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WO2005099705A2 - Preparation of imidazole derivatives and methods of use - Google Patents

Preparation of imidazole derivatives and methods of use Download PDF

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Publication number
WO2005099705A2
WO2005099705A2 PCT/US2005/008904 US2005008904W WO2005099705A2 WO 2005099705 A2 WO2005099705 A2 WO 2005099705A2 US 2005008904 W US2005008904 W US 2005008904W WO 2005099705 A2 WO2005099705 A2 WO 2005099705A2
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WIPO (PCT)
Prior art keywords
chlorophenyl
alkyl
imidazole
phenyl
carboxamide
Prior art date
Application number
PCT/US2005/008904
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French (fr)
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WO2005099705A3 (en
Inventor
Stephen J. Gardell
Original Assignee
Bayer Pharmaceuticals Corporation
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Publication of WO2005099705A2 publication Critical patent/WO2005099705A2/en
Publication of WO2005099705A3 publication Critical patent/WO2005099705A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone

Definitions

  • This invention relates to imidazole compounds which are useful in promoting smoking cessation and maintaining abstinence.
  • Cigarette smoking and tobacco use remain a major threat to global public health with an estimated 1.1 billion users worldwide (George, et al., Trend Pharmacol. Sci. 25:42-48, 2004).
  • Smoking has been associated with an increased risk of a number of diseases such as cardiovascular disease (e.g., coronary artery disease, stroke, hypertension, and peripheral vascular disease), cancer (e.g., lung, stomach, and bladder), respiratory disease (e.g., bronchitis and obstructive pulmonary disease), and gastric ulcers (Okuyemi, et al., Arch Fam. Med. 9:270-281, 2 OOO).
  • cardiovascular disease e.g., coronary artery disease, stroke, hypertension, and peripheral vascular disease
  • cancer e.g., lung, stomach, and bladder
  • respiratory disease e.g., bronchitis and obstructive pulmonary disease
  • gastric ulcers Okuyemi, et al., Arch Fam. Med. 9
  • the compounds of the present invention may provide an effective therapy for promoting smoking cessation and maintaining abstinence.
  • the invention relates to substituted imidazole derivatives that have utility in the treatment of smoking cessation, said derivatives having Formula (I)
  • R 1 and R 2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, ( - C 6 )alkoxy, trifluoromethyl, cyano, nitro, (C ⁇ -C 6 )alkyl sulfonyl, (C 1 -C 6 )alkyl sulfonyl- amino, (C ⁇ -C 6 )alkyl carbonyl-amino, (C ⁇ -C 6 )alkyl amino-carbonyl-amino, or phenyl,
  • R 3 is hydrogen, (C ⁇ -C 6 )alkyl, benzyl, chloro, or bromo;
  • R 4 is hydrogen or (C 1 -C 6 )alkyl
  • R 5 is selected from (C 2 -C 9 )alkyl or (C 7 -C ⁇ )bicycloalkyl, each of which may optionally be substituted with one or more phenyl, hydroxy, benzyloxy, (Ci-C 6 )alkoxy, (C ⁇ -C 6 )alkyl- amino, bis[(C ⁇ -C 3 )alkyl]-amino, 1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-l,4- benzodioxin-2-yl, hydroxy-substituted (C ⁇ -C 6 )alkyl, or fluorine, benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (C ⁇ -C 6 )alkyl, and optionally substituted on the phenyl
  • R 6 is hydrogen or (C ⁇ -C ⁇ )alkyl
  • R 7 is (C ⁇ -C 9 )alkyl; or phenyl optionally substituted with one or more of (C ⁇ -C 6 )alkyl, hydroxy-substituted (C 1 -C 6 )alkyl, (C ⁇ -C 3 )alkoxy- substituted (C ⁇ -C 3 )alkyl, phenyl, hydroxy, benzyloxy, (C ⁇ -C ⁇ )alkoxy, trifluoromethyl, cyano, nitro, or a halogen atom, or
  • R 6 and R 7 taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocycUc ring which is optionally substituted by one or more (C ⁇ - )alkyl, ( - C 6 )alkoxy, hydroxy-substituted (C ⁇ -C 3 )alkyl, (C ⁇ -C 3 )alkoxy-substituted (C ⁇ -C 3 )alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine;
  • R 4 and R 5 taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (C ⁇ -C 6 )alkyl, (C ⁇ -C 6 )alkoxy, (Q- C 6 )aTkyl-amino, bis[(C 1 -C 3 )alkyl]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (C ⁇ -C 6 )alkyl, phenyl-substituted (C 1 -C 6 )alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (C ⁇ -Ce)alkyl, hydroxy, benzyloxy, ( - C 6 )aTkoxy, trifluoromethyl, cyano, nitro, or halogen;
  • R 10 is (C ⁇ -C 9 )alkyl optionally substituted with one or more phenyl, hydroxy, benz;yloxy, (C ⁇ -C 6 )alkoxy, or a fluorine atom, or phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, or halogen;
  • Another embodiment of the invention consists of imidazole derivatives having Formula (I) wherein
  • R 1 and R 2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, ( - C 6 )alkoxy, trifluoromethyl, cyano, nitro, (C ⁇ -C 6 )alkyl carbonyl-amino, (C ⁇ -C 6 )alkyl amino-carbonyl-amino, or phenyl,
  • R 3 is hydrogen, (C ⁇ -C 6 )alkyl, benzyl, chloro, or bromo;
  • R 4 is hydrogen or (C ⁇ -C 6 )alkyl
  • R 5 is phenyl substituted with one or more (C ⁇ -C 6 )alkyl, hydroxy (C ⁇ -C 6 )alkyl, (Ci- C 6 )alkoxy, phenyl, hydroxy, benzyloxy, trifluoromethyl, or halogen, or a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more (C ⁇ -C 6 )alkyl, (CH ⁇ alko y, or trifluoromethyl;
  • X is R 8 where R 8 is a hydrogen or (Ci-C 6 )alkyl; R 9 is a (C ⁇ -C 9 )alkyl or (C 7 -C ⁇ )bicycloalkyl group, each of which is optionally substituted with one or more of phenyl, hydroxy, benzyloxy, (C ⁇ -C 6 )alkoxy, or fluorine, benzyl in which the phenyl ring is optionally substituted with one or more of ( - C 6 )alkyl, hydroxy, benzyloxy, (C ⁇ -C 6 )alkoxy, trifluoromethyl, cyano, nitro, or halogen, or phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, (C ⁇ -C 6 )alkoxy, or halogen; or
  • R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5- to 10- membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of (C ⁇ -C 6 )al yl, benzyl, hydroxy, benzyloxy, (C ⁇ -C 6 )alkoxy, halogen, a 5- to 10-membered saturated or unsaturated heterocyclic radical; or phenyl optionally substituted with one or more of (C ⁇ -C 6 )alkyl, hydroxy, benzyloxy, trifluoromethyl, cyano, nitro, or halogen;
  • X is TR"' where R 11 is (C 2 -C 9 )alkyl optionally substituted with one or more phenyl, hydroxy, benzyloxy, (C 1 -C6)alkoxy, or fluorine, phenyl in which the phenyl ring is optionally substituted with one or more of (C ⁇ -C 6 )alkyl, hydroxy, benzyloxy, (C ⁇ -Ce)alkoxy, trifluoromethyl, cyano, nitro, or halogen, benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may be optionally substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (C ⁇ -Cg)alkyl, and optionally substituted on the phenyl ring with halogen, (C ⁇ -C 6 )alkyl, (C ⁇ -C 6 )alkoxy, trifluoromethyl
  • Halogen means fluorine, chlorine, bromine or iodine.
  • (C ⁇ -C 3 )alkyl mean - , Ci-C ⁇ , C 2 -C 6 , -Cg, and C 2 -C 9 linear or branched alkyl groups, respectively, that may also include a cyclic alkyl radical as part of the alkyl group.
  • this includes groups such as cyclopropyl, cyclohexyl, cyclopropyl-methyl, and cycloheptyl-methyl groups.
  • the preferred alkyl groups are methyl, ethyl, propyl, and isopropyl groups.
  • (C 7 -C ⁇ )bicycloalkyl means a C 7 -C ⁇ bicyclic alkyl group, such as octahydro-2- pentalenyl, bicyclo[2.2.1]hept-2-yl, and bicyclo[3.2.1]oct-8-yl, that is optionally substituted with one or more methyl groups.
