IE911909A1 - Antihypercholesterolemic bis-trifluoromethyl-substituted¹Imidazolines and derivatives thereof - Google Patents

Abstract

Provided are bis-trifluoromethyl-substituted imidazolines, as inhibitors of Acyl-CoA: Cholesterol Acyltransferase (ACAT), processes for their preparation, pharmaceutical compositions, and therapeutic methods for their use as antihypercholesterolemic or antiatherosclerotic agents.

Description

Antihypercholesterolemic Bis-Trifluoromethyl-Substituted imidazolines and Derivatives Thereof Field of the Invention This invention relates to bis-trifluoromethyl-substituted imidazolines as inhibitors of Acyl-CoA:Cho1esterol Acyltransferase (ACAT), processes for their preparation and their use as antihypercholesterolemic and anti atherosclerotic agents.' Background,of the Invention Hypercholesterolemia, elevated blood cholesterol, is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. More important, the accumulation and storage of cholesteryl esters in the arterial wall is associated with Increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of atherosclerotic lesions in mammals by promoting reverse cholesterol transport.

There are a limited number of patents in the literature disclosing compounds that are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For example, U.5. Patent No. 4,623,662, issued to De Vries on ΠΗΥ ΞΙ ’31 11:35 DUPA302-774-770 November 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Patent No. 4,722,927, issued to Holmes on February 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol.

U.S. Patent No, 4,460,598, issued to Lautenschlager et al. on July 17, 1984, discloses 2-substituted-l,4,5-triaryl imidazoles. The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory and/or atherosclerotic diseases is disclosed.

U.S. Patent No. 4,654,358, issued to Lautenschljiger et al. on March 31, 1987, discloses 2-substituted-l,4,5-triaryl imidazoles. The synthesis and the use of these compounds in the treatment of inflammatory diseases, diseases of lipid metabolism, and/or hyperlipidemic diseases is disclosed.

German Laid Open Applications No. OE 3,504,679, and German Laid Open Application No. DE 3,504,680, Lautenschljiger et al., published August 14, 1986, disclose 1,2,4,5-tetrasubstituted imidazoles. The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.

K. Burger, et al., Synthesis, i, 44 (1988) describe an alternative synthesis of the 5-imino-2-phenyl-4,4bis(trifluoromethyl)-4H-imidazole system. This synthesis gives rise to compounds having a 1-mesityl substituent, which is not readily removed and therefore cannot be used to synthesize compounds of this invention, which have hydrogen or methyl at the 1-position. No biological activity was disclosed.

Co-assigned applications, U.S.S.N. 07/279,981 and 07/416,606 filed December 5, 1988 and October 10, 1989, respectively, relate ιίηυ si '91 11:36 DUPA302-774-770 to di aryl imidazoles as inhibitors of the-enzyme ACAT and their use to lower serum cholesterol in mammals.

There are no known literature references disclosing the bistrifluoromethyl-substituted imidazolines of this invention, their use as ACAT inhibitors, or their use in the treatment of atherosclerosis.

The compounds of this invention are very potent ACAT inhibitors and/or inhibitors of cholesterol biosynthesis. As shown by the data presented below in Tables 6 and 7, the compounds of this invention inhibit the ACAT enzyme with a potency equal to or better than the potency of many of the ACAT inhibitors described in the current literature. The compounds of this invention also cause a reduction in the serum cholesterol level of normolipemic (non-cholesterol fed) hamsters, whereas in general known ACAT inhibitors fail to lower serum cholesterol levels in non-cholesterol fed animals. Compounds of the invention have also been shown to inhibit cholesterol synthesis in the liver. The compounds of this invention are systemically active and are therefore expected to be useful for the treatment of atherosclerosis. The compounds of this invention have been shown to lower serum cholesterol and to have systemic ACAT inhibitory activity following oral administration, and this invention should not be construed as limited to any particular antiatherosclerotic mechanism of action.

Summary of the Invention The present invention provides novel compounds of Formula (I), processes for their preparation, pharmaceutical compositions containing bis-trif1uoromethvl-substituted Imidazolines and derivatives thereof, and therapeutic methods for their use as antihypercho1esterolemi c/anti atherosc1 erotic agents.

This invention provides compounds of'Formula (I): ?! ±±:37 DUPA302-774-770 P.7 wherein Ar* CF, CF, t>\\ -N (1) is phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F, -Cl, -Br, -I, -CF3, -C0NH2i -NO2, -CHO, -C02Et, -CN, -O2CR9, -SCH3, -SCF3, -SO2CF3, -SO2CH3, 5-tetrazolyl, -N(O)(CH3)2, OH, C1-C7 alkoxy, N-piperidyl, Ci»Ciq alkyl, C3-C7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar^ may be Cj-Ciq alkyl, C3-C7 cycloalkyl, or C4-C7 substituted cycloalkyl substituted as above, where R9 is H or alkyl, alkenyl, or alkynyl of 1 to 20 carbon atoms; Q is 0 or X-R2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; X is N, NR6, CH, or CHR6, S, and R6 is H, or C1-C3 alkyl, alkenyl, or alkynyl; W is C or CH provided that when & is a single bond, X is NR6 or CH2 and W is CH, and when a is a double bond, X is N or CH and W is C; Y is N or NR?, and R? is H or C1-C3 alkyl; Z is C or CH, provided that when b is a single bond, Y is NR? and Z is CH, and when b is a double bond, Y is N and Z is C; and, a and b are, independently, single or double bonds; R1 is H or C1-C3 alkyl, alkenyl, or alkynyl; R2 is C4 to C15 alkyl, C4 to C15 alkynyl, or C4 to C15 alkenyl, which may be straight, branched or cyclic, optionally with a terminal COOH or OH group; or R2 is DUPA302-774-770 P.8 COR3 where R3 is Cj to C15 alkyl·, C2 to C15 alkynyl, or C2 to C15 alkenyl, which may be straight, branched, or cyclic, optionally with a terminal COOH or OH group; or R2 is COAr2, CH2Ar2, C^r2, C0NR8Ar2, where R8 is H or Cl’^3 alkyl, S02Ar2, SO2NHAr2, or S02R^i Ar2 is phenyl or substituted phenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -CF3, β-Ν02, “CN, -CHO, -N3, C1-C7 alkyl, Cj-C; alkoxy, phenyl, or NR4R5, where and R8 are independently H, or C1-C3 alkyl, or together represent a carbocyclic ring of 3-5 carbons, or Ar2 is C2-C11, saturated, unsaturated, or aromatic, and which may be straight, branched, or cyclic; or Nmorpholyl; 2- or 3-thiophyl; 2- or 3-pyrrolyl; or 2- or 3-furyl; Provided that: when X is CH or CH2 and R2 is COAr2, Ar^ and Ar2 are independently, phenyl or substituted phenyl, and when X is CH2, R2 is COAr2, CH2Ar2, or co2Ar2; or a resolved optical antipode of any chiral form thereof; or a pharmaceutically acceptable salt thereof.

Preferred are compounds of Formula (1) above wherein: Ar^ -js phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F, -Cl, -Br, -I, -CN, -CF3, -CONH2, -OH, -N02, 5-tetrazolyl, C1-C7 alkoxy, N25 piperidyl, -O2CR^, where R^ is C1-C20 alkyl, alkenyl, or alkynyl, Ci-Cjq alkyl, C3-C7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar1 is cyclohexyl; Q is 0 or X-R2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; X is N, NR6, CH, or CHR6, S, and R6 is H, or C1-C3 alkyl, alkenyl, or alkynyl; W is C or CH, provided that when a is a single bond, X is NR6 or CH2 and W is CH, and when a is a double bond, X is N or CH and W is C; MAY 31 '91 11:33 DUPA302-774-770 Y is N or NR/, and R? is H or CH3; Z is C or CH, provided that when b is a single bond, Y is NR? and Z is CH, and when b is a double bond, Y is N and Z is C; and a and b are, independently, single or double bonds; Rl is H or C|-C3 alkyl, alkenyl, or alkynyl; R2 is COAr2, CHoAr2, C02Ar^.· θτ CONR^Ar2, wherein is H or C1-C3 alkyl; and Ar2 is phenyl, or substituted phenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -CF3, -N3, phenyl, C1-C7 alkyl, C1-C7 alkoxy, n-NOg, -CHO, -CN, or NR^R® where R^ and R$ are independently H, or C1-C3 alkyl, or together represent a carbocyclic ring of 3-5 carbon atoms, or Ar2 is C3-C11, saturated, unsaturated, or aromatic, and which may be straight, branched, or cyclic; or N-morpholyl; 2- or 3-thiophyl; 2- or 3-pyrrolyl; or 2- or 3-furyl.

More preferred are compounds of Formula (I) above wherei n: Arl is phenyl, or monosubstituted phenyl, substituted with -F, -Cl, -8r, -CN, -CF3, -OH, C1-C7 alkoxy, -NO?, -CONHj, N-piperidyl, CH3 or -O2CR9 where R9 is C1-C20 alkyl, alkenyl, or alkynyl or Ar^ is cyclohexyl; Q is X-R2 wherein X is bonded to H; X is NR® or CH2, and R& is H, or C1-C3 alkyl, alkenyl, or alkynyl; H is CH; Y is N; 1 is C; r) is H, CH3, or C2H5; and R2 is COAr2 or C0NR®Ar2, wherein is H or C1-C3 alkyl; and THY 31 '91 11 = 39 03^302-7^4-770 p.10 Ar2 is roonosubstituted phenyl, optionally substituted with -F, -CI, -Br, -CN, -CF3, Cj-C? alkyl, C1-C4 alkoxy, μ-Ν02, phenyl, N-piperidyl, or dimethylamino, or Ar2 is saturated C5-C11, which may be straight or branched.

Even more preferred are compounds of Formula (I) above wherein: Ar’ is phenyl, or monosubstituted phenyl, μ-substituted 10 with -F, -Cl, -Br, -CN, -OH, -OCH3, Npiperidyl, -CONH2, or 02CR^ where is C1-C20 alkyl, alkenyl or alkynyl; is X-R2 wherein X is bonded to W; X is NR& or CHg, and R® is H or C1-C3 alkyl, alkenyl, or alkynyl; W is CH; Y is N; Z is C; R1 is CH3; R2 is COAr2 or CONR^Ar2, wherein R$ is H or C1-C3 alkyl; and Ar2 is monosubstituted phenyl, μ-substituted with -F, -Cl, phenyl, C1-C4 alkyl, μ-Ν02, N-piperidyl, C1-C4 alkoxy, -CN, or Ar2 is saturated Cg-Cn, which may be straight or branched. :40 DUPA302-774-770 P.ll Specifically preferred are the compounds of the formula shown below wherein: a) (Ex. 11)RIO' XJP- R10 - F, R6 = CH3> R2 « -c-^2^-otcH, b) (Ex. 13) R10 = F, R6 = CH3, R2 = —c—^^-c(ch9), 15 c) (Ex. 14) R10 = F, R6 = CH3, R2 “ —c—NO, d) (Ex. 31) R10 = F, R6 = H, 20 e) (Ex. 10A) Rio - F, R° ’ CH3, R2 - f) (Ex. 32) R10 = r6 = Hr2 g) (Ex. 16) R10 - F, R6 - CH3 R2 -COC6H13 25 h) (Ex. 30) RlO = F, R6 = H R2 = —och,ch3 i) (Ex. 12) R10 = F, R6 - CH3 r2 = __^_^2^-och8 j) (Ex. 15) R10 = F, R6 = CH3 R2 - 30 k) (Ex. 28) RlO = F, R6 = CH3 R2 = 9 )==^ R2 -COCeHn 1) (Ex. 33) R10 = R6 = CH3 ΙΕ 91ίθ0θ MAY 31 ”31 11=40 DUPA302-774-770 m) (Ex. 34) R10 = CH3O, R6 = CH3 r2 =C0(CH2)3CH(CH3)Z n) (Ex. 27) R10 = F, R6 = CH3 p2 =—c ~N H(C H «)« H 5 0) (Ex. 18) R10 = F, p) (Ex. 29) R10 = F, R6 = CH3 R6 = CH3 r2 =CO(CH2)3CH(CH3)2 r2 <0NH(CH2)7CH3 10 q) (Ex. Q) R10-CN R6 = CH3 0 r2 = -C-(o}-F r) (Ex. R) R10=CN R6 = CH3 0 r2 s -CHg^CN 15 s) (Ex. S) R10=F r6 = ch3 0 r2 -C-/o>CN 20t) R10=C00Ci7H33 R6 r2=C0C6HisU) R10=00CH3 r6=ch3 R2=C0C6Hi3 25v) R10-F r6=ch3 r2=C0C6Fs w> Rl°=CN0 r6-ch3 0 u 30 x) (Ex. 73) R10’CN r6=ch3 0 R2 = -C-@~CN R-i somer πy) (Ex. 75) R10-CN r6«ch3 V r2 « -C-@H2$04Salt,R-i somer MAY 31 ’91 1:41 DUPA302-774-770 P. 13 Also specifically preferred are the compounds: 1-(4-cyanopheny1)-2-[2-(4-fluorophenyl )-4,5-dihydro-l-methyΙΑ, 4-bis (tri f1uoromethy1)-IH-imidazol-5-y1]-ethanone; 1-(4-fluorophenyl)-2-[2-(4-fluorophenyl)-4,5-dihydro-l-methyl 4.4- bis(trifluoromethyIl-lH-imidazol-5-yl]-ethanone; and 1- (4-fluorophenyl)-2-[2-(4-fluorophenyl)-4,5-dihydro-l-ethyl4.4- bis(trifluoromethy1) -IH-i mi dazol-5-y1]-ethanone.

Detailed Description of the Invention Synthesis The novel compounds of Formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the imidazoline and other portions of the molecule must be compatible with the reagents and reaction conditions proposed. Not all compounds of Formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods described must then be used.

The compounds of Formula (I) wherein X is N, W is C, Z is C, Y is N, R2 is COAr2, Ar’ is phenyl or substituted phenyl, and r’ is H or CH3 can be prepared by the route shown in Scheme 1. The requisite 2-hexafluoroisopropylamino-4,5-diarylimidazoles (i) are prepared as described in ll.S. 4,348,404, the teaching of which is hereby incorporated by reference.

Treatment of the 2-hexafluoroisopropylamino-4,5-diarylimidazole (i, r’»H or CH3) with excess peracid such as m-chloroperbenzoic acid (MCPBA), preferably 3 or more equivalents in 2 or more portions in refluxing chloroform for 2 hours, gives the corresponding Ν-Γ(4.4-bis(trifluoromethyl)-4.5-dihvdro2- aryl-l-methyl-lH-imidazol-5-ylidene)]-benzamide (2, r’=H or CH3). Alternatively, monoperoxyphthalic acid magnesium salt (MMPP) in glacial acetic acid may be used instead of MCPBA in -c uurHouc.-1 ι -4-1 ί υ r. 14 chloroform in the conversion of the 2-hexafluoroisopropylamino4,5-diarylimida2ole$ (i) to the bis-trifluoromethyl substituted imidazolines (2).

Alternatively, oxidation of 2-hexafluoroisopropylami no4, 5-diarylimidazoles (1.) with singlet oxygen generated by irradiating oxygen with a Tungsten lamp (400 watt) in the presence of a catalytic amount of methylene blue in chloroform and methanol (1:1) followed by acid treatment gives the bistri fluoromethyl substituted imidazolines (2), as shown in Scheme 1.1.

R1 Scheme 1.1 ^S'WN**^C(CFJaNHJ The compounds of Formula (I) wherein X is NH, Y is N, W is CH, Z is C, R2 is COAr2, and a is a single bond and b is a double bond can be prepared by the route shown in Scheme 2. The benzamides of Formula (1) can be prepared by reducing the requisite imines of Formula (2) with lithium aluminum hydride NAY 31 31 11=42 DUPA302-774-770 P.15 (preferably, 2 equivalents) in tetrahydrofuran at room temperature for 1 to 24 hours or sodium borohydride (preferably 1.1 equivalents) in refluxing ethanol. Lithium aluminum hydride is the preferred reducing agent because reduction with sodium borohydride gives rise to a mixture of 3 and the ring reduction product of 4. Other hydride-type reducing reagents such as lithium aluminum tri-tertiarv-butoxvhvdride may also be used.

