do not act by blocking late stages of cholesterol biosynthesis and thus do not produce accumulation of intermediates such as desmosterol, as equally undesirable as cholesterol itself. compounds with the combination of therapeutically favorable characteristics possessed by those of the present invention can be safely administered to warm-blooded mammals for the treatment of hyperlipidemic and atherosclerotic states found in patients with or prone to heart attacks, to peripheral or cerebral vascular disease and to stroke.
The compounds of this invention exhibit antiatherosclerotic activity and the invention should not be construed as limited to any particular mechanism of antiatherosclerotic action.
More specifically, this invention relates to certain novel compounds which may be represented by formula
wherein X represents at last one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1 -C4 alkynyl, hydroxy, C1-C4 alkoxy, phenoxy, mercapto, C1-C4 alkylthio, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, halo, trihalomethyl, C-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1 -C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl and the group
wherein Y is selected from the group consisting of oxygen and sulfur;R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C1-C10 alkyl, C1-Clo alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro;R3 is selected from the group consisting of hydrogen, C1-C14 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl and phenyl bearing at least one substituent Z, Z being selected independently of X from the group consisting of those from which X is selected.
Preferred embodiments of the invention represented are those in which Y is oxygen. More preferred are those in which X represents at least one C1-C4 alkyl or halo substituent and R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C?-C14 aralkyl and substituted C7-C14 aralkyl. The most preferred are those in which X represents at least one methyl or chloro substituent and Z is hydrogen, methyl, or chloro.
This invention further relates to a process for preparing compounds of formula II:
wherein X represents at least one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1-C4 alkoxy, phenoxy, mercapto, C1-C4 alkythio, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, haio, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group
Y is selected from the group consisting of oxygen and sulfur; R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C-CO alkyl, CI-Clo alkoxy, phenoxy, benzyloxy, methylenedioxy, Cr-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro; and R3 is hydrogen, which comprises reacting an arylisocyanate or arylthioisocyanate of formula Ill with a secondary amine of formula IV,
wherein X, Y, R1, and R2 are as defined hereinabove.
A specific process for preparing the compounds of formula II comprises reacting a compound of formula V:
wherein Y is as defined in formula II and A and B are independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkylthio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy, with a secondary amine of formula IV:
wherein R1 and F2 are as defined in formula II, to yield an intermediate of formula VI:
and then reacting the intermediate with an arylamine of formula VII: VII
wherein X and R3 are as defined in formula II.
A still further specific process for preparing the compounds of formula II comprises reacting a compound of formula V:
wherein Y is as defined in formula II and A and B are independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkythio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy, with an arylamine of formula VII:
wherein X and R3 are as defined in formula II, to yield an intermediate of formula VIII:
and then reating the intermediate with a secondary amine of formula IV:
wherein R1 and R2 are as defined in formula II.
This invention relates to a method of treating atherosclerosis, reducing the cholesterol ester content of the arterial wall, inhibiting atherosclerotic lesion development, and/or treating hyperlipidemia in a mammal in need of such treatment, which comprises administering to said mammal an effective amount of a compound of the generic formula I::
wherein X represents at least one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1 -C4 alkoxy, phenoxy, mercapto, C1-C4 alkylthio, amino, C7-C4 alkylamino, di-(C2-C4 alkyl)amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene tolyi, benzyl, halobenzyl, methylbenzyl, and the group
Y is selected from the group consisting of oxygen and sulfur;R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-Ca2 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C-CrO alkyl, CI-Clo alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro; and R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl, and phenyl bearing at least one substituent Z, Z being selected independently of X from the group consisting of those from which Xis selected, Lastly, this invention relates to a pharmaceutical composition and its preparation suitable for treating atherosclerosis, reducing the cholesterol ester content of the arterial wall, inhibiting atherosclerotic lesion development, and/or treating hyperlipidemia in a mammal in need of such treatment, which comprises an effective amount of a compound of the formula::
wherein X represents at least one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1 -C4 alkoxy, phenoxy, mercapto, C1-C4 alkythio, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene tolyl, benzyl, halobenzyl, methylbenzyl, and the group
Y is selected from the group consisting of oxygen and sulfur;R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C1-C10 alkyl, C-CrO alkoxy, phenoxy, benzyloxy, methylenedioxy, C1 -C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro; and R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl, and phenyl bearing at least one substituent Z, Z being selected independently of X from the group consisting of those from which Xis selected; and a non-toxic, pharmaceutically-acceptable carrier.
Certain of the ureas and thioureas of this invention are prepared by reacting activated derivatives of carbonic acid such as phosgene, thiophosgene, or phenyl chloroformate with secondary amines to yield an intermediate, for instance, a disubstituted carbamyl chloride. This intermediate is in turn reacted with an arylamine to yield the urea or thiourea. The preparation of the intermediate is conducted in an aprotic solvent such as tetrahydrofuran, toluene, xylene, or the like at temperatures from about room temperature up to the boiling point of the solvent. The intermediate may be isolated by evaporation and purified by distillation if necessary. The intermediate is then reacted with an arylamine in an aprotic solvent such as dimethylacetamide in the presence of a base such as sodium hydride at temperatures from about room temperature up to the boiling point of the-solvent used.An example of this process is the reaction of phosgene with N-benzyl-n-butylamine in touene to yield the intermediate N-benzyl-N-(n-butyl)carbamyl chloride, which is then reacted with diphenylamine in N,N-dimethyl-acetamide in the presence of sodium hydride to yield I -benzyl-i -(n-butyl)-3,3-diphenylurea.
Other of the ureas and thioureas of this invention are prepared by reacting arylamines with activated derivatives of carbonic acid such as phosgene or thiophosgene to yield an intermediate, for instance, an arylcarbamyl chloride. This intermediate is then reacted with a secondary amine to yield the urea or thiourea. The preparation of this intermediate is conducted in an aprotic solvent such as tetrahydrofuran, toluene, or xylene at temperatures from about room temperature up to the boiling point of the solvent in the presence of a base, for example, N-N-dimethylaniline. The intermediate is then reacted with a secondary amine in an aprotic solvent such a tol uene at temperatures from room temperature or below up to the boiling point of the solvent.An example of this process is the reaction of phosgene with N-phenyl-3chloroaniline to yield the intermediate N-(3-chlorophenyl)-N-phenyl carbamyl chloride, which is then reacted with N-benzyl-n-butylamine to yield 1 -benzyl-1 -(n-butyl)-3-(3-chlorophenyl )-3-phenyl u rea.
The ureas and thioureas of this invention which contain carboxy groups are prepared by alkaline hydrolysis of the corresponding carboalkoxy ureas and thioureas, prepared by the synthetic methods described above. Likewise, those which contain hydroxy, mercapto, or amino groups are prepared by alkaline hydrolysis of the corresponding O-acetyl, S-acetyl, and N-acetyl ureas and thioureas, respectively, the latter also having been obtained by the urea and thiourea syntheses described above. Alternatively, ureas and thioureas containing hydroxy groups are prepared by cleavage of the corresponding methoxy compounds using Lewis acids such as boron tribromide.
Certain substituted N-benzylanilines which are intermediates required for the synthesis of some of the novel tetrasubstituted ureas and thioureas of th is invention are not known in the art. The requisite N-benzylanilines are prepared by reactions of various benzaldehydes with anilines to yield anils. The anils are then reduced to yield the substituted N-benzylanilines. An example of such a synthesis involves the reaction of 2,4-dimethylbenzaldehyde with 2,4-dichloroaniline to yield N-(2,4-dimethylbenzylidene)-2,4dichloroaniline followed by reduction with sodium borohydride to yield N-(2,4-dimethylbenzyl)-2,4dichloroaniline.
Many of the ureas and thioureas of this invention are prepared by reacting arylisocyanates and arylisothiocyanates with secondary amines. These reactions may be performed in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas and thioureas are isolated by filtering or by evaporating the solvent, and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure. An example of this process is the reaction of 2,4dimethylphenylisocyanate with di-(n-butyl)amine to yield 1,1 -di-(n-butyl)-3-(2,4-dimethylphenyl) urea.
Many of the secondary amines required for the synthesis of the ureas and thioureas of this invention are prepared by diborane reductions of the corresponding amides. An example of this reaction is the synthesis of N-(n-butyl)-2-chlorobenzylamine by diborane reduction of N-(n-butyl)-2-chlorobenzamide. Certain of the amides required by these reductions are prepared by acylation of primary amines with carboxylic acids by methods well known to those skilled in the art, for example, by conversion of the carboxylic acid to the corresponding carboxylic acid chloride using thionyl chloride and then reacting the acid chloride with the primary amine in the presence of a base. One method especially useful for this transformation is the boron trifluoride etherate catalized reaction of a carboxylic acid with a primary amine.An example of this transformation is the boron trifluoride etherate catalyzed acylation of 2-chlornbenzylamine with 3-methoxyphenylacetic acid to yield N-(2-chlorobenzyl)-3-methoxy-phenylacetamide.
The ureas and thioureas of the present invention are obtained as crystalline solids or distillable liquids.
They are characterized by distinct melting or boiling points and unique spectra. They are appreciably soluble in organic solvents but generally less soluble in water. Those compounds which contain carboxylic acid groups may be converted to their alkali metal and alkaline earth salts by treatment with the appropriate metal hydroxides and those which contain amino groups may be converted to their ammonium salts by treatment with organic or mineral acids. Both these types of salts exhibit increased water solubility.
The properties and utility of the compounds of this invention will be illustrated in conjunction with the specific tables shown below.
The compounds of the present invention were assayed for two types of biological activity related to their potential use as antiatherosclerotic agents. Compounds were tested in vitro for their ability to inhibit the enzyme fatty acyl CoA:cholesterol acyl transferase (ACAT) and in vitro for serum hypolipidemic activity as measured by their ability to inhibit lipid absorption in rats. The compounds were tested for their ability to inhibit ACAT according to the following procedure: Rat adrenals were homogenized in 0.2M monobasic potassium phosphate buffer, pH 7.4, and centrifuged at 1,000 times gravity for 15 minutes at 5"C. The supernatant, containing the microsomal fraction, served as the souce of the cholesterol-esterifying enzyme, fatty acyl CoA:cholesterol acyl transferase (ACAT).A mixture comprising 50 parts of adrenal supernatant, 10 parts of albumin (BSA) (50 mg./ml.), 3 parts of test compound (final concentration 5.2g./ml.), and 500 parts of buffer was preincubated at 37 C. for 10 minutes.
After treatment with 20 parts of oleoyl CoA(14C-0.4 Ci) the mixture was incubated at 37"C. for 10 minutes. A control mixture, omitting the test compound, was prepared and treated in the same manner. The lipids from the incubation mixture were extracted into an organic solvent and separated by thin-layer chromatography.
The cholesteryl ester fraction was counted in a scintillation counter. This procedure is a modification of that described by Hashimoto, etal., Life Science, 12 (Part 11), 1-12 (1973).
The results of this test on representative compounds of this invention appear in Table I.