  • 5- to 10-membered saturated or unsaturated heterocyclic radical means a fused or bridged, mono-, bi-, or tri-cyclic, non-aromatic heterocyclic radical which may contain one to three of the heteroatoms nitrogen, oxygen, or sulfur.
  • radicals include the following radicals, for example, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, azepan-1-yl, morpholin-4-yl, hexahydrocyclopenta[c]py ⁇ ol-2(lH)-yl, and thiomorpholin-4-yl.
  • 5- to 10-membered aromatic monocyclic or bicyclic heterocycUc radical means a 5- or 6-membered aromatic heterocyclic radical or a fused bicyclic aromatic heterocyclic radical, which may contain one to three of the heteroatoms nitrogen, oxygen, or sulfur.
  • radicals include the following radicals, for example, furyl, thienyl, isoxazolyl, pyridyl, pyrimidinyl, benzofuranyl, and benzothienyl.
  • any moiety When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence.
  • Representative salts of the compounds of Formula (I) include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate
  • Base salts include alkah metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lauryl
  • the esters in the present invention are non-toxic, pharmaceutically acceptable ester derivatives of the alcohols of Formula (I). This includes ester derivatives prepared from acetic, benzoic, mandeUc, stearic, lactic, saUcylic, hydroxynaphthoic, glucoheptonic, and gluconic acid.
  • the alcohol compounds of Formula (I) may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula (I) compound.
  • anhydride is reacted with the alcohol in the presence of an acylation catalyst such as l,8-bis[dimethylami ⁇ o]naphthalene or DMAP (NN- dimethylaminopyridine).
  • an appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, l-[3-dimethylaminopropyl]-3- ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst- Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of NN-carbonyldiimidazole with pyridine.
  • Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as DMAP or pyridine.
  • an acylation catalyst such as DMAP or pyridine.
  • Sensitive or reactive groups on the compound of Formula (I) may need to toe protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or ($)- configuration, whichever is most active.
  • prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention.
  • Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are " better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc.
  • Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility.
  • compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or Upases in vivo. See for example U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; an 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
  • Another object of this invention is to provide methods of making the compounds of the invention.
  • the compounds may be prepared from readily available materials by the methods outlined in Reaction Schemes 1 and 2 below, and by obvious modifications thereto.
  • prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention.
  • Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc.
  • Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility.
  • compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or Upases in vivo. See for example U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
  • Compounds of Formula (I) are prepared by a variety of methodologies. The selection of the particular method to be used depends upon such factors as the availability of appropriate starting materials, compatibility of functional groups with the reagents used, and the ultimate structural features present in the final compound being prepared. It will be understood by those skilled in the art that more than one method may, in some cases, be useful for the preparation of individual compound examples of Formula (I).
  • the compounds of Formula (I) are prepared from the intermediate compound of Formula (VI) by the methods outlined in Reaction Scheme 2; the compound of Formula (VI) is prepared by the methods outUned in Reaction Scheme 1, by one of the two paths as shown.
  • R, R 1 - R ⁇ , and X are as defined above for Formula (I).
  • Grignard reagent e.g., EtMgBr
  • a neutral solvent e.g., THF
  • Lewis Acid e.g., A1C1 3
  • inert solvent e.g., toluene
  • Formula (VI) This reaction may be further facilitated by the addition of a base (e.g., propyl amine, sodium carbonate, and the like) to remove excess HBr produced as a side product.
  • a base e.g., propyl amine, sodium carbonate, and the like
  • the conversion of IV to VI may be accomplished in a stepwise manner, i.e., first carrying out the reaction of IV with V and isolation of the crude product, and then heating the residue with the R J NH 2 compound in acetic acid complete the cyclization to imidazole VI.
  • ketoesters of Formula (VII) are converted to an oxime compound of Formula (V ⁇ i), by reaction with sodium nitrite in a protic sofvent, typically acetic acid/water, while cooling.
  • a protic sofvent typically acetic acid/water
  • the product (VIII) is then heated with an amine of formula R 1 NH 2 in a polar solvent such as acetonitrile, to provide the imidazole of Formula ( X).
  • N-substitution may be carried out by treatment of (IX) with a base and a compound of formula R 2 Y, where Y is a leaving group such as halogen, mesylate, or tosylate.
  • R 2 when the R 2 is aryl, it is generally an activated (electrophilic) haloarene such as 4-halonitrobenzene or a 2- or 4-halopyridine, capable of undergoing nucleophilic aromatic substitution reactions.
  • activated (electrophilic) haloarene such as 4-halonitrobenzene or a 2- or 4-halopyridine, capable of undergoing nucleophilic aromatic substitution reactions.
  • the compounds of Formula (VI), in which .' is H, may be made from the compounds of Formula (VI) in which R' is alkyl, by ester hydrolysis methods well known in the art.
  • the compounds of Formula (VI), prepared as shown in Reaction Scheme 1, may then be used for the preparation of the compounds of Formula (T).
  • synthetic routes are shown for the more specific compounds of Formula (la), (lb), (Ic), and (Id).
  • an acid halide e.g., using SOCl 2 or TFFH
  • base present such as triethyl amine or PS-DIEA (polystyrene bound-diisopropylethylamine).
  • the acid may be activated as a carbodiimide adduct (e.g., with l-(3-dimethylaminopropyl, triethylamine, and l-hydroxy-7- azabenzotriazole)-3-ethylcarbodiimide hydrochloride) or as a hexafluorophenyl ester (prepared from hexafluorophenol and EDCI).
  • a compound represented as R 4 R 5 NH is added to complete the reaction to the Formula (la) compound.
  • One-pot variations of this conversion may also be carried out, for example, by mixing a coupUng reagent such as HATU and the R 4 R 5 NH compound at the same time.
  • Compounds of Formula (la) may also be prepared as shown, from an ester of Formula (VI) where R 3 is H, by first halogenating the imidazole by standard means (e.g., NBS or S0 2 C1 2 ) to give the haloimidazole of Formula (X). While this intermediate may be used to prepare Formula (VI) intermediates where R 3 ⁇ H, using such methods as Pd-catalyzed organotin coupling reactions (e.g., when R 3 is methyl), Formula (X) compounds may also be converted to the amides of Formula (XI) under the same conditions described above for conversion of Formula (VI) compounds to Formula (IA). The resulting amide of Formula (XI) may then be converted to a Formula (la) compound, where R 3 ⁇ H, by Pd-catalyzed organotin coupl ng reactions.
  • standard means e.g., NBS or S0 2 C1 2
  • Formula (X) compounds may also be converted to the amides
  • DIB AH dnsobutylaluminum hydride
  • a coupling agent such as, for example, a NN'-dialkyl carbodiimide such as NN'-dicyclohexyl carbodiimide and a base such as, for example, DMAP.
  • a organometallic reagent such as, for example, an alkyl or aryl Grignard reagent of Formula R u MgBr
  • This Formula (Id) ketone may also be prepared by similar reaction of aryl- or alkllithium reagents, such as, fox example, R ⁇ Li, with Formula (XD1), or certain Formula (la) amides where R 4 R 5 ⁇ H is 4-piperidone.
  • aryl- or alkllithium reagents such as, fox example, R ⁇ Li
  • Formula (XD1) or certain Formula (la) amides where R 4 R 5 ⁇ H is 4-piperidone.
  • Conversion of the substituted compounds of Formula (la), (lb), (Ic), and (Id) to differently substituted Formula (I) compounds may be carried out using standard functional group conversion chemistry.
  • keto substituents may be reduced with reagents such as Na 2 BH 4 , to the corresponding hydroxy substituted compounds.
  • Other such examples are 1) the conversion of nitrophenyl substituent to the corresponding aminophenyl substituent, and 2) O- or N-alkylation or acylation of OH or NH substituents to give the corresponding O- or N-albyl or O- or N-acyl substituted compounds.
  • Proton ( ⁇ ) nuclear magnetic resonance (NMR) spectra were mea-sured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me Si ( ⁇ OOO) or residual protonated solvent (CHC1 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as reference standard.
  • Carbon ( 13 C) ⁇ MR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; d 3 -MeOD; ⁇ 49.0; d 6 -DMSO ⁇ 39.5) as reference standard.
