United States Patent mi
`
`.[11] Patent Number:
`
`5,015,544
`
`
`
` Roth et a1. [45] Date of -Patent: May 14, 1991
`
`[54] ANTIHYPERLIPIDEMIC AND
`ANTIATHEROSCLEROTIC UREA AND
`CARBAMATE COMPOUNDS
`
`['35]
`
`_
`_
`Inventors. Bruce D. Roth, Ann Arbor, Bharat K.
`T""°d" C"‘"‘°“' "°‘h °r Mm‘
`
`[73] Assignee: Warner-Lambert Company. Morris
`Plains, NJ.
`
`[21] Appl. No.: 359,330
`
`.
`filed‘
`
`[231
`
`J““- 1- 1939
`
`Related US, Application Data
`
`[63]
`
`Continuation-in-part of Ser. No. 232,l6'.r', Dec. 9. 1988,
`abandoned. which is aconlinualion-in-part of Ser. No.
`1-l~?,03?, Feb. 5. 1988, abandoned, which is a continua-
`tion-in-part of Ser. No. 5'r'.5':‘6. Jun. 2. 198?. aban—
`d°“°d'
`
`'
`
`514/247; 514/255;
`[52] U.S.C1.
`514/256; 514/307; 514x311; 514/357; 514/367;
`514/372; 514/3T4; 514/378; 514/381; 514/383;
`514/400; 514/406; 514/415; 514/427; 514/438;
`514/443; 514/469; 514/471; 514/481; 514/488;
`514/510; 514/513; 514/517; 514/542; 514/564;
`514/585; 514/536; 514/587; 514/595; 514/596;
`514/597; 514/598; 544/224; 544/335; 544/336:
`546/146; 546/l':'S; 546/332; 548/U8; 548/214;
`548/236; 548/247; 548/2618; 548/Q53;
`548/342; 543/373; 543/469; 548/560; 564/26;
`564/27; 564/28; 564/29; 564/48; 564/50;
`564/52: 564/53; 564/54; 549/58; 549/77;
`549/471; 549/496; 553/57'; 558/234; 560/10;
`560/13; 560/20; 560/21; 560/22: 560/23;
`560/28; 560/29; 560/31; 560/32; 560/34;
`562/427; 562/430; 562/435; 562./43?; 562/439
`[53] Field of Search
`564/48, 26, 27. 28.
`564/29, 50, 52, 53, 54; 514/596, 595. 597", 598,
`247,255,256.307.311.357,367,372,374,3T8.
`381.333.400.415.427.433,443.469.471,510,
`5l?.542.564,585.586.58?;544/224,335,336;
`546/146,175,332;548/173,214,236.241
`26z8,253.342.373.469,560;549/58,77.4rL
`496;s53/5r;56o/10,13.21,22,34;562/421
`43o,435.437,439
`
`'
`
`_
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3.852.343 1.711974 Krapcko
`4.337.105
`6./1983 DeVrles EL al.
`4,39T.363
`8/i933 DeVrie5
`4,410.69? 10./1983 Torak et al.
`4.623.662 11x'1986 De\«’ries
`
`
`
`504/56
`.. 554/-ms
`5E:-42’-F8
`56-V-4-8
`SI-l-I596
`
`FOREIGN PATENT DOCUMENTS
`
`049538
`lS42l6
`
`_
`al-/1982, European Pat. Off.
`3;/1982 German Democratic Rep.
`
`.
`
`Primary Ex£tmi’rter—RiCha1'd L. Raymond
`Agfgrfl-gy’ Agem; or fi',-m_.Ru1h H, Ngwtgon
`
`ABSTRACT
`[57]
`Certain substituted urea. thiourea, carbarnate, and thi-
`ocarbarnate compounds are potent
`inhibitors of the
`enzyme acyl-CoA: cholesterol acyltransferase and are
`thus useful agents for inhibiting the intestinal absorption
`of cholesterol, and for lowering blood plasma Choles-
`tcrol.
`
`[51]
`
`Int. CL5
`
`A61K 31/17; C0'r'C 275/28;
`COTC 275/30; COYC 215/32
`
`31 Claims, No Drawings
`
`1 of 20
`
`PENN EX. 2193
`
`_ CFAD V. UPENN
`lPR2015-01836
`
`

`
`US. Pat. No. 4.397.868 (De Vries) discloses phenylu-
`tea compounds useful in reducing cholesterol wherein
`one of the nitrogen atoms is disubstituted with, eg.
`aliphatic, alicyclic or aromatic groups.
`US. Pat. No. 4.410.697 (Torok) discloses an im-
`proved process for preparing phenyiurea compounds
`which are useful as herbicides, rodenticides, bacterio-
`static agents, coccidiostatic agents and antiseptic agents.
`The non—aniline nitrogen in these compounds can be
`mono- or di-substituted with alkyl, cycloalkyl, alkoxy
`or phenyl which groups may be further substituted.
`U.S. Pat. No. 4,623,662 (De Vries) discoses phenylu-
`rea and phenylthiourea compounds useful
`in treating
`atherosclerosis wherein the non-aniline nitrogen is di-
`substituted with aliphatic, cycloalkylalkyl, aralykyl
`groups wherein the aryl moiety may be substituted and
`wherein the aniline phenyl moiety is substituted with a
`wide variety of groups.
`SUMMARY OF THE INVENTION
`
`The present invention provides a class of compounds
`with ACAT inhibitory activity having the structure
`
`if
`f_'f)CH:)ir
`Ar--NH—c—Y—tcHgi..—c
`{CI-i3},,“.-°\r'
`
`wherein Ar is phenyl or naphthyl. The phenyl or naph-
`thyl group is unsubstituted, or may be optionally substi-
`tuted with alkyl of from one to six carbon atoms, hy-
`droxy, phenoxy. alkoity of from one to six carbon
`atoms,
`fluorine. chlorine. bromine.