TABLE I COMPOUND % INHIBITION 1 -Benzyl-1 -(n-butyl)-3,3-diphenylurea 75.9 1-Benzyl-1 -(n-butyl)-3-(3-chorophenyl)-3-phenylurea 72.3 1-Benzyl-1-(n-butyl)-3-(2-naphthyl)-3-phenylurea 83.6 1 -Benzyl-1 -(n-butyl)-3-benzyl-3-phenyl urea 81.8 1 -Benzyl-1 -(n-butyl)-3-(3-methylphenyl)-3-phenylurea 82.0 1 -Benzyl-1 -(n-butyl)-3-(3-methoxyphenyl)-3-phenylurea 82.5 1 -Benzyl-1 -(n-butyl)-3-(4-isopropoxyphenyl)-3-phenylurea 77.8 1 -Benzyl-1 -(n-butyl)-3-(1 -naphthyl)-3-phenyl u rea 76.3 1 -Benzyl-1 -(n-butyl )-3-(2-na phthyl )-3-(3-chlorophenyl )urea 82.7 1 -Benzyl-1 -(n-butyl )-3,3-di-(2-naphthyl)u rea 93.2 1 ,3-Dibenzyl-1 ,3-di-(n-butyl)u rea 95.4 1 -Benzyl-1 -(n-butyl )-3-(3-methylphenyl )-urea 92.3 1 -Benzyl-1 -(n-butyl)-3-(3-trifl uoromethyl phenyl )u rea 85.7 1 -Benzyl-1 -(n-butyl )-3-(3,5-dichlorophenyl)u rea 90.7 TABLE I COMPOUND % INHIBITION l-Benzyl-l -(n-butyl)-3-(3,4-dichlorophenyl)urea 95.9 1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)-urea 88.6 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea 91.3 1 -Benzyl-1 -(n-butyl )-3-(2-methylphenyl urea 78.8 1-Benzyl-1-(n-butyl)-3-(4-methylphenyl)urea 78.0 1-Benzy-1-(n-butyl)-3-(2,3-dimethylphenyl)urea 85.8 1 -Benzyl-1 -(n-butyl)-3-(2,5-dimethyl phenyl)urea 92.7 1 -Benzyl-1 -(n-butyl)-3-(2,6-dimethyl phenyl )urea 83.1 1 -Benzyl-1 -(n-butyl)-3-(3,5-dimethyl phenyl)u rea 94.2 1 -Benzyl-1 -[1 - (3-methoxyphenyl)-2-phenylethyl]-3-(2,4-dimethylphenyl )urea 86.4 1-Benzyl-1-[1-(4-benzyloxyphenyl)-2-phenylethyl]-3-(2,4-dimethylphenyl)urea 93.0 1 -Benzyl-1 -(1 ,2-diphenylethyl)-3-(2,4-dimethylphenyl)urea 95.0 1 -Benzyl-1 -(n-butyl )-3-(3,4-dimethylphenyl)urea 87.1 1-benzyl-1-[1-(3-methoxyphenyl)-2-phenylethyl]-3-(3-trifluoromethylphenyl)urea 88.1 1 -Benzyl-1 -(n-butyl )-3-(3-chloro-2-methoxyphenyl )u rea 84.5 1 -Benzyl-1 -(n-butyl )-3-(5-chlorn-2-methoxyphenyl)urea 80.6 1-Benzyl-1-(n-butyl)-3-phenyl thiourea 82.4 1-(n-Butyl)-1-(2-fluorobenzyl)-3-(2,4-dimethylphenyl)urea 82.6 1-(n-Butyl)-1-(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea 80.6 1-(n-Butyl)-1-(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea 95.5 1-(n-Butyl)-1-(2,6-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea 74.5 1-(n-Butyl)-1-(4-bromobenzyl)-3-(2,4-dimethylphenyl)urea 81.0 1-(n-Butyl)-1-[4-(n-butyl)benzyl)]-3-(2,4-dimethylphenyl)urea 94.4 1-(n-Butyl)-1-(4-methylbenzyl)-3-(2,4-dimethylphenyl)urea 96.7 1 (n-Butyl)-1 -(4-tert-butylbenzyl)-3-(2A.dimethylphenyl)urea 96.4 1 -(n-Butyl)-1 -(4-chlorobenzyl)-3-(2,4.dimethylphenyl)urea 94.6 1-(n-Butyl)-1-(4-methoxybenzyl)-3-(2,4-dimethylphenyl)urea 94.2 1-(n-Butyl)-1-(3,4-methylenedioxybenzyl)-3-(2,4-dimethylphenyl)urea 88.2 1-(n-Butyl-)-1-(4-trifluoromethylbenzyl)-3-(2,4-dimethylphenyl)urea 93.3 1 -(n-Butyl)-1 -(4-phenylbenzyl)-3-(2,4-dimethylphenyl)urea 97.1 1 -(n-Decyl)-1 -benzyl-3-(2,4-dimethyl phenyl)urea 96.1 1 -(n-Butyl )-1 -(2-phenylethyl)-3-(2,4-dimethylphenyl)urea 87.9 1-(n-Butyl)-1-[2-(4-fluorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea 96.1 1-(n-Butyl)-1-[2-(4-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea 93.3 1-(n-Butyl)-1-[2-(3-methoxyphenyl)ethyl]-3-(2,4-dimethylphenyl)urea 89.3 1 -(n-Butyl)-1 -(3-phenylpropyl)-3-(2,4-dimethylphenyl)urea 97.4 1-(n-Butyl)-1-benzyl-3-(2,4,6-trimethylphenyl)urea 75.8 1 -(n-Butyl)-1 -[4-(n-hexyl)benzylj-3-(2,4-dimethylphenyl)urea 93.8 1 -(n-Tetradecyl)-1 -benzyl-3-(2,4-dimethylphenyl)urea 80.3 1-(n-Octadecyl)-1-benzyl-3-(2A-dimethylphenyl)urna 80.3 1-(n-Octadecyl)-1-benzyl-3-(2,4-dimethylphenyl)urea 19.7 1-(n-Butyl)-1-[2-(3-bromophenyl)ethyl]-3-(2,4-dimethylphenyl)urea 97.0 1,1-Dibenzyl-3-(2,4-dimethylphenyl)urea 89.9 1,1-Dibenzyl-3-(2-methylphenyl)urea 77.0 1,1-Dibenzyl-3-(3-methylphenyl)urea 88.9 1,1-Dibenzyl-3-(4-methylphenyl)urea 86.5 1,1-Dibenzyl-3-(4-n-butylphenyl)urea 91.3 1,1 -Dibenzyl-3-(2,3-dimethyl phenyl)u rea 88.1 1,1-Dibenzyl-3-((2,5-dimethylphenyl)urea 89.1 1,1-Dibenzyl-3-(2,6-dimethylphenyl)urea 56.1 1,1-Dibenzyl-3-(3,4-dimethylphenyl)urea 71.8 1,1-Dibenzyl-3-(3,5-dimethylphenyl)urea 90.2 1,1-Dibenzyl.3-2,4,6-trimethylphenyl)urea 36.9 1,1-Dibenzyl-3-(4-methoxyphenyl)urea 71.6 1,1-Dibenzyl-3-((4-n-butoxyphenyl)urea 90.2 1,1-Dibenzyl-3-(4-methylthiophenyl)urea 67.1 1,1-Dibenzyl-3-((2-chlorophenyl)urea 87.8 1,1-Dibenzyl-3-(3-chlorophenyl)urea 94.2 1,1-Dibenzyl-3-(4-chlorophenyl)urea 77.5 1,1-Dibenzyl-3-(2-bromophenyl)urea 93.9 1,1-Dibenzyl-3-(4-bromophenyl)urea 79.9 TABLE I COMPOUND % INHIBITION 1,1-Dibenzyl-3-(4-iodophenyl)urea 85.2 1,1-Dibenzyl-3-(2,3-dichlorophenyl)urea 79.7 1,1-Dibenzyl-3-2,4-dichlorophenyl)urea 83.3 1,1-Dibenzyl-3-(2,5-dichlorophenyl)urea 82.4 1,1 -Dibenzyl-3-3,5-dichlorophenyl)u rea 86.1 1,1-Dibenzyl-3-3-trifluoromethylphenyl)urea 94.2 1,1-Dibenzyl-3-(3-acetylphenyl)urea 80.7 1,1-Dibenzyl-3-(4-phenoxyphenyl)urea 94.3 1,1-Dibenzyl-3-(3-chloro-2-methylphenyl)urea 83.8 1,1-Dibenzyl-3-(3-chloro-4-methylphenyl)urea 94.0 1,1 -Dibenzyl-3-(4-ch loro-3-trifluoromethylphenyl )urea 92.0 1,1-Dibenzyl-3-(4-chloro-2-trifluoromethylphenyl)urea 81.8 1,1-Dibenzyl-3-(3-methylphenyl)thiourea 71.2 1,1-Dibenzyl-3-(3-bromophenyl)urea 91.9 1,1 -Dibenzyl-3-(2,3-dibenzophenyl )urea 90.0 1,1-Dibenzyl-3-(5-chloro-2-methylphenyl)urea 71.3 1,1-Dibenzyl-3-(3-methoxyphenyl)urea 87.0 1,1-Dibenzyl-3-(2-methoxyphenyl)urea 91.0 1,1-Dibenzyl-3-(3-nitrophenyl)urea 81.3 1,1-Dibenzyl-3-(2,5-dimethoxyphenyl)urea 87.9 1,1-Dibenzyl-3-(2,6-dichlorophenyl)urea 88.6 1,1-Dibenzyl-3-(3,4-dichlorophenyl)urea 94.5 1,1-Dibenzyl-3-(4-chloro-2-methylphenyl)urea 62.7 1,1 -Dibenzyl-3-(2-methoxy-5-methyl phenyl )u rea 87.8 1,1-Dibenzyl-3-(6-chloro-2-methylphenyl)urea 83.9 1,1-Dibenzyl-3-(6-ethyl-2-methylphenyl)urea 73.6 1,1-Dibenzyl-3-(2,6-diethylphenyl)urea 72.0 1,1-Dibenzyl-3-(2,6-isopropylphenyl)urea 59.1 1,1-Dibenzyl-3-(4-nitrophenyl)urea 52.2 1,1-Dibenzyl-3-(4-ethoxyphenyl)urea 95.8 1,1-Dibenzyl-3-2,5-difluorophenyl)urea 72.0 1,1-Dibenzyl-3-(2,4-dibromophenyl)urea 81.9 1,1-Dibenzyl-3-3-chloro-4methylphenyl)thiourea 94.1 1,1-Dibenzyl-3-(2,4-dimethylphenyl)thiourea 78.7 1,1 -Dibenzyl-3-(3-trifluoromethylphenyl)thiourea 88.6 1,1 -Dibenzyl-3-(2,4,5-trimethyl phenyl)urea 69.1 1,1-Dibenzyl-3-(phenyl-4-carboxylic acid) thiourea ethyl ester 76.6 1,1-Dibenzyl-3-(3,4-dibenzophenyl)urea 97.3 1,1-Dibenzyl-3-(2-trifluoromethylphenyl)urea 68.4 1,1-Dibenzyl-3-(4-methylphenyl)urea 89.8 1,1-Dibenzyl-3-phenylurea 90.4 1,1-Dibenzyl-3-(4-carboxyphenyl)urea 14.1 1,1-Dibenzyl-3-(4-carbethoxyphenyl)urea 94.9 1-Benzyl-1-(n-butyl)-3-(phenyl)urea 82.0 1,1-di-(n-butyl)-3-(2,4-dimethylphenyl)urea 81.1 1,1-di-(n-butyl)-3-(2-methylphenyl)urea 61.8 1,1-di-(n-butyl)-3-(3-methylphenyl)urea 78.4 1,1-di-(n-butyl)-3-(4-methylphenyl)urea 79.9 1,1-di-(n-butyl)-3-(4-N-butylphenyl)urea 93.5 1,1-di-(n-butyl)-3-(2,3-dimethylphenyl)urea 87.6 1,1-di-(n-butyl)-3-(2,5-dimethylphenyl)urea 96.1 1,1-di-(n-butyl)-3-(2,6-dimethylphenyl)urea 85.3 1,1-di-(n-butyl)-3-(3,4-dimethylphenyl)urea 49.2 1,1-di-(n-butyl)-3-(3,5-dimethylphenyl)urea 83.5 1,1-di-(n-butyl)-3-(2,4,6-trimethylphenyl)urea 73.4 1,1-di-(n-butyl)-3-(4-methoxyphenyl)urea 58.7 1,1-di-(n-butyl)-3-(4-ethoxyphenyl)urea 78.6 1,1-di-(n-butyl)-3-(3-methylthiophenyl)urea 84.7 1,1-di-(n-butyl)-3-(2-chlorophenyl)urea 71.0 1,1-di-(n-butyl)-3-(3-chlorophenyl)urea 88.3 1,1-di-(n-butyl)-3-(3-bromophenyl)urea 86.0 TABLE I COMPOUND % INHIBITION 1,1-di-(n-butyl)-3-(4-fluorophenyl)urea 55.9 1,1-di-(n-butyl)-3-(4-iodophenyl)urea 83.1 1,1 -di-(n-butyl)-3-(2,3-dichlorophenyl)urea 71.8 1,1-di-(n-butyl)-3-(2,4-dichlorophenyl)urea 70.0 1,1-di-(n-butyl)-3-(3,5-dichlorophenyl)urea 79.3 1,1 -di-(n-butyl )-3-(3-trifluoromethyl phenyl )u rea 75.0 1,1 -di-(n-butyl )-3-(3-acetyl phenyl)urea 50.9 1,1-di-(n-butyl)-3-(4-acetylphenyl)urea 55.1 1,1 -di-(n-butyl)-3-(3-chloro-2-methyl phenyl )u rea 80.2 1,1 -di-(n-butyl)-3-(3-chloro-4-methylphenyl)u rea 91.2 1,1-di-(n-butyl)-3-(3-chloro-4-fluorophenyl)aurea 90.9 1,1-di-(n-butyl)-3-(2-chloro-4-nitrophenyl)urea 86.7 1,1-di-(n-butyl)-3-(4-chloro-3-trifluoromethylphenyl)urea 87.3 1,1 -di-(sec-butyl )-3-(2,4-dimethylphenyl)urea 78.1 1,1 -di-(n-pentyl)-3-(2,4-dimethylphenyl)u rea 90.3 1,1 -di-(isopentyl)-3-(2,4-dimethylphenyl)urea 88.7 1,1-di-(n-hexyl)-3-(2,4-dimethylphenyl)urea 95.1 1,1 -di-(n-heptyl)-3-(2,4-dimethyl phenyl )urea 91.1 1,1-di-(n-becyl)-3-(2,4-dimethylphenyl)urea 64.0 1,1-di-(n-octyl)-3-(2,4-dimethylphenyl)urea 88.6 1,1-di-(4-cyclohexyl-n-butyl)-3-(2,4-dimethylphenyl)urea 86.3 