  • LC-MS data are given with retention times (RT) determined by using one of the following methods:
  • Method 1 Eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.02% TFA. Elution conditions consisted of a flow rate of 1.0 mL/min with an initial hold at 10% B for 0.5 minutes, followed by gradient elution from 10% B to 95% B over 3.5 minutes, followed by a final hold at 95% B for 0.5 minutes. Total run time was 6.5 minutes.
  • Celite ® diatomaceous earth filter agent ® Celite Corp.
  • the free base form of the product was obtained by dissolving the TFA salt in dichloromethane, washing with saturated aqueous sodium carbonate solution and water, followed by drying the organic phase with magnesium sulfate, and evaporation of the organic phase under reduced pressure.
  • the hydrochloride salt form of the product was obtained by treating the free base in dichloromethane with 1.0 M hydrogen chloride in diethyl ether until no more precipitate was formed, followed by evaporation of solvent under reduced pressure.
  • trans-2-aminocyclohexanol hydrochloride (84 mg, 0.55 mmol) trans-2-aminocyclohexanol hydrochloride was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 53 mg of 2-(2,4-dichlorophenyl)-N-(trans-2- hydroxycyclohexyl)-l-(4-methoxyphenyl)-lH-imidazole-4-carboxamide (amber oU, 23% yield).
  • Step 1 Thionyl chloride (0.66 mL, 9 mmol) was added to a solution of 2-(2- chlorophenyl)-l-(4-cMorophenyl)-lH-imidazole-4-carboxylic acid (1 g, 3 mmol) in toluene (10 mL). The mixture was refluxed under argon for 1.5 h and concentrated to provide 2-(2- chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carbonyl chloride, which was used in the next step without purification.
  • J HNMR 300 MHz, CD 2 C1 2 ) ⁇ 8.40 (s, 1H), 7.69-7.09 (m, 8H).
  • Step 2 Triethylamine (1.46 mL, 10.45 mmol) was added to a suspension of 4- piperidinone trifluoroacetate (0.76 g, 3.58 mmol) in CH 2 C1 2 (10 mL) and a solution of 2-(2- chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carbonyl chloride in CH C1 2 (5 mL) was added.
  • Step 1 To a solution of 5-butyl-2-(2-chlorophenyl)-l-(4-chlorophenyl)-li ⁇ -imidazole-4- carboxylic acid (438 mg, 1.12 mmol) in dry toluene (3 mL), at rt was added thionyl chloride (401 ⁇ L, 3.4 mmol). The solution was stirred overnight at rt, and then heated at 110°C for 5 h.
  • Step 2 To a solution of 5-butyl-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4- carbonyl chloride (227 mg, 0.56 mmol) in CH 2 C1 2 (5 mL), were added 1-aminopiperidine (113 mg, 1.12 mmol) and Et 3 N (234 ⁇ L, 1.68 mmol). The solution was stirred overnight at rt, and then the solvents were evaporated under reduced pressure.
  • Step 2 The pentafluorophenol ester (60 mg, 0.12 mmol) and exo-norbornylamine (40 mg,
  • Step 1 A solution of 2-(2-chlorophenyl)-l-(4-chlorophen5 )-lH-imidazole-4-carboxylic acid (50 mg, 0.15 mmol) and N-bromosuccinimide (88 mg, 0.49 mmol) in dimethylformamide (5 mL) was stirred at 75°C for 3 days. The solution was purified by preparative HPLC to give 5- bromo-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carhoxylic acid as a white solid (30.7 mg, 50%). LC-MS m/z 411.2 (MH*), retention time 2.70 min (method 2).
  • Step 2 As described previously for Example 14, 5-bromo-2-(2-chlorophenyl)-l-(4- chlorophenyl)-li ⁇ -imidazole-4-carboxylic acid was converted to 5-bromo-2-(2-chlorophenyl)-l- (4-chlorophenyl)-N-(l-piperidinyl)-lfl r -imidazole-4-carboxamide.
  • Step 1 To a solution of BF 3 .Et 2 0 (57.5 mL, 0.454 mmol) in CHC1 3 (180 mL) heated at reflux was added dropwise, over a 1-h period, a solution of 1 ,3-propanedithiol (22.7 mL, 0.227 mmol), followed by ethyl diethoxyacetate (40 g, 0.227 mmol) in CHC1 3 (40 mL). The resulting mixture was heated for 30 minutes, and then cooled to rt. The cooled solution was washed 2 times with water, once with saturated aqueous NaHC0 3 , and then re-washed with water.
  • Step 2 To a suspension of NaH (95 %, 2.8 g, 111 mmol) in dry toluene (120 mL) stirring at 0°C was dropwise added, over 10 minutes, a solution of bromomethylcyclopropane (15 g, 111 mmol), and ethyl l,3-dithiane-2-carboxylate (17.77 g, 92.58 mmol) in dry DMF (40 mL). The ice bath was removed and the solution was stirred overnight at rt. Water was added to the solution and the phases were separated.
  • Step 3 A solution of ethyl 2-(cyclopropylmethyl)-l,3-dithiane-2-carboxylate (19.6 g, 79.67 mmol) in CH 3 CN (20 mL) was slowly added, over 30 minutes, to a well-stirred suspension of NBS (N-bromosuccinimide) in CH 3 CN (210 mL) and water (55 rriL). After the mixture was stirred for 1 h, the resulting red solution was poured into an ice-cold CH 2 ⁇ 2 -Hexane solution (1:1 500 mL). The resulting mixture was washed with saturated aqueous NaHS0 3 and water.
  • NBS N-bromosuccinimide
  • Step 4 To a solution of ethyl 3-cyclopropyl-2-oxopropanoate (4.75g, 30.44 mmol) in CC1 4 (60 mL) at rt was added NBS (5.96 g 33.49 mmol).
  • Step 1 To a suspension of Lil (23.61 g, 176.44 mmol) in THF (200 mL) at rt was slowly added Cu 2 Br 2 (25.30 g, 88.22 mmol). A vigorous exothermic reaction occurred, and the mixture was then cooled to -78°C. Pentylrnagnesium bromide (2M, 36.76 mL, 88.22 mmol) was slowly added at -78°C, and followed soon after by ethyl chloro(oxo)acetate (lOg, 73.52 mmol) . The resulting solution was stirred 10 minutes at -78°C, then quenched by dropwise addition of water.
  • Step 2 To a cold solution of ethyl 2-oxoheptanoate (2 g, 11.62 mmol) in AcOH (20 mL), was added Br 2 (596 ⁇ L, 11.62 mmol). The mixture was stirred 20 minutes at 0°C, then the mixture was allowed to warm to rt. After the mixture was stirred for 3 h, water and CH 2 C1 2 were added.
  • trans- 2-bromo-l-indanol 500 mg, 2.35 mmol was dissolved in DMF (5 mL) and sodium azide (305 mg, 4.69 mmol) was added dropwise. The mixture was stirred at rt for 1 h, and then heated to 70°C and stirred for an additional 18 h. The mixture was cooled, water was added, and extracted with ether. The ether was removed and the crude (412 mg) was dissolved in THF (15 mL). This solution was added to Pd/C (41 mg) and stirred under hydrogen at rt for 3 days. The reaction mixture was filtered and the filtrate was concentrated down to provide the desired product, which was used without purification.
  • [183] [(2S)-l-Amino-2-piperidinyl]methanol was prepared according to the method described by Rosling et al., (Heterocycles 95-106, 1997). In a similar manner were prepared [(2R)-l-amino-2- piperidinyl]-methanol, [(2S)-l-amino-2-pyrrolidinyl]methanol, and [(2R)-l-amino-2- pyrrolidinyljmethanol. [184] Intermediate L 3-Methylisonicotinonitrile
  • subject includes mammals (e.g., humans and animals).
  • treatment includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
  • composition therapy means the administration of two or more therapeutic agents to treat a diabetic condition and/or disorder.
  • administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent.
  • administration encompasses use of each type of therapeutic agent in a sequential manner.
  • terapéuticaally effective means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
  • pharmaceutically acceptable means that the subject item is appropriate for use in a pharmaceutical product.
  • the compounds of the present invention are useful in promoting smoking cessation and maintaining abstinence. In addition, these compounds are useful to treat nicotine addiction.
  • the compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of smoking cessation. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.
  • the compounds of the invention may be administered in combination with other pharmacotherapies utilized for nicotine dependence.