`ttitro.
`triflLl0l'0-
`methyl. —CO0H.
`---COO—aIkyl (where alkyl is from
`one to four carbon atoms). or —NRiR3 in which R1 and
`R1 are independently hydrogen or alkyl of from one to
`six carbon atoms.
`The atom X is oxygen or sulfur, Y is oxygen or
`—-NH—, 11 is zero or is an integer of from one to three.
`n’ is an integer of from two to six, and n" is zero, one, or
`two.
`
`20
`
`25
`
`30
`
`35
`
`I
`
`5,015,644
`
`2
`
`INFORMATION DISCLOSURE
`
`A3\'TIHYPERLIPIDE‘.\IIC AND
`ANTIATHEROSCLEROTIC UREA AND
`CARBAMATE COMPOUNDS
`
`CROSS-REFERENCE
`
`This application is a continuation-in-part of co-pend-
`ing application Ser. No. 282.167, filed Dec. 9, 1988. now
`abandoned. which is a continuation-in-part of co-pend- 10
`ing application Ser. No. 147,037, filed Feb. 5, 1983, now
`abandoned, which is a continuation-in-part of co-pend-
`ing application Ser. No. 057,576. filed June 2, 1987, now
`abandoned.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to chemical compounds having
`pharmacological activity. to pharmaceutical composi-
`tions which include these compounds, and to a pharma-
`ceutical method of treatment. More particularly.
`this
`invention concerns certain substituted urea and carba-
`mate compounds which inhibit the enzyme acyl-coen-
`zyme A:cholesterol acyl-transferase (ACAT). pharma-
`ceutical compositions containing these compounds. and
`a method of inhibiting intestinal absorption of choles-
`terol or of regulating cholesterol.
`In recent years the role which elevated blood plasma
`levels of cholesterol plays in pathological conditions in
`man has received _much attention. Deposits of choles-
`terol in the vascular system have been indicated as caus-
`ative of a variety of pathological conditions including
`coronary heart disease.
`this problem were directed
`Initially,
`studies of
`toward finding therapeutic agents which would be ef-
`fective in lowering total serum cholesterol levels. It is
`now known that cholesterol is transported in the blood
`in the form of complex particles consisting of a core of
`cholesterol esters plus triglycerides and an exterior
`consisting primarily of phospholipids and a variety-of 40
`types of protein which are recognized by specific recep-
`tors. For example. cholesterol is carried to the sites of
`deposit in blood vessels in the form of low density lipo-
`protein cholesterol (LDL cholesterol) and away from
`..
`.
`.
`.
`.
`_
`.
`_ 45
`Ar’ is selected from phenyi. naphthyl. or a 5- or 6-
`mettibcrcd monocyclic or fused bic-yclic hcterocycle.
`:::(?I S(11:3E)(ifi:g?:;:et?;I};_]gh densfly hpo pl-mam choles
`Ar is unsubstputed. or may be optionally substituted
`Following these dismveriea the Search for therapem
`‘flth a|k5;,] fr mm one K.‘ 5” cgrbon am"_1Sg hydroxyj
`tic agents which control serum cholesterol turned to
`:1 Oily _° hlroin $2:
`to. 51‘? gar _on.f.?mmS“
`:1nz]¥l°}E3J'
`finding compounds which are more selective in their
`action; that is, agents which are effective in elevating Si) H'E1ErgtCH?r1I:3_’C6O.‘:]n]l_??‘ n1_t_1:((Eg(i)I§_OroE::[03E)’
`the blood serum levels of HDL cholesterol and/or low-
`(when: a1k;'l’ is from one Ego four Garbo}! atoms}
`ering the levels of LDL_chole-sterol. While such agents
`ICOOH; __CH2C0NH2; _NR1R2 in which R1 and R2
`are effective in moderating the levels of serum choles-
`are independently hydrogen alkyl of from one to Six
`terol, they have little or no effect on controlling the 55 carbon atoms which taming] carbon may Contain an
`initial absorption of dietary cholesterol
`in the body
`OR; group where R3. is hydrogen alkyl of from one to
`lhrough the intestinal wan’
`six carbon atoms, alkanoyl haviiig from two to five
`In intestinal mucosal.cells. dietary cholesterol is ab-
`carbon atoms. bcnzoyi, or when joined together form a
`sorbed as free cholesterol which must be esterified by
`5_ 0.. gmembered ring optionally interrupted by an
`the action of the enzyme acyl-CoA: cholesterol acyl- 60 oxygen atom 01. __NR3« wherein R3i5 as defined above;
`transferase (ACAT) before it can be packaged into the
`__CH3NR|R2 where R] and R3 are as defined above:
`chylomicrons which are then released into the blood
`__CH30R3 where R3 is as defined above; ___COO_a]k3-1
`5'“"‘—'3m- Th‘-'5» lh91'3P*3utlC 325139 which effi‘-'CTlVe]Y in‘
`where alkyl is from one to six carbons which terminal
`hibit the action of ACAT prevent the intestinal absorp-
`carbon may contain an OR3g1-oup or NRIR3 where R..
`tion of dietary cholesterol into the blood stream or the 55 R}, and R3 are as defined ab0ve:——i\’H—-(C1-11)_c0Q-
`reabsorption of cholesterol which has been previously
`alkyl (where alkyl is from one to four carbon atoms);
`released into the intestine through the body's own regu-
`—S03NR1R3 where R] and R3 are as defined above;
`latory action.
`—SOgOR;. where R;
`is as defined above. or ——E\'-
`
`2 of 20
`
`PENN Ex. 2198
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`3
`H-—SO;gR.; where R4 is alkyl of one to four carbon
`atoms or phenyl.
