CA1291132C - Anti-atherosclerotic trisubstituted ureas and thioureas - Google Patents

Abstract

ANTI-ATHEROSCLEROTIC TRISUBSTITUTED
UREAS AND THIOUREAS

ABSTRACT OF THE DISCLOSURE
Trisubstituted ureas and thioureas useful as anti-atherosclerotic agents, compositions thereof and processes for their preparation are disclosed. These compounds are of the general formula:

Description

Title: ANTI-ATHEROSCLEROTIC TRISUBSTIUTED
UREAS AND THIOUREAS
BACKGROUND OF THE INVENTION
This invention relates to new ureas and thiourea compounds useful- as pharmaceutical agents. The novel compounds of the present invention are antiatherosclerotic agents c~apabie of ameliorating atherosclerosis by counter-acting the formation or development of atheromatous lesions in the arterial wall of mammals. The invention also relates to the chemical synthesis of the novel compounds disclosed herein. In addition, the invention pertains to novel pharmaceuticaI 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 vari~ety of urea and thiourea compounds can be found;in~the~l~iterature, for example, in~J. ~ed Che_ 18, 102~4 ~(1975~ Chem. Absts. 95: 6758m (1981) and 91:
74.631g~(1979j~; U.S. Paten~t Nos. 2,688,039; 3,335,142;
3,~856~,952; 3,903,~130;~and 4~,252,957 and in West German ~
~Offenlegu~ngsschrlft 29~28 485. The compounds found in litera-~tur~e;~and~disclosed~as~being useful herbicides, plant growth regul~ators,~bac~cericides, pesticides, fungicides, algacides,~photogr~a~pb~i~c~sensitizers, antihelmintics, sympatholytics and~anti~v;~irals.~ Those urea compounds found in Offen-egungss~chr~ift~29~28~485~are disc~osed as use~ul in ~inh~ibi~t~ing~ id~absorptio~n. There are, however, no l~iter~atu~re~references ~d~isclosing the trlsubstituted urea~and~th~i~ourea~compoun~ds of the~present invention or thelr~use ~in~the~trea~tment of a~therosclerosis or hyperlipidem~a.

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- ~ - 61109-7181 Atherosclerosis is a form of arteriosclerosis character-ized 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 lmportance 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 atherosclerosi 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 lO0 years. Various researchers have studied the role of cholest-erol in lesion formation and development and also, more important-ly, whether lesion format:ion can be prevented or lesion develop-ment arrested or reversed. Atheromatous lesions have now been shown [Adams, et al., Atherosclerosis, 13, 429 (1974)] to contain a greater quantity of:esterified as opposed to unesterified cholesterol thsn th~e~surroundlng undlseased arterial wall. The intracellular esterification of cholesterol with fatty acids:is catalyzed by the enzyme~Fatty acyl CoA:cholesterol acyl transfer~
ase or ACAT and the accumulation and storage of cholesteryl esters in~the~arterial wall;ls~associated with increased activity of this sne~me~[Hashimoto~and Dayton, Athsrosolerosis, 28, 447 (1977)].
In add~ition, cholesteryI esters are removed from cells at a slower : :: :
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- 2a - 61109-7181 rate than unesterified cholesterol [~ondjers and Bjorkerud, Atherosclerosis, 15, 273 (1972) and 22, 379 (1975)]. Thus inhibi-tion of the ACAT enzyme would diminish ~he 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 a~heromatous 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 atherosclerotic lesions in `iO mammals.
The evidence that hyperlipidemia is one of the factors involved in coronary heart disease is very im-pressive. A most important study carried out in Framingham, Mass. (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 multipIe, one of the most constant factors has been the elevated concentration of 20~ 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 va~cular disease were found to have hyperlipoproteinemia, involving very low-density and/or low-density lipoproteins (Lewis, et al., 1974).
~ We have now found that certain members of this class of compounds can safely and~effectively lower serum~lipids in warm-blooded animals. Such action on serum lipid~s is considered to be very useful in the treatment of;atherosclerosis. For some time it has ~be~en~cons~idered desirable to lower serum-lipid levels ~and to~correct lipoprotein imbalance in mammals as a ~ preventive~measure against atherosclerosis. The compounds 35~ ~o~the ~present invention do not act by blocking late : ~ :
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stages of cholesterol biosynthesis and thus do not produce accumulation oE intermediates such as desmosterol, as equally undesirable as cholesterol itself. Compounds with the combination of therapeutically fa~orable characteristics possessed by those of the present in-vention can be safely administered to warm-blooded mammals for the treatment of hyperlipidemic and ather-osclerotic 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 anti-atherosclerotic activity and the invention should not be construed as limited to any particular mechanism of .
antiatherosclerotic action.

