EP0536316A1 - Antihypercholesterolemische bis-trifluormethyl-substituierte imidazoline und ihre derivate - Google Patents

Antihypercholesterolemische bis-trifluormethyl-substituierte imidazoline und ihre derivate

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Publication number
EP0536316A1
EP0536316A1 EP91913532A EP91913532A EP0536316A1 EP 0536316 A1 EP0536316 A1 EP 0536316A1 EP 91913532 A EP91913532 A EP 91913532A EP 91913532 A EP91913532 A EP 91913532A EP 0536316 A1 EP0536316 A1 EP 0536316A1
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European Patent Office
Prior art keywords
compound
pharmaceutically acceptable
mammal
methyl
alkyl
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EP91913532A
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English (en)
French (fr)
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EP0536316A4 (en
Inventor
Jeffrey Thomas Billheimer
George Albert Boswell, Jr.
Indawati De Lucca
Spencer Drummond, Jr.
Peter John Gillies
James Michael Trzaskos
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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Publication of EP0536316A1 publication Critical patent/EP0536316A1/de
Publication of EP0536316A4 publication Critical patent/EP0536316A4/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/22—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to bis-trif1uoromethvl-substituted imidazolines as inhibitors of Acyl-CoA:Cholesterol Acyltrans- ferase (ACAT), processes for their preparation and their use as antihypercholesterolemic and antiatherosclerotic agents.
  • ACAT Acyl-CoA:Cholesterol Acyltrans- ferase
  • 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.
  • the synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed. .
  • Burger, et al., Synthesis. 1 , 44 (1988) describe an alternative synthesis of the 5-imino-2-phenyl-4,4- bis(trifluoromethvl)-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.
  • 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.
  • the present invention provides novel compounds of Formula (I), processes for their preparation, pharmaceutical compositions containing t ⁇ s-trifluoro ethyl-substituted imidazolines and derivatives thereof, and therapeutic methods for their use as antihypercholesterolemic/antiatherosclerotic agents.
  • This invention provides compounds of ' Formula (I):
  • Ar* is phenyl, or mono-, di-, or tri-substituted phe ⁇ yl, optionally substituted with -F, -Cl, -Br, -I, -CF3, -C0NH 2 , -NO2, -CH0, -C02Et, -CN, -O2CR 9 , -SCH3, -SCF3, -SO2CF3, -SO2CH3, 5-tetrazolyl , -N(0)(CH 3 ) , OH, C1-C7 alkoxy, N-piperidyl, C ⁇ -C ⁇ o alkyl, C3-C7 cycloalkyl, or
  • Ar 1 may be C ⁇ -C ⁇ o alkyl, C3-C7 cycloalkyl, or C4-C7 substituted cycloalkyl substituted as above, where R 9 is H or alkyl, alkenyl, or alkynyl of 1 to 20 carbon atoms;
  • Q is 0 or X-R ⁇ 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 ⁇ 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 7 , and R 7 is H or C1-C3 alkyl;
  • Z is C or CH, provided
  • R ⁇ is H or C1-C3 alkyl, alkenyl, or alkynyl
  • R ⁇ 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 C00H or OH group
  • R ⁇ is COR 3 where R 3 is Ci to C15 alkyl ' , C2 to C15 alkynyl, or C2 to Cj5 alkenyl, which may be straight, branched, or cyclic, optionally with a terminal COOH or OH group
  • R 2 is COAr 2 , CH2Ar 2 , C02Ar 2 , C0NR 8 Ar 2 , where R 8 is H or C1-C3 alkyl, S02Ar 2 , S ⁇ 2NHAr 2 , or SO2 3 ;
  • Ar 2 is phenyl or substituted phenyl, optionally substituted with one or more of -F, -Cl, -Br, -I, -CF3, _-NG2, -CN, -CHO, -N3, C1-C7 alkyl, C1-C7 alkoxy, phenyl, or NR 4 R 5 , where R 4 and R ⁇ are independently H, or C1-C3 alkyl, or together represent a carbocyclic ring of 3-5 carbons, or
  • Ar 2 is C2-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; Provided that: when X is CH or CH2 and R 2 is COAr 2 , Ar 1 and Ar 2 are independently, phenyl or substituted phenyl, and when X is CH2, R 2 is COAr 2 , CH2Ar 2 , or C02Ar 2 ; or a resolved optical antipode of any chiral form thereof; or a pharmaceutically acceptable salt thereof.