`DETAILED DESCRIPTION
`
`5,015,644
`
`15
`
`5
`
`10
`
`The compounds of the present invention form a class
`of substituted ureas, thioureas, carbamates, and thiocar~
`bamates having potent activity as inhibitors of the en-
`zyme acyl CoA: cholesterol acyltransferase (ACAT).
`Preferred compounds of the present invention are the
`urea and thiourea compounds, with the urea com-
`pounds being most preferred.
`In the urea compounds of the present invention, the
`first nitrogen atom is monosubstituted by an aromatic
`ring system selected from phenyl or naphthyl. The
`phenyl ring is unsubstituted or, alternatively, is substi-
`tuted with one, two, or three groups selected indepen-
`dently from alkyl of from one to six carbon atoms, alk-
`oxy of from one to six carbon atoms, hydroxy, fluorine,
`chlorine, bromine, nitro,
`trifluoromethyl, —-COOH.
`—CO0-alkyl (where alkyl is from one to four carbon 20
`atoms). or —NR1R; in which R1 and R3 are indepen-
`dently hydrogen or alkyl of from one to six carbon
`atoms. Preferred compounds are those in which the
`aromatic ring system is phenyl or substituted phenyl.
`In the urea and thiourea compounds ofthis invention. 25
`the second nitrogen atom is substituted with an aryl-
`substituted cycloalkyl ring which may be attached di-
`rectly to the nitrogen atom, or may separated from the
`nitrogen atom by a bridging group of up to three methy-
`lene (Le. —CH3—) groups. The cycloalkyl ring is cy- 30
`clopropyl. cyclobutyl. cyclopentyl, cyclohexyl, or cy-
`cloheptyl. with cyclopentyl and cyclohexyl being pre-
`ferred.
`
`The cycloalkyl ring is further substituted, at the same
`atom of attachment to the nitrogen of the urea moiety 35
`or the same atom of attachment
`to the methylene
`bridge, by an aryl group. This aryl group is unsubsti-
`tuted phenyl, naphthyl, or a 5- or 6-membered monocy-
`clic or fused bicyclic heterocycle or, alternatively, one
`ofthese aromatic rings may optionally be substituted by 40
`one, two. or three groups independently selected from
`alkyl of from one to six carbon atoms; alkoxy of from
`one to six carbon atoms; benzyloxy: hydroxy; fluorine;
`chlorine;
`35 bromine; nitro: trifluoromethyl, —NH—C0CH3; 45
`'—CONH3; —CODH; —CH3COOH; —CH2CONH2;
`—-l'\lR|R2 in which R; and R; are independently hydro-
`gen. alkyl of from one to six carbon atoms which termi-
`nal carbon may contain an OR; group where R3 is hy-_
`drogen or alkyl of-from one to six carbon atoms, or 50
`when joined together form a 5- or 6-membered ring
`optionally interrupted by an oxygen atom or —NR_=,;
`——CH3NRiR2 where R; and R; are as defined above;
`—_CH3OR3 where R3 is as defined above; —COO—alkyl
`where alkyl is from one to six carbons which terminal 55
`carbon may optionally be substituted with an OR;
`group or NRIR3 where R;, R2 , and R3 are as defined
`above; —NH—(CH1)—COO-alkyl (where alkyl is from
`one to four carbon atoms); ~—SO3NR1R2 where R; and
`R2 are as defined above: —S0gOR3. where R3 is as de- 60
`fined above, or —.\lH—S02R.-, where R4 is alkyl of one
`to four carbon atoms or phenyl.
`A 5- or 6—mernbered monocyclic or fused bicyclic
`hetcrocycle is a rnonocyclic or fused bicyclic aromatic
`ring containing at least one to four hetero atoms in at 65
`least one ring. such as nitrogen, oxygen or sulfur or a
`combination thereof. Such a heterocycle group in-
`cludes. for example, thienyl, benzothienyl. furanyl. ben-
`
`4
`zofuranyl, pyridy]_ pyrimidinyl, pyridazinyl, pyrazinyl,
`pyrrolyl. pyrrazolyl, isothiazolyl, oxazolyl, isoxazolyl,
`triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, indolyl,
`quinolinyl. isoquinolinyl, or N—oxides of a heterocycle
`containing a nitrogen atom.
`More specifically, such a heterocycle may be 2- or
`J-thienyl; 2- or 3-furanyl; 2-, 3-, or 4-pyridyl or or 3-
`thienyl; 2- or 3-furanyl; 2-, 3-, or 4-pyridyl or -pyridyl—
`N-oxide; 2, 4, or S-pyrimidinyl; 3- or 4-pyradazinyl;
`2-pyrazinyl: 2- or 3-pyrrolyl; 3-, 4-, or 5-pyrrazolyl, 3-,
`4-, or 5-isoxazolyl; 3-, 4- or S-oxazolyl; 3-, 4-, or 5-iso-
`thiazolyl; 5-tetrazolyl; 3- or 5-(l,2,4-)triazolyl; 4- or
`5-(l,2,3-)triazolyl; 2-, 4-, or S-imidazolyl; 2-, 3-, 4-, 5-, 6-,
`or 7-indolyl; 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; 1-, 3-, 4-,
`5-, 6-, 7-, or 8-isoquinolinyl; 2-, 4-, 5-, 6-, or ?-benzo-
`thiazolyl; or 2-, 3-, 4-, 5-, 6-. or 7-benzothienyl.