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- 5 - 6110g-7181 UMM~RY OL~ Tll~ INV~N'~'lON
Thi~ invention relate8 to new trl~ub~ti~uted urea and thiourea compounds, their preparatlon, pharmaceutlcal compo~itions containing them, and their uge in the treatment of athe~o~clero~
More particularly, it i~ aoncerned with urea~ and thioureas which may be repr~sented by Formula I:
Il \ Y ~R
X ~ -C-N\

wherein X repre~ents at lea~t on~ ~ub~tituent ~eleeted from the group con~isting of hydrogen, Cl-C4 alkyl, Cl-C4 alkenyl, Cl-C4 alkynyl, hydroxy, Cl-C4 alkoxy, phenoxy, mercapto, Cl-C4 alkylthio, amino, Cl-C4 alkylamino, di-(Cl~C4 alkyl)amino, halo, trihalo-methyl, Cl~Cq alkanoyl, benzoyl, Cl-C4 alkanamido, haloaceta~nido, Cl-C4 alkanesulfinyl, benzenesulfonyl, toluene~ulfonyl, nitro, cyano, carboxy, Cl-C4 carboalkoxy, carbamoyl, ~ul~amyl, methylene-dioxy, phenyl, ortho-phenylene,tolyl, benzyl, halobenzyl, methyl-benzyl, Y i8 Belect~d from the group con~i~ting o~ oxygen and sulEur, with the proviso that when X i8 hydrogen Y mu~t be 6ulfur;
Rl and R2 are dl~ferent and are independently selected from the ~group consisting of C~-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, C4-C12 cycIoalkyl, C~-C12 cycloalkylalkyl C7~Clg aralkyl, and C7-C14 aralkyl in which an aromatic riny bears at least one 8ubstituent selected from the group con~i6tln~ o~ Cl-C10 ~lkyl, Cl-C10 alkoxy, phenoxy, ben~yloxy, urethylene~ioxy, Cl~C4 alkylthio, phenyl, halo, trihalon~hyl, adaman~yl, Cl-C4 carbo-alkoxy, and nltro wlth the pxoviso that when X compri6es one D
~ ~:

~.D~

- 5a - 61109-7181 sub~tltuen~ ln the meta po~ltlon wlth th~ r~pect to the nl~ro~en llnkage to the phenyl rlng and X i~ ~elected fro~ ~he group consl~tinq of hydroxy, alkoxy, mercapto and alkythlo then at lea~t one o~ Rl and R2 1~ othar than C4 alkyl.

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Preferred embodiments o~ the invention are those in which Y is oxygen. More preferred are those in which X
represents at least one Cl-C4 alkyl or halo sùbstituent, Rl is C7-Cl4 aralkyl or substituted C7~C14 aralkyl and ~2 is C4-Cl2 alkyl. The most preferred are those in which X
represents at least one methyl or chloro substituent.
Preferred specific embodiments involve l-ben-zyl-l-(n-butyl)ureas, for example:
l-benzyl-l-(n-butyl)-3-(3-methylphenyl)urea l-benzyi-l-(n-butyl)-3-(3-methylphenyl)urea l-benzyl-l-(n-butyl)-3-(3-chlorophenyl)urea l-benzyl-l-(n-butyl)-3-(3,4-dichlorophenyl)urea l-benzyl-l-(n-butyl)-3-(3,5-dichlorophenyl)urea l-benzyl-l-(n-butyl)-3-(2,4,6-trichlorophenyl)urea lS l-benzyl-l-(n-butyl)-3-(3-chloro-4-methylphenyl)urea l-benzyl-l-(n-butyl)-3-(2,4-dimethylphenyl)urea l-benzyl-l-(n-butyl)-3-(2-methylphenyl)urea l-benzyl-l-(n-butyl)-3-(4-methyIphenyl)urea l-benzyl-l-(n-butyl)-3-(2,3-dimethylphenyl)urea l-benzyl-l-(n-butyl)-3-(2,5-dimethylphenyl)urea l-benzyl-l-(n-butyl)-3-(2,6-dimethylphenyl)urea l-benzyl-I-(n-butyl)-3-(3,5-dimethylphenyl)urea l-benzyl-l-(n-butyl)-3-(3,4-dimethylphenyl)urea l-benzyl-l-(n-buty~ 3-(2,4,6-trimethylphenyl)urea 1-benzyl-1-(n-butyl)-3-(3-phenyl)thiourea l-benzyl-1-(1,2-diphenylethylj-3-(2,4-dimethylphenyl)urea l-benzyl-:1-[1-(3-methoxyphenyl)-2-phenylethyl]-3-(2,4-di-methylphenyl)urea ~ l-bènzyl-1-[1-(:4-benzyloxyphenyl)-2-phenyl]-3-(2,4-di-methylphenyl)urea l-benzyl-1:-~1-(3-methoxyphenyl)-2-phenylethyl]-3-(3-tri-flu~o:rome~thylphenyl)urea~
benzyl-l-(n-butyl)-3-(3-chloro-2-methoxyphenyl)urea l~-benzyl-l-(n-butyl)-3-(5-chloro-2-methoxyphenyl)urea : .