1,1-di(cyclopentyl)-3-(2,4-dimethylphenyl)urea 90.4 1,1 ,l-di-(n-butyl)-3-(2,3-dibenzophenyl) urea 85.1 1,1 -di-(n-butyl)-3-(4-chloro-2-methyl phenyl)u rea 88.0 1,1-dicyclohexyl-3-(2,4-dimethylphenyl)urea 94.3 1,1 -di-(n-butyl)-3-(3-methoxyphenyl)urea 77.1 1,1 -di-(n-butyl)-3-[(3,3-dibutyl)urea-4-methyl phenyl] urea 94.5 1,1-di-(n-butyl)-3-(2,3,5-trichlorophenyl)urea 61.6 1,1-di(isobutyl)-3-(2-chlorophenyl)urea 35.4 1,1 -di-(isobutyl)-3-[(3,3-diisobutyl)u reaA-methyl phenyl)]u rea 94.7 1,1-di-(isobutyl)-3-(2,5-dimethylphenyl)urea 74.3 1 ,1-di-(isobutyl)-3-(2,6-dimethylphenyl)urea 41.2 1,1 -di-(n-butyl )-3-(5-ch loro-2-methyl phenyl )u rea 75.3 1,1-di-(n-butyl)-3-(4-n-butylphenyl)urea 93.5 1,1-di-(n-butyl)-3-(4-isopropylphenyl)urea 76.4 1,1 -di-(3,5,5-trimethylhexyl)-3-(2,4-dimethylphenyl)urea 90.4 1,1 -di-(2-ethyl hexyl )-3-(2,4-dimethylphenyl)urea 86.2 1,1 -di-(n-nonyl)-3-(2,4-dimethylphenyl)urea 90.0 1,1 -di-(n-undecyl)-3-(2,4-dimethylphenyl)urea 48.9 1,1 -di-(n-dodecyl )-3-(2,4-dimethyl phenyl)u rea 26.3 l-[2-(3,4-dimethoxyphenyl)ethyl]-l -(3-chloro-4-methylbenzyl)-3-(2,4-dimethylphenyl)urea 53.3 1-[2-(2-methylphenyl)ethyl]-1-(4-bromobenzyl)-3-(2,4-dimethylphenyl)urea 29.2 1-[2-(3-trifluoromethylphenyl)ethyl]-1-(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea 7.8 1 -(2-fluorobenzyl )-1 -(2-methoxybenzyl )-3-(2,4-dimethylphenyl )urea 41.5 1 -[2-(3,4-dimethoxyphenyl)ethyl]-1 -(4-fl uorobenzyl)-3-(2,4-dimethylphenyl)u rea 57.4 1-[2-(4-ethoxyphenyl)ethyl]-1-(2,4-dimethylbenzyl)-3-(2,4-dimethylphenyl)urea 34.9 1-[2-(3-methylphenyl)ethyl]-1-(3-nitrobenzyl)-3-(2,4-dimethylphenyl)urea 95.7 1-[2-(2,5-dimethoxyphenyl)ethyl]-1-(3-chlorobenzyl)-3-(2,4-dimethylphenyl)urea 97.1 1-(n-butyl)-1-(2-methyl-2,2-diphenyl)ethyl-3-(2,4-dimethylphenyl)urea 97.4 1 -(n-butyl )-1 -(4-hexyloxybenzyl )-3-(2,4,6-trimethylphenyl )urea 97.1 1-(n-butyl)-1-(4-heptyloxybenzyl)-3-(2,4,6-trimethylphenyl)urea 97.3 1-(n-butyl)-1-benzyl-3-(4-trifluoroacetylamino, 3,5-dichlorophenyl)urea 87.8 1 -benzyl-1 -(4-n-butyl benzyl)-3-(2,4-dimethyl phenyl )u rea 91.9 1-benzyl-1-(4-n-butylbenzyl)-3-(2,4,6-trimethylphenyl)urea 92.8 1 -benzyl-1 -(4-n-butyl benzyl )-3-(4-n-butylphenyl )u rea 92.0 1 -benzyl-1 -(4-n-butyl benzyl)-3-(4-phenoxyphenyl )urea 93.5 1 -(n-heptyl)-1 -(4-n-butyl benzyl)-3-(2,4-di methylphenyl)u rea 94.8 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea 95.3 1-benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,5-trimethylphenyl)urea 93.7 1-(n-heptyl)-1-(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea 94.6 1 -(n-heptyl )-1 -(4-butyloxybenzyl)-3-(2,4,5-trimethylphenyl )urea 95.6 TABLE I COMPOUND % INHIBITION 1 -benzyl-1 -(4-butyloxybenzyl)-3-(2,4-dimethyl phenyl)u rea 91.7 1-benzyl-1-(4-butyloxybenzyl)-3-(2,4,5-trimethylphenyl)urea 95.8 1 -(9-octadecenyl)-1 -(4-n-butyl benzyl)-3-(2,4-dimethyl phenyl)urea 42.2 1 -benzyl-1 -(4-n-butyl benzyl)-3-(2,4,5-trimethyl phenyl)urea 90.5 1 -(9-octadecenyl )-1 -(4-n-butyl benzyl )-3-(2,4,5-trimethylphenyl)urea 9.4 1-benzyl-1[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trimethylphenyl)urea 90.0 1 -(n-heptyl)-1 -(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl)urea 90.0 1-(n-heptyl)-(4-n-butoxybenzyl)-3-(2,4-dichlorophenyl)urea 79.9 1-(n-heptyl)-(4-n-butoxybenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea 89.4 1 -benzyl-1 -(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl )u rea 95.2 1 -benzyl-1 -(4-n-butoxybenzyl)-3-(2,4-dich lorophenyl)u rea 80.0 1 -benzyl-1 -(4-n-butoxybenzyl)-3-(2-trifl uoromethyl-4-chlorophenyl)urea 85.0 1 -(n-heptyl)-1 -(4-n-butoxybenzyl)-3-(3-trifluoromethyl phenyl)urea 82.4 1 -(n-benzyl-1 -(4-n-butoxybenzyl)-3-(3-trifluoromethylphenyl)u rea 87.0 1 -(n-heptyl)-1 -(4-n-butyl benzyl)-3-(2,4-dichlorophenyl)urea 80.0 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea 90.0 1 -(n-heptyl)-1 -(4-n-butyl benzyl )-3-(2,4,6-trich lorophenyl)u rea go.o 1 -(n-heptyl)-1 -(4-n-butyl benzyl)-3-(3-trifl uoromethylphenyl)u rea 85.0 1 -(n-heptyl)-1-(4-n-butylbenzyl)-3-(2,4,5-trichlorophenyl)urea 46.5 1 -benzyl-1 -(4-n-butyl benzyl )-3-(2-methyl-4chlorophenyl)urea 94.3 1 -(n-heptyl)-1 -(4-n-butoxybenzyl )-3-(2,4-difluorophenyl)urea 82.7 1-(n-heptyl)-1 -(4-n-butoxybenzyl)-3-(2-methyl-4-chlorophenyl)urea 91.7 1 -(n-heptyl)-1 -(2-furyl)-3-(2,4,5-trimethylphenyl)urea 93.8 1-(n-heptyl)-1-(2-furyi)-3-(2,4,6-trichlorophenyl)urea 96.1 1 -(n-heptyl )-1 -(4-n-butylbenzyl)-3-(2-methyl-4-chlorophenyl)urea 92.5 1 -(n-heptyl )-1 -(4-n-butylbenzyl)-3-(2,4-difluorophenyl)urea 90.0 1 -(n-heptyl )-1 -(4-n-butyl benzyl)-3-(4-carboethoxyphenyl)urea 92.4 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(2-methylphenyl)urea 97.4 1-(n-heptyl)-1-(4-n-butylbenzyl)-3-(3-methylphenyl)urea 93.8 1 -(n-heptyl )-1 -(4-n-butylbenzyl)-3-(4-carboxyphenyl)urea 61.8 1 -(n-heptyl)-1 -(2-phenylethyl)-3-(2-methyl-4-chlorophenyl )u rea 93.8 1 -(n-heptyl )-1 -(2-phenylethyl )-3-(2,4,5-trichlorophenyl)u rea 77.3 1 -(n-heptyl )-1 -(2-phenylethyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea 88.3 1 -(n-heptyl)-1 -(2-phenylethyl )-3-(2,4-dimethyl phenyl)u rea 95.7 1-(n-heptyl)-1 -(2-phenylethyl)-3-(2,4-dichlorophenyl)urea 91.8 1 -(n-heptyl)-1 -(2-phenylethyl )-3-(2,4-difl uorophenyl)urea 94.1 1 -(n-heptyl)-1 -(2-phenylethyl )-3-(3-trifluoromethyl phenyl )u rea 88.4 1 -benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trichlorophenyl)u rea 95.0 1-(4-n-pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4,6-trichlorophenyl)urea 95.5 1 -(4-n-pentylbenzyl)-1 -(4-n-pentyloxybenzyl)-3-(2,4-dich lorophenyl)urea 85.0 1 -(4-n-pentyl benzyl)-1 -(4-n-pentyloxybenzyl)-3-(2,4,5-trich lorophenyl)u rea 80.0 1 -(4-n-pentylbenzyl)-1 -(4-n-pentyloxybenzyl)-3-(24rifluoromethyl-4-chlorophenyl)urea 81.0 1-(4-n-pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(3-trifluoromethylphenyl)urea 85.0 1-(4-n-pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-difluorophenyl)urea 90.0 1 -(4-n-pentylbenzyl)-1 -(4-n-pentyloxybenzyl)-3-(2-methyl-4-ch lorophenyl)u rea 91.0 1-(4-chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4,6-trichlorophenyl)urea 77.0 1-(4-chlorobenzyl)-1-(1-naphthylmethyl)-3-(2-methyl-4-chlorophenyl)urea 94.0 1-(4-chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4-difluorophenyl)urea 84.0 1 -(4-chlorobenzyl )-1 -(1 -naphthyl methyl)3-(3-trifluoromethylphenyl)urea 80.0 1-(4-chlorobenzyl-1-(1-naphthyimethyl)-3-(2,4,5-trichlorophenyl)urea 86.0 1-benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,5-trichlorophenyl)urea 95.0 1-benzyl-1-(4-n-butyloxybenzyl)-3-(2,4,5-trichlorophenyl)urea 89.0 1-benzyl-1-[-2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4-difluorophenyl)urea 70.0 1 -benzyl-1 -(4-n-butoxybenzyl )-3-(2,4-difluorophenyl)urea 88.0 1-benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4-difluorophenyl)urea 91.0 1-benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2-trifluoromethyl-4-chlorophenyl)urea 92.0 1-benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(3-trifluoromethylphenyl)urea 74.0 1 -benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl)ethyl]-3-(2-methyl-4-ch lorophenyl)urea 89.3 1-(4-n-pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-dichlorophenyl)urea 92.0 1-(4-n-pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea 83.0 Inhibition of cholesterol absorption was determined by feeding male Sprague-Dawley rats, weighing 150-170 g., a 1% cholesterol : 0.5% cholic acid diet for 2 weeks. The diet also contained compounds being tested at a dose of 0.03% of the diet. Control rats wree fed the same diet without any compound. At the end of the test, the rats were sacrificed by decapitation. Blood is collected, centrifuged at 1.5 kg times gravity for 10 minutes at 4 C., and the serum is then analyzed for cholesterol and triglycerides enzymatically by the method of Trinder, P., Analyst, 77,321(1952) on a Centrifichem 400 Analyzer. Livers are removed, a 0.4 g.
sample is taken from the center of the large lobe, adn the sample is subjected to saponification using 25% saturated potassium hydroxide in ethanol. The resulting neutral sterols are extracted with petroleum ether, and the extract was analyzed for for cholesterol. The effectiveness of the compound in inhibiting cholesterol absorption is measured by the lowering of either serum cholesterol or liver cholesterol relative to the values for control rats.
The results of this test on typical compounds of this invention appear in Table II.