Scheme 2 Scheme 2.1 IE 91190» ... _·± ι±·43 DUPA302-774-770 P.16 The ring reduction product 4, can be converted to the corresponding alkali metal salt by the addition of a base such as sodium hydride, and the salt is alkylated with methyl iodide in a polar solvent such as dimethyl formamide at room temperature to give compound 4^ (Scheme 2.1) The amides, carbamates and ureas of Formula (i) wherein R2 is as defined above can be prepared by the route shown in Scheme 3. The requisite benzamide of Formula (3) is converted to the corresponding alkali metal salt by the addition of a base such as sodium hydride, and the salt is alkylated with methyl iodide in a polar solvent such as dimethylformamide at room temperature. The N-methyl benzamides of Formula (5) can be cleaved to the N-methyl aminals of Formula (6) by the route shown in Scheme 3. Treatment of the requisite N-methyl benzamide with potassium tert-butoxide (6 equivalents) and water (2 equivalents) in ether at room temperature gives the corresponding N-methyl aminals of Formula (6), which can be converted into the hydrochloride salt with hydrochloric acid in ether. The amides, ureas and carbamates of Formula (7) are prepared by coupling the aminals of Formula (£) with an acyl chloride, isocyanate or chloroformate by the route shown in Scheme 3. Alternatively, other literature methods for forming amide bonds may be employed which involve reaction of carboxylic acids and amines.

One method for amide bond formation is to use a coupling reagent which generates a reactive intermediate such as a mixed anhydride or active ester. Examples of such coupling agents are disubstituted carbodiimides, Ν,Ν'-carbonyldiimidazole, diphenylphosphoryl azide, and the like. For example, the coupling can be carried out with a disubstituted carbodiimide such as dicyclohexylcarbodiimide in an appropriate solvent such as methylene chloride, acetonitrile, toluene, or dimethylformamide. Nucleophilic hydroxy compounds such as 1-hydroxy-lHbenzotriazole, which form highly active esters, may be added to catalyze the reaction.

NAY 31 '91 11=44 DUPA302-774-770 P.17 Reaction of the requisite aminal (fi) -with the appropriate acyl or aroyl chloride in pyridine and methylene chloride at room temperature gives the corresponding amides of Formula (7).

Similarly, reaction of the aminal with alkyl or aryl isocyanates in methylene chloride at room temperature gives the corresponding ureas of Formula (2). The carbamates of Formula (Z) are prepared by allowing the requisite N-methyl aminal of Formula (fi) to react with alkyl or aryl chloroformates in methylene chloride at room temperature to the reflux temperature of the solvent.

Scheme 3 NH The benzamides of Formula (7) having different parasubstituents on the benzamide group and the pendant phenyl group are prepared by the route shown in Scheme 4. By starting with ofluorophenyl analogs, which can be prepared according to Scheme 1 wherein Ar^ = Ar2 = o-fluoro-phenyl, ortho substituted analogs can be prepared by aromatic nucleophilic substitution as shown in Scheme 4. Compounds wherein Ar2 may be ortho, meta, and/or para substituted may be prepared using Scheme 3 by reacting compound (6) with the appropriate mono-, di-, or trisubstituted (any ι ιι-, I οι Oi 11 = 44 DUPA302-774-770 Ρ. 18 combinations at any positions) benzoyl chloride, to yield the desired compounds of Formula (7). Treatment of the requisite benzamide of Formula (g) with the appropriate nucleophile, e.g., cyanide, ethoxide, or piperidine, in a polar solvent such as dimethyl sulfoxide (DMSO) at a temperature from room temperature to the boiling point of the solvent gives the benzamides of Formulas (2), (10) and (11), which may be separated by conventional means such as crystallization, high pressure liquid chromatography (HPLC), conventional column chromatography and other procedures known to those skilled in the art.

Scheme 4 As an alternative, the amides of Formula (13) wherein R^ COR3, where R3 is Cj to C15 alkyl, C2 to C15 alkenyl, or C2 to C15 alkynyl, with a terminal CO2H or OH group, may be prepared according to the route shown in Scheme 5. Treatment of the jun o± iu-o6 DU PONT 302 774 7322& requisite amide of Formula (12) with the desired nucleophile, e.g., methoxide, piperidine, etc., gives the corresponding amide of Formula (L3) wherein the para-fluorine of the pendant phenyl group has been replaced by the new group.

IS DUPA302-774-770 P.20 Scheme 5 The £is-trifluoromethyl substituted imidazolines of Formula (1£) are prepared by the route shown in Scheme 6. The requisite 2-hexafluoroisopropylamino-4,5-diaryl pyrroles of Formula (14), are prepared according to the method of U.S. 4,335,136, the teaching of which is hereby incorporated by reference. These compounds of Formula (14) are oxidized with singlet oxygen (see Scheme 6.1 below) as described above for Scheme 1.1. Alternatively, compounds of Formula (14) are allowed to react with excess MCPBA as described above for Scheme 1 to give the bis-trifluoromethyl substituted imidazoles of Formula (W and the novel hydroxypyrrolinene of Formula (15), which can be separated by chromatography or other means known to those skilled in the art. The alkylated derivatives of Formula (17) are made by converting the requisite imidazoline of Formula (1£) into the corresponding alkali metal salt by addition of a base such as sodium hydride, and the salt is alkylated with methyl iodide in a polar solvent such as dimethylformamide at temperatures from room temperature to the reflux temperature of the solvent.

IE 911909 ------MAY 31 '91 12:04 DUPA302-774-770 P.2 Scheme 6 ''TV A r* N H CF C(CF3)2NH2 A r' >CF CF Ar\-N i_ I Xc3)2NH: OH is Cp3 νΛ θ 2 nA X >CHC-Ar2'*— χ > α?^ν α?Λν CH C“Ar2 R 1 17 H ie Scheme 6,1 C(CF3)2NH2CF3\^CP3 O ZyCH-C-Ar2 /-N Ar,r I H The imidazoles of Formula (17.1) can be prepared by reducing the imidazoles of Formula (17) with zinc dust in refluxing acetic acid, as shown in Scheme 7.1.

The imidazoles of Formula (17 or 17.ll having different parasubstituents on the phenyl ketone and the pendant phenyl group are prepared by the route shown in Scheme 7. Compounds having — .x xu-d4 DUPA302-774-770 ortho and/or meta substituted phenyl groups can be prepared by starting with compound (14) having appropriately substituted Ar1 and Ar^ groups. Treatment of the requisite imidazole of Formula (18) with the appropriate nucleophile in a polar solvent such as dimethyl sulfoxide (DMSO) at a temperature from room temperature to the boiling of the solvent gives the imidazoles of Formulas (19) , (20), and (21) which may be separated by conventional means such as crystallization, high pressure liquid chromatography (HPLC), conventional column chromatography and other procedures known to those skilled in the art.

Scheme 7 -MAY 31 ·9ΐ i2;05 DUPA30 4-,74-770 P.4 Scheme 7.1 CF’vCF3 5? CF,. xf.

Ar1 ?$> M 17.1 -U The carbamates of Formula (£2) wherein the para-substituent of Ar2 is an electron-donating group such as alkoxide or alkyl are prepared as shown in Scheme 8. Allowing the requisite 2-hexafluoroisopropylamino-4,5-diarylimidazole of Formula fl) to react with excess MCPBA as described in Scheme 1 gives either the corresponding carbamates of Formula (22) or a mixture of the carbamates of Formula (2?) and benzamides of Formula (2) depending on the reaction time, degree of excess MCPBA, and the electron-donating ability of the para-substituents. — -ό DUPA302-774-770 CF Λ 8, CF.

N—N’C-Ar* CFS CF3 αΡ'Λ R it The carbamates of Formula (24, R2=C02Ar2), the benzamides of Formula (24, R2=COAr2), and the ureas of Formula (24, R2-CONHAr2) can also be prepared as shown in Scheme 9. Treatment of the requisite benzoyl imine of Formula (2) with ammonium hydroxide or ammonia in methanol at room temperature to the temperature of the refluxing solvent for 1 to 48 hours, or with a strong acid such as concentrated sulfuric acid at room temperature for 10-15 minutes, affords the amidine of Formula (22). Other solvents known to those skilled in the art that are compatible with the reactants and products can be used in place of methanol. The benzamides, ureas, and carbamates of Formula (24) wherein R2 is COAr2, CONHAr2, or C02Ar2 and Ar2 is different from the Ar’ of the benzamide of Formula (2), are prepared by reacting the requisite amidine of Formula (24) with a compound of the formula ClCOAr2, ClCONHAr2, C1C0NHR3, Cl COR3, 0=C=N-Ar2, or O=C=N-R3 in a polar solvent such as pyridine or benzene with dimethyl ami nopyridine.

It 911909 · MAY 31 '91 12:06 DUPA302-774-770 P.6 Scheme 9 An alternative synthesis of the benzoyl imines of Formula (2) of Scheme 1 wherein Afl is different from Ar^ or Ar* is alkyl, cycloalkyl or substituted cycloalkyl, is shown 1n Scheme 10. Acylation of the requisite 2-hexafluoroisopropylamino-4,5diarylimidazole of Formula (1}, wherein Rl is CH3 or H, in refluxing benzene for 4 days, or neat for 4 hours at 150* or acid chloride and pyridine at 120**, with the appropriate acid chloride, R^COCl, wherein rH can be Arl, C3 to C10 alkyl, C3 to C7 cycloalkyl, or C3 to C7 substituted cycloalkyl, gives the corresponding bicyclic derivatives of Formula (2$)♦ Compounds wherein Arl is ortho, meta, and/or para substituted phenyl can be prepared using Scheme 10, wherein compound (1) is reacted with an acid chloride, R^COCl, where R11 is a mono-, di-, and/or trisubstituted phenyl (any combinations at any positions). Or Rll may be heteroaromatic, or aliphatic (straight chain, branched, cycloalkyl), which may have additional substitutions, ..... -x ±c-o? DUPA302-774-770 e.g·. OH. Higher boiling solvents such as toluene, xylenes, or chlorobenzenes can be employed to accelerate the reaction. The requisite bicyclic derivative of Formula (25) is allowed to react with excess MCPBA in refluxing chloroform to give the bis-trifluoromethyl substituted imidazoline of Formula (2£), which loses the Ar^CO substituent on nitrogen during the workup to afford (27). The N-substituted bis-trifluoromethyl substituted imidazolines of Formula (2fi) can be synthesized by converting the requisite benzamide of Formula (£Z) into the corresponding alkali metal salt by the addition of a base such as sodium hydride, and the resultant salt is alkylated with methyl iodide in a polar solvent such as dimethylformamide.

IE 911909 ___ ..... -χ .'X xu-u7 DUPA302-774-770 Scheme 10 2$ The imidazolinones of formula (22) are prepared as shown in 25 Scheme 11. Exposure of the requisite benzoyl imine of Formula (2) (Scheme 1) to chromatographic grade basic alumina (Activity II-IV) in ether at room temperature to the temperature of the refluxing solvent for 1 to 48 hours gives rise to the corresponding imidazoline-2-ones of Formula (22). Other solvents such as tetrahydrofuran may be used. 14-08 DUPA302-774-770 P.9 Scheme II Preparation of pharmaceutically suitable salts o' Formula (i) can be cone in accordance with well known techniques of forming salts. Physiologically acceptable salts include but are not limited to acid addition salts, such as the hydrochloric, sulfuric, acetic, trifluoroacetic, succinic, citric, and benzenesulfonic acid salts.

The compounds of this application that have a chiral center may be resolved into the pure or partially pure optical isomers by any of the appropriate procedures known to those skilled in the art.

The compounds of this invention and their preparation can be further understood by the following examples, which do not constitute a limitation of the invention. In these examples, unless otherwise indicated, all temperatures are in degrees centigrade and parts and percentages are by weight.

Example 2 Preparation of N-f4.4-bis(trifluororoethvl)-2-(4-fluorophenvl)4,5-dihydro-1-methvl-lH-imidazol-5-vlidene!-4-fluoro-benzamide Method A To a solution of a.a-bis(tri fluoromethyl)-4.5-bis(4fluorophenyl)-l-methyl-lH-imidazole-2-methanaraine (36.0 g, 0.076 ιίητ οι -ι 1^:09 DUPA302-774-770 P.10 mole) in chloroform (1.8 L) was added portionwise, inch loroperbenzoic acid (MCPBA, 26.1 g, 0.152 mole). The reaction mixture was refluxed under nitrogen for one hour. Then additional MCPBA (13.0 g, 0.076 mole) was added and the mixture was refluxed for 1 hour. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (1 L). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with hexane to give the title compound (23.2 g, 68%) as an off-white solid. An analytical sample was prepared by recrystallization from methanol-hexane to give a white solid: mp 112-113*; HRMS m/e calcd for CigHn^OFa (M*) 449.0774, found 449.0770; NMR (CDCI3/TMS) 6 3.13(s,3H,NCH3), 7,13’7.30(m,4H,Harora), 7.73(q,2H,Harom), 3·06(q,2H,. Analysis Calcd for C19H11N3OF3: C,50.79; H,2.47; N,9.35. Found: C.50.81; H.2.72; N.9.10.

Method B To a solution of a.a-bis(trifluoromethyl)-4.5-bis(4fluorophenyl)-l-methyl-lH-imidazole-2-methanamine (17.6 g, 0.04 mole) in chloroform (1.25 L) was added portionwise, mchloroperbenzoic acid (MCPBA, 17.2 g, 0.10 mole). The reaction mixture was refluxed under nitrogen for one hour, coded to room temperature and poured into 10% sodium bicarbonate (1 L). The organic layer was washed successively with 10% sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with hexane to give the title compound (8.8 y, 50%) as a white solid: mp 109-114*; NMR (CDC13/TMS) δ 3.13(s,3H.NCH3), 7.137.30(m,4H,Harom), 7.73(q,2H,Harom). 8.06(q,2H,Harom). x_.i0 DUPA302-774-770 P.ll Method C To a solution of a,a-bis(trifluoromethyl)-4.5-bis(4fluorophenyl)-1-methyl-IH-imidazole-Z-methanamine (0.24 g, 0.5 mmole) in acetic acid (10 mL) was added portionwise, monoperoxyphthalic acid magnesium salt (MMPP, 0.30 g, 1.0 mmole). The reaction mixture was stirred under nitrogen overnight. Then additional MMPP (0.15 g, 0.5 mmole) was added and the mixture was heated at 112° for 4 hours. The solution was cooled to room temperature and poured into water. The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with hexane to give the title compound (0.60 g, 25%) as a yellow solid: *H NMR (COCI3/TMS) δ 3.13 (S.3H.NCH3), 7.13-7.30(m,4H,Harom), 7.73(q,2H,Harom), 8.06(q,2H,Harom).

Method D To a solution of a,a-bis(trifluoromethyl)-4.5-bis(420 fluorophenyl)-l-methyl-lH-imidazole-2«methanamine (0.5 g, 1.1 mole) in methanol (1.5 1) was added methylene blue (10 mg).