~ 3 This invention also relates to a method of re-ducing the cholesterol content of the arterial walls of mammals which comprises administering to said mammal an effective amount of a compound as recited above.
This invention also'relates to a method of treat-ing hyperlipidemia in mammals which comprises administer-ing to said mammal an effective amount of a compound as recited above.
This invention further relates to,a method of inhibiting atherosclerotic lesion development in mammals which comprises administering to said mammal an effective amount of a compound as recited above.
This invention still further relates to a pharm-aceutical composition which comprises an effective anti-i5 -atherosclerotic amount of a compound as recited above in association with a pharmaceutically acceptable carrier.
Finally, this invention relates to processes for preparing,compounds as rècited above. One process especi-ally useful for the preparation of trisubstituted ureas and thioureas involves reacting an arylisocyanate or arylisothiocyanate of formula II with a secondary amine of formula III, wherein X, Y, Rl and R2 are as deined above.

~ ` X ~ ~ HN
~R2 ~ II III

A second~process for the preparation of ureas and~th~ioureas involves reacting a compound ot formula IV;
~wherein~ A and B are leaving groups, which may be the same or~ dif~ferent, selected from the group consisting of halo, Cl-C4 alkoxy,~Cl-C4 alkylthio phenoxy, 4-chlorophenoxy and : ~::
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- ~ -4-nitrophenoxy; with a secondary amine of formula III to yield an intermediate of formula V and then reacting the intermediate with an arylamine of formula V~ wherein X, Y, Rl and R2 are as defined above.

A C B III > A ~ ~ 1 X ~ NH2 IV V VI
A third process for the preparation of ureas and thioureas involves reacting a compound of formula IV
with an arylamine of formula VI to yield an intermediate of formulaVII, wherein X, Y and B are as defined above and then reacting this intermediate with a secondary amine of formula III

i5 A-C-B + X ~ ~H2 X ~ N-C-B - >

IV VI VII
:
~ DETAILED DESCRIPTION OF THE INVENTION
... . .
Many of the novel ureas and thioureas of this invention are prepared by reacting arylisocyanates and arylisothiocyanates with secondary amines. These re-actions may be performed in aprotic~solvents such as hexane, diethyl ether, toluene, tetrahydrofuran, and the li~e~at temperatures from room temperature or below up to the bo~iling point oE the solvent used. The ureas and ; thioureas are isolated by filtration 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 ~ ~ d ~ ~
_9_ 2,4-dimethylphenylisocyanate with N-benzyl-N-(n-butyl)-amine to yield l-benzyl-l-(n-butyl)-3-(2,4-dimethyl-phenyl)urea.
Many of the secondary amines required for the 5 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 con-version of the carboxylic acid to the corresponding carboxylic acid chloride using thionyl chloride and then reacting the acid chloride wi~h the primary amine in the presence of a base~ One method especially useful for this transformation is the boron trifluoride etherate catalyzed reaction of a carboxylic acid with a primary amine. An example of this transformation is the boron trifluoride etherate catalyzed acylation of 2-chlorobenzylamine with 3-methoxyphenylacetic acid to yield N-(2-chlorobenzyl)--3-methoxyphenylacetamide.
Certain of the novel ureas and thioureas of this invention are prepared by reacting activated deriva-tives of carbonic acid such as phos&ene, 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 boil-ing point of the solvent. The intermediate may be iso-lated 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 temp-eratures 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 ~oluene to yield the intermediate N-benzyl-N-(n~butyl)-carbamyl chloride, which is then reacted with 3-bromo-aniline in N,N-dimethylacetamide in the presence of sodium hydride to yield l-benzyl-l-(n-butyl)-3-(3-bromophenyl)-urea.
Other of the novel ureas and thioureas of this invention are prepared by reacting arylamines with acti-vated 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 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 reaGted with a second-ary amine in an aprotic solvent such as toluene at temp-eratures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with 3-chloroaniline to yield the intermediate N-(3-chlorophenyl)carbamyl chloride which is ~hen reacted with N-benzyl-n-butylamine to yield l-ben-zyl-~l-(n-butyl)-3-(3-chlorophenyl)urea.