  • Ar* is phenyl, or mono-, di-, or tri-substituted phenyl, optionally substituted with -F, -Cl, -Br, -I, -CN, -CF3, -CONH2, -OH, -NO2, 5-tetrazolyl, C1-C7 alkoxy, N- piperidyl, -O2CR 9 , where R 9 is C1-C20 alkyl, alkenyl, or alkynyl, C1-C10 alkyl, C3-C7 cycloalkyl, or C3-C10 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;
  • X is N, NR 6 , CH, or CHR 6 , S, and R 6 is H, or C1-C
  • Z is C or CH, provided that when b is a single bond, Y is NR 7 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 , C02Ar 2 , or C0NR 8 Ar 2 , wherein R 8 is H or C1-C3 alkyl;
  • 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, E-NO2, -CH0, -CN, or NR 4 R 5 where R 4 and R ⁇ 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
  • Ar* is phenyl, or onosubstituted phenyl, substituted with -F, -Cl, -Br, -CN, -CF3, -OH, C1-C7 alkoxy, -NO2, -CONH2, N-piperidyl, CH3 or -O2CR 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;
  • X is NR 6 or CH2, and R 6 is H, or C1-C3 alkyl, alkenyl, or alkynyl; W is CH;
  • R 1 is H, CH3, or C2H5;
  • R 2 is COAr 2 or C0NR 8 Ar 2 , wherein R 8 is H or C1-C3 alkyl; and Ar 2 is monosubstituted phenyl, optionally substituted with -F, -Cl, -Br, -CN, -CF3, C1-C7 alkyl, C1-C4 alkoxy, P.-NO2, phenyl, N-piperidyl, or dimethylamino, or Ar 2 is saturated C ⁇ -Cu, which may be straight or branched.
  • Ar* is phenyl, or monosubstituted phenyl, ⁇ -substituted with -F, -Cl, -Br, -CN, -OH, -OCH3, N- piperidyl, -CONH2, or O2CR 9 where R 9 is C1-C20 alkyl, alkenyl or alkynyl;
  • Q is X-R 2 wherein X is bonded to W;
  • X is NR 6 or CH2, and R 6 is H or C1-C3 alkyl, alkenyl, or alkynyl;
  • R 10 CN ⁇
  • R 6 CH 3 -C-@-0(CH 2 )3CH 3
  • 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, R 2 is COAr 2 , Ar 1 is phenyl or substituted phenyl, and R 1 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 U.S. 4,348,404, the teaching of which is hereby incorporated by reference.
  • MMPP monoperoxyphthalic acid magnesium salt
  • glacial acetic acid may be used instead of MCPBA in chloroform in the conversion of the 2-hexafluoroisopropylamino- 4,5-diarylimidazoles (I) to the bis-trifluoromethvl substituted imidazolines (2).
  • the compounds of Formula (I) wherein X is NH, Y is N, W is CH, Z is C, R 2 is COAr 2 , 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 (!) can be prepared by reducing the requisite imines of Formula (2) with lithium aluminum hydride (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.
  • 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 * (Scheme 2.1)
  • the amides, carbamates and ureas of Formula (J_) wherein R 2 is as defined above can be prepared by the route shown in Scheme 3.
  • the requisite benza ide 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.
  • N-methyl aminals of Formula (6) 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 (6) with an acyl chloride, isocyanate or chloroformate by the route shown in Scheme 3.