`A preferred class of urea compounds is represented
`by a compound of the formula
`
`{"iCH3}H'
`.\'HcoNH—t<:H:t..—C
`
`R
`
`(CH3],,--Ar‘
`
`where R is alkyl of one to four carbon atoms, especially
`isopropyl or otherwise referred to as l-rnethylethyl: n is
`0 or 1, especially 1; n‘ is an integer from 2 to 6. espe-
`cially 4 or 5; 1'1" is 0 or 1, especially 0, and Ar’ is phenyl
`or phenyl substituted by alkyl of from one to six carbon
`atoms; hydroxy: all-toxy of from one to six carbon atoms;
`benzyloxy; fluorine: chlorine; bromine: nitro: trifluoro-
`methyl; —NH—COCH3; —CONH2: —COOH:
`—C0O-alkyl (where alkyl is from one to four carbon
`atoms); —-CH2COOH; —CH2CONH2; —NR1R2 in
`which R1 and R3 are independently hydrogen. alkyl of
`from one to six carbon atoms which terminal carbon
`may contain an OR; group where R3 is hydrogen or
`alkyl of from one to six carbon atoms, or when joined
`together form a 5- or 6-membered ring optionally inter-
`rupted by an oxygen atom or —NR3; —CH3I\lR1R3
`where R; and R3 are as defined above:
`-—CHgOR3
`where R; is as defined above; —CO0-alkyl where alkyl
`is from one to six carbons which terminal carbon may
`contain an OR; group or NR1Rg where R1, R3, and R3
`are as defined above; —NH—(CH3)—CClO—alkyl
`(where alkyl
`is
`from one to four carbon atoms);
`—SO3NR1R3 where R] and R3 are as defined above;
`—S020R3 where R;
`is as defined above, or —N-
`H—SO3R4 where R4 is alkyl of one to four carbon
`atoms or phenyl. Especially preferred is a compound as
`defined above where Ar’ is phenyl or phenyl substituted
`by alkyl. hydroxy. alkoxy,
`fluorine, chlorine. nitro,
`triiluoromethyl, or —NR1R;.
`A particularly valuable class of urea compounds hav-
`ing a heterocyclic group defined above is a compound
`of the formula
`
`(EH3lrf
`.\_HCONH—{CH3}"—C
`\
`{CHILI AF
`
`.
`
`R
`
`where R is alkyl of one to four carbon atoms. especially
`isopropyl or otherwise referred to as 1-methylethyl: n is
`
`3of2l]
`
`PENN EX. 2198
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,015,644
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`5
`0 or 1, especially 1; n‘ is an integer from 2 to 6, espe-
`cially 4 or 5; n" is 0 or 1, especially 0, and Ar’ is a 5- or
`6-membered monocyclic or fused bicyclic heterocycle
`defined above.
`Preferred compounds of this invention are those in 5
`which the aromatic ring system attached to the cycloal—
`ky] ring is thienyl, tetrazolyl, isoxazolyl, triazolyl, py-
`razolyl, pyridyl. pyridyl-N-oxide, unsubstituted phenyl.
`or unsubstituted naphthyl.
`Examples of compounds contemplated as falling to
`within the scope of the invention are the following:
`N-(2,6-Dimethylphenyl)-\J'-{1-phenylcycopentynurea.
`N-{2.6-Diethylphenyl)-N’-(l-phenylcyclobutyflurea.
`N-(2,6-Diethylphenyl)-N’-(1-phenylcyclopentyhurea.
`N-(2,6-Diethylphenyl)-N’-{l-phenyIcyclopropy])me-
`thyl]ui-ea.
`N-(l -Phenylcyclopemyl)-N‘-{2,4,6-t1-imethoxyphenyb
`)urea.
`N-(2,6-Dimethylphenyl)-N’-[l-(2-thienyl]cyclohexyl-
`]urea.
`N-(2.6-Diethylphenyl)-N'-[l-(2-thienyl)cyclohexyl~
`]urea.
`N-[2,6-bis(I-Methylethyh]-N’-[1—(2—tl1ienyl)cyclohexyl—
`]urea.
`N-(2.6-Diethylphenyl)-N’-[(l-phenylcyclohexyl)me-
`thy1]ut'ca.
`N-(2.6-Dimethylphenyl)-N‘-(l-phenylcyclopenIyl)me-
`thyl]urea.
`N-(2.6-Dimethylphenyl)-N'-[(l—phenylcyclohexyl)me-
`thy1]urea.
`N-(2,6-Diethylphenyl)-N’-[(1-phenylcyclopentyl}me-
`thy]]urea.
`N-[2,6-bis(l—Methylethyl)phenyl]~N‘-(1-phenyIcy-
`c]opentyl)methyl]urea.
`N-E2,6-bis(l-Methylethyl]phenyl]~N'—[(l—pE1enylcy-
`c1ohexyl)methyl]urea.
`N-[2-Methy]—6-(1-methylethy])phenyl]—N'-1-(2-thienyl}
`cyclohexyl]urea.
`N-[2-(1,1-Dimethy1ethyl)-6-methylphenyl]-N3[l-(2-
`thienyl)cyClohexyl]_urea.
`N-[2-Methyl—6—(l—methylethyl]phertyl]-N'-[(1-phenyI-
`cyclohexyllmethyflurea.
`N-[2-[1,l-Dimethylethyl)-6-methylphenyl]-N‘-[(1-
`phenylcyclohexyljumethylurea.
`N-2-Eth l~6-1-meth leth 1
`hen 1-N'-
`1- hen lc -
`iiohexiiymithyiiuria. W H K P
`y y
`N—[2-Methyl—6—(1—methylethyl)phenyl]~N'-[(1-phenyl-
`cyclopentyl)methyl]urea.
`N-[2-{l,1-Dimethylethyl}-6-methylphenyl]-N'-[(I-
`phenylcyclopentyl)methyl]urea.