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The ureas and thioureas of this invention which contain carboxy groups are prepared by alkaline hydroly sis of the corresponding carboalkoxy ureas and thioureas, prepared by the synthetic methods described above. Like-wise, those which contain hydroxy, mercapto, or amino groups are prepared by alkaline hydrolysis of the corres-ponding O-acetyl, S-acetyl, and N-acetyl ureas and thio-ureas, respectively, the latter also having been obtained by the urea and thiourea syntheses described above.
Alternatively, the ureas and thioureas which contain hydroxy groups are prepared by cleavageof the corresponding methoxy compounds by Lewis acids such as borontribromide.
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 of these types of salts exhibit increased water solubility.
The preparation and properties of the compounds of this invention will be described in greater detail in conjunction with the specific examples shown below.
The compounds of the present invention were assayed for two types of biological activity related to their potential use as antiatherosclerotic agents. Com-pounds were tested in vitro for the ability to inhibit the enzyme fatty acyl CoA:cholesterol acyl transferase (ACAT) and in vivo for serum hypolipidemic activity as measured by the ability to inhibit lipid absorption in rats.

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-~2-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 lO00 times gravity for 15 minutes at 5C. The super-natant, containing the microsomal fraction, served as the source of the cholesterol-esterifying enzyme, fatty acyl CoA:choiesterol acyl transferase (ACAT). A mixture com-prising 50 parts o adrenal supernatant, lO parts of albumin tBSA) (50 mg./ml.), 3 parts of test compound (final concentration 5.2 g./ml.) and 500 parts of buffer was preincubated at 37C. for 10 minutes. After treat-ment with 20 parts of oleoyl CoA (14C - 0.4 Ci) the mixture was incubated at 37C. for 10 minutes. A control mixture, omitting the test compound, was prepared and treated in the same manner. The lipids from the incuba-tion 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 mod~ification o that described by Hashlmoto,~et.; al., Life Scie., 12 (Part II), 1-12 (1973).
~ The results of this test on representatlve compounds of thi~s 1nvention appear in Table I.