  • 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.
  • a coupling reagent which generates a reactive intermediate such as a mixed anhydride or active ester.
  • such coupling agents are disubstituted carbodiimides, N,N'-carbonyldiimidazole, diphenylphosphoryl azide, and the like.
  • the coupling can be carried out with a disubstituted carbodiimide such as dicyclohexylcarbodiimide in an appropriate solvent such as methylene chloride, acetonitrile, toluene, or dimethyl- formamide.
  • Nucleophilic hydroxy compounds such as 1-hydroxy-lH- benzotriazole, which form highly active esters, may be added to catalyze the reaction. Reaction of the requisite a ⁇ ' nal (6) "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 a inal with alkyl or aryl isocyanates in methylene chloride at room temperature gives the corresponding ureas of Formula (7).
  • the carbamates of Formula (7) are prepared by allowing the requisite N-methyl aminal of Formula (6) to react with alkyl or aryl chloroformates in methylene chloride at room temperature to the reflux temperature of the solvent.
  • benzamides of Formula (7) having different para- substituents on the benzamide group and the pendant phenyl group are prepared by the route shown in Scheme 4.
  • ortho substituted analogs can be prepared by aromatic nucleophilic substitution as shown in Scheme 4.
  • Compounds wherein Ar 2 may be ortho. eta, and/or para substituted may be prepared using Scheme 3 by reacting compound (6) with the appropriate mono-, di-, or trisubstituted (any combinations at any positions) benzoyl chloride, to yield the desired compounds of Formula (7).
  • benzamides of Formulas (9), (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.
  • a polar solvent such as dimethyl sulfoxide (DMSO)
  • HPLC high pressure liquid chromatography
  • the amides of Formula (13) wherein R 2 is COR 3 , where R 3 is Ci to C15 alkyl, C2 to C15 alkenyl, or C to C15 alkynyl, with a terminal CO2H or OH group may be prepared according to the route shown in Scheme 5.
  • Formula Qjj) are prepared by the route shown in Scheme 6.
  • the requisite 2-hexafluoroisopropylamino-4,5-diarylpyrroles 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.
  • compounds of Formula (14) are allowed to react with excess MCPBA as described above for Scheme 1 to give the bis-trif1uoromethvl substituted imidazoles of Formula (16) 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 (!£) 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.
  • the imidazoles of Formula (17.1) can be prepared by reducing the imidazoles of Formula (j ) with zinc dust in refluxing acetic acid, as shown in Scheme 7.1.
  • the imidazoles of Formula (17 or 17.1) having different para- substituents on the phenyl ketone and the pendant phenyl group are prepared by the route shown in Scheme 7.
  • Compounds having ortho and/or meta substituted phenyl groups can be prepared by starting with compound (14) having appropriately substituted Ar* and Ar 2 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.
  • a polar solvent such as dimethyl sulfoxide (DMSO)
  • Other solvents known to those skilled in the art that are compatible with the reactants and products can'be used in place of methanol.
  • a polar solvent such as pyridine or benzene with dimethyla ino- pyridine.
  • the requisite bicyclic derivative of Formula (25) is allowed to react with excess MCPBA in refluxing chloroform to give the bis-trifluoromethvl substituted imidazoline of Formula (26), which loses the Ar*C0 substituent on nitrogen during the workup to afford (27).
  • the N-substituted bis-trif1uoromethvl substituted imidazolines of Formula (2 ⁇ ) can be synthesized by converting the requisite benzamide of Formula (27) 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.
  • the imidazolinones of Formula (£9) are prepared as shown in 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 (2£). Other solvents such as tetrahydrofuran may be used. Sc.a e 11
  • 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.
  • Example 9R 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.
  • reaction mixture was stirred overnight at room temperature under nitrogen.
  • 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 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 hexane- dichloromethane mixture.