`N-[2~Ethyl-6-(1-rnethylethyl)pl1eny]]—N‘-[(l-phenylcy-
`c10pemy])methy]]u1-ea_
`N-(2,4-Difluorophenyl)-N’-[1-(2-thienyl)-cyclohex},=l-
`Jm-ea‘
`N-(2,4-Difluorophenyl)-N’-[(I-phenylcyclopemyl)me-
`t]-1y1]u1-.-_a_
`N-[2,4-Difluorophenyl)-N‘-[(1-phenylcyclohexyl)me-
`1hy]]u;-ea_
`'
`N-(2,6-Dibromo-4-fluorophenyl)-N’-[(1-pl1enylcy-
`c]ohe;;y1)me:hy1]ur¢a_
`N-(2,4-Dimethylphenyl}-N'—{(l-phenylcyclohexyl)me-
`thyl]urea.
`2~[[[[(lPhenyleyelohexyl)methyl]amino]carbonyl-
`]amino]benzoic acid, butyl ester.
`N-[2.6—bis(l-Methylethy]]phenyl]-N’-[1-{2-naph-
`thalenyl)cyclobutylrnethyljurea.
`N-(2,5-Dimethylphenyl)-N’-{l-phenylcyclohexyl)me-
`thyl]ut-ea.
`
`6
`N-(2,3-Dic]1|oropheny])—N'~[( I —phenylcyclohexyl}rne~
`thyl]ut'ca.
`N-(3,4-Dichlorophenyl)-N’-[( l -phenylcyc|ohexyl]me-
`thyl]ut'ea.
`N-[4-(I -Methylethyhphenyl]-N‘—[( l -phenylcyclohe»
`yl]rnethyl]urea.
`N-(4-Bromophenyl)-N‘-(1-phenylcyclohexyl)methy1-
`]urea.
`N-(4-Butoxyphenyl)-N'~[1~'pl1enylcyc]ohexyl)methyl-
`]urea.
`N‘(4-Phenoxyphenyl)-N‘~[( l—pher1ylcyclohexyl)me-
`thyl]urea.
`N-(4-Nitropl-1enyl)—N‘—[( l —phenylcyc1ohex yl)meth yl-
`]urea.
`N-(4-Methoxyphenyl)-N’-[(1-phenylcyclohei-:yl)me—
`lhyl]urea.
`N-(4-Ethoxyphenyl)-N’-[(1-phenylcyc]ohexyl)methyl-
`] urea.
`' N-(4-Acetylphenyl)-N’-[(1-phenylcycl0hexyl)methyl-
`]urea.
`4-[[[{l-Phenylcyelol1e:tyl)t'netl‘lyl]amino]carbonyl-
`]amino]benzc:-ic acid. ethyl ester.
`N-(4-Methylpheuyl)-N’-[(1-phenylcyelohexyl}meth)']-
`]urea.
`N-(4-Ethylphenyl)-N‘-[(l—phenylcyclohcxyl)methyl—
`]urea.
`N—(3—Methoxyphenyl)-N'-[(1-pheny]cyclohexy1)me-
`thy-l]urea.
`N-[(1-1,l'-Biphenyl]-4-ylcyclobutyl)methyl]N'-[2.6~
`bis(l-methylethyl)pher1yl]u1-ea.
`N—{4-Chlorophenyl)-N’-[l—pher1ylcyc]ohexy|]tnetl1yl~
`]urea.
`N-(4-lodophenyl)~N'—[(1-phenylcyclohexyl)methyl—
`]urea.
`_
`N-(2-Methylphenyl)-l\"—[(1-phenylcyclohexyl)meth}:1—
`]urea.
`N—(3—Methylphenyl)-N’-[1-phenylcyclohexyl)methy1-
`.
`]urea.
`N-[?.,6-bis(l-Methylethyhphenyl]-N’-[[l-4-(n-if'luororne—
`thy]}phenyl]cyclobuty1]rnethyl]urea.
`N—[2,6-bis(l-Me-thylethyl)pheny]]—N’-[[l-(4-methyl-
`phenyl)cyclc-butyl]rnethyl]urea.
`N-[2,6-bis(l-3/Iethylethy])phenyl]—N‘—[]-(2-methyl-
`PhenvIJ05/C10butvllmethv1]ur~=av
`N-[2.6-bis(1-Math:-rlethyl)phenyl]-N'-[1-(1-naph-
`Ihalen5-llcyclobutylirnethylurea.
`N-[2.6-bis(1-Mathy1ethyl)ph&ny1]-N’-ll-(3-methy1-
`phenyl)cyciobuty1]methyl]urca-
`-
`50 N'i(1'Pl1€fiYlCYCl0l1€XYllm¢‘l'1Yll'N"3'(t1'lfll10T0m€-
`thyllphenylurea
`N-[2—Chloro-5-(trifluoromethyl)phenyl]-N’-(]-phenyl-
`c yclohexyllmethyll urea-
`N-(5-Chloro-2-methoxypheny])-N’-(l—phenylcyclohex-
`Yl)m€1h)’li11T€a-
`N-(4-Chloro-2-methylphenyl)-N‘-[(1-phenylcycloheb
`&'1lm-°-‘tl'i3’l]Ui'e3-
`N-[2,6-bis(l-Methylethyl)phenyl]-N,-[[l-(3,4,5-trime-
`thoxyphenyl)cyc1obutyl]urea.
`50 N-[2.6-bis(1-Methylethyl)pheny]]-N'—[[l-[3-(tri-
`fluoromethyl)phenyl]cyclobutyl]methyl]urea.
`2-[[[[(l-Phenylcyelohexyl)methy]]amino]carbonyl-
`]amino]benzoic acid, methyl ester.
`2;[[[[(l-Phenylcyclohexyl)methyl]amir1o]carbon)-l-
`]amino]benzoic acid, ethyl ester.
`N—Phenyl-N'—(1—phenylc;.-clohexyl)methyl]urea.
`N-[2,5-Dimethoxyphenyl}-N‘-(l-phenycyclohexyl)me—
`thyl]urea.