  • these compounds may be co- administered with nicotine replacement therapy (NRT) such as nicotine gum, nicotine patch, nicotine spray, nicotine lozenge, nicotine inhaler, and the like.
  • NRT nicotine replacement therapy
  • the compounds of the present invention may also be administered in combination with a nicotinic receptor modulator (e.g., Varenicline).
  • the compounds of the present invention may also be used in combination with antidepressant agents such as bupropion (e.g., Zyban®).
  • antidepressant agents such as bupropion (e.g., Zyban®).
  • Anti-obesity drugs include ⁇ -3 agonists; CB-1 antagonists; neuropeptide Y5 inhibitors; appetite suppressants, such as, for example, sibutramine (Meridia); and lipase inhibitors, such as, for example, orlistat (Xenical).
  • Compounds of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, ⁇ -blockers and ACE inhibitors.
  • additional anti- hypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone),
  • ET receptor antagonists e.g., sitaxsentan, atrsentan, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual ⁇ EP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
  • Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the invention in combination with nicotine replacement therapy and an anti-obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day.
  • a unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day.
  • the daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg.
  • the daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight.
  • the transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds described herein may be administered with a pharmaceutically- acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
  • the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • Suitable excipients for use in oral liquid dosage forms include diluents, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums, (2) naturally occurring phosphatides, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, and (4) condensation products of partial esters.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil; or in a mineral oil.
  • the oily suspensions may contain a thickening agent.
  • the suspensions may also contain one or more preservatives; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent, or emulsifying agent and other pharmaceutical adjuvants.
  • a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent, or emulsifying agent and other pharmaceutical adjuvants.
  • compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents; dispersing or wetting agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such material are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release.
  • Such fo ⁇ nulations can be comprised of synthetic polymers or copolymers.
  • Such formulations allow for injection, inhalation, nasal or oral administration.
  • the construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., U.S. Patent No. 6, 706,289, incorporated herein by reference).
  • compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generaUy referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
  • the compounds described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with known anti-obesity, or with known nicotine replacement therapeutics or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • compositions which are comprised of an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof.
  • An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried.
  • An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.
  • Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20 th edition, 2000).
  • Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for smoking cessation, the following assays may be used.
  • An intravenous nicotine self-administration model or place preference model may be used to assess the effects of a test compound on nicotine dependence (see, e.g., Vastola, et al. Physiol. Behav. 77:107-114, 2002; Brower, et al., Brain Res. 930:12-20, 2002).
  • Sprague-Dawley rats are used in this study (Vastola, et al., 2002). Animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. Conditioning and testing are conducted in a chamber divided into two compartments with a door separating the two compartments. Behavior of the animals is recorded by video camera.
  • Sprague-Dawley rats are used in this study. Initially, animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. The animals are then implanted with jugular catheters which exit through the animal's back, and each animal is placed in an individual operant chamber (Brower, et al., 2002). The catheters are connected to a computer-driven syringe pump which is located outside of the chamber. The chamber contains two levers with a green light located above each lever. The light is illuminated when nicotine is available.
  • test compound After stable nicotine self-administration is obtained, the effect of a test compound on the nicotine- reinforced behavior may be evaluated. Administration of this test compound prior to the session can either potentiate, extinguish, or produce no change to the self-administrating behavior. Tests are conducted every two days, and the order of the administration of the test compound doses is controlled.

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Abstract

This invention relates to imidazole compounds which are useful in promoting smoking cessation and maintaining abstinence.

Description

PREPARATION OF IMIDAZOLE DERIVATIVES AND METHODS OF USE
[001] This application claims benefit of U.S. Provisional Application Serial No. 60/555,920, filed on March 24, 2004, the contents of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[002] This invention relates to imidazole compounds which are useful in promoting smoking cessation and maintaining abstinence.
BACKGROUND OF THE INVENTION
[003] Cigarette smoking and tobacco use remain a major threat to global public health with an estimated 1.1 billion users worldwide (George, et al., Trend Pharmacol. Sci. 25:42-48, 2004). Smoking has been associated with an increased risk of a number of diseases such as cardiovascular disease (e.g., coronary artery disease, stroke, hypertension, and peripheral vascular disease), cancer (e.g., lung, stomach, and bladder), respiratory disease (e.g., bronchitis and obstructive pulmonary disease), and gastric ulcers (Okuyemi, et al., Arch Fam. Med. 9:270-281, 2 OOO). However, quitting tobacco use has proven to be a difficult task for many smokers.
[004] hi fact, it is widely recognized that cigarette smoking is an addictive behavior, and nicotine is the primary ingredient in tobacco smoke that is responsible for this addiction. Thus, the development of effective therapies for the prevention of self-administratioo of nicotine, attenuation of the nicotine withdrawal syndrome, and prevention of relapse of nicotine-seeking behavior is critical.
[005] The compounds of the present invention may provide an effective therapy for promoting smoking cessation and maintaining abstinence.
DETAILED DESCRIPTION OF THE INVENTION
[006] The invention relates to substituted imidazole derivatives that have utility in the treatment of smoking cessation, said derivatives having Formula (I)
Figure imgf000002_0001
( I ) wherein R1 and R2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (C1-C6)alkyl, ( - C6)alkoxy, trifluoromethyl, cyano, nitro, (Cι-C6)alkyl sulfonyl, (C1-C6)alkyl sulfonyl- amino, (Cι-C6)alkyl carbonyl-amino, (Cι-C6)alkyl amino-carbonyl-amino, or phenyl,
(C2-C6)alkyl, cyclohexyl optionally substituted with (Cχ-C6)alkyl, (Cι-Ce)alkoxy, trifluoromethyl, cyano, or with one or more fluorine,
1 -naphthyl or 2-naphthyl optionally substituted with halogen, (Cι-C6)alkyl, (Ci- C6)alkoxy, trifluoromethyl, or cyano, benzyl optionally substituted on the phenyl ring with one or more halogen, (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, or cyano, a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine, (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, or cyano, and a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (Cι-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano, nitro, or phenyl;
R3 is hydrogen, (Cι-C6)alkyl, benzyl, chloro, or bromo;
Figure imgf000003_0001
where R4is hydrogen or (C1-C6)alkyl;
R5 is selected from (C2-C9)alkyl or (C7-Cπ)bicycloalkyl, each of which may optionally be substituted with one or more phenyl, hydroxy, benzyloxy, (Ci-C6)alkoxy, (Cι-C6)alkyl- amino, bis[(Cι-C3)alkyl]-amino, 1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-l,4- benzodioxin-2-yl, hydroxy-substituted (Cι-C6)alkyl, or fluorine, benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Cι-C6)alkyl, and optionally substituted on the phenyl ring with one or more halogen, (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro, piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, each of which may optionally be substituted on the nitrogen atom of the piperidine or pyrrolidine ring with ( - C6)alkyl, hydroxy-substituted (C1-C6)alkyl, (Cι-C3)alkoxy-substituted (Q- C3)alkyl, benzyl, or phenyl optionally substituted with one or more of ( - C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, nitro, or halogen,
-NR6R7 where R6 is hydrogen or (Cι-Cβ)alkyl;
R7 is (Cι-C9)alkyl; or phenyl optionally substituted with one or more of (Cι-C6)alkyl, hydroxy-substituted (C1-C6)alkyl, (Cι-C3)alkoxy- substituted (Cι-C3)alkyl, phenyl, hydroxy, benzyloxy, (Cι-Cδ)alkoxy, trifluoromethyl, cyano, nitro, or a halogen atom, or
R6 and R7, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocycUc ring which is optionally substituted by one or more (Cι- )alkyl, ( - C6)alkoxy, hydroxy-substituted (Cι-C3)alkyl, (Cι-C3)alkoxy-substituted (Cι-C3)alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine;
or
R4 and R5, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (Cι-C6)alkyl, (Cι-C6)alkoxy, (Q- C6)aTkyl-amino, bis[(C1-C3)alkyl]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (Cι-C6)alkyl, phenyl-substituted (C1-C6)alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (Cι-Ce)alkyl, hydroxy, benzyloxy, ( - C6)aTkoxy, trifluoromethyl, cyano, nitro, or halogen;
or
Figure imgf000005_0001
where R10 is (Cι-C9)alkyl optionally substituted with one or more phenyl, hydroxy, benz;yloxy, (Cι-C6)alkoxy, or a fluorine atom, or phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy,
Figure imgf000005_0002
or halogen;
and pharmaceutical salts and esters thereof.