  • the racemic mixture of the title compound was separated to the R and S enantioners using HPLC with a Ch racel-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 22"l5F6N5 ⁇ °H2S0 4 :
  • Example 17 MS m/e 525; -H NMR (CDCI3) ⁇ 0.87(s f 3H,CH3), 1.27(m,16H f (CH 2 )s) . 1.67(m r 2H f CH 2 ) , 2.37(m,2H,CH 2 ), 2.93(s f 6H,2NCH 3 ) , 6.63(s,lH,CH) , 7.17(m f 2H l H arom ), 7.63(m,2H,H aroni ) .
  • Example 22 MS m/e 454; *H NMR (CDCI3) ⁇ 3.00(s,3H,NCH3), 3.20(s,3H f NCH 3 ) , 6.70(s,lH,CH) , 7.20(m l 4H,H arom ), 7.60(m,2H f H arom ) , 7.70(m l 2H l H aro ⁇ ⁇ ) •
  • Example 23 MS m/e 438; ⁇ H NMR (CDC1 3 ) ⁇ 2.97(s,3H,NCH 3 ), 3.20(s,3H,NCH 3 ) , 6.57(s,lH,CH) , 6.73(s,lH,CH), 7.23(m f 3H,H arom ), 7.67(m,3H,H arom ) .
  • 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.
  • Example 120 1-(4-f1uorophenyl-2-f2-(4-f1uorophenyl)-4.5-dihvdro-1-methyl- 4.4-bis(trif1uoromethyl)-lH-imidazol-5-yl1-ethanone
  • the reaction mixture was refluxed under nitrogen for two hours.
  • the solution was cooled to room temperature and poured into saturated sodium bicarbonate (100 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 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 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 antiatherosclerotic effects, including inhibiting esterification and transport of cholesterol across the intestinal wall.
  • ACAT acyl CoA:cholesterol acyl transferase
  • 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.
  • ACAT Cholesterol Acyltransferase
  • ACAT the enzyme responsible for the intracellular synthesis of cholesteryl esters.
  • EDTA ethylenediaminetetraacetic acid
  • 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 ho ogenization 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 ⁇ g of microsomal protein, 75 ⁇ fl 14 C-oleoyl-CoA (10,000 dpm/nmol) in 0.1 M phosphate, pH 7.4, that contained 1 mM glutathione.
  • the esterification of cholesterol was determined in the murine acrophage-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% CO2 and 93% humidity. After 24 hours the media was changed to 0.68 is 10% FBS-DMEM containing 34 ⁇ g 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 *l/ml maximum).
  • the cells were pulsed with 0.1 mM 14 C oleic acid (10,000 dpm/nmol) complexed with BSA (bovine serum albumin) to follow cholesterol ester formation.
  • BSA bovine serum albumin
  • 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 3 H-cholesteryl linoleate and 10 ⁇ g 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 ⁇ ] 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 system.
  • 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.
  • the compounds of the invention are administered to the patient at dosage levels of 7 to 7000 mg per day.
  • dosage levels 7 to 7000 mg per day.
  • 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, health, and weight of the recipient nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • Tablets Tablets are prepared by conventional procedures so that the dosage unit is 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 10 milligrams of magnesium stearate.
  • Capsules are prepared by conventional procedures so that the dosage unit is 500 milligrams of active ingredient, 100 milligrams of cellulose and 10 milligrams of magnesium stearate.
  • the final volume is brought up to 100% by the addition of distilled water.
  • 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.
  • each ingredient is finely pulverized and then uniformly mixed together.
  • the powder can be prepared as a suspension and then spray dried.
  • 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 filled into a suitable packaging container and cooled down to form the gel.
  • Gelcarin® is dissolved in hot water (around 80°C) and then the fine-powder active ingredient is suspended in this solution. 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.

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EP19910913532 1990-06-05 1991-05-31 Antihypercholesterolemic bis-trifluoromethyl-substituted imidazolines and derivatives thereof Withdrawn EP0536316A4 (en)

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