`
`55
`
`65
`
`4 0‘ 2"
`
`PENN Ex. 2198
`_CFAD V. UPENN
`lPR2015-01836
`
`

`
`.
`7
`N-[2,6-bis{l-Methylethyl)phenyl]—N‘-[l—2—(trifluorome-
`thyl}phenyl]cyclobutyl]methyl]urea.
`N-[2,6-bis(l—Methylethyl)phenyl]-N'-[[1-{4-methyl-
`phenyllcyclopentyl]methyl]urea.
`N-[2,6-bis(l-Methylet.hyl)pl1enyl]-N’-[J-[4-(l-methyle-
`thyl)phenyl]cyclopentyl]methyl]urea.
`N—[2,6~bis(1-Methylethynphenyl]-N’-[l -(2-methyl-
`phenyl)cyclopentylmethyl]urea.
`N-{2,6-bis(l-Methylethyl)phenyl]-N’-(1-phenylcyclch
`propyl)methyl]urea.
`-
`N-(5-Chloro—2—methylphenyl)-N‘-[(1-phenylcyclohex-
`yl)methyl]urea.
`N—[2.5-Dichlorophenyl)—N'—[(1—phenylcyclol1exyl)me-
`thyllurea.
`N-[2.6-bis(l-Methylethyl)phenyl]-N’-[[l-{4-methoxy-
`phenyl)cyclopentyl]methylurea.
`N-[2,6-bis-(l-Methylethyl)pheny]]-N’-[(l-phenylcy-
`clobutyl)methyl]urea.
`N-[2,6-bis(l-Methylethyl)phenyl]-N’-[l-(2-naph-
`thalenyl)cyclopentyl]methyl]'urea.
`N-[2.6-bis{l-Methylethyl)phenyl]-N’-[l-(2-naph-
`thalenyl]cyclobutyl]methyl]urea.
`N-[2,6-bis(1-Methylethyl)phenyl]-N’-[[1-[3-{phenylme-
`thoxy)phenyl]cyclopentyl]methyljurea.
`N-[2,6-bis(1-Methylethyhphenyl]-N'-[[l-(4-flLIor0-
`phenyl)cyclopentyl]methyl]urea.
`N-[2.6-bis{l-Methylethyl)phenyl]-N’-[[l-[4-(phenylme-
`thoxy)phenyl]cyclopentyl]methyl]urea.
`N-[2,6-bis(l-Metl‘tylCthy])phcnyl]-N’-[[l-[4-(tri-
`fluoromethyl)phenyl]cyclopentyl]methyl]urea.
`N-[2,6-bis(l-Methylethyl)phenyl]-N'-[[l-(2,6-dichloro-
`phenyl)cyclobutyl]methyl]urea,
`N-[2,6-bis(l-Methylethyl)phenyl]-N’-[[l-[3,5-bis(tri-
`fluoromethyllphenyl]cyclopentyl]-meIhyl]urea.
`N—[2.6—bis(l—Methylethyl)phenyl]—N‘—[l—[2—{tril'luorome— 35
`thyl)phenyl]cyclopentyl]meIhyl]urea.
`N-[2.6-bis(l-Methylethyl]phenyl]~N'—[[1-(4-«chloro-
`phenyl)cyclopentyl]methyl]urea.
`N-[2,6-bis(l-Methylethyhphenyl]-N'-[[l-(4-nitro-
`phenyl)cyclopentyl]methyl]urea.
`N-[1-(4-Aminophenyl)cyclopentyl]rnethyl]—N’-[2,6-
`bis(l-methylethyl}pheny|]urea.
`'
`N-[4-[l-[[[[[2,6-bis(l-Methylethyl)phenyl]amino]car-
`bonyl]amino]methyl]cyclopentyl]phenyl]acetamide.
`N-[2,6-'bis(1-Methylethyl)phenYl]-N’-{ll-(4-dime-
`thylaminophenyhcyclopentyl]me1hyl]urea or its hy-
`drochloride salt.
`'
`N-[2,6-bis(l-methylelhyl)phe11yl]-N'-[l-(4-clirr1e-
`thylaminophenyl)cyclohexyl]methyl]urea.
`N~[2.6-bis{l-methylethylphenyl]«N‘-[[l-(4-die-
`thylaminophenyhcyclopentyl]methyl]urea.
`N-[2,6-bis{ l-methylethyllphenyl]-N’-[[[l -4-(2-hydro»
`yethyl)amino]phenyl]cyclopentyl]methyl]urea. _
`N“-[[l-[4-[-bis(2-hydroxyethylamino]phenyl]cyclopen-
`tyl]methyl]-N-[2,6-bis(l-methylethyl]phenyl]urea.
`N-[2,6-bis(l-methylethyljphenyl]-N’-[[[l-(2-tri-
`fluoromethyl-4-dimethylamino)phenyl]cyclopentyl]-
`methyl]urea.
`'
`N-[2,fi-bis(l-methylethyljphenyl]-N’-[[[l-(2-tri-
`fluoromethyl-4-methylamino]phenyl]cyclopentyl]-
`methyl]urea.
`Additional examples of compounds contemplated as '
`falling within the scope of the invention are the follow-
`ing
`N-(2,6-bis(l~methylethyl)-N’-[l-heterocyclecy-
`clopentyllmethyllureas
`where the heterocycle is:
`5-( l -methyltetrazolyl).
`5-{l-H~tetrazolyl),
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`45
`
`50
`
`SS
`
`60
`
`65
`
`5,015,644
`
`8
`
`4—(2,5—dimethylisoxazolyl}.
`4—[(l-benzyl-5-[N,N—dimethylamino)]-l,2.3~triazolyl],
`4-[l -methyl-5-(N,N-dimethylamino)-l .2.3-triazol yl].