[007] Another embodiment of the invention consists of imidazole derivatives having Formula (I) wherein
R1 and R2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (C1-C6)alkyl, ( - C6)alkoxy, trifluoromethyl, cyano, nitro, (Cι-C6)alkyl carbonyl-amino, (Cι-C6)alkyl amino-carbonyl-amino, or phenyl,
(C2-C6)alkyl, cyclohexyl optionally substituted with (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, or with one or more fluorine,
1- or 2-naphthyl optionally substituted with halogen, (Cι-C6)al yl, (Cι-C6)alkoxy, trifluoromethyl, or cyano, benzyl optionally substituted on the phenyl ring with one or more halogen, (Cι^6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, or cyano, a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine, (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, or cyano, and a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (C1-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, nitro, or phenyl, with the proviso that R2 is not an unsubstituted 4-pyridyl or an unsubstituted 4-pyrimidinyl group;
R3 is hydrogen, (Cι-C6)alkyl, benzyl, chloro, or bromo;
Figure imgf000006_0001
where R4is hydrogen or (Cι-C6)alkyl;
R5 is phenyl substituted with one or more (Cι-C6)alkyl, hydroxy (Cι-C6)alkyl, (Ci- C6)alkoxy, phenyl, hydroxy, benzyloxy, trifluoromethyl, or halogen, or a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more (Cι-C6)alkyl, (CH^alko y, or trifluoromethyl;
or CH2 R9
X is R8 where R8 is a hydrogen or (Ci-C6)alkyl; R9 is a (Cι-C9)alkyl or (C7-Cπ)bicycloalkyl group, each of which is optionally substituted with one or more of phenyl, hydroxy, benzyloxy, (Cι-C6)alkoxy, or fluorine, benzyl in which the phenyl ring is optionally substituted with one or more of ( - C6)alkyl, hydroxy, benzyloxy, (Cι-C6)alkoxy, trifluoromethyl, cyano, nitro, or halogen, or phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, (Cι-C6)alkoxy, or halogen; or
R8 and R9, together with the nitrogen atom to which they are attached, form a 5- to 10- membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of (Cι-C6)al yl, benzyl, hydroxy, benzyloxy, (Cι-C6)alkoxy, halogen, a 5- to 10-membered saturated or unsaturated heterocyclic radical; or phenyl optionally substituted with one or more of (Cι-C6)alkyl, hydroxy, benzyloxy,
Figure imgf000007_0001
trifluoromethyl, cyano, nitro, or halogen;
or
O ^o
X is TR"' where R11 is (C2-C9)alkyl optionally substituted with one or more phenyl, hydroxy, benzyloxy, (C1-C6)alkoxy, or fluorine, phenyl in which the phenyl ring is optionally substituted with one or more of (Cι-C6)alkyl, hydroxy, benzyloxy, (Cι-Ce)alkoxy, trifluoromethyl, cyano, nitro, or halogen, benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may be optionally substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Cι-Cg)alkyl, and optionally substituted on the phenyl ring with halogen, (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy or nitro, or a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical;
and pharmaceutical salts and esters thereof.
[008] The terms identified above have the following meaning throughout: "Halogen" means fluorine, chlorine, bromine or iodine.
[009] The terms "(Cι-C3)alkyl", "(C1-C6)alkyl", "(C2-C6)alkyl", "(Cι-C9)alkyr', and "(C2- C9)alkyl" mean - , Ci-Cβ, C2-C6, -Cg, and C2-C9 linear or branched alkyl groups, respectively, that may also include a cyclic alkyl radical as part of the alkyl group. For example, this includes groups such as cyclopropyl, cyclohexyl, cyclopropyl-methyl, and cycloheptyl-methyl groups. The preferred alkyl groups are methyl, ethyl, propyl, and isopropyl groups.
[010] "( -Q alkoxy" and "(C1-C6)alkoxy" mean (C1-C3)alkyl-oxy and (Cι-C6)alkyl-oxy, respectively.
[011] "(C7-Cιι)bicycloalkyl" means a C7-Cπ bicyclic alkyl group, such as octahydro-2- pentalenyl, bicyclo[2.2.1]hept-2-yl, and bicyclo[3.2.1]oct-8-yl, that is optionally substituted with one or more methyl groups.
[012] The term "5- to 10-membered saturated or unsaturated heterocyclic radical" means a fused or bridged, mono-, bi-, or tri-cyclic, non-aromatic heterocyclic radical which may contain one to three of the heteroatoms nitrogen, oxygen, or sulfur. These radicals include the following radicals, for example, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, azepan-1-yl, morpholin-4-yl, hexahydrocyclopenta[c]pyπol-2(lH)-yl, and thiomorpholin-4-yl.
[013] The term "5- to 10-membered aromatic monocyclic or bicyclic heterocycUc radical" means a 5- or 6-membered aromatic heterocyclic radical or a fused bicyclic aromatic heterocyclic radical, which may contain one to three of the heteroatoms nitrogen, oxygen, or sulfur. These radicals include the following radicals, for example, furyl, thienyl, isoxazolyl, pyridyl, pyrimidinyl, benzofuranyl, and benzothienyl.
[01 ] When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence. [015] Representative salts of the compounds of Formula (I) include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
[016] Base salts include alkah metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
[017] The esters in the present invention are non-toxic, pharmaceutically acceptable ester derivatives of the alcohols of Formula (I). This includes ester derivatives prepared from acetic, benzoic, mandeUc, stearic, lactic, saUcylic, hydroxynaphthoic, glucoheptonic, and gluconic acid. The alcohol compounds of Formula (I) may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula (I) compound. The appropriate anhydride is reacted with the alcohol in the presence of an acylation catalyst such as l,8-bis[dimethylamiτιo]naphthalene or DMAP (NN- dimethylaminopyridine). An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, l-[3-dimethylaminopropyl]-3- ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst- Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of NN-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as DMAP or pyridine. One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification of alcohols. Sensitive or reactive groups on the compound of Formula (I) may need to toe protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
[018] It will be appreciated that diastereomers and enantiomers of the exemplified structures will often be possible, and that pure isomers represent preferred embodiments. It is intended that pure stereoisomers, and mixtures thereof, are within the scope of the invention.
[019] The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or ($)- configuration, whichever is most active.
[020] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.
[021] Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (= Z-) or trans (= E-) form, and both isomeric forms are encompassed within the scope of this invention.
[022] The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.
[023] For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.
[024] It is anticipated that prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention. Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are "better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc. Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility. For example, compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or Upases in vivo. See for example U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; an 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
[025] In the Reaction Schemes below, one skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. When specific reagents or solvents are shown in a Reaction Scheme, therefore, they are meant to be illustrative examples of conditions desirable for the execution of that particular -Reaction Scheme. Abbreviations not identified in accompanying text are listed later in this disclosure under "Abbreviations and Acronyms."
[026] Another object of this invention is to provide methods of making the compounds of the invention. The compounds may be prepared from readily available materials by the methods outlined in Reaction Schemes 1 and 2 below, and by obvious modifications thereto.
General Preparation of Compounds of Formula (I)
[027] It is anticipated that prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention. Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc. Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility. For example, compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or Upases in vivo. See for example U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
[028] Compounds of Formula (I) are prepared by a variety of methodologies. The selection of the particular method to be used depends upon such factors as the availability of appropriate starting materials, compatibility of functional groups with the reagents used, and the ultimate structural features present in the final compound being prepared. It will be understood by those skilled in the art that more than one method may, in some cases, be useful for the preparation of individual compound examples of Formula (I).
[029] In general, the compounds of Formula (I) are prepared from the intermediate compound of Formula (VI) by the methods outlined in Reaction Scheme 2; the compound of Formula (VI) is prepared by the methods outUned in Reaction Scheme 1, by one of the two paths as shown. For the compounds of Formulas (Ia)-(Id) and (H)-(XIII), unless specifically defined otherwise, R, R1- Rπ, and X are as defined above for Formula (I).