Oxygen gas or air was bubbled through the solution wh'le irradiating with a Tungsten lamp (400 watt) for 8 hours. IM hydrochloric acid in ether (10 ml) was added to the reaction mixture and stirred for 1 hour at room temperature. The mixture was treated with saturated sodium carbonate solution (15 ml) and then concentrated in vacuo. The concentrate was resuspended in ethyl acetate (200 ml) and water (50 ml). The organic layer was washed with saturated ammonium chloride and sodium chloride solution, dried over sodium sulfate (anhyd.) and evaporated under vacuum. The residue was purified by column chromatography, eluting with hexane-ethyl acetate (10:1) to give the title compound (312 mg, 61%). iif-,ι ji 21 id: 10 DUPA302-774-770 P.12 Example 5 Ν-Γ4,4-bis(trifluoromethyl)-2-(4-methyl phenyl )-4,5-dihvdro-lHimi_dazol-5-yl idenel-4-methvlbenzamide To a solution of a,a-bis(tri fluoromethyl )-4.5-bis(4methylphenyl)-l-methyl-lH-imidazol-2-methanamine (1.0 g, 2.3 mmole) in chloroform (10 mL) was added portionwise, inch loroperbenzoic acid (0.40 g, 2.3 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue (75% benzamide and 25% ester analyzed by HPLC with a (DL)phenylglycine column eluted with 10% isopropanol-hexane) was purified by HPLC on a silica sorbax column which was eluted with dichloromethane to give the title compound (40 mg, 4%) as a semisolid: MS m/e 442 (M++H); ’h NMR (CDCI3/TMS) δ 3.00(s,6H,CH3), 3.13(s,3H,NCH3), 7.27-7.37(m,4H,Harom), 7.57(d,J=7Hz,2H,Harom), 7.90(d,J=7Hz,2H,Harom).

The compounds of Examples 2 and 5, and other compounds of Formula (I) wherein a is a double bond which have been prepared or which could be prepared using the same or similar synthetic methods, are listed in Table 1. The additional compounds listed in Table 1 were prepared according to the procedure of Example 2, Method 8. The yields may be improved by using the procedure of Example 2, Method A. Alternative peracids such as monoperoxyphthalic acid magnesium salt (MMPP) can be used as shown in Example 2, Method C.

MAY 31 '31 12:11 DUPA302-774-770 P. 13 C\ ,CF3 g« ..JY o JL Table 1 G- Ex. # R1 N I G· G \_ ii >=Ν-0 — *N 'r1 G’1 < Λ Vsa^Q.. mpCC) G' G' 10 1 CH3 H H H H 80-81 2 CH3 fi‘F fi-F H H 112-113 3 CW3 a-ci fi-Cl H H 94-96 4 CH3 m-CH3 m-CH3 H H 113-114 5 CH3fi-CH3 e-ch3 H H Semi-Sol id 15 6 H H H H H 134-135 7 H fi-Cl fi-Cl H H 182-183 8 H m-CH3 m-CH3 H H 118-120 9 H p-CH3 e-ch3 H H 136-137 9a CH3 e-f o(ch2)3ch3 H H 106-107 20 9b H fi-F e-f H H 161.9-163.9 9c CH2CH] I fi-F fi-F H H oil 9d CH3 fi-CN fi-F H H - 9e CH3 fi-CF3 0 1) £-CF3 0 I) m-N02 H 25 9f CH3 e-occh3 e-occh3 H H - 9g CH3 fi-SCH3 e-sch3 H H - 9h CH3 fi-N02 £-N02 H H - 91 CK3 β-Ν02 £-N02 m-CF3 m-CF3 - 9j CH3 fi-CN fi-CN H H - 30 9k CH3 fi-CH3S02 fi-N3 m-F H 91 H rn-CN rn-CN H H - 9m CH3 fi-N3 fi-N3 H H ·» 9n CH3 fi-CF3S02 E-0C4Hg-n H m-CH3 - 9o CH3 β-CN fi-C6Hi3-n H H 35 9p CH3 9q CH3 fi-N(O)(CH3)2 £-(CH3)2CC6H4 H fi-(CH3)2N e-C02H H m-F H IE 911909 _ HAY 31 ’91 12: 12_D'uPA302-774-770 p<14 Notes.

Example 1: MS m/e 414; NMR (CDCI3) δ 3.10 (s,3H,NCH3), 7.43- 7.66(m,8H,Haroin), 8.00-8.03(m,2H,Harom).

Example 2: MS m/e 449; ]H NMR (COCI3) δ 3.13(s,3H,NCH3), 7.13-7.30(m,4H,Harom), 7.73(m,2H,Harom), 8.06(m,2H,Harom). Example 3: MS m/e 481; ZH NMR (COCI3) δ 3.10(s,3H,NCH3), 7.43- 7.66(m,6H,Harom), 7.90-7.97(m,2H,HarOm).

Example 4: MS m/e 442; ]H NMR (COCI3) δ 2.40(s,6H,2ArCH3), 3.07(s,3H,NCH3), 7.33-7.50(ra,6H,Har.Om). 7.77-7.83(m,2H,Harom).

Example 5: MS m/e 442; *H NMR (COCI3) δ 3.00(s,6H,ArCH3), 3.13(sf3H,NCH3), 7.27-7.37(m,4N,Harom), 7.57(d,2H,J=7Hz,Harom), 7.90(d,2H, J=7Hz.Haroffl).

Example 6: MS m/e 400; NMR (COCI3) δ 7.477.70(m,6H,Harom), 8.00-8.O3(m,2H,Harom), 8.338.37(m,ZH,HarOm), 11.73(s,IH,NH).

Example 7: MS m/e 468; NMR (COCI3) δ 7.437.53(m,4H,Harom), 7.93-8.00(m,2H,Harom)· 9-208.23(m,2H,HarOm), 11.73(s,ΙΗ,ΝΗ).

Example 8: MS m/e 428; NMR (CDCI3) δ 2.50(2s,6H,2ArCH3), 7.43- 7.57(m,4H,Harom), 7.77-7.90(m,2H,Haroni), 8.178.23(m,2H,Haroin), 11.70(s,ΙΗ,ΝΗ).

Example 9: MS m/e 428; NMR (CDCI3) δ 2.46(2s,6H,2ArCH3), 7.27-7.40(m,4H,HarOm) 1 7.87-7.9Q(m,2H,Harom), 8.238.30(m,2H,Harom). ll-70(s,ΙΗ,ΝΗ).

Example 9R: Preparation of N-i2.cvclohexvl-4.5-dihydro-4.4-bis(trifluoromethyl). lH-imidazol-5-ylidenelT4-fluorobenzene carboxamide Part A To a solution of a.a-bls(trifluoromethyl)-4,5-bis(4fluorophenyl)-l-methyl-lH-imidazole-2-methanamine (3.38gr, 7.8 mmole) in pyridine (1.7gr) was added cyclohexane carbonyl chloride (3.5gr, 23.9 mmole). The reaction mixture was heated at 130*C for 4 hours. The mixture was purified IE 911909 Ξ „ 13 DUPA302-774-770 Ρ. 15 by column chromatography, eluting with hexane, then mixture of hexane-ethyl acetate (9:1) to give 5-cyclohexy1-2,3-bis(4fl uorophenyl)-7,7-bi s(tri fluoromethyl)-7H-imidazo[l,5-A]imidazole (1.88gr,37%) as a white solid: mp 162.2-162.6. Anal. Calcd for C25H19F3N3:C,58.60;Η,3.54;N,8.20. Found: C,58.43;H,3.79;N,8.16.

Part B To a solution of 5-cyclohexyl-2,3-bis(4-fluorophenyl)7,7-bis(trifluoromethyl)-7H-imidazo[l,5-A]imidazole (3.88gr,7.6mmole) in chloroform (300ml) was added m-chloroperbenzoic acid (MCPBA, 2.6gr, 15.2 mmole). The mixture was refluxed under nitrogen for one hour. Then additional MCPBA (1.3gr, 7.6 mmole) was added and the mixture was refluxed for one hour. The mixture was worked up and columned as described in Example 2 Method A to give the title compound (0.56gr, 17%): mp 128-128.6 MS m/e 424 (M++H). Compounds listed in Table 1.1 were prepared according to the procedure of Example 9R.

WsJLd 9s “O H 128.0-128.6 O 9t -C6h13 H ND .....— 13 DUPP302-77J-77Q P. 16 Example 10 Prep_aration of N-f4,4-bis-(trif1uoromethvl)-2-(4-f1uorophenyl)-4,5-dihydro-l-methy1-lH-imidazol -5-yll-4-fluorobenzamide Method A To a solution of Ν-Γ4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-di hydro-1-methy1-ΙΗ-imi dazol-5-y1i dene]4-fluorophenylbenzamide (8.8 g, 19.6 mmole) in anhydrous tetrahydrofuran (100 mL) at -78’C under nitrogen was added dropwise lithium aluminum hydride in tetrahydrofuran (40 mL of 1 M solution). The reaction mixture was stirred at room temperature for two hours, cooled to O’C, quenched with water then extracted with methylene chloride. The organic layer was washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum. The residue was triturated with hexane to give the title compound (5.65 g, 75%) as a white solid; mp 145-146’; MS m/e 452 (M++H); !h NMR (CDCI3/TMS) δ 2 - 97(s,3H,NCH3), 6.43(d,1H,J= 7Hz,CH), 6.63(d,IH,J=7Hz,NH), 7.13-7.27(m,4H,Harom), 7.6020 7.70(m,2H,HarOffl), 7.83-7.90(m,2H,HapQjjj). Anal. Calcd for C19H13N3OF8: C,50.57; H,2.90; N,9.31. Found: C.50.79; H.3.05; N.9.61.

Method B To a solution of N-i4.4-bis(trifluoromethyl)-2-(4f1uoropheny1)-4,5-di hydro-1-methy1-IH-imidazol-5-y1i dene]4-fluorobenzamide (1.8 g, 4 mmole) in ethanol (50 mL) at room temperature under nitrogen, was added portionwise sodium borohydride (170 mg, 4.5 mmole). The reaction mixture was heated at reflux for three hours, and then stirred at room temperature overnight. The reaction mixture was cooled in an ice bath, quenched with water and hydrochloric acid (10 mL, 1 N solution), made basic using sodium hydroxide (1 N) and then extracted with ether. The organic layer was washed successively with sodium hydroxide (1 N), water and saturated sodium chloride solution, IE 911909 ;_ ..... 12:14 DUPA302-774-770 . 17 dried over anhydrous magnesium sulfate.' The solvent was removed under vacuum and the residue was purifi-ed by column chromatography, eluted with hexane followed by hexane-ethyl acetate (20:1 to 50:50) to give two products. The major product (0.8 g, 45%) is the same as the product of Example 10, Method A: mp 145-146’; MS m/e 452(M++H); NMR (CDCI3/TMS) δ 2.97(s,3H,NCH3), 6.43(d,lH,J-7Hz,CH), 6.63(d,lH,J=7Hz,NH), 7.137.27(m,4H, Hjpqjjj) , 7.60-7.70(m, 2H,Harom)· 7.83-7.90(m,2H,Hgroro) · The minor product, N-[2-(4-fluoropbenyl)-2,3,4,5-tetrahydro-l10 methy1-4,4-bis (tri fluoromethyl)-lH-imidazo1-5-ylidene]-4fluorobenzamide, (0.5 g, 27%) was isolated as a solid: mp 132133’; MS m/e 452 (M++H); NMR (CDCI3/TMS) δ 2.57 3.17(d,li,J=7Hz,NH), 5.63(d,lH,J=7Hz,CH), 7.03-7.20(m,4H,Harom), 7.40-7.5C(m,2H,Harom), 8.03-8.l3(m,2H,Harom). Anal. Calcd for C19H13N3OFQ: C.50.57; H.2.90; N,9.3l. Found: C.50.34; H,2.68; N,9.l5.

Example 10A Preparation of N-r4,4-bis(trifluoromethy1)-2-(4f1uoropheny!)-4,5-dihydro-1-methvl-lH-imidazoI-5-yl1-420 fluoropheny1-N-methy1benzami de Sodium hydride (1.5 g, 3.75 mmole) 60% suspension in oil was washed with hexane and then it was suspended in anhydrous dimethylformamide (50 mL). To this suspension was added portion*;se N-[4,4-bis(trif1uoromethyl)-2-(4-f1uoropheny1)-4,525 dihydro-l-methyl-lH-imidazol-5-y1]-4-fluorobenzamide (6.85 g, mmole) and the mixture was allowed to stir at room temperature for one hour. Iodomethane (4.50 g, 30 mmole) was adced dropwise and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into water and extracted with ether. The organic layer was washed successively with water and saturated sodium chloride solution, dried over anhydrous iiiaynes ί uni sulfate and concentrated to give the title compound (6.46 g, 91%) as a crystalline solid: mp 112-113’; MS m/e 466(M++H); *H NMR (CDCI3/TMS) δ 2.93(S,3H,NCH3), 3.00(s,3H,NCH3), 6.79(s,1H,CH), 7.17(m,4H,Harom), 7.43-7.50(ra,2H,Harom), 7.63-7.70(m,2H,Haroro). ....... ^.15 DUPA302-774-770 · P-18 Example 11 Preparation of N-i4.4-bis(trif1uoromethy1)-2-(4fluprophenv1)»4.5-dihydro-l-methv1-lH-imidazol-5-yl]-4butoxv-N-methylbenzamide 5 Part A To a solution of N-Γ4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihydro-1-methy1-lH-imidazol-5-yl]-4fluoro-N-methylben2amide (6.46 g, 13.9 mmole) in ether (300 mL) was added potassium tert-butoxide (9.35 g, 6 equiv.) and water (0.5 g, 2 equiv.). The reaction mixture was allowed to stir overnight at room temperature. The suspension was poured into water and the phases were separated. The organic layer was washed successively with water, then saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum to give a yellow oil (4.83 g, 100%). Treatment with hydrochloric acid (1M) in ether gave the 4.4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4f5-dihydro-5-amine-N,N-l,5-dimethyl1H-imidazole hydrochloride as a white solid: mp 206-207·; MS m/e 344 (M++H); NMR (CDCI3/TMS) δ 2.67(s,3H,NCH3), 2.93(s,3H,NCH3), 4.67(s,lH,CH), 7.10-7.20(m,2H,HarOm). 7.537.63(m,2H,Harom); Anal. Calcd for C}3Hi2N3F7‘HCl: C.41.12; H.3.45; N,11.07; Found: C,41.36; H.3.79; N,11.24.

Part B To a solution of 4.4-bls(trifluoromethyl)-2-(4fluorophenyl)-4,5-di hydro-5-ami ne-N,N-1,5-dimethy1-1Himidazole (0.34 g, 1 mmole) in dichloromethane (10 mL) was added β-butoxybenzoyl chloride (0.64 g, 3 mmole) and pyridine (0.24 g, mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane.19 It 911909 DUPA302-774-770 ethyl acetate (20:1 to 50:50). The crude product (0.48 g, 92%) was recrystallized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 84-85’; MS m/e 520 (M++h); ’H NMR (CDCI3/TMS) δ 1.00(t,3H,J»7Hz,CH3), 1.435 1.60(m,2H,CH2), 1.73-1.87(m,2H,CH2). 2.97(s,3H,NCH3), 3.00(s,3H,NCH3), 4.00(t,2H,J=7Hz,OCH2), 6.73(s,1H.CH), 6.93,(d,2H,J=10Hz, Harom), 7.13-7.27(m,2H,Harom), 7.43(d,2H,J=7Hz,Harom), 7.63-7.70(m,2H,Harom). Anal. Calcd for C24H24N3O2F7: C,55.49; H.4,66; N,8.09. Found: C.55.27; H.4.56; N,8.02.