TABLE II COMPOUND RESULT 1 -Benzyl-1 -(n-butyl )-3-(3-methoxyphenyl)-3-phenylu rea Active 1,1-di-(n-butyl)-3.(2,4-dimethylphenyl)urea Active 1,1 -di-(n-butyl)-3.(3,5-dimethylphenyl)urea Active 1,1 -di-(n-butyl)-3-(2-methyl-3-chlorophenyl)urea Active 1,1 -di-(n-butyl)-3-(3,5-dichlornphenyl)urea Active 1,1-di-(n-butyl)-3-(4-n-butylphenyl)urea Active 1,1 -di-(n-hexyl)-3-(2,4-dimethylphenyl)urea Active 1,1 -di-(n-octyl)-3-(2,4-dimethylphenyl )u rea Active 1,1 -di-(n-butyl)-3-(2-methylphenyl )urea Active 1,1-di-(n-pentyl)-3-(2,4-dimethylphenyl)urea Active 1,1 -di-(n-decyl)-3-(2,4-dimethylphenyl)urea Active 1,1 -di-(isopentyl)-3-(2,4-dimethylphenyl)urea Active 1,1-di-(3,5,5-trimethylhexyl)-3-(2,4-dimethylphenyl)urea Active 1,1 -Dibenzyl-3-(2-methyl-5-chlorophenyl)urea Active 1,1-Dibenzyl-3-(2,4-dichlorophenyl)urea Active 1,1-Dibenzyl-3-(2-methyl-4-chlorophenyl)urea Active 1,1-Dibenzyl-3-(2,4-dimethylphenyl)urea Active 1,1-Dibenzyl-3-(3-chloro-4-methylphenyl)urea Active 1,1 -Dibenzyl-3-(2-methoxy-5-methylphenyl)urea Active 1,1 -Dibenzyl-3-(2,3-dimethylphenyl)urea Active 1,1 -Dibenzyl-3-(3,4-dimethylphenyl)urea Active 1,1 -Dibenzyl-3-(2,4,6-tri methyl phenyl)u rea Active 1,1-Dibenzyl-3-(4-n-butylphenyl)urea Active 1,1-Dibenzyl-3-(3-methylphenyl)thiourea Active 1,1-Dibenzyl-3-(4-phenoxyphenyl)urea Active 1,1 -Dibenzyl-3-(3-ch loro-4-methyl phenyl)thiou rea Active 1,1 -Dibenzyl-3-(2,4.dimethylphenyl)thiourea Active 1,1-dibenzyl-3-(2,4-5.trimethylphenyl)urea Active 1,1 -Dibenzyl-3-(2-trifluoromethyl-4-chlorophenyl)urea Active 1,1-Dibenzyl-3-(3-bromophenyl)urea Active 1,1-Dibenzyl-3-(2-trifluoromethylphenyl)urea Active 1,1 -Dibenzyl-3-(4-carboethoxyphenyl)urea Active 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea Active 1-Benzyl-1-(n-butyl)-3-(2,6-dimethylphenyl)urea Active 1-Benzyl-1-(n-butyl)-3-(3,5-dimethylphenyl)urea Active 1-Benzyl-1-(1,2-diphenylethyl)-3-(2,4-dimethylphenyl)urea Active 1 -(2-Fluorobenzyl )-1 -(2-methoxybenzyl )-3-(2,4-dimethyl phenyl)urea Active 1 -(n-Butyl )-1 -(4-hexyloxybenzyl)-3-(2,4,6-trimethylphenyl)urea Active 1 -(n-Butyl )-1 -(4-heptyloxybenzyl)-3-(2,4,6-tri methylphenyl)urea Active 1 -Benzyl-1 -(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea Active 1 -Benzyl-1 -(4-n-butyl benzyl )-3.(2,4,6-trimethyl phenyl )urea Active 1 -Benzyl-1 -(4-n-butyl benzyl)-3-(4-n-butylphenyl)u rea Active 1 -(n-heptyl)-1 -(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea Active 1 -(n-heptyl)-1 -(4-n-butylbenzyl)-3-(2,4-5-trimethylphenyl)urea Active 1-(n-heptyl)-1-(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea Active 1-(n-heptyl)-1-(4-butyloxybenzyl)-3-(2,4,5-trimethylphenyl)urea Active 1 -Benzyl-1 -(4-butyloxybenzyl-3-(2,4-dimethyl phenyl)u rea Active TABLE II COMPOUND RESULT 1 -Benzyl-1 -(4butyloxybenzyl)-3-(2,4,S4rimethylphenyl)urna Active 1 -Benzyl-1 -(4-n-butylbenzyl )-3-(2,4,5-trimethylphenyl )urea Active 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trimethylphenyl)urea Active 1 -(n-Heptyl )-1 -(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl)urea Active 1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2,4-dichlorophenyl)urea Active 1-(n-Heptyl)-4-n-butoxybenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea Active 1 -Benzyl-1 -(4-butoxybenzyl )-3-(2,4,6-trich lorophenyl)urea Active 1 -Benzyl-1 -(4-n-butoxybenzyl)-3-(2,4-dich lorophenyl)urea Active 1 -Benzyl-1 -(4-n-butoxyphenyl)-3-(2-trifluoromethyl-4-chlorophenyl )urea - Active 1 -(n-Heptyl)-1 -(4-n-butoxybenzyl)-3-(3-trifl uoromethylphenyl)u rea Active 1 -(n-Heptyl)-1 -(4-n-butylbenzyl)-3-(2,4-dichlorophenyl)urea Active 1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea Active 1 -(n-Heptyl)-1 -(4-n-butylbenzyl)-3-(2,4,6-trich lorophenyl)urea Active 1 -Benzyl-1 -(4-n-butylbenzyl)-3-(2-methyl-4-chlorophenyi)u rea Active 1 -(n-Heptyl)-1 -(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea Active 1 -(n-Heptyl)-1 -(4-n-butoxybenzyl )-3-(2-methyl-4-ch lorophenyl)urea Active 1 -(n-Heptyl-1 -(2-fu ryl)-3-(2,4,5-trimethyl phenyl)urea Active 1 -(n-Heptyl)-1 -(2-furyl )-3-(2,4,6-trichlorophenyl)u rea Active 1 -(n-Heptyl)-1 -(4-n-butyl benzyl )-3-(2-methyl-4-chlorophenyl)urea Active 1 -(n-Heptyl )-1 -(4-n-butylbenzyl)-3-(2,4-difluorophenyl)urea Active 1 -(n-Heptyl)-1 -(4-n-butyl benzyl)-3-(4-carboethoxyphenyl)u rea Active 1 -(n-Heptyl)-1 -(4-n-butyl benzyl)-3-(2-methyl phenyl )urea Active 1 -(n-Heptyl)-1 -(4-n-butyl benzyl)-3-(3-methyl phenyl )urea Active 1 -(n-Heptyl)-1 -(2-phenylethyl)-3-(2-methyl-4-chlorophenyl )u rea Active 1 -(n-Heptyl)-1 -(2-phenylethyl)-3-(2-trifl uoromethyl-4-chlorophenyl)u rea Active 1 -(n-Heptyl)-1 -(2-phenylethyl )-3-(2,4-dimethyl phenyl)urea Active 1 -(n-Heptyl-1 -(Z-phenylethyl )-3-(2,4-dichlorophenyl)u rea Active l-(n-Heptyl )-1 -(2-phenylethyl )-3-(2,4-difl uorophenyl )u rea Active 1-(n-Heptyl)-1-(2-phenylethyl)-3-(3-trifluoromethylphenyl)urea Active 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trichlorophenyl)urea Active 1 -(4-n-Pentyl benzyl)-1 -(4-n-pentyloxybenzyl)-3-(2,4,6-trichlorophenyl)urea Active 1 -(4-n-pentylbenzyl)-1 -(4-n-pentyloxybenzyl)-3-(2,4-dichlorophenyl )urea Active 1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4,5-trichlorophenyl)urea Active 1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-difluorophenyl)urea Active 1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2-methyl-4-chlorophenyl)urea Active 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4,6-trichloromphenyl)urea Active 1 -(4-Chlorobenzyl)-1 -(1 -naphthylmethyl)-3-(2-methyl-4-chlorophenyl)urea Active 1 -(4-Chlorobenzyl )-1 -(1 -naphthylmethyl)-3-(2,4-difluorophenyl)urea Active 1 -(4-Chlorobenzyi )-1 -(1 -naphthylmethyl)-3-(3-trifl uoromethyl phenyl )urea Active 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4,5-trichlorophenyl)urea Active 1 -Benzyl-1 -(4-n-butyloxybenzyl )-3-(2,4,5-trich lorophenyl )u rea Active 1 -Benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl)ethyl]-3-(2,4-difluorophenyl )u rea Active 1 -Benzyl-1 -(4.n-butoxybenzyl)-3-(2,4-difluorophenyl )urea Active 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2-trifluoromethyl-4-chlorophenyl)urea Active 1 -Benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl )ethyl]-3-(2-methyl-4-chlorophenyl)u rea Active 1 -(4-Chlorobenzyl )-1 -(1 -naphthylmethyl)-3-(2,4-dichlorophenyl)urea Active The tests reported or shown in Tables l-ll, inclusive, have been actually carried out and the results therein actually obtained or concluded therefrom.
Inhibition of cholesterol absorption was also determined by feeding male Sprague-dawley rats weighing 150-170 g. a 1% cholesterol :0.5% cholic acid diet for 2 weeks. The diet also contained compounds bring tested at doses of between 0.01% and 0.1% of the diet. After the rats had been on the test diet for 9 days, each rat is given by gavage a sonicated mixture of [4.14C] cholesterol (6 Ci), 0.2 ml. triolein, 10 mg. cholic acid, 20 mg. cholesterol, and 2 mg. of test compound in 0.8 ml. of 10% non-fat dry milk. Feces were collected for each 24 hour period for the remaining 5 days during which the rats were maintained on the 1% cholesterol:0.5% cholic acid plus test compound diet.Fecal 14C-neutral sterols were extracted with petroleum ether from saponified feces by the method of grundy, S. M. metal., J. Lipid Res., 6,397 (1965) and counted in a scintillation counter. Acidic sterols (bile acids) were extracted by acidifying the saponified feces and extracting in chloroform: methanol (2:1) and counting the chloroform phase in a scintillation counter. Total extraction of radioactivity (98-100%) from saponified feces is realized by this procedure.
Radioactivity in liver and adrenals were determined by saponification and extraction into petroleum ether and counting by scintillation techniques. Total cholesterol in liver and adrenals was determined by the cholorimetric method of Zlatkis, A., etal., J. Lab. Clin. Med., 41486 (1953) on saponified organic solvent extracted tissue prepared bythe method of Trinder, P., Analyst, 77321(1952). Serum cholesterol and triglycerides were assayed enzymatically by the method of Allain, C. C., metal., Clin. Chem.20470 (1974) on a centrifichem 400 Analyzer. 14C-cholesterol in serum was determined by direct scintillation counting.
The effect of a test compound on cholesterol absorption was determined by: 1. increase in excreted 14C-neutral sterol.
2. decrease in excreted 14C-acidic sterol.
3. decrease in 14C-cholesterol or 14C-cholesteryl ester in the liver.
4. decrease in 14C-cholesterol or 14C-cholesteryl ester in the serum.
A compound is considered active in inhibiting cholesterol absorption if it meets at least the first two criteria.
The results of this test on typical compounds of this invention appear in Table III.
TABLE III COMPOUND RESULT 1 -Benzyl-1 -(n-butyl)-3-(2,4-dimethyl phenyl )u rea Active 1,i-Dibenzyl-3-(2,4-dimethylphenyl)urea Active The tests reported or shown in Table II have been actually carried out, and the results therein actually obtained or concluded therefrom.
When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, dilutents, and the like and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, suspensions containing, for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.
The antiatherosclerotic effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, and the severity of the condition being treated.
However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 2 mg. to about 500 mg./kg. of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 100 mg. to about 5,000 mg., preferably from about 100 mg. to 2,000 mg.
Dosge forms suitable for internal use comprise from about 25 mg. to 500 mg. of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that these active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes if necessary.Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut, and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, e.g., vitamin E, ascorbic acid, BHT, and BHA.
The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The preparation of representative compounds of this invention is illustrated by the following specific examples.
EXAMPLE 1 l-Benzyl- l-{n-butyl)-3,3-diphenylurea A solution of 20.0 g. of phosgene in 100 ml. of toluene is stirred at 0 C. while a solution of 32.6 g. of N-benzyl-n-butylamine in 50 ml. of toluene is added during 15 minutes. The mixture is filtered, and the filtrate is evaporated. The residue is evaporatively distilled at 1050C. under reduced pressure (250-350 microns) to yield N-benzyl-N-(n-butyl)carbamyl chloride as a colorless liquid.
A solution of 3.89 g. of diphenylamine in 25 ml. of dimethylacetamide is added during one hourto a stirred mixture of 5.19 g. of N-benzyl-N-(n-butyl)carbamyl chloride, 0.685 g. of sodium hydride, and 65 ml. of dimethylacetamide under a nitrogen atmosphere at 45-500C. The mixture is stirred for 2 hours at 50 C. and then poured into water. The mixture is extracted with methylene chloride, and the extract is evaporated. The residue is purified by chromatography using silica gel as the adsorbant and the acetone-hexane as the eluent. After evaporation of the eluent, the residue is evaporatively distilled at 165 C. under reduced pressure (150 microns) to yield 1-benzyl-1-(n-butyl)-3,3-diphenylurea as a viscous, clear, colorless liquid.
EXAMPLE 2 1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea A solution of 5.09 g. of N-phenyl-3-chloraniline in 20 ml. of toluene is added to a solution of 4.70 g. of phosgene and 3.64 g. of N,N-dimethylaniline in 55 ml. of toluene and the mixture is warmed to 40 C. and then stirred while cooling to room temperature during 45 minutes. The mixture is extracted with water, and the organic layer is separated and evaporated to about one-half its volume. To this solution is added 100 ml.
oftoluene followed by 9.80 g. of N-benzyl-n-butylamine. The resulting mixture is stirred under reflux for 30 minutes and then washed with water, 1 N hydrochloric acid, and saturated sodium bicarbonate solution. The organic layer is separated, dried over sodium sulfate, decolorized using activated charcoal, and evaporated.