[030] Reaction Scheme 1 Path l
Figure imgf000012_0001
R2Y base
R' .JAA, NaNOs
Figure imgf000012_0002
Path 2 R' = H or lower alkyl R" = lower alkyl Y = halo, OTs or OMs
Preparation of Intermediates of Formula (VI) (Reaction Scheme 1)
[031] In Path 1, an imidamide of Formula (IV) is prepared by reaction of an amine of Formula
(HJ) with a nitrile of Formula (II). This reaction is either conducted using a strong base such as a
Grignard reagent (e.g., EtMgBr) in a neutral solvent (e.g., THF) at room temperature, or with a
Lewis Acid (e.g., A1C13) in an inert solvent (e.g., toluene) with heating. The product, imidamide
TV, is then allowed to react with a 3-bromopyruvate of Formula (V) by mixing together in an inert solvent (e.g., toluene or THF), with optional heating, to give the imidazole intermediate of
Formula (VI). This reaction may be further facilitated by the addition of a base (e.g., propyl amine, sodium carbonate, and the like) to remove excess HBr produced as a side product. Alternatively, the conversion of IV to VI may be accomplished in a stepwise manner, i.e., first carrying out the reaction of IV with V and isolation of the crude product, and then heating the residue with the RJNH2 compound in acetic acid complete the cyclization to imidazole VI.
[032] In path 2, ketoesters of Formula (VII) are converted to an oxime compound of Formula (Vπi), by reaction with sodium nitrite in a protic sofvent, typically acetic acid/water, while cooling. The product (VIII) is then heated with an amine of formula R1NH2 in a polar solvent such as acetonitrile, to provide the imidazole of Formula ( X). Finally, N-substitution may be carried out by treatment of (IX) with a base and a compound of formula R2Y, where Y is a leaving group such as halogen, mesylate, or tosylate. For this patlrway, when the R2 is aryl, it is generally an activated (electrophilic) haloarene such as 4-halonitrobenzene or a 2- or 4-halopyridine, capable of undergoing nucleophilic aromatic substitution reactions.
[033] The compounds of Formula (VI), in which .' is H, may be made from the compounds of Formula (VI) in which R' is alkyl, by ester hydrolysis methods well known in the art.
[034] Reaction Scheme 2
Figure imgf000014_0001
Z = halogen R1 = H or lower alkyl R" = lower alkyl
Preparation of Compounds of Formula (D (Reaction Scheme 2)
[035] The compounds of Formula (VI), prepared as shown in Reaction Scheme 1, may then be used for the preparation of the compounds of Formula (T). To illustrate the methods which are useful for the preparation of the Formula (I) compounds, synthetic routes are shown for the more specific compounds of Formula (la), (lb), (Ic), and (Id). These four structures represent the variants of the Formula (I) compounds when X = -C(=0)NR4R5, -CH2NR.8R9, -C(=0)NHS02R10, and -C(=0)Rπ, respectively.
[036] The synthetic methods for the preparation of each of these variants of the Formula (I) compounds are illustrated in Reaction Scheme 2.
[037] In one such method, compounds of Formula (VI), in which R' = FT, the carboxylic acid group is first activated as an acid halide (e.g., using SOCl2 or TFFH) and subsequently treated with a compound of formula R4R5NH, usually with base present such as triethyl amine or PS-DIEA (polystyrene bound-diisopropylethylamine). Alternatively, the acid may be activated as a carbodiimide adduct (e.g., with l-(3-dimethylaminopropyl, triethylamine, and l-hydroxy-7- azabenzotriazole)-3-ethylcarbodiimide hydrochloride) or as a hexafluorophenyl ester (prepared from hexafluorophenol and EDCI). Following activation, a compound represented as R4R5NH is added to complete the reaction to the Formula (la) compound. One-pot variations of this conversion may also be carried out, for example, by mixing a coupUng reagent such as HATU and the R4R5NH compound at the same time.
[038] Compounds of Formula (la) may also be prepared from compounds of Formula (VI) where R' = alkyl by heating together the R R5NH compound and trimethydaluminum.
[039] Compounds of Formula (la) may also be prepared as shown, from an ester of Formula (VI) where R3 is H, by first halogenating the imidazole by standard means (e.g., NBS or S02C12) to give the haloimidazole of Formula (X). While this intermediate may be used to prepare Formula (VI) intermediates where R3 ≠ H, using such methods as Pd-catalyzed organotin coupling reactions (e.g., when R3 is methyl), Formula (X) compounds may also be converted to the amides of Formula (XI) under the same conditions described above for conversion of Formula (VI) compounds to Formula (IA). The resulting amide of Formula (XI) may then be converted to a Formula (la) compound, where R3 ≠ H, by Pd-catalyzed organotin coupl ng reactions.
[040] Formula (lb) compounds may be prepared from Formula (VI) compounds in the presence of an amino compound of Formula R8R9NH under reductive conditions. "When R8 is hydrogen, a Formula (VI) compound where R' = alkyl, is first partially reduced to the aldehyde with, for example, dnsobutylaluminum hydride (DIB AH), the R8R9NH compound is added to form an imine intermediate in situ, which is then reduced with sodium borohydride. When R8≠ H, the reductive alkylation may be accomplished in one step with the R8R9NH compound and lithium aluminum hydride by using the procedure described by Khanna et al, (Synthesis όO^-όOS, 1975). [041 ] The acylsulfonamides of Formula (Ic) may be prepared by reaction of the Formula (VI) compound (where R' = H) with a sulfonamide of Formula R10SO2NH2> facilitated by a coupling agent such as, for example, a NN'-dialkyl carbodiimide such as NN'-dicyclohexyl carbodiimide and a base such as, for example, DMAP.
[042] Formula (Id) compounds may be prepared by conversion of an acid chloride represented by Formula (XII), prepared as described above from VI (where R' = H) and SOCl , to an amide of Formula (XIH), which is then allowed to undergo reaction with a organometallic reagent such as, for example, an alkyl or aryl Grignard reagent of Formula RuMgBr, prepared by standard methods. The resulting product is the ketone of Formula (Id). This Formula (Id) ketone may also be prepared by similar reaction of aryl- or alkllithium reagents, such as, fox example, RπLi, with Formula (XD1), or certain Formula (la) amides where R4R5ΝH is 4-piperidone.
[043] Conversion of the substituted compounds of Formula (la), (lb), (Ic), and (Id) to differently substituted Formula (I) compounds may be carried out using standard functional group conversion chemistry. For example, keto substituents may be reduced with reagents such as Na2BH4, to the corresponding hydroxy substituted compounds. Other such examples are 1) the conversion of nitrophenyl substituent to the corresponding aminophenyl substituent, and 2) O- or N-alkylation or acylation of OH or NH substituents to give the corresponding O- or N-albyl or O- or N-acyl substituted compounds.
EXPERIMENTAL EXAMPLES
[044] The following specific preparative examples are included as illustrations of preparation of specific compounds of the invention, and are not to be construed as limiting the scope of the invention in any way.
NMR methods:
[045] Proton (Η) nuclear magnetic resonance (NMR) spectra were mea-sured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me Si (δ OOO) or residual protonated solvent (CHC13 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as reference standard. Carbon (13C) ΝMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC13 δ 77.0; d3-MeOD; δ 49.0; d6-DMSO δ 39.5) as reference standard.
LC-MS instrumentation:
[046] (a) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23mm, 120 As , and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization_ Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data was also acquired as an analog channel.
[047] (b) a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120- 1200 amu using a variable ion time according to the number of ions in the source.
HPLC conditions.
[048] In the Examples and Tables provided below, LC-MS data are given with retention times (RT) determined by using one of the following methods:
[049] Method 1. Eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.02% TFA. Elution conditions consisted of a flow rate of 1.0 mL/min with an initial hold at 10% B for 0.5 minutes, followed by gradient elution from 10% B to 95% B over 3.5 minutes, followed by a final hold at 95% B for 0.5 minutes. Total run time was 6.5 minutes.
[050] Method 2. Eluents as above; elution at a flow rate of 1.5 mL/min with an initial hold at 10% B for 0.5 minutes, followed by gradient elution from 10% B to 90% B over 3.5 minutes, followed by a final hold at 90% B for 0.5 minutes. Total run time was 4.8 minutes.
Abbreviations and Acronyms
[051] When the following abbreviations are used herein, they have the following meaningς:
BEMAP 2,2'-bis(diphenylphosphino)-l , 1 '-binaphthyl
CD3OD methanol-^
Celite® diatomaceous earth filter agent, ®Celite Corp.