Example 12 Preparation of N-T4,4-bis(trifluoromethyl)-2-(4f1uorophenvl)-4,5-dihvdro-l-methy1-lH-imidazol-5-/11-415 methoxv-N-methvlbenzamide To a solution of 4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-lHimidazole (0.34 g, 1 mmole) in di chloromethane (10 mL) was added p-anisoyl chloride (0.51 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexaneethyl acetate (20:1 to 50:50). The crude product was recrystallized from dichloromethane-methanol-petroleum ether to give the title compound (0,25 g, 52%) as a white solid: mp 13630 137’; MS m/e 478 (M++H). *H NMR (CDCI3/TMS) δ 2.93(s,3M,NCH3), 2.97(s,3H,NCH3), 3.83(s,3H.OCH3), 6.73(s,lH,CH), 6.97(d,2HJ»7Hz,Harom). 7.13-7.2Q(ffl,ZH,Harow), 7.43(d,2H, J-7Hz,Haroro); 7.60-7.70(m,2H,Harom). .20 πηυ hi ic..i6 DUPA302-774-770 f Example 13 Preparation of N-r4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihydro-1-methvl-lH-imidazol-5-vll4-(1.1-dimethylethvl)-N-methvlbenzamide 5 To a solution of 4.4-bis(trifluoromethyl1-2-(4f1uorophenyl)-4,5-di hydro-5-ami ne-N,N-1,5-d imethy1-1Himidazole (0.34 g, 1 mmole) in di chloromethane (10 mL) was added jo-(t-butyl)benzoyl chloride (0.59 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexaneethyl acetate (20:1 to 50:50). The crude product (0.40 g, 79%) was recrystallized from di chloromethane-methanol-petroleum ether to give the title compound (80 mg, 16%) as a white solid: mp 129130°; MS m/e 504 (M++H); NMR (CDCI3/TMS) <5 1.33(s,9H,(CH3)3), 2.93(s,3H,NCH3), 3.00(s,3H,NCH3), 6.83(s,lH,CH), 7.177.27(m,2H,Harora), 7.20-7.50(m,4H,Harom), 7.63-7.70(»,2H,Harom). Anal. Calcd for C24H24N3OF7: C,57.26; N,4.81; N,8.35. Found: C,57.20; H.4.82; N,8.29.

Example 14 Preparation of N-i4.4-bis(trifluoromethv1)-2-(4fluorophenyl)-4.5-dihydro-1-methy1-1H-imidazol-5-v11-Nmethvl-4-nitrobenzamide To a solution of 4.4-bis(trifluoromethyl)-2-(430 fluorophenyl)-4,5-dihydro-5-amine-N,N-1,5-dimethy1-1Himidazole (0.34 g, 1 mmole) in dichloromethane (10 mL) was added fi-nitrobenzoyl chloride (0.56 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer ^•4? DUPA302-774-770 P.21 was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane5 ethyl acetate (20:1 to 50:50). The crude product (0.40 g, 81%) was recrystallized from di chloromethane-methanol-petroleum ether to give the title compound (200 mg, 41%) as a white solid: mp 174-175e; MS m/e 493 (M++H); *H NMR (CDCI3/TMS) δ 2.90(s,3H,NCH3), 3.07(s,3H,NCH3), 6.77(s,1H,CH), 7.1710 7.27(m,2H,Harom), 7.60-7.73(ro,4H,Harom)« 8*37(d,2H,J-7Hz,HarQm).

Anal. Calcd for C^qHi5N4O3F7: 0,48.79; H.3,07; N,11.38. Found: C.48.76; H.2.81; N.11.27.

Example 15 Preparation of N-r4.4-bis(trifluoromethvl)-2-(4fluorophenvl)-4.5-dihydro-l-methvl-lH-imidazol-5-y11-Nmethyl-Γΐ.1*-biphenyll-4-carboxamide To a solution of 4,4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-lH20 imidazoie (0.34 g, 1 mmole) in dichloromethane (10 mL) was added p-bipheryl carbonyl chloride (0.65 g, 3 mmole) and pyridine (0.24 g, 3 mmcle). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexaneethyl acetate (20:1 to 50:50). The crude product was recrystallized from di chloromethane-methanol-petroleum ether to give the title compound (0.09 g, 17%) as a white solid: mp 186187% MS m/e 524 (M++H); NMR (CDCI3/TMS) δ 3.00(s,3H,NCH3), 3.03(s,3H,NCH3), 6.87(s,lH,CH), 7.17-7.77(m,14H,Harora). Anal. Calcd for C26H20N3F7O: C,59.66; H,3.85; N,8.03. Found: C,59.48; H.3.72: N.7.89. ΜΠ, 13 DUPA302-774-770 .22 Example 16 Preparation of N-f4.4-bis(trif1uoromethvl)-2-(4fluorophenvl)-4,5-dihydro-1-methvl-ΙΗ-imidazol-5-vll-Nmethylheptanamide hydrochloride 5 To a solution of 4.4-bis(trifluoromethyl1-2-(4f1uoropheny1)-4,5-di hydro-5-ami ne-N,N-1,5-dimethy1-1Himidazole (0.34 g, 1 mmole) in dichloromethane (10 mL) was added heptanoyl chloride (0.45 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexaneethyl acetate (20:1 to 50:50). The crude product (0.20 g, 41%) was treated with HCl in ether and recrystallized from di chloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 134-136’; MS m/e 456 (M++H); NMR (CDC13/TMS) δ 1.90(m,3H,CH3), 1.33(m,6H(CH2)3), 1.7O(m,2H,CH2), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,IH.CH), 7.20-7.40(m,2H,Harom), 7.93-8.17(m,2H,Haroffl).

Example 18 Preparation of N-i4,4-bis(trifluoromethvl)-2-(4fluorophenvl)-4,5-dihvdro-l-methvi-lH-imidazol-5-vn-N(5dimethy1-hexanamide hydrochloride To a solution of 5-methylhexanoic acid (0.53 g, 4 mmole) in dichloromethane was added oxalyl chloride (0.77 g, 6 mmole). The reaction mixture was stirred at room temperature for 2 hours and then evaporated under vacuum to give crude 5-methylhexanoyl chloride. To a solution of 4.4-bis(trifluoromethyl)-2-(4f1uoropheny1)-4,5-di hydro-5-ami ne-N,N-1,5-dimethy1-IH-imi dazole (0.60 g, 1.76 mmole) in di chloromethane (15 mL) was added 535 methylhexanoyl chloride and pyridine (0.42 g, 5 mmole). The , -. π 1^19 DUPA302-774-770 reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50).

The crude product (0.42 g, 85%) was treated with HCl in ether and recrystal 1ized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 112-114·; MS m/e 456 (M++H); !H NMR (CDCI3/TMS) δ 0.90(5,3H,CH3), 0.93(s,3H,CH3), 1.27(m,2H,CH2), 1.67(m»3H,C«2. CH), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,lH,CH), 7.33(m,2H,Harom)· 8.00(m,2H,Harom)· Examples 25 and 26 Preparation of the diastereomers of Ν-Γ4.4bis(trifluoromethvl)-2-(4-f1uorophenvl)-4.5-dihvdro-lmethyl-lH-imidazol-5-y11-camphanylamide To a solution of 4.4-bis(trifluoromethyl1-2-(4fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethyl-lH-imidazole (0.34 g, 1 mmole) in dichloromethane (10 ml) was added camphanyl chloride (0.85 g, 3 mmole) and pyridine (0.24 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (10:1) to give the diastereomers which were recrystallized from hexanedichloromethane mixture. The diastereomer that eluted first (100 mg, 19%) is a solid: mp 126-127·; [a]^ = -8.91· (c,0.606, MeOH); MS m/e 524(M++H); *H NMR (CDC13/TMS) ff 1.03(s,3H,CH3), 1.13(5,3H,CH3), 1.23(5,3H,CH3), 1.63-2.43(m,4H,(CH2)2>. ιίηυ ji -yi 12:22 DUPA302-774-770 2.97(s,3H,NCH3), 3.13(s,3H,NCH3), 6.53(s,1H,C)H, 7.20(m,2H,Harom), 7.67(m,2H,Harom). Anal. Calcd for C23H24N3F7O3: C,52.78; H.4.62; N,8.03. Found: C,52.70; H.4.65; Nf7.97. The diastereomer that eluted last (80 mg, 15%) is a solid: mp 87-88; [a] 25D = + 7.04* (c,0.610, MeOH); MS m/e 524(M++H); *H NMR (CDCI3/TMS) δ 1.03(s,3H,CH3), 1.13(s,3H,CH3), 1.17(s,3H,CH3), 1.60-2.67(m,4H,(CH2)2), 2.97(s,3H,NCH3), 3.17(s,3H,NCH3), 6.60(s,1H,CH), 7.20(m,2H,Harom), 7.67(m,2H,Harom). Anal. Calcd for C23H24N3F7O3: C,52.78; H.4.62; N,8.03. Found: C,52.82; H.4.39; N,8.03.

Example 27 Preparation of N-i4-4-bis(trifluoromethvl)-2-(4f1uoropheny11-4,5-dihydro-1-methyl-lH-imidazol-5-yll-N1-415 i sopropylpheny1-N-methv1 urea To a solution of 4.4-bis(trifluoromethyl1-2-(4f luorophenyl )-4,5-di hydro-5-ami ne-N, N-l, 5-dimettiy 1 - 1Kimidazole (0.34 g, 1 mmole) in dichloromethane (2 mt) and hexane (10 mt) was added 4-isopropylphenyl isocyanate (0.45 g, 3 mmole).

The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N), and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (10:1) to give the title compound (0.20 g, 40%) as a white solid: mp 203-204·; MS ro/e 505 (M++H); *Η NMR (CDCI3/TMS) δ 1,23(s,3H,CH3), 1.27(5,3H,CH3), 2.93(m,IH,CH). 3.00(s,6H,2 NCH3), 6.53(s,lH,NH), 6.67(s,lH,CH), 7.20-7.43(m,6H,Harom). 7.677.77(m,2H,Haroffl). Anal. Calcd for C23H23N4F70: C,54.76; H,4.60; N.ll.ll, Found: C,54.85; H,4.62; N,11.02. ........... -23 DUPA302-774-770 Example 28 Preparation of N-r4.4-bis(trifluoromethyl)-2-(4fluorophenvD-a.S-dihvdro-l-methvl-lH-imidazol-S-yll-N12,4-difluorophenyl-N-methylurea 5 To a solution of 4.4-bis(trifluoromethvl)-2(4-fluorophenyl)-4,5-di hydro-5-ami ne-N, N-l,5-dimethy1-1Himidazole (0.34 g, 1 mmole) in di chloromethane (2 ml) and hexane (10 mL) was added 2,4-difluorophenyl isocyanate (0.47 g, 3 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 Ν), and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue (0.51 g, 100%) was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (10:1) to give the title compound (100 mg, 20%) as a white solid: mp 176-177’; MS m/e 499 (M++H); JH NMR (CDCI3/TMS) δ 2.97(s,6H,2 NCH3), 6.57(s,lH,NH), 6.67(5,IH,CH), 6.85-6.93(m,2H,Harom), 7.17-7.27(m,2H,Harom), 7.63-7.73(m,2H,Harom)f 8.00-8.13(m,IH,Harom). Anal. Calcd for c2Oh15f9n4O: C,48.20; H,3.03; N,11.24. Found: C,48.13; H.2.97; N,11.08 Example 29 Preparation of N-f4.4-bis(trifluoromethyl)-2-(4f luoroplienvl )-4,5-di hydro-1-methvl-lH-imidazol-5-νη-Ν\octvl-N-methvlurea hydrochloride To a solution of 4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihydro-5-amine-N,N-l,5-dimethy1-1H30 imidazole (0.34 g, 1 mmole) in dichloromethane (2 mL) and hexane (10 mL) was added n-octyl isocyanate (0.47 g, 3 mmole).· The reaction mixture was stirred over 3 days at room temperature then refluxed for 4 hours under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1 N), IE 91190?----MAY 31 ’91 12=24 DUPA302-774-770 and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was treated with HCl in ether then purified by flash chromatography eluting with hexane and hexane-ethyl acetate (10:1) to give the title compound (50 mg, 9%) as a light brown solid: mp 45-47’; MS m/e 499 (M++H); *H NMR (CDCI3/TMS) 5 0.90(m,3H,CH3), 1.27(m,12H,(CH2)6), 2.60(d,3H,NCH3), 2.93(s,3H,NCH3), 3.13(m,2H,CH2), 4.77(m,ΙΗ,ΝΗ), 6.60(s,1H.CH), 7.l7(m,2H,Harora). 7.63(m,2H,Harora).

Example 30 Preparation of N-r4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihvdro-1-methvl-IH-imidazol-5-yl1-4ethoxybenzamide To a solution of Ν-Γ4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihydro-lH-imidazol-5-y1]-4fluorobenzamide (0.26 g, 0.6 mmole) in ethanol (10 ml) was added sodium hydroxide solution (1 ml, 50%). The reaction mixture was allowed to reflux overnight. The solution was cooled to room temperature, poured into water and extracted with ether. The organic layer was washed successively with water, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by HPLC with 85:15 hexane-ethyl acetate to give the title compound (20 mg, 7%) as a white solid: mp 115-116’; XH NMR (CDCI3/TMS) δ 1.43(t,J=7Hz,3H,CH3), 2.97(s,3H,NCH3), 4.07(q,J-7Hz,2H,CH2), 6.37(d,IH,J=14Hz,CH), 6.60(d,2H,J=14Hz,NH), 6.97(d,2H,Je10Hz,Harom), 7.17(q,2H,J=7Hz,Harom)· 7.57(d,2H,J=10Hz,Harom), 7.83(m,2H,Harom).

DUPA302-774-770 P.2 Examples 31 and 32 Preparation of N-r4,4-bis(trlf1uoromethvl)-2-(4fluorophenvl)-4.5-dihvdro-l-methy1-lH»imidazol-5»y11-4-(1piperidinyl) benzamide (Example 31) and N-f4,4bis(trifluoromethvl)-4.5-dihydro-l-methvl-2-r4-(lpiperidinvl)phenvn-l.H-imidazol-5-y 11-4-f luorobenzamide (Example 32) To a solution of Ν-Γ4.4-bis(trifluoromethyl)-2-(4fluorophenyl)-4,5-dihydro-ΙΗ-imidazol-5-yl]-4-fluorobenzamide (0.9 g, 2 mmole) in dimethyl sulfoxide (5 mt) was added potassium carbonate (0.83 g, 3 equiv.) and piperidine (0.51 g, 3 equiv.). The reaction mixture was heated at 145’ overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by MPLC with 9:1 hexane-ethyl acetate to give two products. N-[4,4-bis(trifluoromethyl)-2-(4-f 1 uorophenyl)-4,5dihydro-1-methy1-1H-imidazol-5-yl]-4-(1-piperidinyl) benzamide (160 mg, 15%) was isolated as a white solid: mp 128-129’; MS m/e 517 (M+*H); NMR (CDCI3/TMS) δ 1.67(m,6H, (CH2)3), 2.93(s,3H,NCH2), 3.33(m,4H,CH2NCH2), 6.43-6.60(m,2H,NK,CH), 6.90(d,2H,J’7,Haronj), 7.13-7.20(m,2H,Harora), 7.607.73(m,2H,Harom). N-[4,4-bis(tri f1uoromethyl)-4,5-di hydro-1methy1-2-[4-(1-piperidinyl)phenyl]-lH-imidazo1-5-yl]-4fluorobenzamide (80 mg, 8%) was isolated as a white solid: mp 123-124’; MS m/e 517 (M++H); lH NMR (CDCI3/TMS) δ 1.67(m,6H,(CH2)3), 3.00(s,3H,NCH3), 3.30(m,4H,CH2NCH2). 6.37(d,lH,CH), 6.60(m,2H,NH), 6.90(d,2H,J«7,HarOffl), 7.13-7.22(m,2H,Harora), 7.53(d,2H,J=7,Harom), 7.807.90(m,2H,Harom). ιίι-ιι oi si 14 = 38 DUPA302-774-770 p.3 Example 33 Preparation of N-i4.4-bis(trif1uoromethvl)-4.5-dihvdro-lmethvl-2-F4-(1-piperi dinyl)phenyl1-1H-imidazol-5-yΊ1-Νmethylheptanamide, hydrochloride 5 To a solution of Ν-Γ4.4-bis(trifluoromethyl1-2-(4fluorophenyl)-4,5-dihydro-lH-imidazol-5-yl]-Nmethylheptanamide hydrochloride (0.20 g, 0.4 mmole) in dimethyl sulfoxide (5 mL) was added potassium carbonate (0.29 g, 1.2 mmole) and piperidine (0.10 g, 1.2 mmole). The reaction mixture was heated at 145’ overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with ether. The ether layer was washed with 1 N HCl to give unreacted starting material. The aqueous layer was made basic and 1t was extracted with ether. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was treated with HCl in ether to give the title compound (50 mg, 22%) as a semi solid: MS m/e 521 (M++H); rH NMR (CDC13/TM5) δ O.9O(m,3H,CH3), 1.30(m,8H,(CH2>4), 1.67(m,6H,(CH2)3), 2.40(t,2H,CH2), 2.90(s,3H,NCH3), 2.97(s,3H,NCH3), 3.30(m,4H,2CH2), 6.53(s,lH,CH), 6.90(d,2H,Harom), 7.53(d,2H,Harom).