The residue is evaporatively distilled at 185-190 C. under reduced pressure (105 microns) to yield 1-benzyl-1 -(n-butyl)-3-(3-chlorophenyl)-3-phenylurea as a viscous, pale-yellow liquid.
The compounds in Table IV were prepared from the appropriate amines using phosgene orthiophosgene bythe methods of Examples 1 and 2.
TABLE IV EX. COMPOUND MELTING POINT 3 1,3-Dibenzyl-1-(n-butyl)-3-phenylurea Yellow Oil 4 1 -Benzyl-1 -(n-butyl)-3-(2-naphthyl)-3-phenylurea Orange Oil 5 1 -Benzyl-1 -(n-butyl )-3-(3-methylphenyl )-3-phenyl u rea Oil 6 1 -Benzyl-1 -(n-butyl )-3-(4-isopropyl phenyl )-3-phenyl u rea Amber Oil 7 1 -Benzyl-1 -(n-butyl)-3-(3-methoxyphenyl)-3-phenylurea Amber Oil 8 1 -Benzyl-1 -(n-butyl)-3-(3-chlorophenyl)-3-(2-naphthyl)urea Yellow Oil 9 1 -Benzyl-1 -(n-butyl)-3-(1 -naphthyl)-3-phenylurea Amber Oil 10 1 -Benzyl-1 -(n-butyl)-3,3-dibenzylurea Yellow Oil 11 1 -Benzyl-1 -(n-butyl )-3,3-di(2-naphthyl)urea Amber Oil 12 1-Benzyl-1-(n-butyl)-3-benzyl-3-(4-chlorophenyl)urea Oil 13 1 -Benzyl-1 -(n-butyl)-3-benzyl-3-(2,4-dimethylphenyl)urea Oil 14 1 -Benzyl-1 -(n-butyl)-3-benzyl-3-(2,4-dichlorophenyl)urea Oil 15 1 -Benzyl-1 -(n-butyl)-3-(3-nitrobenzyl)-3-(3,5-dimethoxyphenyl)u rea Oil 16 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylbenzyl)-3-(2,4-diphenyl)urea Oil 17 1-Benzyl-1 -(n-butyl)-3-(2,4-dichlorobenzyl)-3-(2,4-dichlorophenyl)urea Oil 18 1 -Benzyl-1 -(n-butyl)-3-(2-chlorobenzyl)-3-(2-chlorophenyl)urea Oil 19 1 -Benzyl-1 -(n-butyl)-3-(4-methyl phenyl)-3-(4-methyl benzyl)urea Oil 20 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylbenzyl)-3-(2,4-dichlorophenyl)urea Oil 21 1-Benzyl-1-(n-butyl)-3-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea Oil 22 1 -Benzyl-1 -(n-butyl)-3-(3-chloro-4-methyl benzyl )-3-(4-methylphenyl)urea Oil 23 1 -Benzyl-1 -(n-butyl)-3-(2,4-dimethylbenzyl)-3-phenyl urea 'Oil 24 1-Benzyl-1-(n-butyl)-3-[3,5-di(trifluoromethyl)benzyl]-3-phenyl urea Oil 25 1 -Benzyl-1 -(n-butyl)-3-(3-aminobenzyl)-3-(3,5-dimethoxyphenyl)urea picrate 1 56-1 580 26 1 -Benzyl-1 -(n-butyl)-3-benzyl-3-(3-aminophenyl)urea 96-98 27 1 -Benzyl-1 -(n-butyl )-3-benzyl-3-(2,4,6-trimethyl phenyl)u rea 63-69" 28 1 -Benzyl-1 -(n-butyl)-3-benzyl-3-(3-nitrophenyl)urea Yellow Oil 29 1 -Benzyl-1 -(n-butyl )-3-benzyl-3-(3-acetamidophenyl)urea Oil EXAMPLE 30 N-(2,4-Dimethylbenzylidene)-3,4-dichloroaniline A mixture of 26.8 g. of 2,4-dimethylbenzaldehyde, 32.4 g. of 2,4-dichloroaniline, 0.20 g. of ptoluenesulfonic acid, and 150 ml. of toluene is stirred under reflux using a Dean-Stark moisture trap.
Evaporation of the mixture affords a solid which is recrystallized from ethanol to yield N-(2,4dimethylbenzylidene)-2,4-dichloroaniline, mp 102-106 .
Anilines prepared by the method of Example 30 are set forth in Table V.
TABLE V EX. COMPOUND MELTING POINT 31 N-benzylidene-2,4,6-trimethylaniline Yellow Oil 32 N-benzylidene-2,4-dichloroaniline 60-63" 33 N-(4-methylbenzyl idene)-3-chloro-4-methylaniline 86-89" 34 N-(2,4-dimethylbenzylidene)-2,4-dimethylaniline 118-121" 35 N-(2,4-dichlorobenzylidene)-2,4-dimethylaniline 105-107" 36 N-(3-nitrobenzylidene)-3,5-dimethoxyaniline 113-116" 37 N-benzylidene-4-chloroaniline 60-62" 38 N-benzylidene-2,4-dimethylaniline Oil 39 N-(2,4-dichlorobenzylidene)-2,4-dichloroaniline 134-139 40 N-(2-chlorobenzylidene)-2-chloroaniline 111-117" 41 N-(4-methylbenzylidene)-4-methylaniline 90-93 42 N-benzylidene-3,5-di(trifluoromethyl)aniline Yellow Oil 43 N-(4-benzyloxybenzylidene)-4-carboethoxy aniline 140-142" 44 N-benzylidene-3-nitroaniline 69-72 EXAMPLE 45 N-(2,4-dimethylbenzyl)-2,4-dichloroaniline A mixture of 13.9 g. of N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, 1.89 g. of sodium borohydride, and 150 ml. of ethanol is stirred under reflux for one hour, allowed to cool, and poured into water.
Recrystallization from ethanol yields N-(2,4-dimethylbenzyl)-2,4-dichloroaniline, mp. 88-90'.
Anilines prepared by the method of example 45 are set forth in Table VI.
TABLE VI EX. COMPOUND MELTING POINT 46 N-benzyl-2,4,6-trimethylaniline Oil 47 N-benzyl-2,4-dichloroaniline Oil 48 N-(4-methylbenzyl)-3-chloro-4-methylaniline Oil 49 N-(2,4-dimethylbenzyl)-2,4-dimethylaniline 72-74 50 N-(2,4-dichlorobenzyl)-2,4-dimethylaniline 70-72 51 N-(3-nitrobenzyl)-3,5-dimethoxyaniline Amber Oil 52 N-benzyl-4-chloroaniline 48-49 53 N-benzyl-2,4-dimethylaniline 28-33 54 N-(2,4-dichlorobenzyl)-2,4-dichloroaniline 84-86 55 N-(2-chlorobenzyl)-2-chloroaniline 41-44 56 N-(4-methylbenzyl)-4-methylaniline 50-54 57 N-benzyl-3,5-di(trifluoromethyl)aniline Oil 58 N-(4-benzyloxybenzyl)-4-carboethoxyani line 147-150" 59 N-benzyl-3-nitroaniline 106-108" EXAMPLE 60 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 4.41 g.
of N-benzyl-n-butylamine in 150 ml. of hexane and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1 -benzyl-1 -(n-butyl)-3-(2,4- dimethylphenyl)urea, m.p. 70-71 C.
Those compounds in Table VII were prepared from the appropriate arylisocyanates or arylisothiocyanates and secondary amines by the method of Example 60.
TABLE VII EX. COMPOUND MELTING POtNT 61 1-Benzyl-1-(n-butyl)-3-(2-methylphenyl)urea 48-53 62 1 -Benzyl-1 -(n-butyl)-3-(3-methyl phenyl )urea 91-92" 63 1 -Benzyl-1 -(n-butyl)-3-(4-methylphenyl)urea 102-103 64 1-Benzyl-1-(n-butyl)-3-(2,3-dimethylphenyl)urea 77-78 65 1-Benzyl-1-(n-butyl)-3-(2,5-dimethylphenyl)urea 87-89 66 1-Benzyl-1-(n-butyl)-3-(2,6-dimethylphenyl)urea 125-126 67 1 -Benzyl-1 -(n-butyl)-3-(3,4-dimethyl phenyl)u rea 94-95" 68 1 -Benzyl-1 -(n-butyl )-3-(3,5-dimethylphenyl )urea 108-109 69 1-Benzyl-1-(n-butyl)-3-(2,4,6-trimethylphenyl)urea 141-144 70 1-Benzyl-1-(n-butyl)-3-(3,4,5-trimethoxyphenyl)urea 144-145 71 1-Benzyl-1-(n-butyl)-3-(3,4-dichlorophenyl)urea 102-105 72 1-Benzyl-1-(n-butyl)-3-(3,5-dichlorophenyl)urea 100-103" 73 1-Benzyl-1-(n-butyl)-3-(3-trifluoromethylphenyl)urea 86-87" 74 1 -Benzyl-1 -(n-butyl)-3-(3-chloro-2-methoxyphenyl)u rea 52-54" 75 1 -Benzyl-1 -(n-butyl)-3-(5-chloro-4-methoxyphenyl)urea 61-63" 76 1 -Benzyl-1 -(n-butyl)-3-(3-ch loro-4-methylphenyl )u rea Yellow Oil 77 1-Benzyl-1-(1,2-diphenylethyl)-3-(2,4-dimethylphenyl)urea 157-158 78 1-Benzyl-1-[1-(3-methoxyphenyl)-2-phenylethyl]-3-(2,4-dimethylphenyl)urea 124-126 79 1-Benzyl-1-[1-(4-benzyloxyphenyl)-2-phenyl-3-(2,4-dimethylphenyl)urea 140-141 80 1-Benzyl-1-[1-(3-methoxyphenyl)-2-phenylethyl]-3-(3-trifluoromethylphenyl)urea 125-126 81 1 -Benzyl-1 - (n-pentyl)-3-(2,4-dimethylphenyl)urea Oil 82 1-Benzyl-1-(n-hexyl)-3-(2,4-dimethylphenyl)mrea Oil 83 1 -Benzyl-1 -(n-octal)-3-(2,4-dimethylphenyl)urea Oil 84 1-Benzyl-1-(n-undecyl)-3-(2,4-dimethylphenyl)urea Oil 85 1-Benzyl-1-(n-butyl)-3-(3-phenyl)thiourea 83-85 86 1 -Benzyl-1 -(n-butyl)-3-(3-chl oro-2-methoxyphenyl)u rea 52-54" 87 1 -Benzyl-1 -(n-butyl)-3-(5-chloro-2-methoxyphenyl)urea 161-163" 88 1 -(n-Butyl)-1 -(2-fl uorobenzyl )-3-(2,4-dimethylphenyl)urea 76-77" 89 1-(n-Butyl)-1-(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea 78-79" 90 1 -(n-Butyl)-1 -(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea 101-1020 91 1-(n-Butyl)-1-(2,6-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea 145-146 92 1-(4-Bromobenzyl)-1 -(n-butyl)-3-(2,4-dimethylphenyl)urea 61-63" 93 1-(n-Butyl)-1-(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea 60-62 94 1 -(n-Butyl)-1 -(4-methylbenzyl)-3-(2,4-dimethylphenyl)urea Oil 95 1 -(n-Butyl)-1 -(4-tert-butylbenzyl)-3-(2,4-dimethylphenyl)urea 28-31" 96 1 -(n-Butyl)-1 -(4-chlorobenzyl)-3-(2,4-dimethylphenyl)urea Oil 97 1 -(n-Butyl)-1 -(4-methoxybenzyl)-3-(2A-dimethylphenyl)urna Oil 98 1-(n-Butyl)-1-(3,4-methylenedioxylbenzyl)-3-(2,4-dimethylphenyl)urea Oil 99 1-(n-Butyl)-1-(4-trivluoromethylbenzyl)-3-(2,4-dimethylphenyl)urea Oil 100 1-(n-Butyl)-1-(4-phenylbenzyl)-3-(2,4-dimethylphenyl)urea 82-83 101 1 -(n-Butyl)-1 -(2-phenylethyl)-3-(2,4-dimethylphenyl)urea Oil 102 1 -(n-Butyl)-1 -[2-(4-fl uorophenyl)ethyl]-3-(2,4-dimethyl phenyl)urea Oil 103 1-(n-Butyl)-1-[2-(4-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 104 1 -(n-Butyl)-1 -[2-(3-methoxyphenyl )ethyl]-3-(2,4-dimethyl phenyl)urea Oil 105 1 -(n-Butyl-)-1 -(3-phenylpropyl)-3-92,4-dimethylphenyl)urea Oil 106 1 -(n-Butyl)-1 -[4-(n-pentyl)benzyl]-3-(2,4-dimethylphenyl)urea 65-67 107 1-(n-Butyl)-1-[4-(n-hexyl)benzyl]-3-(2,4-dimethylphenyl)urea Oil 108 1 -(n-Butyl)-1 -(3-chlorobenzyl)-3-(2,4-dimethylphenyl)urea Oil 109 1-(n-Butyl)-1-[4-(n-butoxyl)benzyl]-3-(2,4-dimethylphenyl)urea Oil 110 1-(n-Butyl)-1-[4-(n-pentyloxy)benzyl]-3-(2,4-dimethylphenyl)urea Oil 111 1-(n-Butyl)-1-[4-(n-hexyloxy)benzyl]-3-(2,4-dimethylphenyl)urea Oil 112 1-(n-Butyl)-1-[4-(n-heptytoxy)benzyl]-3-(2,4-dimethylpheny)urea 'Oil 113 1 -(n-Butyl )-1 -(4-nitrobenzyl)-3-(2,4-dimethylphenyl)urea Oil 114 1-(n-Butyl)-1-[2-(2-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)urea 102-103 115 1-(n-Butyl)-1-[2-(3-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 116 1-(n-Butyl)-1-[2-(4-methylphenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 117 1-(n-Butyl)-1-[2-(4-methoxyphenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 118 1-(n-Butyl)-1-[2-(3-fluorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 119 1-(n-Butyl)-1-[2-(2-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 120 1-(n-Butyl)-1-[2-(3-chlorophenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 