`4-(l,3,5-trimethylpyrazolyl),
`4-(1-H,-3,S-dimethylpyrazolyl), and
`3-pyridyl-N-oxide.
`By the term "lower alkyl“ or "alkyl" as used
`throughout this specification and the appended claims is
`meant a branched or unbranched hydrocarbon group-
`ing derived from a saturated hydrocarbon of from one
`to six carbon atoms by removal of a single hydrogen
`atom. Examples of alkyl groups contemplated as falling
`within the scope ofthis invention include methyl, ethyl,
`propyl, Lmethylethyl,
`butyl,
`1-rnethylpropyl.
`2-
`methylpropyl, and 1,1-dimethylethyl.
`By the term “alkoxy" is meant a lower alkyl group. as
`defined above, attached to the parent molecular moiety
`through an oxygen atom.
`In those instances where the compounds of the pres-
`ent invention bear a basic nitrogen atom as. for example.
`when Ar or Ar’ is substituted by amino. alkylamino, or
`dialkylamino, or when Ar’ is pyridyl, the compounds _
`are capable of forming acid addition salts. These acid
`addition salts are also contemplated as falling within the
`scope OF this invention.
`While the acid addition salts may vary from the free
`base form of the compounds in certain properties such
`as melting point and solubility,
`they are considered
`equivalent to the Free base forms for the purposes ofthis
`invention.
`The acid addition salts may be generated From the
`free base forms of the compounds by reaction of the
`latter with one equivalent of a suitable non-toxic, phar-
`rnaceutically acceptable acids followed by evaporation
`ofthe solvent employed for the reaction and recrystalli-
`zation of the salt, if required. The free base may be
`recovered from the acid addition salt by reaction of the
`salt with a water solution of the salt with a suitable base
`
`such as sodium carbonate, sodium bicarbonate. potas-
`sium carbonate. sodium hydroxide, and the like.
`Suitable acids for forming acid addition salts of‘ the
`compounds of this invention include. but are not neces-
`sarily limited to acetic. benzoic. benzenesulfonic,
`tar-
`taric. hydrobromic, hydrochloric, citric, fumaric, glu-
`conic. glucuronic, glutamic, lactic, rnalic, maleic. meth-
`anesulfonic. pamoic. salicylic, stearic, succinic, sulfuric.
`and tartaric acids. The class of acids suitable for the
`formation of non—toxic, pharma-ceutically acceptable
`salts is well known to practi-tioners ofthe pharmaceuti-
`cal formulation arts. (See,
`for example, Stephen N.
`Berge. el al. J. Phorm. Sciences, 6621-19 (1977).
`In those instances where the compounds of the pres-
`ent invention bear a basic nitrogen atom in a heterocy—
`clic group as, for example, when Ar’ is pyridyl,
`the
`compounds are capable of forming N-oxides. These
`N-oxides are also contemplated as falling within the
`scope of this invention.
`The N-oxides may be prepared from the free base
`forms of the compounds by reaction of the latter with
`an oxidizing agent, such as, for example, hydrogen per-
`oxide. peracetic acid or perbenzoic acid in a suitable
`solvent.
`Further, the compounds ofthis invention may exist in
`unsolvated as well as solvated forms with pharma-centi-
`cally acceptable solvents such as water, ethanol and the
`like.
`In general.
`the solvated forms are considered
`equivalent to the unsolvated forms for the purposes of
`this invention.
`
`5uf2l]
`
`PENN EX. 2193
`
`_ CFAD V.UPENN
`lPR2015-01836
`
`

`
`The compounds ofthe present invention are prepared
`by the general method outline in Reaction Scheme 1.
`The appropriately substituted isocyanate, 2a (where
`X=0), or thioisocyanate compounds, 2b (where X=S).
`are reacted with the desired amine. 3. to obtain the
`
`substituted urea compounds of the present invention.
`la—lb. or with the desired alcohol, 4, to obtain the sub-
`
`stituted carbamate com pounds of the present invention,
`lc—1d.
`‘
`
`in a polar
`The reaction is generally carried out
`aprotic organic solvent such as ethyl acetate, at any
`temperature between room temperature and the boiling
`point of the solvent. with room temperature being pre-
`ferred.
`
`The reaction is allowed to proceed until analysis of
`the mixture by a means such as chromatography indi-
`cates that tile reaction is substantially complete. Reac-
`tion times may vary between about two hours to about
`24 hours, depending upon the particular reagents and
`reaction temperature employed. The starting isocyanate
`or thioisocyanate compounds are known or commer-
`cially available or, if not previously known. are pre-
`pared by methods well known in the art from the corre-
`sponding amine compounds.
`The amine compounds, 3. are prepared by the general
`method detailed inJ. Org. Chem., 36(9): 1308 (l9't'l)artd
`depicted schematically in Reaction Scheme 2. Referring
`to Reaction Scheme 2, phenylacetonitrile or the substi-
`tuted phenylacetonitrile 5,
`is reacted with the desired
`alpha-omega dibromoalkalne, 6. in the presence of base
`to produce the eycloalkyl nitrile, 7. This compound is
`catalytically reduced by the action of hydrogen over a
`noble metal catalyst to produce the aryl(aminomethy1)-
`cycloalkane compound, 8. Acid hydrolyis ofcompound
`6, produces the corresponding aryl(cycloalkyl) carb0x-
`amide, 9, which is then subjected to the Hofrnann deg-
`radation reaction (Ber. 14: 2725 (1881)) to produce the
`aryltcycloall-:y'l)amine 10.