Example 34 Preparation of N-F4.4-bis(trlf1uoromethv1)-2-(4methoxyphenvl)-4,5-di hydro-1-methvl-lH-imidazgi-5-vll-N. 5dimethylhexanamide hydrochloride To Ν-Γ4.4-bis(trifluoromethyl)-2-(4-fluorophenvl)-4.5dihydro-lH-imidazol-5-yl]-N,5-dimethy1hexanamide (0.05 g, 0.1 mmole) was added sodium methoxide solution (10 mL, 25%). The reaction mixture was allowed to reflux for 3 hours. The solution was cooled to room temperature, poured into water and extracted with ether. The organic layer was washed successively with water, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The J9 DUPA302-774-770 P.4 residue was treated with HCl in ether to give the title compound (50 mg, 99%) as a white solid: mp 68-69·; MS m/e 468 (M++H); *H NMR (CDCI3/TMS) δ 0.87(s,3H,CH3), 0.90(s,3H,CH3), 1.27(m,2H,CH2)» 1.60(m,3H,CH2CH); 2.37(m,2H,CH2), 2.90(m,6H,2NCH3), 3.83(s,3H,0CH3), 6.60(s,1H,CH), 6.97(d,2H,Harora), 7.60(d,2H,Harom).

Examples Q and R Preparation of N-r4.4-bis(trifluoromethvl)-2-(410 cvanophenv1)-4,S-dihydro-l-methvl-iH-imidazol-S-yll-Nmethyl-4-fluorobenzamide (Example Q) and Ν-Γ4.4bis(trifluoromethyl)-4.5-dihydros1-methvl-2-f4-cvanophenvlllH-imidazo1-5-yTl-N-methvl-4-cvanobenzamide (Example R) To a solution of Ν-Γ4.4-bis(trifluoromethy1)-2-(415 f1uoropheny1)-4,5-dihydro-lH-ireidazol-5-yl]-4-fluoromethyl benzamide (0.46 g, 1 mmole) in dimethyl sulfoxide (5 mL) was added potassium carbonate (0.41 g, 3 equiv.) and potassium cyanide (0.47 g, 3 equiv.). The reaction mixture was heated at 120 overnight under nitrogen. The solution was cooled to room temperature, poured into water and extracted with di chloromethane. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified on silica gel eluting with hexane, then a mixture of hexane25 ethylacetate (20:1 to 50:50) to give two products. N[4,4-b£s (tri fluoromethyl)-2-(4-cyanophenyl)-4,5-dihydro-1-methy1lH-imidazol-5-yl]-4-fluoromethylbenzamide (130 mg, 28%) was isolated as a white solid: mp 189-190*; M$ m/e 473 (M++H); *H NMR (CDC13/TMS) δ 2.93 (s,3H,NCH3), 2.98(s,3H,NCH3), 6.80(bs,lH,CH). 7.18(m,2H,Haroro), 7.45(m,2H,Hapon)» 7.80(m,4H,Hapon)). Anal.

Calcd for C21H15N4OF7: C,53.40; H.3.20; N,11.86. Found: C,53.12; H,3.16; N,11.69. Ν-Γ4.4-bis(trifluoromethyl)4,5-di hydro-1-methy1-2-[4-cyanophenyl]-ΙΗ-imi dazol-5-y1] -4cyanomethylbenzamide (40 mg, 8%) was isolated as a white solid: mp 128-129·; MS m/e 480 (M++H); NMR (CDCI3/TMS) δ -,x _ 40 DUPA302-774-770 p.5 2.9O(s,3H,NCH3), 3.00(m,3H,NCH3), 6.80(bs,lH,CH), 7.55(m,2H,Harorn), 7.80(tn,6H,Η^οπι) · Recrystallization of N-f4.4-bisftrifluoromethvl)-4.5di hydro-1-methyl-2-[4-cyanophenyl]-lH-imidazol-5-yl]-N-methyl-4cyanobenzamide from methylene chloride-hexane gave the polymorphic crystalline form that melts at 132 to 134’C. Recrystallization from ethyl acetate-hexane gave a polymorphic form melting at 181-183’C. X-ray powder diffraction showed that each polymorph has a distinct crystalline form. The polymorphs are interconvertible based on the solvent used for recrystallization. Differential scanning calorimetry of the compound of Example R resulted in three peaks at 131.7°C, 182.6%, and 253.5%, which correspond to polymorphic transitions from the 131% form to the 182.6% form, followed by decomposition at 253.5%. The 132-134® melting polymorph is 3 fold more water soluble than the 181-183*C melting polymorph and has greater oral bioavailability leading to improved systemic ACAT inhibitory activity, compared to the higher melting form.

Separation of [R] and [S] enautiomers of [4,4 bis(tri fluoromethyl )-4,5-dihydro-l-methy1-2-[4-cyanophenyl]-lHimidazole-5-yl]-N-methyl-4-cyano-benzamide(exan»ple 73, 74) and their sulfate salts (Ex. 75, 76).

The racemic mixture of the title compound was separated to the R and S enantioners using HPLC with a Cbiracel-OJ column eluted with 50% ethanol-hexane. Upon concentration, the enantiomers are triturated with hexane to give amorphous solid. The sulfate salt can be obtained by dissolving the amorphous solid in ether and adding sulfuric acid (cone) to give white solid which can be recrystalized from methanol-ether to give the sulfate salt of the [S] enautiomer:mp 181.-183.7 Anal. Calcd for C22H15F6N5°*H2S°4 ; C,45.76; H.2.97; N.12.13: S5.55. Found: C,46.22; H,3.13; 11.60; 5,5-91The sulfate salt of the [R] enantiomer: mp 181.1-181.8 Anal. Calcd for C22Hi5F6N50*H2S04S C.45.76; H.2.97; N.12.13; S5.55. Found C.46.32; H,3.13; N,11.63; S.5.99. -- —_·40 DUPA302-774-770 The compounds of Examples 10-18, 22-23, 25-34, Q, R, and S and other compounds of Formula (I) wherein a is a single bond which have been prepared or could be prepared using the same or similar synthetic methods, are listed in Table 2 and Table 2.1.

N-R® U G’ Ex. # G z r1 r£ r? gp(-.Q 15 0 10 fi-F H ch3 h -c-Q-f n 145-146 10A fi-F H V ch3 ch3 -C-0-F Λ 112-113 20 11 e-f H V ch3 ch3 -chQ-o(ch2)3ch3 n 84-85 12 fi-F H V ch3 ch3 -c-^-och3 π 136-137 25 13 fi-F H V ch3 ch3 -c-^7“C(ch3)3 0 129-130 14 fi-F H CH3 CH3 -C-Q-N02 n 174-175 15 fi-F H V CH3 CH3 -C-Q-C6H5 186-187 30 16 fi-F H ch3 ch3 coc6h13 134-136 (HCl salt) 17 fi-F H CH3 CH3 C0(CH2)10CH3 72-74 (HCl salt) 18 fi-F H CH3 CH3 C0(CH2)3CH(CH3)2 112-114 (HCl salt) ιίητ '91 14·41 DUPA309-774-7<0 Table 2 (continued) Ex. 1 6 £1 Rl R6 R2 5 22 23 fi-F fi-F H H ch3 ch3 -c-£jj 0 ch3 ch3 -c^ 10 25 fi-F H0 cy^CH3 ch3 ch3 -cZ>3 26 fi-F H 0 0 C§JH3 ch3 ch3 -c-^\-ch3 15 27 fi’F H 11 0 ch3 ch3 -c-nh~Q-ch(ch3)2 28 fi-F H ch3 ch3 H 29 fi-F H CH3 CH3 CONHCgHp 20 30 fi-F H 0 CH3 h -c-Q-och2ch3 0 31 fi-F H V CH3 h -c^-kQ 0 25 32 fi-O H ch3 h -c-Q-f 33 4-0 H CH3 CH3 COCgHy 34 P-0CH3 H ch3 ch3 co(ch2)3ch(ch3)2 30 Q p-CH H 0 ch3 ch3 -cy^-F R p-CN H 0 CH3 CH3 -C-0-CN 0 ch3 ch3 -c-Q-ck 35 S fi-F H nffiT.C) 111-112 128-129 126-127 87-88 203-204 176-177 45-47 (HCl salt) 115-116 128-129 123-124 Semi-Sol id (HCl salt) 68-69 (HCl salt) 189-190 128-129 149.3-150.2 =42 DUPA302-774-770 P.8 Table 2 (continued) Ex. * G £1 R| R6 R2 mp(’C) 35 β-CN υ m-N02 CH3 CH3 -C*-^^^-F n 36 fi“CF3 H CHj ch3 -c-Q-f n 37 e-f H ch3 ch3 -chQ-no2 38 β-CN H ch3 ch3 COC6Hi3 39 β-Ν02 m-Cl CH3 CH3 COC6Hi3 π 40 fi-F H V ch3 ch3 -C-^^-cf3 n 41 E-C02Et H ch3 ch3 -c-®-f Λ 42 fi-CN H V CH3 CH3 -C'-(^-0C4Hg-n 183.3-184.8 43 β-CN H 0 ch3 ch3 -c-Q-c(ch3)3 n 44 «< m-CH3 CHj CH3 -C— 45 S-C H U CH3 CH3 -C—^^-004^9 0 C«3 CH3 -C-Q-hQ> n 141.2-143.4 46 b-O H 189.5-191.5 47 β-Ο Cl ch3 ch3 -c-Q-f 0 48 a-iQo H ch3 ch3 -c-Q-f 0 146-147 49 β-ΟΗ H CH3 CH3 -C-C6H13 n 198 50 E-0CH3 H V CH3 CH3 -C-C6Hi3 semi-solid ..... -χ xi 1^-42 DUPA302-774-770 50 Table 2 (continued) Ex. # G G' R1 R6 R2 51 Π-Γ H CH3 CH3 -(CH2)6CH3 o 152.4(d) 5 52 β-F It H ch3 ch3 -C-^N(CH3)2 o 128-129 53 fi-N02 m-CF3 CH3 CH3 -C-Q-0C4Hg-n n 10 54 £-Cl 2J-C1 CH3 CH3 -C-®-C(CH3)3 n 55 E-O u H CH3 CH3 -C-®-CN no2 15 56 fi-N02 0 m-CF3 CH3 CH3 -C-CgHo 57 0 £-0CC«3 H CH3 CH3 COCgHn n oil 20 58 fi-0CH3 H CH3 CH3 -C-<£>-F 153.2-158.8 59 fi-0CH3 0 H CH3 CH3 C-0-OCH3 140.7-141.8 25 60 fi-F H CH3 CH3 0 FF 115-116 61 £-Ci7H33C02 0 H CH3 CH3 -C-C6H13-11 _ H oil 30 62 p-CN 0 I H CH3 CH3 -c-n-c-Q CM, ND 63 P’^O H CH3 CH3 -i-QuC) 165.6 64 p-OH H CH3 CH3 -C-Q-cn ND DUPA302-774-770 Ρ. 10 Table 2 (continued) Ex. * s Hi 86 o®2 65 p-CN H ch3 h -o-Q-cn ND 66 p-CN H ch3 h 0 -c-O ND 67 P-F H ch3 h 0 -c-n-Q-cn NO 68 p-F H ch3 h -cO 120 69 p-CN H ch3 h Q ND (R-isomer) 70 p-CN H ch3 h -c-Q-f ND (S-isomer) 71 p-F H ch3 CH2CH.CH2 -C-0-F 154.9(HClsalt) 72 P-F ' H ch3 h -chQ-f ND (S-isomer) 73 p-CN H ch3 ch3 -C-Q-CN ND (R-isomer) 74 p-CN H ch3 ch3 u II /S5\ -c-OCN NO (S-isomer) 75 p-CN H ch3 ch3 -Ο-θ-CN 0 181.1-181.8 (R-isomer H2SO4 salt) 76 p-CN H ch3 ch3 ”cOcn 181.8-183.7 (S-isomer H2SO4 salt) 77 p-F o It H CHi CH-j •a u 0 V /=\ 0 173.0-173.3 78 P-C-0CH3 H ch3 ch3 -C-O-F 162.4-163.7 πηϊ JI JI 12;43 DUPA302-774-770 P.ll Table 2 (continued) Ex. 79 * G p-CN Gi H e! ch3 R6 R2 0 CH3 NO (R-isomer) 80 p-CN H ch3 0 CH3 “C”£^-(CH2>3CH3 no (S-isomer) 10 81 p-CN H ch3 ch3 -J-Q 201.0-201.9 82 p-CN H ch3 0 CH3 -c-^^-ch, 209.9-210.9 15 83 N fl P-C-OCH3 H ch3 ch3 4-Q-f 142.7-143.2 84 p-F H CH3ch3 -c-Q 103-105 85 p-F H ch3 0 CH3 -c-Q-cn ND (R-isomer) 20 86 P-F H ch3 ch3 -e-Q-CM NO (S-isomer) 87 P-F H ch3 “3 _j_Q 132-133.2 25 88 P-SCH3 H ch3 CH3 -Ο-θ-SCH, 0 186.6-187.7 89 p-CN H ch3 ch3 ’C-Q-cn 118 (d.HCl salt) 90 P-F H ch3 0 m”® 0 e*» CH’ -Lu-o 177.9 (isomer 1-R) 30 91 P-F H ch3 101.0 (isomer 2-R) 92 P-F N ch3 ch3 0 ND (isomer 1-S) IE 91190? DUPA302-774-770 Ρ. 12 Table 2 (continued) Ex. * £ £1 Rl R6 R2 mp(*C) O pH3 p-F H CH3 CH3 -C—N—C-Q ND (isomer 2-S) Notes.

Example 17: MS m/e 525; NMR (CDC13) δ 0.87(5,3H,CH3), 1.27(m,16H,(CH2)8)» 1.67(m,2H,CH2), 2.37(m,2H,CH2), 2.93(s,6H,2NCH3), 6.63(s,lH,CH), 7.17(m,2H,Harom), 7.63(m,2H,HapQni) * Example 22: MS m/e 454; NMR (CDC13) δ 3.00(s,3H,NCH3), 3.20(s,3H,NCH3), 6.70(s,1H,CH), 7.2O(m, 4H,Haroni), 7.60(m,2H,Harom), 7.70(m,2H,Harom) · Example 23: MS m/e 438; NMR (CDC13) δ 2.97(s,3H,NCH3), 3.20(s,3H,NCH3), 6.57(s,IH,CH), 6.73(s,1H,CH), 7.23(m,3H,Harom), 7.67(m,3H,HarQjj,), Table 2.1 Ex. # Ar£ fii R6 95.1 o ch3 H 95.2 o ch3 fkb 0 s-Q mp CC) 137.9-140.4 125.9-126.9 Γ1ΑΥ 31 '91 13:45 DUPA302-774-770 Ρ. 13 Example 96 Preparation of 2-Γ4.4-bis(trifluoromethyl)-2-(4-fluorophenyl)4.5-dihydro-1-methvl-lH-imidazol-5-ylidenel-I-(4-fluorophenyl)1-ethanone Part A-l To a solution of a.a-bis(trifluoromethyl)-4.5-bis(4fluorophenyl)-lH-pyrrole-2-methanamine (4.0 g, 0.009 mole) in chloroform and methanol (1.5 1, bl) was added methylene blue (10 mg). Oxygen gas or air was bubbled through the solution while irradiating with a Tungsten lamp (400 watt) for 1 hour. 1M hydrochloric acid in ether (10 ml) was added to the reaction mixture and stirred for 1 hour at room temperature. The mixture was treated with saturated sodium carbonate solution (15 ml) and the organic layer was separated, concentrated, resuspended in ethyl acetate (200 ml), and washed with saturated ammonium chloride solution, saturated sodium chloride solution, dried over sodium sulfate (anhyd.) and evaporated under vacuum. The residue was purified by column chromatography, eluting with hexane-ethyl acetate (10:1) to give the 2-Γ4.4-bis(trifluoromethyl)-2-(420 f)uoropheny1)-4,5-dihydro-lH-imidazol-5-ylidine]-l-(4fluoropheny!)-l-ethanone (2.03 g, 49%).