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Table I
Com ound % Inhibition P
l-Benzyl-l-(n-butyl)-3-(3-methylphenyl)- 92.3 urea .
l-Benzyl-l-(n-butyl)-3-(3-trifluoromethyl- 85.7 phenyl)urea l-Benzyl-l-(n-butyl)-3-(3,5-dichlorophen- 90.7 yl)urea l-Benzyl-l-(n-butyl)-3-(3,4-dichlorophen- 95.9 yl)urea _ l-Benzyl-l-(n-butyl)-3-(3-chlorophenyl)- 88.6 urea ~ _ _ l-Benzyl-l-(n-butyl)-3-(2,4-dimethylphen- 91.3 yl)urea _ _ _ l-Benzyl-l-(n-butyl)-3-(2-methylphenyl)- 78.8 urea _ l-Benzyl-l-tn-butyl)-3-(4-methylphenyl)- 78.0 urea _ l-Benzyl-l-(n-butyl)-3-(2,3-dimethylphen- ;85.8 yl)urea _ l-Benzyl-l-(n-butyl)-3-(2,5-dimethylphen- 92.7 yl)urea _ . _ l-Benzyl-l-(n-butyl~-3-t2,6-dimethylphen- 83.1 yl)urea ..
l-Benzyl-l-(n-butylj-3-(3,5-dimethylphen- 94.2 yl)urea l-Benzyl-1-[1-(3-methoxyphenyl)-2-phenyl- 86.4 ethyl]-3-(2,4-dimethylphenyl)urea _ Table I (continued) Com o~nds % Inhibition . _ P
l-Benzyl-l-[l-(4-benzyloxyphenyl)-2-phen- 93.0 ylethyl]-3-(2,4-dimethylphenyl)urea _ l-Benzyl-l-(l,2-diphenylethyl)-3-(2,4-di- 95.0 methylphenyl)urea l-Benzyl-l-(n-butyl)-3-(3,4-dimethylphen- 87.l yl)urea _ _ _ ._ _ l-Benzyl-l-[l-(3-methoxyphenyl)-2~phenyl- 88.l ethyl]-3-(3-trifluoromethylphenyl)urea _ _ l-Benzyl-l-(n-butyl)-3-(3-chlc,ro-2-methoxy 84.5 phenyl)urea l-Benzyl-l-(n-butyl)-3-(5-chloro-2-methoxy 80.6 phenyl)urea l-Benzyl-l-(n-butyl)-3-phenyl thiourea 82.4 _ _ l-(n-Butyl)-1-(2-fluorobenzyl)-3-(2,4-di-methylphenyl)urea 83.6 l-(n-Butyl)-1-(4-fluorobenzyl)-3-(2,4-di-methy1phenyl)urea 80.6 _ _ .
l-(n-Butyl)-1-~(2-chlorobenzyl)-3-(2,4-di-methylphenyl)urea 95.5 , , .
l-(n-Butyl)-1-(2,6-dichlorobenzylj-3-(2,4--dimethylphenyl)urea 74.5 ~ _ . _ _ .
.l-(n-Bu~tyl)-1-(4-bromobenzyl)-3-(2,4-di-methylphenyl)urea 81.0 Table I (continued) .
Compound % Inhibition _ l-(n-Butyl)-l-~4-(n-butyl)benzyl) -3-(2,4 54 4 -dimethylphenyl)urea _ , l-(n-Butyl~-1-(4-methylbenzyl)-3-(2,4-di- 96.7 methylphenyl)urea l-(n-Butyl)-1-(4-tert-butylbenzyl)-3-(2,4 96.4 -dime~hylphenyl)urea .. _ .
l-(n-Butyl)-1-(4-chlorobenzyl)-3-(~,4-di- 94.6 methylphenyl)urea _ _ _ __ . .
l-(n-Butyl)-1-(4-methoxybenzyl)-3-(2,4-di 94 2 methylphenyl):urea .
: ~
l-(n-Butylj-l-(3~4-methylenedioxybenzyl)- 2 3-(2,4-dimethylphenyl)urea as ~ -- :
1-(n-Butyl)-1-(4-trifluoromethylbenzyl)-3 3 3 : -(;2,4-dimeth~yl~heny1)urea : 9 .

l-(n-Butyl)-1-(4-phenylbenzyl)-3-(2,:4-di- 97 1 ~ethylphenyl:)~urea~ .

l-~(n-De~y~ benzyl-3-(2~4-dimeehyl- 96.1 pheny~1~)ur~ea~

1-(n-~But:y1):-1-(2-phenylethyl)-3-(2,4-di- 87.9 methy1~phenyl)urea ~

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Table I (continued) ¦ ComDound % Inhibition _ . r l-(n-Butyl)-1-[2-(4-fluorophenyl)ethyl]
-3-(2,4-dimethylphenyl)urea 96.1 . _ l-(n-Butyl)-1-[2-(4-chlorophenyl)ethyl]
-3-(2,4-dimethylphenyl)urea 93.3 _ _ .
l-(n-Butyl)-1-[2-(3-methoxyphenyl)ethyl]
-3-(2,4-dimethylphenyl)urea 98.3 _ _ l-(n-Butyl)-1-(3-phenylpropyl)-3-(2,4-di- 97 4 ~ethylphenyl)urea l-(n-Butyl)-l-benzyl-3-(2,4,6-trimethyl- 75 8 phenyl)urea _ l-(n-Butyl)-1-[4-(n-hexyl)benzyl]-3-(2,4-dimethylphenyl)urea 93.8 .
l-(n-Tetradecyl)-l-benzyl-3-(2,4-dimethyl- 80 3 phenyl)urea ,, l-(n-Octadecyl)-l-benzyl-3-(2,4-dimethyl- 19 7 phenyl)urea , l-(n-Butyl)-1-[2-(3-bromophenyl)ethyl]-3-(2,4-dimethylphenyl)urea 97.0 ~ : , .