DMAP 4-(NN-dimethylamino)pyidine
DMF NN-dimethylformamide
DMSO dimethylsulfoxide
EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
ELSD evaporative light scattering detector
EtOAc ethyl acetate
EtOH ethanol (100%)
Et20 diethyl ether
Et3Ν triethylamine h hour(s)
HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N -tetramethyluronium hexafluorophosphate HPLC high performance liquid chromatography
LC-MS liquid chromatography-mass spectroscopy min minute(s) m/z mass-to-charge ratio
MeCN acetonitrile
Ms methanesulfonyl
NBS N- bromosuccinimide
NMM 4-methylmorpholine
OMs methanesulfonyl-oxy
OTs 4-toluenesulfonyl-oxy
PS-DIEA Polystyrene-bound diisopropylethylamine
Rf retention factor (TLC)
RT retention time (HPLC) rt room temperature
THF tetrahydrofuran
TFA trifluoroacetic acid
TFFH Fluoro-N,NN',N'-tetramethylformamidinium hexafluorophosphate
TLC thin layer chromatography
Ts 4-toluenesulfonyl
[052] Example 1 Preparation of 2.4-dichloro-N-f4-chlorophenyl')benzenecarboximidamide
Figure imgf000018_0001
[053] Under argon, 4-chloroaniline (6.67 g, 52.5 mmol) was slowly added to EtMgBr (52 mL, 1 M in THF, 52 mmol) portion wise. After the solution was stirred for 0.5 h, 2,4- dichlorobenzonitrile (9.03 g, 52.5 mmol) was added. The resulting solution was stirred at rt overnight. The reaction mixture was carefully quenched with water and extracted with ethyl acetate. The organic layer was dried over MgS0 , filtered, and concentrated. Crude product (16.26 g,) was obtained as a sticky brown foam which was used without purification for the next step. LC-MS m/z 299.3 (MH+), retention time 1.75 min (MDLC 1); H NMR (300 MHz, CDC13) δ 4.92 (2H, br), 7.09-7.51 (7H, m).
[054] Example 2 Preparation of N-f4-chlorophenyl -3-methylbutanimidamide
Figure imgf000019_0001
[055] To a solution of 3-methylbutanenitrile (250 mg, 3.0 mmol) and A1C13 (400 mg, 3.0 mmol) in toluene (6 mL) was added 4-chloroaniline (383 mg, 3.0 mmol). The resulting solution was stirred at reflux for 2 h, diluted with water, and extracted with EtOAc. The aqueous layer was neutralized with saturated ΝaHC03 solution and extracted with EtOAc. The combined extracts were dried over MgS04, filtered, and concentrated. The crude product (364 mg, 58% yield) was used for the next step without purification.
[056] Example 3 Preparation of ethyl l-(4-fluorophenyl)-2-f2-chlorophenyl liE-'-imidazole-4-carboxylate
Figure imgf000019_0002
[057] To a solution of crude 2-chloro-N-(4-fluorophenyl)benzenecarboximidamide (6.8 g, 27 mmol) in toluene (100 mL), ethyl bromopyruvate (3.5 mL, 27 mmol) was added. The resulting solution was heated at 115°C for 90 minutes. The reaction mixture was cooled to rt. Propylamine (2.2 mL, 27 mmol) was added. The reaction mixture was diluted with ethyl acetate and washed with saturated ΝaCl solution. The organic layer was dried over MgS04) filtered, and concentrated. The residue was purified by flash chromatography over silica gel (30 % ethyl acetate in hexane) to give the product (3.4 g, 37% overall yield from 4-fluoroaniUne) as a light yellow solid: LC-MS m/z 345.2 (MH+), retention time 2.78 min (method 1); Rf = 0.20 (30% EtOAc in hexane). *H ΝMR (300 MHz, CDC13) δ 1.38-1.43 (3H, t, J = 6.9 Hz), 4.39-4.46 (2H, q, J = 3.9 Hz), 6.98-7.52 (8H, m), 7.89 (1H, s). [058] Example 4 Preparation of ethyl l-("4-chloroρhenyl)-2-(2.4-dichlorophenyl')-lH-imidazole-4-carboxylate
Figure imgf000020_0001
[059] To a solution of crude 2,4-dichloro-N-(4-chlorophenyl)benzenecarboximidamide (10.3 g, 34.6 mmol) in toluene (100 mL), ethyl bromopyruvate (4.3 mL, 34.6 mmol) and Νa2CO 3 (7.3 g, 41.6 mmol) were added. The resulting solution was heated at reflux for 3 h. The reaction mixture was cooled to rt. The solid was filtered off and the solvent was evaporated. The residue was purified by flash chromatography over silica gel (40 % ethyl acetate in hexane) to give the product (7.5 g, 52% overall yield from 4-chroloaniline) as a Ught yellow solid: LC-MS m/z 395 (MH+), retention time 3.91 min (method 1); mp 143-144°C; Rf = 0.63 (50% EtOAc in hexane). JH NMR (300 MHz, CDC13) δ 1.39-1.43 (3H, t, J = 7.2 Hz), 4.39-4.46 (2H, q, J = 6.9 Hz), 7.04-7.08 (2H, m), 7.25-7.50 (5H, m), 7.89 (1H, s).
[060] Example 5 Preparation of ethyl 2-(2-chlorophenyl -l-(4-chlorophenyl)-5-ethyl-l-t-'-imidazole-4-carboxylate
Figure imgf000020_0002
[061] A solution of 2-diclιloro-N-(4-chlorophenyl)benzenecarboximidamide (10 g, 37.7 mmol) in THF (100 mL) was treated with K2C03 (5.2g, 37.7 mmol) followed by the slow addition of ethyl 3-bromo-2-oxopentanoate (10.1 g, 45 mmol) over 3 h. The reaction mixture was stirred at rt overnight. The solid was then filtered off and the solvent was evaporated. The residue (20 g, 37.7 mmol) was dissolved in acetic acid (100 mL) and heated at reflux for 1 h. The reaction mixture was cooled to rt, diluted with water (200 mL), and extracted with ethyl acetate. The organic layer was washed with water. The aqueous layer was neutralized with saturated NaHC03, and extracted with ethyl acetate. The combined extracts were dried over MgS04, filtered, and concentrated. The residue was purified by flash chromatography over sihca gel (40% ethyl acetate in hexane) to give the product (8.5 g, 40% overall yield from 4-chroloaniline) as a light yellow solid: LC-MS /z 389 (MH+), retention time 3.31 min (method 1); Rf = 0.28 (40% EtOAc in hexane). JH NMR (300 MHz, CDC13) δ 1.05-1.10 (3H, t, J = 7.5 Hz), 1.40-1.44 (3H, t, J = 7.2 Hz), 2.85-2.92 (2H, q, J = 4.2 Hz), 4.39-4.46 (2H, q, J = 7.2 Hz), 7.09-7.41 (8H, m).
[062] Example 6 Preparation of 2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-5-ethyl-N-( 1 -piperidinyl)- 1 iJ-imidazole-4- carboxamide
Figure imgf000021_0001
[063] To a solution of 1-aminopiperidine (2.48 mL, 23 mmol) in CH2CI2 (15 mL) was added trimethylaluminum (11.5 mL, 2 M in hexane, 23 mmol). After the mixture was stirred for 0.5 h, a solution of ethyl 2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-l -imidazole-4-carboxylate (3.0 g, 7.7 mmol) in CH2C12 (10 mL) was added. The reaction mixture was heated at reflux for 2 h and cooled to rt. Water was slowly added dropwise to the reaction mixture at 0°C until no more gas bubbled out. The mixture was dried over Mg2S04, filtered, and concentrated. The residue was purified by flash chromatography over silica gel (40 % then 60% ethyl acetate in hexane) to give the product (2.4 g, 64 % yield) as a white solid: LC-MS m/z 443 (MH+), retention time 2.95 min (method 1); mp 208-209 °C; Rf = 0.74 (EtOAc). *H ΝMR (300 MHz, CDC13) δ 0.98-1.03 (3H, t, 7.8 Hz), 1.35-1.37 (2H, m), 1.58-1.70 (4H, m), 2.77-2.88 (6H, m), 6.70-7.30 (8H, m), 7.84 (1H, s).