Part A-2 To a solution of a.a-bis(tri-fluoromethy1)-4.5-bis(425 fluorophenyl)-lH-pyrrole-2-methanamine (5.0 g, 0.012 mole) in chloroform (100 mL) was added portionwise, m-chloroperbenzoic acid (MCPBA, 4.09 g, 0.024 mole). The reaction mixture was refluxed under nitrogen for one hour. Then additional MCPBA (2.05 g, 0.012 mole) was added and the mixture was refluxed for 1 hour, (he solution was cooled tu ruu»« te»npe« ature and poured into saturated sodium bicarbonate (200 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and DUPA302-774-770 Ρ. 14 evaporated under vacuum. The residue was columned in silica gel eluted with hexane-ethyl acetate 20:1 then 10:1 to give the 2-(4, 4-bis (tri fluoromethy1)-2-(4-fluorophenyl)-4,5-dihydro-1Himidazol-5-ylidene]-l-(4-fluorophenyl)-l-ethanone (1.02 g, 20%) as a yellow solid: mp 121-123’; MS m/e 435 (M*+H); ’h NMR (CDCI3/TMS) δ 6.73(s,lH,C>CH), 7.17-7.30(m,4H,Haro(n), 8.008.10(m,4H,Harom), 11.80(s,ΙΗ,ΝΗ). Another product, N[2-(4f1uorophenyl)-4,5-di hydro-1-methyl-5,5-bis(tri f1uoromethy1)-1Himidazol-5-yl]-N-methylacetamide (2.09 g, 56%) was also isolated as a solid: mp 114-115’; MS m/e 437 (mAh); ’h NMR (CDCI3/TMS) δ 2.57(s,2H,NH2), 3.87(s,ΙΗ,ΝΗ), 6.77(s,lH,C=CH), 6.907.03(rn,4H,Harom)· 7.23-7.40(m,2H,Ha^om)» 7.15-7.17(m,2H,Harom)· Part B Sodium hydride (80 mg, 2.0 mmole) 60% suspension in oil was washed with hexane and then it was suspended in anhydrous dimethyl formamide (5 mL). To this suspension was added portionwise 2-[4,4-bis(trif1uoromethy1)-2-(4-f1uorophenyl)-4,5dihydro-lH-imidazol-5-ylidene]-1-(4-fluorophenyl)-1-ethanone (0.43 g, 1 mmole) and the mixture was allowed to stir at room temperature for one hour. Iodomethane (0.28 g, 2 mmole) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into water and extracted with ether. The organic layer was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from dicbloromethane-hexane to give the title compound (0.20 g, 91%) as a crystalline solid: mp 128129’; MS m/e 449(MAh); !H NMR (CDCI3/TMS) δ 3.17(s,3H,NCH3), 6.67(s,1H,OCH), 7.13-7.30(m,4H,Harom), 7.77-7,87(m,2H,Harom), 7.93-8.07(m,2H,Harom).

The compound of Example 96, and other compounds of Formula (I) wherein X is CH which have been prepared or could be prepared using the same or similar synthetic methods, are listed in Table 3. — -6 DUPA302-774-770 .15 Ex. # G fi-F H R6 mp(*C) 100 101 102 103 104 105 106 107 108 109 110 111 112 113 fi-F b-och3 b-f E-OC4H9 H fi-CN H B-0CH3 H £-0CH3 H B-0C4Hg H fi-CN H fi-CN fi-CF3 fi-CH3 fi-Cl fi-Cl fi-F fi-N3 fi-«3 B-O B-fO fi-C0CH3 H fi-N02 fi-N02 H m-Cl 2-F H H m-Cl fi-F B-CF3 E-CH3 fi-Cl fi-Cl fi-F b-n3 fi-F £-C H H H H m-Cl 2-F H H H H CH3 ch3 ch3 ch3 ch3 ch3 ch3ch2 ch3ch2 H H H H H H H H H H 128-129 ND ND ND ch2«chch2 h ch3 ch3ch2 CH2=CHCH2 H fi-F 0 fi-C0CH3 H fi-N02 H fi-N02 m-Cl ch3 ch3 CH3CH2 ch3 H H H H H H IE 911909 ----Jl Π 12'· 47 DUPA302-774-770 p θ Table 3 (continued) Ex. # G G' G” G’ R1 r6 mp(’C) 114 £-N02 m-CN £-N02 m-CN CH3CH2 H 5 115 H >—\ a-N 0 H ch3 H 116 E-N(CH3)2 H £F H CH2=CHCH2 H 10 117 fi-F H b-n(ch3)2 H ch3 H 118 e-so2ch3 n H a-so2cn3 H ch3 H 119 V t E-N(CH3)2 H 2-F H CH2CH3 H 15 119.1 £-F H 2-F H ch3 ch3 172-176 119.2 2-f H 2-OCH3 H ch3 ch3 ND 119.3 i-<0 H Ε-Q H ch3 H 209-211 (E-isomer) 20 119.4 H Ε-Q H ch3 H 138-139 (Z-isomer) 119.5 fi-F H Ε-Q H ch3 H 154.5-155.5 (Z-isomer) Notes.

Example 97: MS m/e 473; !H NMR (CDCI3) δ 3.17(s,3H,NCH3), 3.87(2s,6H,0CH3), 6.63(s,lH,CH), 7.00(m,4H,Harora), 7.73(d,2H,J=10Hz,Haroin), 7.93(d,2H,J»10Hz ,Harom).

Example 98: MS m/e 461; JH NMR (CHCI3) δ 3.17(5,3H,NCH3), 3.9O(s,3H,0CH3), 6.63(s,1H.CH), 7.00(d,2H,J=10Hz,Harom). 7.23(m,2H,Haro-j); 7.93(m,2H,Harotn) > 8.OQ(d,2H,JlOHz,Hap0|j|). Example 99: MS m/e 557; NMR (CHC13) 5 0.93(m,6H,2CH3). 1.50(m,4H,2CH2), 1.60(m,4H,2CH2), 3.17(s,3H,NCH3), 4.03(m,4H,20CH2) 6.60(s,lH,CH), 6.97(m,4H,Haroni), 7.00(d,2H,>10Hz,Harom), 7.93(d,2H,J«10Hz,Harom)♦ MAY 31 '91 12=48 DUPA302-774-770 Ρ. 17 Example 120 l-(4-f1uoropheoyl-2-r2-(4-fluoroDhenyl)»4.5-dihvdro-l-methvl4,4-bis(trifluoromethyl)-IH-imidazol-S-yll-ethanone To a refluxing solution of 2-Γ4.4-bis(trifluoromethyl 1-2-(45 fluorophenyl)-4,5-dihydro-1-methyl-lH-imidazol-5-ylidene]-1-(4fluoropheny1)-l-ethanone (100 mg, 0.22 mmole) in acetic acid (15 ml) was added zinc dust (3.7 g, 56.6 mmole) over a period of 5 minutes. After 10 minutes, the mixture was filtered and washed with hot acetic acid. The filtrate was diluted with saturated sodium bicarbonate solution (120 ml) and extracted with ether (4x50 ml). The combined organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate (anhyd.) and evaporated under vacuum to give the title compound (78 mg, 79%) as colorless needles, mp 145-146.6%; NMR (CDCI3/TMS) δ 2.79(s,3H,CH3), 2.54-2.60(m,2H,CH2), 5.89-5.97(m,1H,CH); 7.10-7.30(m,4H,Hgrom), 7.55-7.68(m,2H,Harom), 8.02-8.09(m,2H,Η3Γοηι) · The compound of Example 120-120.2, and other compounds of formula (I) wherein X is CHg which have been prepared or could be prepared using the same or similar synthetic methods, are listed in Table 4.

Table 4 MAY 31 '91 12:43 DUPA302-774-770 Ρ. 13 IE 911909 Ex. # G G’ R1 120 fi-F H ch3 5 120.1 β-F H ch2ch3 120.2 fi-F H ch3 120.3 fi-F H ch3 10 120.4 fi-F H ch3 15 120.5 fi-OCH3 H ch3 120.6 fi-OCH3 H ch3 120.7 fi-OCH3 H ch3 20 120.8 fi-F H CH2CH=CH2 120.9 £’OCH3 H CH3 25 120.10 fi-F H ch2ch3 • 120.11 fi-F H ch2ch3 30 120.12 fi-F H ch2ch3 120.13 fi-N H ch3 R6 R2 ch3 H H OH I ~?“O CH.

OCH.

OH I -C-0-OCH, CH, OH -fO-00'’ CH, -KF -Ο-θ-OCH, OH -c-Q-f OH -ο-0·ρ mp(’C) 145-146 NO NO ND (2S-isomer) NO (2R-isomer HCl salt) NO 151-152 (2S-isomer) ND (2R-isomer; HCl salt) ND 188.5 185-186 (5-isomer) 168-170 (R-isomer) NO NO MAY 31 '91 13=49 DUPA302-774-770 P.13 Example 121 Preparation of T4,4-bis(trifluoromethvl)-2-(4-methoxyphenyl)-4.5dihydro-lH-iiwidazol-S-ylidenel-carbamic acid-(4-methoxyphenvl)ester To a solution of a.a-bis(tri-fluoromethyl)-4.5-bis(4methoxyphenyl)-l-methyl-lH-imidazol-2-methanamine (0.40 g, 87 mmole) in chloroform (10 ml) was added portionwise, inch loroperbenzoic acid (0.75 g, 4.30 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with hexane to give the title compound (0.20 g, 40%) as a white solid: mp 141-142”; MS m/e 489 (M++H); NMR (CDCI3/TMS) δ 3.33(s,3H,NCH3), 3.83(s,3H,0CH3), 3.93(s,3H,0CH3), 6.85-7.20(m,6H,Harom), 7.67-7.73(m,2H,Harom); Anal. Calcd for C2lHi7N304Fe: C.51.54; H,3.50; Found: C,50.92; H.3.68.

Example 122 Preparation of r4,4-bis(trifluoromethvl)-2-(4-methvlDhenv11-4.5dlhydro-lH-imidazol-5-ylidenel-carbamic acid-(4-methvlphenvl)ester To a solution of a.a-bi s (t ri f 1uoromethy1)-4.5-bis(4methylphenyl)-l-methyl-lH-imidazol-2-methanamine (1.0 g, 2.3 mmole) in chloroform (10 mL) was added portionwise, inch loroperbenzoic acid (1.20 g, 7 mmole). The reaction mixture was refluxed under nitrogen for two hours. The solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate solution, 10% sodium sulfite solution, water, and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum. The residue was triturated with petroleum ether to give the title compound MAY 31 '91 12=50 DUPA302-774-770 P.20 (0.15 g, 14%) as a solid: mp 161-163®; MS m/e 458 (M++H); NMR (CDC13/TMS) δ 2.43 (s,6H,CH3), 3.06(s,3H,NCH3), 7.237.40(m,4H,Harom)< 7.50-7.63(m,2H,Harom), 7.87-7.93(m,2H,Harom).

The compounds of Examples 120 and 121, and other compounds of 5 Formula (I) wherein a is a double bond and Ar2 is C02Ar which could be prepared using the same or similar synthetic methods, are listed in Table 4. 122 -ch3 161-163 Example 123 Preparation of 2-(4-fluorophenyl)-3,5-dihydro-3-methyl-4,4-bis(tri fluoromethyl)-4H-imi dazol-4-one A solution of Ν-Γ4.4-bis(trifluoromethyl)-2-(4fluoropheny1)-4,5-d i hydro-1-methy1 -1H-imi dazol-5-y1i dene] 4-fluorophenylbenzamide (1.1 g, 2.3 mmole) in diethyl ether was eluted to the center of a basic alumina (III) column with ether at room temperature. After two hours, the material was eluted from the column with ethyl acetate and the crude product was purified by column chromatography with hexane-ethyl acetate (10:1) to give the title compound in quantitative yield (0.80 g) as a white solid: mp 59-61*. MS m/e 329 (M++H). NMR .21 (CDCI3/TMS) δ 3.25{s,3H,NCH3), 7.25(m,2H,HarOTn), MAY 31 'gi 12:50 DUPA302-774-770 7.80(m,2H,Harom).

Ex. * Ari 123 O“r CH3 59-61 Utility The compounds of the invention are effective .antiatherosclerotic agents that act in a variety of ways. The compounds may be inhibitors of the enzyme acyl CoA:cholesterol acyl transferase (ACAT). Inhibition of ACAT has a variety of anti atherosclerotic effects, including inhibiting esterification and transport of cholesterol across the intestinal wall. In addition, by inhibiting cholesterol ester formation, the compounds may be useful in preventing the formation of cholesterol ester rich macrophages {foam cells) in the arterial wall. Foam cells are a source of the large quantity of cholesterol ester found in atheromatous lesions, as compared to the surrounding undiseased tissue. Other compounds of the invention may be inhibitors of cholesterol biosynthesis in the liver. Some compounds of the invention are both ACAT inhibitors and inhibitors of cholesterol biosynthesis.

A. Assay of the Inhibition of acy'i-Coa: Cholostorol Acyl transferase (ACAT) in Hepatic Microsomes The ability of the compounds to inhibit ACAT, the enzyme responsible for the intracellular synthesis of cholesteryl MAY 31 '91 12=51 DUPA302-774-770 P.22 esters, was tested as follows. Male Sprague Dawley rats weighing 150-300 g were fed rat chow ad 1Ibiturn. The animals were fasted for twenty-four hours prior to being sacrificed by decapitation. The livers were perfused in situ with 50 ml of cold 0.25 M sucrose, excised, and homogenized in three volumes of 0.1 M phosphate buffer, pH 7.4, that contained 0.5 mM EDTA (ethylenediaminetetraacetic acid), 1.0 mM glutathione, 0.25 M sucrose and 20 mM leupeptin. Microsomes were obtained by differential centrifugation; the supernatant from an initial spin at 15,000 x g for 15 minutes was centrifuged at 105,000 x g for 1 hour to pellet the microsomes. The microsomes were suspended in homogenization buffer, reisolated by centrifugation, and stored at -70®C. Microsomes were used within one month of preparation.

The control assay in a final volume of 200 /*1 consisted of 200 pg of microsomal protein, 75 pM ^C-oleoyl-CoA (10,000 dpm/nmol) in 0.1 M phosphate, pH 7.4, that contained 1 mM glutathione. Compounds were added in 5-10 pi of DMSO (dimethyl sulfoxide or ethanol) and additional controls were run with DMSO or ethanol only. A11 components, except the oleoyl-CoA, were preincubated for 15 min. at 37*C prior to the initiation of the reaction by the addition of oleoyl CoA. The assay was terminated after 10 min by the addition of 4 ml of chloroform:methanol (2:1, v/v). 20,000 dpm of ^-cholesteryl oleate and 10 pg of unlabeled cholesteryl oleate and oleic acid were added as an internal standard and carrier, respectively. After allowing 10 min. for lipid extraction, 0.8 ml of deionized water was added to separate the solution into two phases. The lower chloroform phase was collected, dried under nitrogen and resuspended in 100 pi of chloroform. The sample containing the neutral lipids was spotted onto a Gelman ITLC-SA polysilicic acid gel-impregnated sheet, which wac developed using a hexane: diethyl ether: acetic acid (170:30:1 v/v/v) mobile phase. The lipids were visualized by their interaction with iodine vapor and the cholesteryl ester spot was scraped into a scintillation vial and counted. The specific activity of ACAT in the control incubation averaged 260 JUM 04 '91 10--36 DU PONT 302 774 72223« P.3 pmol/min/mg microsomal protein. The inhibition of ACAT activity by the compounds is shown in Table 7; the data are expressed as the concentration at which ACAT activity is inhibited by 50% (IC50).