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Inhibition of choles~erol absorpcion was determined by feed-ing male Sprague-Dawley ra~s, 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 o 0.3~ oE the diet. Con~rol rats were 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 4C; and the serum is then analyzed for cholesterol and 1~ 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 ~he center of the large lobe, and the sample is subjected to saponi-fication using 25% saturated potassium hydroxide in ethanol.
The resulting neutral sterols are extracted with petroleum ether and extract analyzed for cholesterol. The effective-ness of the compound in inhibiting cholesterol absorption i~ measured by the lowering of either serum cholesterol or liver choiesterol relative the values ~or control ra~s.
The resul~s o~ this test on typical compounds of this invention appear in Table II.

Table II
_ _ _ _ _ _ .
_ Compound Result l-Benzyl-l-(n-butyl)-3-~2,4-dimethylphenyl)urea Active l-Benzyl-l-(n-butyi)-3-(2,6-dimethylphenyl)urea Active I-Benzyl~ n-b~utyl)-3-(3,5~dimethylphenyl)urea Active l-Benzyl-1-(1,2-diphenyle~hyl)-3-(2,4-dime~hyl- Active phenylJurea ~

Trademark .~j , d Inhibition o~ cholesteroi absorp~ion was a;so de~ermined by feeding male Sprague-dawley rats wei~hing 150-170 g. a 1% cholesterol:0.5% cholic acid diet for 2 weeks. The diet also contained compounds being tes~ed a t doses of between 0.01% and 0.1% of the diet. After the rats had been on the test diet ior 9 days each rat is given by gavage a sonicated mixture o~ [4-14C] choles~erol (6~ Ci), G.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 miik. 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 tes~ compound diet. Fecal 14C-neutral sterois were extracted with petro-ieum ether rrom saponified feces by ~he method of Grundy, S. M. et. al., J. Lipid Res., 6, 397 (1565) and counted in a scintillation counter. Acidic s~erols (Bile acids) were extracted by acidifying the saponified feces and extracting in chloroform:methanol (2:1) ana 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 deter-mined by saponification and extraction into petroleum ether and counting by scijntillation techniques. Total cholesterol in liver and adrenals was determined by the cholorimetric method of Zlatkis, A., et. al., J. Lab. Clin. Med., 41, 486 (1953j on saponified organic solvent extracted tissue pre-pared by the method of Trinder, P., Analyst, 77, 321 (1952j.
Serum choles~erol and triglycerides were assayed enzymaticaly by the method~of Allain, C. C., et. al., Clin. Chem. 20, 470 (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-choles~erol or 14C-cholesteryl ester in the serum.
A compound is considered active in inhibiting cholesterol absorption if it meets at least the first ~wo criteria.
The results of this test on a typical compound of this invention appear in Table III.
~ Table III
_ . _ _ I
Compound Result -- :-: _ lS l-Benzyl- } (n-butjl)-3-(2,4-dlmetbylphenyl)-: : :
:

~" The;;tests~reported~ orshown in Tables l-III, inclusive have~been actually carr~led out and the results therein actually obtained or `concluded thererom.

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When the compounds are employed for the above utility, they may be combined with one or more pharma-ceutically acceptable carriers, e.g., solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or 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 solu-tions or suspensions containing from about 0.5 to 5%
suspending agent in an isotonic medium. These pharmaceu-tical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combina-tion with the carrier, more usually between 5% and 60% by weight.
The antiatherosclerotic effective dosage of active ingredient employed may vary depending on the par-ticular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the com-pounds of the invention are administered at a daily dos-age of from about 2 milligrams to about 500 milligrams per kilogram 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 millisrams to about 5,000 milli-grams preferably from about 10G millgrams to 2,000 milli-grams. Dosage forms suitable for internal use comprise from ~about 25 to 500 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutic-ally~ accept~able carrier. This GOSage regimen may be adjusted to provide the optimal therapeutic response.
For example, seve~ral divided dcses may be administered daily or the~dose may be proportionally reduced as in-dlcated by~the exigenCies of the therapeutic situation.