`
`Reaction Scheme 1
`
`Ar.—N=C=X
`
`5
`
`I0
`
`i5
`
`20
`
`25
`
`30
`
`35
`
`45
`
`S0
`
`H1N—(CH;:_}fl"'C
`
`F (CHEM
`HO—(CH2),.,—C
`
`55 CHEM
`(CH2ln"Ar'
`
` tCH2},.-'Ar'
`
`10
`
`Reaction Scheme 2
`
`l'CH_1_];-.'
`Br—fCH3L,‘Br 6
`C»
`Ar'—CH3—CN Ar'—C\ CN
`5
`7
`
`/ F'dr‘CJ/H]
`
`F lCH2)n‘
`Ar'—(]I
`C—NHg
`I/'70
`9
`
`(CH2).-r‘
`
`Ar'— I
`CH3--.‘-"H3
`
`3
`
`at
`
`(j{)CH3ln'
`Ar‘—C
`/'
`NH1
`
`to
`
`For the amines, where Ar‘ can be substituted with
`—NR1R1 where R1 and R3 are other than hydrogen as
`defined above.
`the intermediate
`l-cyano-l—(4-nitro-
`'pheny1}cycloall<yl derivative is first reductively alkyl-
`ated using Pd/c in the presence of appropriate alde-
`hyde. This dialkylamino nitrile derivative is then re-
`duced to the requisite amine (8) using Ra-Ni and hydro-
`gen in methanolic ammonia preferably at room temper-
`ature. For compounds (I) where Rt and R3 may contain
`OR; where R3 is hydrogen, the parent molecule where
`R]=R3=H is reacted with electrophile such as ethyl-
`ene oxide in an alcohol solution at reflex temperature.
`For compounds where the phenyl ring has more than
`one substituent (such as in example 93, 94), the required
`amine is prepared as Follows:
`the l-cyano—l-(2-tri-
`lluoromethyl}phenyl cyclopentane is first nitrated using
`fuming nitric acid at 5° C. to room temperature then
`reductively alkylatccl as described above. The nitrile
`derivative is then reduced to the corresponding amine
`(8) using Ra-Ni
`in methanolit: ammonia. For com-
`pounds, where Ar‘ is substituted it
`is preferred to hy-
`drolyse with —CO0H, the corresponding ester deriva-
`tive (I) using base such as sodium or potassium hydrox-
`ide.
`
`As shown by the data presented below in Table 1, the
`compounds of the present invention are potent inhibi-
`tors of the enzyme acyl-CoA:cholcsterol aeyl—transfe—
`rase (ACAT), and are thus'ef‘fective in inhibiting the
`esterification and transport of cholesterol across the
`intestinal cell wall. The compounds of the present in-
`vention are thus useful in pharmaceutical formulations
`for the inhibition of intestinal absorption of dietary
`cholesterol,
`the reabsorption of cholesterol
`released
`into the intestine by normal body action. or the modula-
`tion of cholesterol.
`
`9
`
`5,015,644
`
`3
`
`x
`ll
`.-5tr—NH—C—Y—{CH3),,—
`
`4
`
`,
`.
`K-_j°”"”
`\
`[CH2},,"Ar'
`
`E3xxxx
`
`nunn
`
`£fi_O.U‘_O
`
`-<.4-<14
`
`“nunooéé
`
`IN VITRO TESTS
`
`65
`
`The ability of representative compounds of the pres-
`ent invention to inhibit ACAT was measured using an
`in vitro test more fully described in Field. F. J. and
`Salone. R. C'r.. Bincltemtca er Bt'oplt_vst’ca 712: 557-570
`
`6uf2l]
`
`PENN EX. 2198
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,015,644
`
`12
`TABLE 2-continued
`Compound
`Total Blood Cholesterol
`of Example
`lmgfdll
`[Control = 10-1)
`
`
`
`9% Change
`
`5
`
`In therapeutic use as agents for the inhibition of intes-
`tinal absorption of cholesterol. or as hypolipidemic or
`hypocholesierolemic agents, the compounds utilized in
`lo the pharmaceutical method of this invention are admin-
`istered to the patient at dosage levels of from 250 to
`1000 mg per day. For a normal human adult of approxi-
`mately 70 kg of body weight, this translates into a dos-
`age of from 5 to 20 mg/kg of body weight per day. The
`15 specific dosages employed, however, may be varied
`depending upon the requirements of the patient,
`the
`severity of the condition being treated, and the activity
`ofthe compound being employed. The determination of
`optimum dosages for a particular situation is within the
`Skin of the art.
`For preparing pharmaceutical compositions from the
`compounds of this invention,
`inert, pharmaceutically
`acceptable carriers can be either solid or liquid. Solid
`form preparations include powders, tablets, dispersible
`25 granules, capsules, and cachets.
`A solid carrier can be one or more substances which
`
`-
`11
`(1932). The test assesses the ability of a test compound
`to inhibit the acylation of cholesterol by oleic acid by
`measuring the amount of radio-labeled cholesterol ole-
`ate formed from radio-labeled oleic acid in a tissue prep-
`aration containing rabbit intestinal microsomes.
`The data appear in Table l where they are expressed
`as lC5o values; ie. the concentration of test compound
`required to inhibit 50% expression of the enzyme.
`TABLE 1
`
`Comiwund
`_1Cs-:1
`
`°r E"a'"p‘e
`[M‘°"°""“l3’l
`'
`093
`§
`4
`5
`6
`g
`9
`10
`ii
`'3
`
`0:383
`030
`0J3
`3-3:‘
`0:05!
`(}_154
`0.08!
`0-UI5
`33;:
`0:23
`0,355
`0.053
`
`'5
`15,
`ii
`
`30
`
`3-gig
`E
`Dime
`10
`dete
`21
`0.025
`22
`0-37
`3’-3
`3::
`:
`0:039
`26
`dggt
`37
`0.052
`as
`0-043
`39
`333
`3?
`eeet
`92
`0.050
`93
`94
`0-