B. Assay of the Inhibition of Cholesterol Esterification in Mammalian Cells The esterification of cholesterol was determined in the murine macrophage-like cell line J774.A1. Cells were seeded in 35 mm wells at a density of 300,000 cells per well in 2 mis of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS). Cells were incubated at 37*C in an atmosphere of 5% C02 and 93% humidity. After 24 hours the media was changed to 0.68 mis 10% FBS-DMEM containing 34 μς of acetylated human low density lipoprotein (ac-LDL) to increase the intracellular concentration of cholesterol and promote esterification. At 41 hours, various inhibitors were added to the cells in DMSO (10 ^1/ml maximum). At 43 hours, the cells were pulsed with 0.1 mM 14C oleic acid (10,000 dpm/nmol) complexed with BSA (bovine serum albumin) to follow cholesterol ester formation. The experiment was terminated at 45 hours by washing the monolayers 3 times with 3 ml of Tris-buffered saline at 4*C. The lipids were extracted by incubating the monolayers with 1.5 ml of hexane; isopropanol (3:2, v/v) for 30 min. under gentle agitation. During this period, 10,000 dpm 3H-cholesteryl 1 inoleate and 10 pg of cholesteryl oleate were added as an internal standard and carrier respectively. The organic solvent was removed and the cells were washed with an additional 1.0 ml of hexane: isopropanol which was combined with the original extract. The cells were allowed to dry overnight, digested with 1.5 ml of 0.2 N sodium hydroxide for 1 hour and an aliquot of the solubilized protein used for protein determination using the Lowry method. The organic extract was taken to dryness, the residue resuspended in 100 pi of chloroform and the lipids separated on silica gel impregnated glass fiber plates using a hexane: diethylether: acetic acid (170:30:1, v/v/v) solvent P.24 MAY 31 '31 12:53 DUPA302-774-770 system. Individual lipids were visualized with iodine and the cholesteryl ester spot cut out and transferred to scintillation vials to determine the amount of radioactivity. The conversion of oleic acid to cholesteryl ester in the control averaged 0.54 mmol/hr/mg protein and was increased upon the addition of ac-LDL to about 10.69 ± 0.69 mmol/hr/mg protein. The inhibition of esterification by the compounds is shown in Table 8; the data are expressed as the concentration at which ACAT activity is inhibited by 50% (IC50)· MAY 31 '91 12=54 DUPA302-774-770 P.25 Table 7 Inhibition of In Vitro Hepatic ACAT Activity By Various Compounds Compound of Example In Vitro ACAT IC50 Z 20 μΜ 5 20 μΜ 10 41 μΜ 10A 22 uM 11 2 μΜ 12 6 μΜ 13 4 μΜ 14 8 μΜ 15 17 μΜ 16 2 μΜ 17 6 μΜ 18 4 μΜ 25 41 μΜ 26 45 μΜ 27 3 μΜ 28 22 μΜ 29 16 μΜ 30 6 μΜ 34 9 μΜ 31 10 μΜ 32 2 μΜ 33 10 μΜ 96B 19 μΜ 121 64 μΜ 122 49 μΜ 123 >100 μΜ 0 1.91 μΜ R 2.0 μΜ P.26 Table 8 Inhibition of Cholesterol Esterification in Macrophage by Various Compounds MAY 31 ’91 12=54 DUPA302-774-770 Compound Cholesterol of Example Esterification (IC50) 2 > 100 μΜ 5 62 μΜ 10A 105 μΜ 11 14 μΜ 13 18 μΜ 14 18 μΜ 15 11 μΜ 16 17 μΜ 25 98 μΜ 26 96 μΜ 27 16 μΜ 31 13 μΜ 32 17 μΜ 33 13 μΜ R 13 μΜ Q 34 μΜ Dosage Forms: The compounds of the present invention can be administered using a variety of pharmaceutically acceptable dosage forms known in the art. The active ingredient will normally be administered orally and can be supplied in solid dosage forms such as dry powders, granules, tablets, capsules, or bars, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. These compounds may be administered in combination with other active ingredients.

In their therapeutic use as antihypercholesterolemic and/or antiatherosclerotic agents, the compounds of the invention are administered to the patient at dosage levels of 7 to 7000 mg per day. For a normal male adult human of approximately 70 kg of body weight, this translates into a dosage of 1 to 100 mg per kilogram body weight per day. The dosage administered will, of course, vary depending upon known factors such as the age, DUPA302-774-770 P.27 health, and weight of the recipient nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.

The various classes of pharmaceutical preparations are discussed in Remington's Pharmaceutical Sciences, a standard reference text in this field. See also, the USP/NF for solvents and other pharmaceutical necessities suitable for use in pharmaceutical dosage forms. The teaching of these references is hereby incorporated by reference. Useful pharmaceutical dosage forms for administration of the compounds of this invention can be illustrated as follows: Tablets Tablets are prepared by conventional procedures so that the 15 dosage unit is 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 10 milligrams of magnesium stearate.

Capsules Capsules are prepared by conventional procedures so that the 20 dosage unit is 500 milligrams of active ingredient, 100 milligrams of cellulose and 10 milligrams of magnesium stearate.

Svrup Wt. % Active Ingredient 10 Liquid Sugar 50 Sorbitol20 Glycerine 5 Flavor, Colorant and Preservative as required Water as required P.28 DUPA302-774-770 The final volume is brought up to 100% by the addition of distilled water.

Aqueous Suspension Wt. % Active Ingredient 10 Sodium Saccharin 0.01 Keltrol® (Food Grade Xanthan Gum) 0.2 Liquid Sugar 5 Flavor, Colorant and Preservative as required Water as required Xanthan gum is slowly added into distilled water before adding the active ingredient and the rest of the formulation ingredients. The final suspension is passed through a homogenizer to assure the elegance of the final products.

Resuspendible Powder Active Ingredient 50.0 25 Lactose 35.0 Sugar 10.0 Acacia 4.7 Sodium Carboxylmethylcellulose 0.3 Each ingredient is finely pulverized and then uniformly mixed together. Alternatively, the powder can be prepared as a suspension and then spray dried. .29 MAY 31 '91 12=56 DUPA302-774-770 P 70 Semi-Solid Gel wt. % Active Ingredient 10 5 Sodium Saccharin 0.02 Gelatin 2 Colorant, Flavor and as required Preservative 10 Water as required Gelatin is prepared in hot water. The finely pulverized active ingredient is suspended in the gelatin solution and then the rest of the ingredients are mixed in. The suspension is 15 filled into a suitable packaging container and cooled down to form the gel.

Semi-Solid Paste Wt. % 20 Active Ingredient 10 Gelcarin® (Carrageenin gum) 1 Sodium Saccharin 0.01 25 Colorant, Flavor and Preservative as required Water as required Gelcarin® is dissolved in hot water (around 80*C) and then the fine-powder active ingredient is suspended in this solution. 30 .30 Sodium saccharin and the rest of the formulation ingredients are added to the suspension while it is still warm. The suspension is homogenized and then filled into suitable containers.

Emulsifiable Paste ..... — -i ic··5? DUPA302-774-770 Wt, % Active Ingredient 30 Tween® 80 and Span® 80 6 Keltrol® 0.5 Mineral Oil 63.5 All the ingredients are carefully mixed together to make a homogenous paste.

The term consisting essentially of in the present disclosure is intended to have its customary meaning; namely, that all specified materials and conditions are very important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

P.31 =57 DUPA302-774-770

Claims (96)

WHAT IS CLAIMED IS:

1. A compound of the formula: wherein Ar* is phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F, -Cl, -Br, -I, -CF 3 , -C0NH 2 , -N0 2 , -CHO, -CO 2 Et, -CN, -O 2 CR 9 , -SCH3, -SCF3, -SO 2 CF3, -SO 2 CH 3 , 5-tetrazolyl, -N(O)(CH 3 ) 2 , OH, C1-C7 alkoxy, N-piperidyl, Ci-Cjo alkyl, C3-C7 cycloalkyl, or C3-C10 substituted cycloalkyl, or Ar* may be Cj-Cjo alkyl, C3-C7 cycloalkyl, or C4-C7 substituted cycloalkyl substituted as above, where R 9 is H or alkyl, alkenyl, or alkynyl of I to 20 carbon atoms; Q is 0 or X-R 2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; X is N, NR 6 , CH, or CHR 6 , S and R 6 is H, or C1-C3 alkyl, alkenyl, or alkynyl; W is C or CH provided that when a is a single bond, X is NR 6 or CH 2 and W is CH, and when a is a double bond, X is N or CH and W is C; Y is N or NR/, and r/ is H or Ci-C 3 alkyl; Z is C or CH, provided that when b is a single bond, Y is NR/ and Z is CH, and when b is a double bond, Y is N and Z is C; and, a and b are, independently, single or double bonds; R l is H or C1-C3 alkyl, alkenyl, or alkynyl; R 2 is C4 to C15 alkyl, C4 to C15 alkynyl, or C4 to C15 alkenyl, which may be straight, branched or cyclic, P.32 58 DUPA302-774-770 optionally with a terminal COOH or OH group; or R 2 is COR 3 where R 3 is Cj to C15 alkyl, C2 to Cjg alkynyl, or C2 to Cl5 alkenyl, which may be straight, branched, or cyclic, optionally with a terminal COOH or OH group; or R 2 is COAr 2 , CH2Ar 2 , CO2Ar 2 , CONR^Ar 2 , where R® is H or C1-C3 alkyl, 502Ar 2 , S02NHAr 2 , or SO2R 3 ; Ar 2 is phenyl or substituted phenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -CF3, β-Ν02, -CN, -CHO, -N3, C1-C7 alkyl, Cj-Cy alkoxy, phenyl, or NR^R 3 , where R^ and R 3 are independently H, or Cj-C3 alkyl, or together represent a carbocyclic ring of 3-5 carbons, or Ar 2 is C 2 -Cu, saturated, unsaturated, or aromatic, and which may be straight, branched, or cyclic; or Nmorpholyl; 2- or 3-thiophyl; 2- or 3-pyrrolyl; or 2- or 3-furyl; Provided that: when X is CH or CH 2 and R 2 is COAr 2 , Ar^ and Ar 2 are independently, phenyl or substituted phenyl and when X is CH2, R 2 is COAr 2 , CH2Ar 2 , or C0 2 Ar 2 ; or resolved optical antipode of any chiral form thereof; or pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 wherein Ar^ is phenyl, or mono-, di-, or trisubstituted phenyl, optionally substituted with -F, -Cl, -Br, -I, -CN, -CF 3 , -C0NH 2 , -OH, -N0 2 , 5-tetrazolyl, C1-C7 alkoxy, N-piperidyl, -O 2 CR9, where r9 is C1-C20 alkyl* alkenyl, or alkynyl, Ci-Cjo alkyl, C 3 -C7 cycloalkyl, or C 3 -Cjo substituted cycloalkyl, or Ar^ is cyclohexyl: Q is 0 or X-R 2 wherein X is bonded to W, provided that when Q is 0, a is a double bond; , ΜΗΥ 31 '31 12:53 DUPA302-774-770 P.33 X is Ν, NR 6 , CH, or CHR 6 , S and R 6 is H, or C1-C3 alkyl, alkenyl, or alkynyl; W is C or CH, provided that when a is a single bond, X is NR 6 or CH 2 and W is CH, and when a is a double bond, X is N or CH and H is C; Y is N or NR?, and R? is H or CH3; Z is C or CH, provided that when b is a single bond, Y is NR? and Z is CH, and when b is a double bond, Y is N and Z is C; and a and b are, independently, single or double bonds; R 1 is H or C1-C3 alkyl, alkenyl, or alkynyl; R 2 is COAr 2 , CH2Ar 2 , CO2Ar 2 , or C0NR 8 Ar 2 , wherein R 8 is H or C1-C3 alkyl; and Ar 2 is phenyl, or substituted phenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -CF3, -N3, phenyl, C1-C7 alkyl, C1-C7 alkoxy, β-Ν0 2 , -CHO, -CN, or NR 4 R 5 where R 4 and R 5 are independently H, or C1-C3 alkyl, or together represent a carbocyclic ring of 3-5 carbon atoms, or Ar 2 is C3-C11, saturated, unsaturated, or aromatic, and which may be straight, branched, or cyclic; or N-morpholyl; 2- or 3-thiophyl; 2- or 3-pyrrolyl or 2- or 3-furyl.

3. A compound of Claim 1 wherein: Ar’ is phenyl, or monosubstituted phenyl, substituted witii -r, -Ci, -Si, -CN, -€Γ 3 , -OH, C1-C7 alkoxy, N0 2 -, -C0NH 2 , N-piperidyl, CH3, or -O 2 CR 9 where R 9 is C1-C20 alkyl. alkenyl, or alkynyl, or Ar’ is cyclohexyl; Q is X-R 2 wherein X is bonded to W; IE 911909 _ 59 DUPA302-774-770 P.34 f X is NR® or CHg, and R® is H, or Cj-C 3 alkyl, alkenyl, or alkynyl; W is CH; Y is N; 5 Z is C; r1 is H, CH 3 , or C2H5; and R® is COAr® or C0NR®Ar2, wherein R® is H or C1-C3 alkyl; and Ar^ is monosubstituted phenyl, optionally substituted 10 with -F, -Cl, -Br, -CN, -CF 3 , C1-C7 alkyl, C1-C4 alkoxy, g-NOg, phenyl, N-piperidyl, or dimethylamino, or Ar^ is saturated Ce-Cn, which may be straight or branched. 15

4. A compound of Claim 1 wherein Ar^ i s phenyl, or monosubstituted phenyl, g-substituted with -F, -Cl, -Br, -CN, -OH, -OCH 3 , Npiperidyl, -CONHg or OgCR^, where R^ is C1-C2O alkyl, alkenyl, or alkynyl; 20 Q is X-R^ wherein X is bonded to H; X is NR® or CHg, and R® is H or Cj-C 3 alkyl, alkenyl, or alkynyl; W is CH; Y is N; 25 1 is C; R 1 is CH 3 ; r2 is COAr^ or CONR^Ar^, wherein R® is H or C1-C3 alkyl; and Ar^ is monosubstituted phenyl, g-substituted with -F, 30 -Cl, phenyl, C1-C4 alkyl, C1-C4 alkoxy, -CN, g-NQg, N.ninpridyl or Ar^ is saturated Cg-Cjj, which may be straight or branched.

5. The compound of Claim 1 which is N-[4,4-liii(trif1uoro35 methyl)-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol’-5IE 911909 30 DUPA302-774-770 yl]-4-butoxy-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

6. The compound of Claim 1 which is N-Γ4.4-bi5(tri fluoromethyl )-2-(4-f luorophenyl )-4,5-di hydro-1-methy 1-1H-imi dazol-55 yl]-4-(l,1-dimethylethyl)-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 1 which is N-f4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-lH-imidazol-5yl]-N-methy1-4-nitrobenzamide, or a pharmaceutically acceptable 10 salt thereof.