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~21-A decided practical advantage is that these active com-pounds may be administered orally as well as by intra-venous, intramuscular, or subcutaneous routes if nec-essary. Solid carriers include starch, lactose, di-calcium phosphate, microcrystalline cellulose, sucrose, and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible olls such as corn, peanut and sesame oils, as are appro-priate 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 eg. vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the stand-point of ease of preEaration and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administra-tion of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspen-sions of these active compounds as a free base or phar-macologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypro-pylcellulosè. Dispersions can also be prepared in gly-cerol, 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.
3Q The pharmaceutical forms suitable for inject-able 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 steril~ 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 micro~
organisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene S glycol and liquid polyethylene glycol), suitable mix tures thereof, and vegetable oils.
Example 1 l-Benzyl-l-(n-butyl3-3-(2,4-dimethylphenyl)urea _ A solution of 4.89 g. of 2,4-dimethylphenyl-isocyanate in 100 ml. of hexane is added to a solution of 4.41 g. of N-benzyl-n-butylamine in 150 ml. of hex-ane and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield l-benzyl-l-(n -butyl)-3-(2,4-dimethylphenyl)urea, m.p. 70-71C.
With reference to Example 1 and Table IV, only Example 1-4; 9-13; 15; 18; 29-30; 33; 39-40;43i 79-81; 83; 86-89; 150; and 202-266, inclusive have been actually carried out. Those compounds of the other actual Examples in Table IV were prepared from the appropriate arylisocyanates or arylisothiocyanates and secondary amines by the method of Example 1. All other Examples are simulated or predicted.

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Example 262 l_Benzyl_l_(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 mix-ture 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-chloro-phenyl)carbamate.
A solution of 1.46 g. of phenyl N-(3-chloro-phenyl)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 reflux for 24 hours. The mixture is diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane affords l-benzyl-l-(n-butyl)-3-(3-chloro-phenyl)urea, m.p. 69-70C.
~ Exam~ e 263 l-Benzyl-l-(n-butyl)-3-(4-carboxyphenyl~urea A solution of 5.30 g. of l-benzyl-l-(n-butyl) -3-~4-carboethoxyphenyi)urea in 100 ml of ethanol is treated with 25 ml of IN aqueous sodium hydroxide, stirred under reflux for i6 hours, allowed to coo~, acidif;ied with IN hydrochloric acid, and filtered. The soiid is recrystallized from ethanol to yield l-benzyl-l--(n-butyl)-3-(4-carboxyphenyl)urea as a white solid.
Examnle 264 :
roxy-3-chlorophenyl)urea ; ~ ~ A so;lution of 1.73 g of l-benzyl-l-tn-butyl) ~-3-(2~-meth~oxy-3-~chlorophenyI)urea and 1.00 ml of boron tribrom~ide 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.

:
::

-38- ~ ~3~

The residue is crystallized from hexane to yield l-benzyl--l-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea, mp 59-62.
Example 26$
N-(2-Chlorobenzyl)-3-methoxyphenylacetamide A mixture of 12.5 g oE 3-methoxyphenylacetic acid, 21.2 g of 2-chlorobenzylamine, 15.1 g of tri-ethylamine, 19.3 ml of borontri~luoride 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-chlrobenzyl)-3-methoxyphenyl-acetamide as a yellow solid, mp ~9-91.
Example 266 N-(n-Butyl)-2-chlorobenzylamine A solution of 21.2 g of N-(n-butyl)-2-chloro-benzamide~in 100 ml of tetrahydrofuran is added with cooling~to 200 ml of 1 M borane in tetrahydrofuran and the mixture is stirred under reflux for 18 hours, allowed to cool, and treated with 6 N hydrochloric acid. The organic solvent ~is evaporated and the residue is partitioned between ether andi aqueous sodium hydroxide solution. The ethèr~ layer is separated~, dried, and evaporated. The residue~is~distilled to yield N-(n-butyl)-2-chlorobenzyl-amine~as a colorless liquid, bp 65-75 at 60~ .

:

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Claims (21)

1. A process for the preparation of a compound of the Formula I:

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, C1-C4 alkylamino, di-(C2-C4 alkyl) amino, halo, trihalomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfinyl, benzenesulfonyl, toluene-sulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl; Y is selected from the group consisting of oxygen and sulfur, with the proviso that when X is hydrogen Y must be sulfur: and R1 and R2 are 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-C10 alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy, and nitro, with the proviso that when X
comprises one substituant in the meta position with the respect to the nitrogen linkage to the phenyl ring and X is selected from the group consisting of hydroxy, alkoxy, mercapto and alkythio then at least one of R1 and R2 is other than C4 alkyl, which comprises:
a) reacting an arylisocyanate or arylthioisocyanate of formula II with a secondary amine of formula III

II III
wherein X, Y, R1 and R2 are as defined above b) reacting a compound of formula IV

IV

wherein Y is as defined above 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 III:

III

wherein R1 and R2 are as defined above; to yield an intermediate of formula V, wherein A, Y, R1 and R2 are as defined above; and then reacting the compound of formula V with an arylamine of formula VI

VI

wherein X is as defined above;
c) reacting a compound of formula IV

IV
wherein Y, A and B are as defined above, with an aryl-amine of formula VI

VI

wherein X is as defined above, to yield an intermediate of Formula VII, VII

wherein X, Y and B are as defined above and then reacting the compound of Formula VII with a secondary amine of formula III

III

wherein R1 and R2 are as defined above.