121 1 -(n-Butyl)-1 -[2-(3-bromophenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil TABLE VII EX.COMPOUND MELTING POINT 122 1 -(n-Butyl)-1 -[2-(3,4-methylenedioxyphenyl)ethyl]-3-(2,4-dimethylphenyl)urea Oil 123 1 -(n-Butyl)-1 -(2-adamantylethyl)-3-(2,4-dimethylphenyl)urea 134-135 124 1-(n-Butyl)-1-(a-cyclohexylbenzyl)-3-(2,4-dimethylphenyl)urea 112-113 125 1 -(n-Butyl)-1 -(di-(4-chlorophenyl)methyl)-3-(2,4-dimethylphenyl)urea 145-147" 126 1 -(n-Butyl )-1 -(3,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea 120-121 127 1 -(n-Butyl)-1 -(3-trifluoromethylbenzyl)-1 -(4-fl uorobenzyl )-3-(2,4-dimethylphenyl )u rea 114-115 128 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl-3-(2,4-dimethylphenyl)urea 134-136 129 1-(4-Methoxybenzyl)-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea 124-126 130 1 -(3-Chlorobenzyl)-1 -(4-methoxybenzyl)-3-(2,4-dimethylphenyl)urea 108-109" 131 1 -(4-Phenylbenzyl)-1 -(3,4-dichlorobenzyl)-3-(2,4-dimethyl phenyl)urea 103-105 132 1(4-Fl uorobenzyl )-1 -(4-methylbenzyl)-3-(2,4-dimethyl phenyl)u rea 128-130 133 1 -(4-Chl orobenzyl)-1 -(3,4-dimethoxybenzyl)-3-(2,4-dimethyl phenyl)urea 94-96 134 (1 -(4-Fluorobenzyl)-1 -(3,4-methylenedioxybenzyl)-3-(2,4-dimethylphenyl)urea 122-124 135 1-(n-Butyl)-1-(4-methylthiobenzyl)-3-(2,4-dimethylphenyl)urea Oil 136 1 -(2,4-Dichlorobenzyl)-1 -(4-methylthiobenzyl )-3-(2,4-dimethylphenyl)u rea 124-125" 137 1 -[2-(3,4-Dimethoxyphenyl )ethyl]-1 -(3,4-methylenedioxybenzyl)-3-(2,4- dimethylphenyi)urea Oil 138 1-[2-(2-Methylphenyl)ethyl]-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea 120-122 139 1-[2-(4-Methylphenyl)ethyl]-1-(4-chlorobenzyl)-3-(2,4-dimethylphenyl)urea Oil 140 1-[2-(4-Ethoxyphenyl)ethyl]-1-(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea Oil 141 1-[2-(3-Fluorophenyl)ethyl]-1-(3-methoxybenzyl)-3-(2,4-dimethylphenyl)urea 94-95 142 1 -[2-(3-Methoxyphenyl )ethyl]-1 -(2-ch lorobenzyl)3-(2,4-dimethyl phenyl)urea 73-74 143 1-(3,3-Diphenylpropyl)-1-(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea 109-110 144 1-(n-Butyl)-1-(3,3-diphenylpropyl)-3-(2,4-dimethylphenyl)urea 94-95 145 1 -(n-Butyl)-1 -(4-cyclohexylbutyl)-3-(2,4-dimethylphenyl)urea Oil 146 1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(3-chloro-4-methylbenzyl)-3-(2,4-dimethylphenyl)urea Gum 147 1-[2-(2-Methylphenyl)ethyl]-1-(4-bromobenzyl)-3-(2,4-dimethylphenyl)urea 126-127 148 1-[2-(3-Trifluoromethylphenyl)ethyl]-1-(2-chlorobenzyl)-3-(2,4-dimethylphenyl)urea 115-117 149 1 -(2-Fluorobenzyl)-1 -(2-methoxybenzyl )-3-(2,4-dimethylphenyl )u rea 96-98 150 1-[2-(3,4-Dimethoxyphenyl)ethyl]-1-(4-fluorobenzyl)-3-(2,4-dimethylphenyl)urea Gum 151 1 -[2-(4-Ethoxyphenyl )ethyl]-1 -(2,4-dimethyl benzyí)-3-(2,4-dimethyíphenyl )u rea Gum 152 1-[2-(3-Methylphenyl)ethyl]-1-(3-nitrobenzyl)-3-(2,4-dimethylphenyl)urea 99-101 153 1-[2-(2,5-Dimethoxyphenyl)ethyl]-1-(3-chlorobenzyl)-3-(2,4-dimethylphenyl)urea 86-88 154 1-(n-Butyl)-1-(2-methyl-2,2-diphenyl)ethyl-3-(2,4-dimethylphenyl)urea 159-160 155 1 -in-Butyí)-1 -(4-hexyloxybenzyl)-3-(2,4,6-trimethyl phenyl)u rea 90-91 156 1-(n-Butyl)-1-(4-heptyloxybenzyl)-3-(2,4,6-trimethyl phenyl)u rea 86-87 157 1-(n-Butyl)-1-benzyl-3-(4-trifluoroacetylamino-3,5-dichlorophenyl)urea 173-75 158 1 -Benzyl-1 -(4-n-butyl benzyl)3-(2,4-dimethylphenyl)u rea Oil 159 1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,6-trimethylphenyl)urea Oil 160 1 -Benzyl-1 -(4-n-butylbenzyl)-3-(4-n-butylphenyl)urea Yellow Oil 161 1-Benzyl-1-(4-n-butylbenzyl)-3-(4-phenoxyphenyl)urea 79-80 162 1 -(n-Heptyl)-1 -(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)urea Yellow Oil 163 1 -(n-Heptyí)-1 -(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea Yellow Oil 164 1 -Benzyl-1 [2-phenyl-1 -(4-benzyloxyphenyí)ethyl]-3-(2,4,5-tri methylphenyí)u rea 157-158 165 1 -(n-Heptyl)-1 -(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea Oil 166 1-(n-Heptyl)-1-(4-butyloxybenzyl)-3-(2,4,5-trimethylphenyl)urea Yellow Oil 167 1 -Benzyl-1 -(4-butyloxybenzyl)-3-(2,4-dimethylphenyl)urea Solid 168 1 -Benzyl-1 -(4-butyloxybenzyl)-3-(2,4,5-trimethylph )urea Solid 169 1-(9-Octadecenyl)-1-(4-n-butylbenzyl)-3-(2,4-dimethylphenyl)u rea Yellow Oil 170 1-Benzyl-1-(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea Yellow Oil 171 1-(9-Octadecenyl)-1-(4-n-butylbenzyl)-3-(2,4,5-trimethylphenyl)urea Yellow Oil 172 1 -Benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl)ethyl]-3-(2,4,6-trimethylphenyl)urea 140-141 173 1 -( n-Heptyl)-1 -(4-n-butoxybenzyl)-3-(2,4,6-trich lorophenyl)u rea 63-64 174 1 -(n-Heptyl)-(4-n-butoxybenzyl)-3-(2,4-dichlorophenyí)u rea Gum 175 1-(n-Heptyl)-(4-n-butoxybenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea Gum 176 1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4,6-trichlorophenyl)urea 91-93 177 1 -Benzyl-1 -(4-n-butoxybenzyl)-3-(2,4-dichlorophenyl)urea Gum 178 1-Benzyl-1-(4-n-butoxybenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea Gum TABLE VII EX.COMPOUND MELTING POINT 179 1 -(n-Heptyl)-1 -(4-n-butoxybenzyl)-3-(3-trifluoromethyl phenyl)urea Gum 180 1-(n-Benzyl)-1-(4-n-butoxybenzyl)-3-(3-trifluoromethylphenyl)urea Gum 181 1 -(n-Heptyl)-1 -(4-n-butylbenzyl)-3-(2,4-dichlorophenyl)urea Gum 182 1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2-trifluoromethyl-1-chlorophenyl)urea Gum 183 1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,6-trichlorophenyl)urea Gum 184 1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(3-trifluoromethylphenyl)urea Gum 185 1-(n-Heptyl)-1-(4-n-butylbenzyl)-3-(2,4,5-trichlorophenyl)urea Gum 186 1-Benzyl-1-(4-n-butylbenzyl)-3-(2-methyl-4-chlorophenyl)urea 107-108 187 1 -(n-Heptyl)-1 -(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea - Gum 188 1 -(n-Heptyl)-1 -(4-n-butoxybenzyl)-3-(2-methyl-4-chlorophenyl)urea Gum 189 1 -(n-Heptyl)-1 -(2-furyl)-3-2,4,5-trimethylphenyl)u rea 65-67" 190 1-(n-Heptyl)-1-(2-furyl)-3-(2,4,6-trichlorophenyl)urea Yellow Oil 191 1-(n-Heptyl)-1-94-n-butylbenzyl)-3-(2-methyl-4-chlorophenyl)urea Oil 192 1 -(n-Heptyl)-1 -(4-n-butylbenzyl)-3-(2,4-difluorophenyl)urea Oil 193 1 -(n-Heptyl )-1 -(4-n-butyl benzyl)-3-(4-carboethoxyphenyl)urea 65-66" 194 1 -(n-Heptyl)-1 -(4-n-butylbenzyl)-3-(2-methylphenyl)urea Oil 195 1 -(n-Heptyl )-1 -(4-n-butyl benzyl)-3-(3-methylphenyl)urea Oil 196 1 -(n-Heptyl)-1 -(4-n-butyl benzyl)-3-(4-carboxyphenyl)u rea 147-149" 197 1 -(n-Heptyl)-1 -(2-phenylethyl)-3-(2-methyl-4-chlorophenyl)urea Gum 198 1 -(n-Heptyl)-1 -(2-phenylethyl)-3-(2,4,5-trichlorophenyl)urea Gum 199 1-(n-Heptyl)-1-(2-phenylethyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea Gum 200 1-(n-Heptyl)-1-(2-phenylethyl)-3-(2,4-dimethylphenyl)urea Gum 201 1 -(n-Heptyl)-1 -(2-phenylethyl)-3-(2,4-dichlorophenyl)urea Gum 202 1 -(n-Heptyl)-1 -(2-phenylethyl)-3-(2,4-difluorophenyl)urea Gum 203 1 -(n-Heptyl)-1 -(2-phenylethyl)-3-(3-trifluoromethylphenyl)urea Gum 204 1 -Benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl)cthyl]-3-(2,4,6-trichlorophenyl)urea 131-133" 205 1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4,6-trichlorophenyl)urea Oil 206 1 -(4-n-Pentyl benzyl)-1 -(4-n-pentyloxybenzyl )-3-(2,4-dichlorophenyl)urea Oil 207 1 -(4-n-Pentyl benzyl)-1 -(4-n-pentyloxybenzyl)-3-(2,4,5-trichlorophenyl)u rea Oil 208 1 -(4-n-Pentyl benzyl)-1 -(4-n-pentyloxybenzyl)-3-(2-trifluoromethyl-4-chlorophenyl)urea Oil 209 1 -(4-n-Pentyl benzyi)-1 -(4-n-pentyloxybenzyl)-3-(3-trifl uoromethylphenyl)urea Oil 210 1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2,4-difluorophenyl)urea Oil 211 1-(4-n-Pentylbenzyl)-1-(4-n-pentyloxybenzyl)-3-(2-methyl-4-chlorophenyl)urea Oil 212 1 -(4-Chlorobenzyl)-1 -(1 -naphthylmethyl)-3-(2,4,6-trichlorophenyl)urea 157-159 213 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2-methyl-4-chlorophenyl)urea 168-169 214 1-(4-Chlorobenzyl)-1-(1-naphthylmethyl)-3-(2,4-difluorophenyl)urea 122-124 215 1 -(4-Chlorobenzyl)-1 -(1 -naphthylmethyl)-3-(3-trifluoromethylphenyl)urea 127-129" 216 1 -(4-Chlorobenzyl)-1 -(1 -naphthylmethyl)-3-(2,4,5-trichlorophenyl)urea 110-113" 217 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4,5-trichlorophenyl)urea 142-145 218 1-Benzyl-1-(4-n-butyloxybenzyl)-3-(2,4,5-trichlorophenyl)urea Oil 219 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4-difluorophenyl)urea 84-85 220 1-Benzyl-1-(4-n-butoxybenzyl)-3-(2,4-difluorophenyl)urea Oil 221 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2,4-difluorophenyl)urea 126-128 222 1-Benzyl-1-[2-phenyl-1-(4-benzyloxyphenyl)ethyl]-3-(2-trifluoromethyl-4-chlorophenyl)urea 99-101" 223 1 -Benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl)ethyl]-3-(3-trifluoromethylphenyl)urea 102-104" 224 1 -Benzyl-1 -[2-phenyl-1 -(4-benzyloxyphenyl)ethyl]-3-(2-methyl-4-chlorophenyl)u rea 125-126" 225 1 -(4-Chlorobenzyl)-1 -(1 -naphthylmethyl)-3-(2,4-dichlorophenyl urea 96-98" 226 1 -(4-Chlorobenzyl )-1 -(1 -naphthyl methyl)-3-(2-trifl uoromethyl-4-chlorophenyl)urea Yellow Glass EXAMPLE 227 1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)urea A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 2.55 g. of 3-chloroaniline in 35 ml. of ether. The mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated and the residue is crystallized from hexane to yield phenyl N-(3chlorphenyl)carbamate.