8. The compound of Claim 1 which is Ν-Γ4.4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-ΙΗ-imidazol-5yl]-4-(1-piperidiny1) benzamide, or a pharmaceutically acceptable salt thereof. 15

9. The compound of Claim 1 which is N-[4,4-bis(trifluoromethyl )-2-(4-f1uoropheny1)-4,5-di hydro-1-methy1-IH-imi dazol-5yl]-4-fluorophenyl-N-methylbenzamide, or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 1 which is N-[4,4-bis(trifluoro20 methy1)-4,5-dihydro-1-methy1-2-[4-(l-piperidinyl)phenylj-lHimidazol-5-yl]-4-fluorobenzamide, or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 1 which is N-[4,4-bis.(trifluoromethyl) -2-(4-f1uoropheny1)-4,5-di hydro-l-methy1-ΙΗ-imidazol-525 yl]-N-methylheptanamide, or a pharmaceutically acceptable salt thereof.

12. The compound of Claim 1 which is Ν-Γ4.4-bis(tri fluoromethyl )-2-(4-f1uoropheny1)-4,5-di hydro-1-methy1-IH-iraidazol-5ylj-4-ethoxybenzamide, or a pharmaceutically acceptable salt 30 thereof. 22, The compound of claim i which is Ν-Γ4.4-bis(trifluoromethyl )-2-(4-fluorophenyl)-4,5-dihydro-l-methyl-ΙΗ-imidazol-5yl]-4-methoxy-N-raethylbenzamide, or a pharmaceutically acceptable salt thereof. ......

Λ DUPA302-774-770

14. The compound of Claim 1 which is Ν-Γ4.4-bis(trifluoromethyl)-2-(4-fluorophenyl )-4,5-dihydro-i-methyl-lH-imidazol-5yl3-N-metbyl-[l,r-biphenylJ«4-carboxamide, or a pharmaceutically acceptable salt thereof. 5

15. The compound of Claim 1 which is N-[4,4-bjs(trifluoromethy1)-2-(4-fluorophenyl)-4,5-di hydro-l-methyl-ΙΗ-imi dazol-5yl]-N'-2,4-difluorophenyl-N-methylurea, or a pharmaceutically acceptable salt thereof.

16. The compound of Claim 1 which is N-[4,4-bis(trifluoro10 methyl )-4,5-dihydro-1-methyl-2-[4-(1-piperidinyl)phenyIj-IHimidazo1-5-yl3-N-methylheptanamide, or a pharmaceutically acceptable salt thereof.

17. The compound of Claim 1 which is N-[4,4-bii(trifluoromethyl )-2-(4-methoxyphenyl )-4,5-dihydro-l-methyl-lH-imidazol-515 yl]-N,5-dimethylhexanamide, or a pharmaceutically acceptable salt thereof.

18. The compound of Claim 1 which is N-[4-4-bis(trifluoromethyl )-2-(4-f1uoropheny!)-4,5-di hydro-l-methyl-lH-imidazol-5y1]-N'-4-isopropylphenyl-N-methylurea, or a pharmaceutically 20 acceptable salt thereof.

19. The compound of Claim 1 which is Ν-Γ4.4-bis(trifluoromethy1)-2-(4-fluorophenyl)-4,5-dihydro-1-methyl-lH-imidazol-5yl]-N,5-dimethyl-hexanamide, or a pharmaceutically acceptable salt thereof. 25

20. The compound of Claim 1 which is Ν-Γ4.4-bis(trifluoromethy1)-2-(4-f1uoropheny1)-4,5-di hydro-l-methyl-IH-imidazol-5yl]-N'-octyl-N-methylurea, or a pharmaceutically acceptable salt thereof.

21. The compound of Claim 1 which is 1-(4-cyanophenyl)-230 [2-(4-fluorophenyl)-4,5-dihydro-1-methyl4.4-b is (trif luoromethy! l-lH-imidazol-S-yllethanone, or a pharmaceutically acceptable salt thereof. ..... -- ^-J2 DUPA302-774-770 P.37

22. The compound of Claim 1 which is'9-octadecenoic acid, [4-[4,5-dihydro-1-methyl-5-[metby1(1-oxoheptylJamino]4,4-bis(trifluoromethy1)-lH-imidazol-2-y1]phenyl]ester, or a pharmaceutically acceptable salt thereof. 5

23. The compound of Claim 1 which is benzamide, N[2-(4-cyanopheny1)-4,5-d i hydro-1-methy1-4,4bis(trifluoromethyl)-lH-imidazol-5-yl]-4-cyano-N-methyl, or a pharmaceutically acceptable salt thereof.

24. The compound of Claim I which is benzamide, N10 [2-(4-cyanopheny1)-4,5-di hydro-1-methy1-4,4-bis(tri f1uoro methyl)-lH-imidazol-5-yl]-4-cyano-N-methyl. R-isomer, ora pharmaceutically acceptable salt thereof.

25. The compound of Claim 1 which is phenol, 4-[4,5dihydro-1-methyl-5-[methyl(l-oxoheptyl)amino]-4,415 bis(trifluoromethyl)-lH-imidazol-2-y1]-. acetate (ester), ora pharmaceutically acceptable salt thereof.

25. The compound of Claim 1 which is benzamide, N[2-(4-fluorophenyI)-4,5-d i hydro-1-methy1-4,4bis(trifluoromethyl)-lH-imidazol-5-yl1-4-cyano-N-methyl, or a 20 pharmaceutically acceptable salt thereof.

27. The compound of Claim 1 which is benzamide, N-[2(4-cyanophenyl)-4,5-di hydro-1-methy1-4,4-bis(tri fluoromethyl)lH-imidazo1-5-yl]-4-fluoro-N-methyl, or a pharmaceutically acceptable salt thereof. 25

28. The compound of Claim 1 which is benzamide, N-[2-(4fluorophenvl)-4.5-dihydro-1-methvl-4.4-bis(trifluoromethyl)-lHinndazol-5-yl]-2,3,4,5,6-pentafluoro-N-methyl, or a pharmaceutically acceptable salt thereof.

29. The compound of Claim 1 which is 1-(4-fluorophenyl)-230 [2-(4-f1uorophenyl)-4,5-dihydro-l-methy1)-4,4bis(trifluoromethyl)-lH-imidazol-5-vl]-ethanone, or a pharmaceutically acceptable salt thereof. ..... -- 12 DUPA302-774-770

30. The compound of Claim 1 which is l-(4-fluoropbenyl)-2-[2-(4-fluoropheny1)-4,5-dihydro1-ethy1)-4,4-bis(trif1uoromethy1)-ΙΗ-imidazol-5-y1]-ethanone, or a pharmaceutically acceptable salt thereof. 5

31. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim I and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of 10 Claim 2 and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 3 and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising an effective 15 ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 4 and a pharmaceutically acceptable carrier.

35. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 5 and a pharmaceutically acceptable carrier. 20

36. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 6 and a pharmaceutically acceptable carrier.

37. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of 25 Claim 7 and a pharmaceutically acceptable carrier.

38. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 8 and a pharmaceutically acceptable,carrier.

39. A pharmaceutical composition comprising an effective 30 ACAT inhibiting or antiatherosclerotic amount of the compound of Claim y anu a piiariiioCcuviv-ei ly acceptable carrier,

40. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 10 and a pharmaceutically acceptable carrier. IE 91190S --- + 4.j-03 DUPA382-774-778 P.39

41. A pharmaceutical composition comprising an effective ACAT inhibiting or anti atherosclerotic amount of the compound of Claim 11 and a pharmaceutically acceptable carrier.

42. A pharmaceutical composition comprising an effective 5 ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 12 and a pharmaceutically acceptable carrier.

43. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 13 and a pharmaceutically acceptable carrier. 10

44. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 14 and a pharmaceutically acceptable carrier.

45. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of 15 Claim 15 and a pharmaceutically acceptable carrier.

46. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 16 and a pharmaceutically acceptable carrier.

47. A pharmaceutical composition comprising an effective 20 ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 17 and a pharmaceutically acceptable carrier.

48. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 18 and a pharmaceutically acceptable carrier. 25

49. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 19 and a pharmaceutically acceptable carrier.

50. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of 30 Claim 20 and a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 21 and a pharmaceutically acceptable carrier. , ιπ , -χ rx ±α·04 DUPA302-774-770 Ρ·40

52. A pharmaceutical composition comprising an effective ACAT inhibiting or anti atherosclerotic amount of the compound of Claim 22 and a pharmaceutically acceptable carrier.

53. A pharmaceutical composition comprising an effective 5 ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 23 and a pharmaceutically acceptable carrier.

54. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 24 and a pharmaceutically acceptable carrier. 10

55. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 25 and a pharmaceutically acceptable carrier.

56. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of 15 Claim 26 and a pharmaceutically acceptable carrier.

57. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 27 and a pharmaceutically acceptable carrier.

58. A pharmaceutical composition comprising an effective 20 ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 28 and a pharmaceutically acceptable carrier.

59. A pharmaceutical composition comprising an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 29 and a pharmaceutically acceptable carrier. 25

60. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 1.

61. A method of treating hypercholesterolemia or athero30 sclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 2. .41 ,,,-,, ox ij:05 DUPA302-774-770

62. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 3. 5

63. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of a compound of Claim 4.

64. A method of treating hypercholesterolemia or athero10 sclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 5.

65. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an 15 effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 6.

66. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the 20 compound of Claim 7.

67. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 8. 25

68. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 9.

69. A method of treating hypercholesterolemia or athero30 sclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 10. .. ---06 DUPA302-774-770

70. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 11. 5

71. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 12.

72. A method of treating hypercholesterolemia or athero10 sclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 13.

73. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an 15 effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 14.

74. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the 20 compound of Claim 15.

75. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 16. 25

76. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 17.

77. A method of treating hypercholesterolemia or athero30 sclerosis in a mammal comprising administering to the mammal an effective ACAT iuiiiuiLmy υι antiatherosclerotic amount of the compound of Claim 18. MAY 31 '31 lj:06 DUPA302-774-770 P.43

78. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 19. 5

79. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 20.

80. A method of treating hypercholesterolemia or athero10 sclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 21.

81. A method of treating hypercholesterolemia or athero 4 · sclerosis in a mammal comprising administering to the mammal an 15 effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 22.

82. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the 20 compound of Claim 23.

83. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 24. 25

84. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 25.

85. A method of treating hypercholesterolemia or athero30 sclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound Claim 2§·

86. A method of treating hypercholesterolemia or dlherosclerosis in a mammal comprising administering to the mammal an 35 effective ACAT inhibiting or antiatherosclerotic amount of the cotfaaiui »1 cUiwt Tf __ 07 DUPP302-774-770 P.44

87. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 28. 5

88. A method of treating hypercholesterolemia or atherosclerosis in a mammal comprising administering to the mammal an effective ACAT inhibiting or antiatherosclerotic amount of the compound of Claim 29.

89. A process for preparing a compound of Formula (I): wherein Ar^ ph en yi ( or mono-, di-, or tri-substituted phenyl, 20 optionally substituted with -F, -Cl, -8r, -I, -CF 3 , -CONHg, -NOg, -CHO, -COgEt, -CN, -OgCR 9 , -SCH3, -SCF3, -SOgCF 3 , -SOgCH 3 , 5-tetrazolyl, -N(O)(CH 3 )g, OH, C1-C7 alkoxy, N-piperidyl, Ci-Cjo alkyl, C 3 -C7 cycloalkyl, or C 3 -Cio substituted cycloalkyl, or Afl may be Cj-Cjo 25 alkyl, C 3 -Cy cycloalkyl, or C4-C7 substituted cycloalkyl substituted as above, where R® is H or alkyl, alkenyl, or alkynyl of 1 to 20 carbon atoms; Q is 0 or X-R® wherein X is bonded to.H, provided that when Q is 0, a is a double bond; 30 X is N, NR®, CH, or CHg, and R® is H, or C1-C3 alkyl, alkenyl., or alkynyl; H is C or CH provided that when a is a single bond, X is NR® or CH2 and W is CH, and when a is a double bond, X is N or CH and W is C; Y is N or NR?, and ti? is H or C1-C3 alkyl; 38 DUPA302-774-770 P.45 Z is C or CH, provided that when b is a single bond, Y is NR? and Z is CH, and when b is a double bond, Y is N and Z is C; and, a and b are, independently, single or double bonds; 5 r’ is H or C1-C3 alkyl, alkenyl, or alkynyl; R 2 is C4 to Cj5 alkyl, C4 to C15 alkynyl, or C4 to C15 alkenyl, which may be straight, branched or cyclic, optionally with a terminal COOH or OH group; or R 2 is COR 3 where R 3 is Ci to C15 alkyl, C 2 to C15 alkynyl, or 10 C 2 to C15 alkenyl, which may be straight, branched, or cyclic, optionally with a terminal COOH or OH group; or R 2 is COAr 2 , CH2Ar 2 , CO^r 2 , C0NR 8 Ar 2 , where R 8 is H or C1-C3 alkyl, S02Ar 2 , SO2NHAr 2 , or SO2R 3 ; Ar 2 is phenyl or substituted phenyl, optionally substituted 15 with one or more of -F, -Cl, -Br, -I, -CF3, β-ΝΟ 2 , -CN, -CHO, -N3, C1-C7 alkyl, C1-C7 alkoxy, phenyl, or NR 4 R 8 , where R 4 and R 3 are independently H, or C1-C3 alkyl, or together represent a carbocyclic ring of 3-5 carbons, or Ar 2 is C 2 -Cn, saturated, unsaturated, or aromatic, and 20 which may be straight, branched, or cyclic; or Nmorpholyl; 2- or 3-thiophyl; 2- or 3-pyrrolyl; or 2- or 3-furyl; Provided that: when X is CH or CH 2 and R 2 is COAr 2 , Ar’ and Ar 2 are independently, phenyl or substituted phenyl and when 25 X is CH 2 , R 2 is COAr 2 , CH2Ar 2 , or CO2Ar 2 ; or a resolved optical antipode of any chiral form thereof; or a pharmaceutically acceptable salt thereof; comprising the steps of:

4. DUPA302-774-770 a) reacting in an inert solvent an imidazole of the formula IE 911903 P.2 where Ar^, Ar 2 and are defined above, with an organic peracid, such as m-chloroperoxybenzoic acid; or b) reacting in an organic acid an imidazole of the formula where Ar*, Ar 2 and R 1 are defined above, with monoperoxyphthalic acid magnesium salt to yield a compound of Formula (I) above; c) reacting in an inert solvent a pyrrole of the formula where Ar^, Ar 2 and R^ are as defined above, with an organic peracid, such as m-chloroperoxybenzoic acid or IE 911909 _____ 15 DUPA302-774-770 P.3 oxidizing with singlet oxygen followed by acid treatment, to yield a compound of Formula (I) above where Q is X-R 2 and X is CH; d) and, optionally, reacting the product of a) or b) with a reducing agent such as lithium aluminum hydride in an inert solvent with sodium borohydride in a protic organic solvent to yield a compound of the Formula (I) where Y, Z, Ar*, R 1 , W, Q and b are as defined above and where a is a single bond; e) and, optionally, reacting the product of d) with (1) sodium hydride in dimethylformamide and iodomethane followed by, (2) potassium tert-butoxide in an inert solvent followed by, (3) reaction of the resultant amine with an acylating reagent, such as a benzoyl chloride, in the presence of an organic base to yield a compound of Formula (I) where Y, Z, Ar^, R^, W, Q and b are as defined above and where a is a single bond; f) and optionally, reducing the product of c) where X is CH with an appropriate reducing agent, preferably zinc dust in acetic acid, to yield a compound of Formula (I) where X is CH 2 .

90. A crystalline form of the compound of Claim 23 which has a melting point of about 131-134 e C.

91. A crystalline form of the compound of Claim 23 which has a melting point of about 181-183 fl C.

92. A compound substantially as hereinbefore described with reference to the examples.

93. A composition substantially as hereinbefore described with reference to the examples.

94. A method substantially as hereinbefore described with reference to the examples.

95. A process substantially as hereinbefore described with reference to the examples.

96. Use of a compound as defined in claim 1 for the preparation of a medicament for use in a method of prophylaxis or treatment.