2. A process for the preparation of 1-benzyl-1-(n-butyl)-

3-(2,4-dimethylphenyl)urea which comprises reacting 2,4-dimethyl-phenylisocyanate with N-benzyl-n-butylamine.

3. A process for the preparation of 1-benzyl-1-(n-butyl)-3-(trifluoromethylphenyl)urea which comprises reacting 3-tri-fluoromethylphenylisocyanate with N-benzyl-n-butylamine.

4. A process for the preparation of 1-benzyl-1-(n-butyl)-3-(2,4,6-trimethylphenyl)urea which comprises reacting 2,4,6-trimethylphenylisocyanate with 1-benzyl-n-butylamine.

5. A compound of the 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 alkyl-thio, amino, C1-C4 alkylamino, di-(C2-C4 alkyl)amino, halo, tri-halomethyl, C1-C4 alkanoyl, benzoyl, C1-C4 alkanamido, C1-C4 alkanesulfinyl, benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C1-C4 carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl, ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl;
Y is selected from the group consisting of oxygen and sulfur, with the proviso that when X is hydrogen Y must be sulfur; and R1 and R2 are different and are independently selected from the group consisting of C4-C12 alkyl, C1-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-C10 alkoxy, phenoxy, benzyloxy, methylenedioxy, C1-C4 alkylthio, phenyl, halo, trihalomethyl, adamantyl, C1-C4 carboalkoxy and nitro with the proviso that when X comprises one substituent in the meta position with the respect to the nitrogen linkage to the phenyl ring and X
is selected from the group consisting of hydroxy, alkoxy, mercapto and alkythio then at least one of R1 and R2 is other than C4 alkyl.

- 43a - 61109-7181

6. A compound of Formula I according to claim 5 wherein Y
is oxygen.

7. A compound of Formula I according to claim 5 wherein X represents at least two C1-C4 alkyl substituents.

8. A compound of formula I according to claim 6 wherein X represents at least one substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, carboxy, C1-C4 carboalkoxy and benzyl.

9. A compound of Formula I according to claim 8 wherein R1 is C7-C14 aralkyl and R2 is C5-C12 alkyl

10. A compound of Formula I according to claim 9 wherein R1 is benzyl and R2 is C5-C12 alkyl.

11. A compound of Formula I according to claim 10 wherein X represents at least one substituent selected from the group consisting of C1-C4 alkyl and halo.

12. The compound 1-benzyl-1-(n-butyl)-3-(2,4-dimethyl-phenyl)urea.

13. The compound 1-benzyl-1-(n-butyl)-3-(trifluoromethyl-phenyl)urea.

14. The compound 1 benzyl-1-(n-butyl)-3-(2,4,6-trimethyl-phenyl)urea.

15. A pharmaceutical composition comprising a compound of Formula I according to any one of claim 5 to claim 14 as a pharmaceutically active ingredient in association with a pharmaceutically acceptable diluent or carrier.

16. A composition according to claim 15 wherein the active ingredient is 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea.

17. A composition according to claim 15 wherein the active ingredient is 1-benzyl-1-(n-butyl)-3-(trifluoromethylphenyl)urea.

18. A composition according to claim 15 wherein the active ingredient is 1-benzyl-1-(n-butyl)-3-(2,4,6-trimethylphenyl)urea.

19. A process for preparing a pharmaceutical composition compriring a compound of Formula I according to claim 5 as a pharmaceutically active ingredient which process comprises admixing said active ingredient with a pharmaceutically acceptable diluent or carrier.

20. Use of a compound according to any one of claim 5 to claim 14 as and anti-atherosclerotic agent in a mammal.

21. A commercial package comprising a pharmaceutically effective amount of a compound according to any one of claim 5 to claim 14 together with instructions for use thereof as an anti-atherosclerotic agent in a mammal.