A solution of 1.46 g. of phenyl N-(3-chlorophenyl)carbamate in 15 ml. of tetrahydrofuran is added to a solution of 1.92 g. of N-benzyl-n-butylamine in 20 ml. of tetrahydrofuran and the mixture is stirred under refluxfor 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration.
Recrystallization from pentane affords 1 -benzyl-1 -(n-butyl)-3-(3-chlorophenyl )urea, m.p. 69-70'C.
EXAMPLE 228 1-Benzyl- I-ln-butyl)-3-(4-carboxyph enyllurea A solution of 5.30 g. of 1-benzyl-1-(n-butyl)-3-(4-carboethoxyphenyl)urea in 100 ml. of ethanol is treated with 25 ml. of IN aqueous sodium hydroxide, stirred under reflux for 16 hours, allowed to cool, acidified with IN hydrochloric acid, and filtered. The solid is recrystallized from ethanol to yield 1-benzyl-1-(n-butyl)-3-(4carboxyphenyl)urea as a white solid.
EXAMPLE 229 1-Benzyl- 1-6n-butyl)-3-62-hydroxy-3-chlorophenyl)urea A solution of 1.73 g. of 1 -benzyl-1 -(n-butyl)-3-(2-methoxy-3-chlorophenyl)urea and 1.00 ml. of boron tribromide in 40 ml. of methylene chloride is stirred at ambient temperature for 3 days and diluted with water. The organic layer is separated, dried, and evaporated. The residue is crystallized from hexane to yield 1 -benzyl-1 -(n-butyl)-3-(2-hydroxy3-chlorophenyl )u rea, m.p.59-62 .
EXAMPLE 230 N-(2-Chlorobenzyll-3-methoxyphen ylacetamide A mixture of 12.5 g. of 3-methoxyphenylacetic acid, 21.2 g. of 2-chlorobenzylamine, 15.1 g. of triethylamine, 19.3 ml. of borontrifluoride etherate, and 500 ml. of toluene is stirred under reflux for 18 hours using a Dean-Stark moisture trap and allowed to cool. The mixture is extracted with aqueous sodium hydroxide, dilute hydrochloric acid, and water. The remaining organic solution is then evaporated and the residue crystallized from hexane to yield N-(2-chlorobenzyl)-3-methoxyphenylacetamide as a yellow solid, m.p.89-91".
EXAMPLE 231 N-{n-Butyl)-2-chlorobenzylamine Asolution of 21.2 g. of N-(n-butyl)-2-chlorobenzamide in 100 ml. oftetrahydrofuran is added with cooling to 200 ml. of 1M borane in tetrahydrofuran, and the mixture is stirred under refluxfor 18 hours, allowed to cool, and treated with 6N hydrochloric acid. The organic solvent is evaporated, and the residue is partitioned between ether and aqueous sodium hydroxide solution. The ether layer is separated, dried, and evaporated.
The residue is distilled to yield N-(n-butyl)-2-chlorobenzylamine as a colorless liquid, b.p. 65-75" at 60.
EXAMPLE 232 1, 1-Dibenzyl-3-62,4-dimethylphenyl)urea A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 5.32 g.
of dibenzylamine in 150 ml. of hexane, and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1,1 -dibenzyl-3-(2,4dimethylphenyl)urea, m.p. 124-126".
The ureas and thioureas shown in Table VIII were prepared from the appropriate arylisocyanates or arylisothiocyanates and secondary amines by the method of Example 60, or they were obtained commercially.
TABLE VIII EX. COMPOUND MELTING POINT 233 1,1-Dibenzyl-3-(2-methylpehnyl)urea White Solid 234 1,1-Dibenzyl-3-(3-methylphenyl)urea 126-128" 235 1,1 -Dibenzyl-3-(4-methylphenyl)urea 170-172" 236 1,1-Dibenzyl-3-(4-n-butylphenyl)urea 104-106" 237 1,1-Dibenzyl-3-(2,3-dimethylphenyl)urea White Solid 238 1,1-Dibenzyl-3-(2,5-dimethylphenyl)urea White Solid 239 1,1 -Dibenzyl-3-(2,6-dimethylphenyl)urea White Solid 240 1,1 -Dibenzyl-3-(3,4-dimethylphenyl)urea White Solid 241 1,1 -Dibenzyl-3-(3,5-dimethylphenyl)urea Yellow Solid 242 1,1-Dibenzyl-3-(2,4,5-trimethylphenyl)urea 141-142 243 1,1 -Dibenzyl-3-(2,4,6-trimethylphenyl )u rea 163-165" 244 1,1 -Dibenzyl-3-(4-methoxyphenyl)urea Cream Solid 245 1,1 -Dibenzyl-3-(4-n-butoxyphenyl)urea 119-120" 246 1,1 -Dibenzyl-3-(4-methylthiophenyl)urea 196-198" 247 1,1-Dibenzyl-3-(2-chlorophenyl)urea White Solid 248 1,1 -Dibenzyl-3-(3-chlorophenyl)urea White Solid 249 1,1 -Dibenzyl-3-(4-chlorophenyl)urea White Solid 250 1,1-Dibenzyl-3-(2-bromophenyl)urea 118-119" 251 1,1-Dibenzyl-3-(4-bromophenyl)urea White Solid 252 1,1-Dibenzyl-3-(4-iodophenyl)urea 233-235" 253 1,1 -Dibenzyl-3-(2,3-dichlorophenyl)urea White Solid 254 1,1 -Dibenzyl-3-(2,4-dichlorophenyl)urea White Solid 255 1,1-Dibenzyl-3-(2,5-dichlorophenyl)urea White Solid 256 1,1 -Dibenzyl-3-(3,5-dichlorophenyl)urea 144-145" 257 1,1 -Dibenzyl-3-(3-trifluoromethylphenyl)urea Cream Solid 258 1,1-Dibenzyl-3-(3-acetylphenyl)urea 124-127 259 1,1-Dibenzyl-3-(4-carboethoxyphenyl)urea 91-93 260 1,1-Dibenzyl-3-(4-phenoxyphenyl)urea 144-146 261 1,1 -Dibenzyl-3-(3-chloro-2-methylphenyl)urea 138-139" 262 1,1 -Dibenzyl-3-(3-ch loro-4-methylphenyi)u rea White Solid 263 1,1-Dibenzyl-3-(4-chloro-3-trifluoromethylphenyi)urea 146-148 264 1,1-Dibenzyl-3-(4-chlro-2-trifluoromethyl phenyl)urea 82-83 265 1,1-Dibenzyl-3-(3-methylphenyl)thiourea 95-96 266 1,1 -Dibenzyl-3-(2,3-dibenzophenyl)urea White Solid 267 1,1-Dibenzyl-3-(5-chloro-2-methylphenyl)urea White Solid 268 1,1 -Dibenzyl-3-(3-methoxyphenyl)urea White Solid 269 1,1-Dibenzyl-3-(2-methoxyphenyl)urea Cream Solid 270 1,1-Dibenzyl-3-(3-nitrophenyl)urea Yellow Solid 271 1,1-Dibenzyl-3-(2,5-dimethoxy-phenyl)urea Cream Solid 272 1,1 -Dibenzyl-3-(2,6-dichlorophenyl)urea White Solid 273 1,1-Dibenzyl-3-(3,4-dichlorophenyl)urea White Solid 274 1,1 -Dibenzyl-3-(4-chloro-2-methylphenyl)urea White Solid 275 1,1-Dibenzyl-3-(2-methoxy-5-methylphenyl)urea White Solid 276 1,1-Dibenzyl-3-(6-chloro-2-methylphenyl)urea White Solid 277 1,1-Dibenzyl-3-(6-ethyl-2-methylphenyl)urea White Solid 278 1,1 -Dibenzyl-3-(2,6-diethylphenyl)urea White Solid 279 1,1-Dibenzyl-3-(2,6-diisopropylphenyl)ures White Solid 280 1,1 -Dibenzyl-3-(4-nitrophenyl)urea Yellow Solid 281 1,1-Dibenzyl-3-(4-ethoxyphenyl)urea 129-130" 282 1,1-Dibenzyl-3-(2,5-difluorophenyl)urea 67-68 283 1,1-Dibenzyl-3-(2,4-dibromophenyl)urea 107-108 284 1,1-Dibenzyl-3-(3-chloro-4-methylphenyl)thiourea 109-110 285 1,1-Dibenzyl-3-(2,4-dimethylphenyl)thiourea 159-161 286 1,1-Dibenzyl-3-(3-trifluoromethylphenyl)thiourea 107-108 287 1,1-Dibenzyl-3-(4-carboethoxyphenyl)thiourea 108-110 288 1,1-Dibenzyl-3-(3,4-dibenzophenyl)urea 170-172 289 1,1 -Dibenzyl-3-(2-trifluoromethylphenyl)urea 111 -114 290 1,1 -Dibenzyl-3-(4-methylphenyl)urea White Solid 291 1,1-Dibenzyl-3-phenyl urea White Solid EXAMPLE 292 1, 1-Diphenyl-3-{3-bromophenyl)urea A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether, the mixture is stirred for one hour at room temperature and then filtered.The filtrate is evaporated, and the residue is crystallized from hexane to yield phenyl N-(3-bromophenyl)carbamatel, m.p. 89-90 C.
A solution of 1.46 g. of phenyl N-(3-bromophenyl)carbamate in 15 ml. of tetrahydrofuran is added to a solution of 2.32 g. of dibenzylamine in 20 ml. oftetrahydrofuran and the mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords l,l-dibenzyl-3-(3bromophenyl)urea, m.p. 102-103 .
EXAMLE 293 1, 1-Dibenzyl-3-f4carboxyphenyl)urea A solution of 5.61 g. of 1,1-dibenzyl-3-(4-carboethoxyphenyl)urea in 100 ml. of ethanol is treated with 25 ml. of 1N aqueous sodium hydroxide solution, stirred under reflux for 16 hours, allowed to cool, acidified with 1N hydrochloric acid, and filtered. The solid is crystallized from ethanol to yield 1,1-dibenzyl-3-(4carboxyphenyl)urea as a white solid, m.p. 210-214'.
EXAMPLE 294 1-Benzyl- 1-{n-butyl)-3-phenyl)urea A solution of 4.89 g. of phenylisocyanate in 100 ml. of hexane was added to a solution of 4.41 g. of N-benzyl-n-butylamine in 150 ml. of hexane, and the solution was stirred at room temperature for 2 hours and then evaporated. The residual solid was recrystallized from pentane to yield 1-benzyl-1 (n-butyl)-3-(2,4dimethylphenyl)urea, m.p. 49-50 C.
The ureas and thioureas shown in Table IX were prepared from the appropriate arylisocyanates or arylisothiocyanates and secondary amines by the method of Example 60, or they were obtained commercially.
TABLE IX EX. COMPOUND MELTING POINT 296 1,1 -Di (n-butyl)-3-(2-methylphenyl)urea Yellow Oil 297 1,1-Di-(n-butyl)-3-(3-methylphenyl)urea White Solid 298 1,1 -Di-(n-butyl)-3-(4-methyl phenyl )urea 90-91" 299 1,1-Di-(n-butyl)-3-(4-isopropylphenyl)urea 60-61.5 300 1,1 -Di-(n-butyl )-3-(4-n-butyl phenyl)u rea 44-46" 301 1,1-Di-(n-butyl)-3-92,3-dimethylphenyl)urea White Solid 302 1,1-Di-(n-butyl)-3-(2,5-dimethylphenyl)urea White Solid 303 1,1 -Di-(n-butyl)-3-(2,6-dimethylphenyl)urea 131-134" 304 1,1 -Di-(n-butyl)-3-(3,4-dimethylphenyl)urea 74-76" 305 1,1-Di-(n-butyl)-3-(3,5-dimethylphenyl)urea White Solid 306 1,1-Di-(n-butyl)-3-(2,4,6-trimethylphenyl)urea 119-120 307 1,1 ,-Di-(n-butyl)-3-(4-methoxyphenyl)urea White Solid 308 1,1 -Di-(n-butyl-3-(4-ethoxyphenyl )u rea 59-60" 309 1,1 -Di-(n-butyl )-3-(3-methylthiophenyl )urea 64.5-65.5 310 1,1 -Di-(n-butyl)-3-(2-chlorophenyl)urea Oil 311 1,1 -Di-(n-butyl)-3-(3-chlorophenyl)urea White Solid 312 1,1 -Di-(n-butyl)-3-(4-fluorophenyl)urea White Solid 313 1,1-Di-(n-butyl)-3-(4-iodiphenyl)urea 113-114" 314 1,1 -Di-(n-butyl)-3-(2,3-dichlorophenyl)urea Oil 315 1,1-Di-(n-butyl)-3-(2,4-dichlorophenyl)urea Oil 316 1,1-Di-(n-butyl)-3-(3,5-dichlorophenyl)urea 80-81 317 1,1 -Di-(n-butyl)-3-(2,3,5-trichlorophenyl)urea Yellow Solid 318 1,1-Di-(n-butyl)-3-(3-acetylphenyl)urea 80-81 319 1,1 -Di-(n-butyl )-3-(4-acetyl phenyl)u rea 94.5-95.5 320 1,1-Di-(n-butyl)-3-(3-chloro-2-methylphenyl)urea 73-75 321 1,1 -Di-(n-butyl)-3-(3-chloro-4-methylphenyl) urea Yellow Solid 322 1,1 -Di-(n-butyl )-3-(3-chloro-4-fluorophenyl )urea 80-81" 323 1,1-Di-(n-butyl)-3-(2-chloro-4-nitrophenyl)urea Yellow Solid 324 1,1 -Di-(n-butyl )-3-(4-ch loro-3-trifl uoromethyl phenyl)urea 84-85 325 1,1-Di-(sec-butyl)-3-(2,4-dimethylphenyl)urea 97-99 326 1,1-Di-(n-pentyl)-3-(2,4-dimethylphenyl)urea 45-46 327 1,1-Di-(n-isopentyl)-3-(2,4-dimethylphenyl)urea 66-68 328 1,1 -Di-(n-hexyl)-3-(2,4-dimethylphenyl )urea Oil 329 1,1-Di-(n-heptyl)-3-(2,4-dimethylphenyl)urea Yellow Oil 330 1,1-Di-(n-octyl)-3-(2,4-dimethylphenyl)urea Oil 331 1,1-Di-(n-undecyl)-3-(2,4-dimethylphenyl)urea Yellow Oil 332 1,1 -Di-(n-decyl)-3-(2,4-dimethylphenyl)urea Yellow Oil 333 1,1 -Di-(n-dodecyl)-3-(2,4-dimethylphenyl)urea Yellow Oil 334 1,1 -Di-(n-nonyl)-3-(2,4-dimethylphenyl)urea Oil 335 1,1 -Di-(4-cyciohexyl-n-butyl )-3-(2,4-dimethyl phenyl)u rea 85-86 336 1,1 -Di-(cyclopentyl)-3-(2,4-dimethylphenyl)urea 136-138 337 1,1-di-(n-butyl)-3-(2,3-dibenzophenyl)urea White Solid 338 1,1 -di-(n-butyl )-3-(4-chloro-2-methyl phenyl)urea White Solid 339 1.1-dicyclohexyl-3-(2,4-dimethylphenyl)urea White Solid 340 1,1 -di-(n-butyl)-3-(3-methoxyphenyl)urea White Solid 341 1,1 -di-(n-butyl)-3-[(3,3-dibutyl-u rea-4-methylphenyl] urea White Solid 342 1,1 -di-(isobutyl)-3-(2-chlorophenyl)urea White Solid 343 1,1-di-(isobutyl)-3-[(3,3-di-isobutyl)urea-4-methylphenyl]urea Tan Solid 344 1,1 -di-(isobutyl)-3-(2,5-di-methylphenyl)urea White Solid 345 1,1 -di-(isobutyl)-3-(2,6-di-methylphenyl)urea White Solid 346 1,1-di-(n-butyl)-3-(5-chloro-2-methylphenyl)urea 55-56 347 1,1-di-(3,5,5-trimethylhexyl)-3-(2,4-dimethylphenyl)urea 69-70 348 1,1 -di-(2-ethylhexyl)-3-(2,4-di-methyl phenyl )urea 40 EXAMPLE 349 1,1-Di(n-butyl)-3-(3-bromophenyl)ures A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether and the mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated, and the residue is crystallized from hexane to yield phenyl N-(3-bromophenyl)carbamate, m.p. 88-90 C.
A solution of 1.46 g. of phenyl N-(3-bromophenylcarbamate in 15 ml. of tetrahydrofuran is added to a solution of 1.52 g. of di-n-butylamine in 20 ml. of tetrahydrofuran, and the mixture is stirred under reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords 1,1 -di-(n-butyl)-3-(3-bromophenyl)urea, m.p. 80-81"C.

Claims (11)

1. A compound of the formula:
wherein X represents at least one substituent selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1-C4 alkoxy, phenoxy, mercapto, C1-C4 alkylthio, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl, and the group
wherein Y is selected from the group consisting of oxygen and sulphur;R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C1-C110 alkyl, C1-C1o alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro; and R3 is selected from the group consisting of hydrogen, C1 -C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl and phenyl bering at least one substituent Z, Z being selected independently of X from the group consisting of those from which X is selected; with the proviso that when R3 is hydrogen, then R1 and R2 cannot be the same.
2. A compound as recited in Claim 1, wherein Y is oxygen.
3. A compound as recited in Claim 1, wherein X represents at least one halo substituent.
4. A compound as recited in Claim 1, wherein X represents at least one substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, C1-C4 carboalkoxy, and benzyl.
5. A process for preparing a compound as defined in Claim 1, which comprises reacting a compound of the formula:
wherein Y is as defined in Claim 1 and A and B are independently selected from the group consisting of halo, C1-C4 alkoxy, C1 -C4 alkylthio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy; with an arylamine of the formula:
wherein X and R3 are as defined in Claim 1 to yield an intermediate of the formula:
and then reacting the intermediate with a secondary amine of the formula:
wherein R1 and R2 are as defined in Claim 1.
6. A process for preparing a compound as defined in Claim 1, which comprises reacting a compound of the formula:
wherein Y is as defined in Claim 1 and A and B are independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkylthio, phenoxy, 4-chlorophenoxy, and 4-nitrophenoxy; with a secondary amine of the formula:
wherein R1 and R2 are as defined in Claim 1 to yield an intermediate of the formula:
and then reacting the intermediate with an arylamine of the formula:
wherein X and R3 are as defined in Claim 1.
7. A process for preparing a compound as defined in Claim 1, wherein R3 is hydrogen, which comprises reacting an arylisocyanate or arylthioisocyanate of the formula:
with a secondary amine of the formula:
wherein X, Y, R1 and R2 are as defined in Claim 1.
8. A pharmaceutical composition suitable for treating atherosclerosis, reducing the cholesterol ester content of the arterial wall, inhibiting atherosclerotic lesion development and/or treating hyperlipidemia in a mammal in need of such treatment, which comprises a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the formula::
wherein X represents at least one substituent selected from the group consisting of hydrogen, C1 -C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, hydroxy, C1-C4 alkoxy, phenoxy, mercapto, C1-C4 alkythio, amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfonyl, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene tolyl, benzyl, halobenzyl, methylbenzyl, and the group
Y is selected from the group consisting of oxygen and sulfur;R1 and R2 are the same or different and are independently selected from the group consisting of C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycloalkyl, C4-C12 cycloalkylalkyl, C7-C14 aralkyl, and C7-C14 aralkyl in which an aromatic ring bears at least one substituent selected from the group consisting of C1-C1o alkyl, C1-C1o alkoxy, phenoxy, benzyloxy, methylenedioxy, C1 -C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1 -C4 carboalkoxy, and nitro; and R3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, benzyl, benzyl bearing at least one substituent Z, naphthyl, phenyl, and phenyl bearing at least one substituent Z, Z being selected independently of X from the group consisting of those from which X is selected.
9. A compound according to Claim 1 and substantially as described in any one of the Examples herein.
10. A process for preparing a compound according to Claim 1, substantially as described in any one of the Examples herein.
11. A pharmaceutical composition according to Claim 8 and substantially as hereinbefore described.
GB08301863A 1982-01-26 1983-01-24 Antiatherosclerotic substituted ureas and thioureas Expired GB2113684B (en)

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GB2138804A (en) * 1983-04-27 1984-10-31 Sumitomo Chemical Co Fungicidal N-phenylcarbamates
FR2549473A1 (en) * 1983-07-19 1985-01-25 American Cyanamid Co UREES AND THIOUREES, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS
EP0271251A1 (en) * 1986-12-03 1988-06-15 Minnesota Mining And Manufacturing Company Second harmonic generation by carbamic acid derivatives
EP0335374A3 (en) * 1988-03-30 1991-04-10 Warner-Lambert Company N-[[(2,6-disubstituted)phenyl]-N'-diarylalkyl] ureas as antihyperlipidemic and antiatherosclerotic agents
EP0344425A3 (en) * 1988-03-30 1991-04-10 Warner-Lambert Company N-[[(2,6-disubstituted)phenyl]-N'- arylalkyl] ureas as antihypercholesterolemic and antiatherosclerotic agents
EP0477778A3 (en) * 1990-09-25 1992-08-19 Eisai Co., Ltd. Benzene, pyridine and pyrimidine derivative
EP0528146A1 (en) * 1991-07-01 1993-02-24 Sandoz Ltd. N-phenylthiourea derivatives and pharmaceutical use thereof
EP0515684A4 (en) * 1990-02-14 1993-04-21 Chugai Seiyaku Kabushiki Kaisha Inhibitor of denatured ldl formation
US5462958A (en) * 1992-07-20 1995-10-31 Eisai Co., Ltd. Benzene derivatives and method of treating arteriosclerosis with benzene derivatives

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TW415942B (en) * 1997-09-03 2000-12-21 American Home Prod Novel substituted 1-aryl-3-heteroaryl-thioureas and substituted 1-aryl-3-heteroaryl-isothioureas as antiatherosclerotic agents
US6455566B1 (en) 1997-09-03 2002-09-24 Wyeth Substituted 1-aryl-3-heteroaryl-thioureas (or isothioureas) as antiatherosclerotic agents
EP0975589A2 (en) * 1998-01-21 2000-02-02 ZymoGenetics, Inc. Dialkyl ureas as calcitonin mimetics
WO2009009122A2 (en) * 2007-07-10 2009-01-15 Amgen Inc. Derivatives of urea and related diamines, methods for their manufacture, and uses therefor

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2138804A (en) * 1983-04-27 1984-10-31 Sumitomo Chemical Co Fungicidal N-phenylcarbamates
FR2549473A1 (en) * 1983-07-19 1985-01-25 American Cyanamid Co UREES AND THIOUREES, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS
EP0271251A1 (en) * 1986-12-03 1988-06-15 Minnesota Mining And Manufacturing Company Second harmonic generation by carbamic acid derivatives
US4818899A (en) * 1986-12-03 1989-04-04 Minnesota Mining And Manufacturing Company Second harmonic generation by carbamic acid derivatives
EP0335374A3 (en) * 1988-03-30 1991-04-10 Warner-Lambert Company N-[[(2,6-disubstituted)phenyl]-N'-diarylalkyl] ureas as antihyperlipidemic and antiatherosclerotic agents
EP0344425A3 (en) * 1988-03-30 1991-04-10 Warner-Lambert Company N-[[(2,6-disubstituted)phenyl]-N'- arylalkyl] ureas as antihypercholesterolemic and antiatherosclerotic agents
EP0515684A4 (en) * 1990-02-14 1993-04-21 Chugai Seiyaku Kabushiki Kaisha Inhibitor of denatured ldl formation
EP0477778A3 (en) * 1990-09-25 1992-08-19 Eisai Co., Ltd. Benzene, pyridine and pyrimidine derivative
US5668136A (en) * 1990-09-25 1997-09-16 Eisai Co., Ltd. Trisubstituted benzene derivatives, composition and methods of treatment
EP0528146A1 (en) * 1991-07-01 1993-02-24 Sandoz Ltd. N-phenylthiourea derivatives and pharmaceutical use thereof
US5462958A (en) * 1992-07-20 1995-10-31 Eisai Co., Ltd. Benzene derivatives and method of treating arteriosclerosis with benzene derivatives

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IE54683B1 (en) 1990-01-03
GB8301863D0 (en) 1983-02-23
DK160869B (en) 1991-04-29
PL240284A1 (en) 1985-01-02
PL143836B1 (en) 1988-03-31
SE8300370L (en) 1983-07-27
IT8347605A0 (en) 1983-01-25
AU1068183A (en) 1983-08-04

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