[064] Example 7 Preparation of l-(4-chlorophenyl)-2-('2,4-dichlorophenyl -5ic-"-imidazole-4-carboxylic acid
Figure imgf000022_0001
[065] To a solution of ethyl l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-l -imidazole-4- carboxylate (1.1 g, 2.79 mmol) in MeOH (20 mL), a solution of KOH (2.2 g, 39 mmol) in H20 (20 mL) was added. The mixture was heated at 90°C for 3 h. The reaction mixture was cooled to rt and the MeOH was evaporated. HCI (IN) was added until a white precipitate formed. The solid was filtered off, and dried under vacuum. The product (1.0 g, 98% yield) was obtained as a white solid: LC-MS m/z 367 (MH+), retention time is 3.43 min (method 1); mp 150-151 °C; !H NMR (300 MHz, CDC13) δ 7.24-7.65 (7H, m), 8.26 (1H, s).
[066] Example 8 Preparation of l-(4-chlorophenylV2-(2.4-dichlorophenyl)-N-('4-morpholinyl')-liJr-imidazole-4- carboxamide
Figure imgf000022_0002
[067] To a solution of l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5ic-'-imidazole-4-carboxylic acid (50 mg, 0.137 mmol) in CH2C12 (5 mL), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.164 mmol), l-hydroxy-7-azabenzotriazole (40 mg, 0.164 mmol), and triethylamine (1.5 mL) were added. After the mixture was stirred for 15 minutes, 4- morpholinamine (0.164 mmol) was added. The reaction mixture was stirred at rt overnight, and washed with water. The organic layer was dried over MgS04, filtered, and concentrated. The residue was purified by HPLC (YMC-packed PRO C18 15 x 200 mm column, 10-90% CH3CN in H20/TFA, 20 mL/min.) to give the product (10 mg, 16% yield) as a yellow oil: LC-MS m/z 451 (MH+), retention time 3.03 min (method 1); Rf = 0.57 (50% EtOAc in hexane); XH NMR (300 MHz, CDC13) δ 2.97-3.00 (4H, t, J = 4.5 Hz), 3.83 - 3.86 (4H, t, J = 4.2 Hz), 7.04 - 7.39 (8H, m), 7.92 (1H, s).
[068] Example 9 Preparation of 2-(f2-chlorophenyl)-l-(4-chlorophenyl)-N-(3-pyridinyl)-lic/'-imidazole-4- carboxamide
Figure imgf000023_0001
[069] 2-(2-chlorophenyl)-l-(4-chlorophenyl)-liϊ-imidazole-4-carboxylic acid (403 mg, 1.2 mmol) was dissolved in dichloromethane (5 mL) and treated with 0-(7-azabenzotriazol-l-yl)- Λ NN'.N'-tetramethyluronium hexafluorophosphate (HATU) (459 mg, 1.56 mmol) and N- methylmorpholine (ΝMM) (182 mg, 1.8 mmol). The mixture was stirred under argon for 15 minutes before 3-aminopyridine (349 mg, 3.6 mmol) was added. Stirring at rt was continued overnight. The reaction mixture was then adsorbed onto silica gel and chromatographed (2-3% MeOH in CH2C12) to afford 2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-(3-pyridinyl)-lic-"-imidazole- 4-carboxamide (266 mg, 54% yield): LC-MS m/z 409.3, retention time 2.43 min (method 1).
[070] Example 10 Preparation of 2-('2-chlorophenyl -l-(4-chlorophenyl')-N'-r2-('trifluoromethyl)phenyll-liy- imidazole-4-carbohydrazide
Figure imgf000023_0002
[071] In a 20-mL screw-cap vial, 100 mg (0.3 mmol) 2-(2-chlorophenyl)-l-(4-chlorophenyl)- lH-imidazole-4-carboxylic acid, 87 mg (0.33 mmol) TFFH (Advanced Chemtech, LouisviUe, KY), and 5.0 equiv. PS-DIEA (Argonaut Technologies Inc., San Carlos, CA) (loading level: 3.50 mmol/g, 429 mg, 1.5 mmol) were heated in 8 mL 1,2-dichloroethane at 35°C ovemight. The formation of acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv. (58 mg, 0.33 mmol) 2-(trifluoromethyl)phenyl hydrazine was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 41.8 mg of 2~(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[2- (trifluoromethyl)phenyl]-lH-imidazole-4-carbohydrazide as the trifluoroacetate salt (light yellow solid, 23% yield). XH NMR (400 MHz, CDC13) δ 8.70 (s, 1 H), 7.85 (s, 1 H), 7.45 (m, 2 H), 7.20- 7.38 (m, 6 H), 7.12 (d, 1 H), 7.00 (d, 2 H), 6.88 (t, 1 H), 6.60 (s, 1 H); LC-MS m/z 491.2 (MH+), retention time 4.02 min (method 2).
[072] The free base form of the product was obtained by dissolving the TFA salt in dichloromethane, washing with saturated aqueous sodium carbonate solution and water, followed by drying the organic phase with magnesium sulfate, and evaporation of the organic phase under reduced pressure. The hydrochloride salt form of the product was obtained by treating the free base in dichloromethane with 1.0 M hydrogen chloride in diethyl ether until no more precipitate was formed, followed by evaporation of solvent under reduced pressure.
[073] Example 11 Preparation of 1-1 r2-("2-chlorophenyl')-l-('4-chlorophenyl)-l ff-imidazol-4-vπcarbonyl)-4-r4- (trifluoromethyl) phenyilpiperazine
Figure imgf000024_0001
[074] In a 20-mL screw-cap vial, 100 mg (0.3 mmol) 2-(2-chlorophenyl)-l-(4-chlorophenyl)- lH-imidazole-4-carboxylic acid, 87 mg (0.33 mmol) TFFH, and 5.0 equiv. PS-DIEA (loading level: 3.50 mmol/g, 429 mg, 1.5 mmol) were heated in 8 mL 1,2-dichloroethane at 35°C overnight. The formation of acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv. (76 mg, 0.33 mmol) l-(4-trifluormethylphenyl)-piperazine was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 45.9 mg of l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4- yl]carbonyl}-4-[4-(trifluoromethyl)phenyl]piperazine as the trifluoroacetate salt (yellow oil, 23% yield). XH NMR (400 MHz, CD3COCD3) δ 7.95 (s, 1 H), 7.60 (m, 1 H), 7.30-7.50 (m, 7 H), 7.25 (d, 2 H), 7.05 (d, 2 H), 4.5 (bs, 2 H), 3.80 (bs, 2 H), 3.35 (m, 4 H); LC-MS m/z 545.3 (MH+), retention time 4.21 min (method 2).
[075] Example 12 2-(2.4-dichlorophenylVN-(trans-2-hvdroxycyclohexyl)-l-('4-methoxyphenyl)-lic-'-imidazole-4- carboxamide
Figure imgf000025_0001
[076] In a 20-mL screw-cap vial, 182 mg (0.5 mmol) 2-(2,4-dichlorophenyl)-l-(4- methoxyphenyl)-liϊ-imidazole-4-carboxylic acid, 145 mg (0.55 mmol) TFFH, and 5.0 equiv. PS- DIEA (loading level: 3.50 mmol g, 716 mg, 2.5 mmol) were heated in 10 mL 1,2-dichloroethane at 35°C overnight. The formation of acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv. (84 mg, 0.55 mmol) trans-2-aminocyclohexanol hydrochloride was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 53 mg of 2-(2,4-dichlorophenyl)-N-(trans-2- hydroxycyclohexyl)-l-(4-methoxyphenyl)-lH-imidazole-4-carboxamide (amber oU, 23% yield). XH ΝMR (400 MHz, CD2C12) δ 7.90 (s, 1 H), 7.30-7.50 (m, 4 H), 7.10 (d, 2 H), 6.90 (d, 2 H), 3.85 (s, 3 H), 3.80 (m, 1 H), 3.50 (m, 1 H), 3.25 (bs, 1 H), 2.0 (m, 2 H), 1.75 (m, 2 H), 1.30-1.50 (m, 4 H); LC-MS m/z 460.2 (MH+), retention time 3.31 min (method 2). [077] Example 13 Preparation of 1-f r2-f2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yncarbonyl)-4-
Figure imgf000026_0001
[078] Step 1. Thionyl chloride (0.66 mL, 9 mmol) was added to a solution of 2-(2- chlorophenyl)-l-(4-cMorophenyl)-lH-imidazole-4-carboxylic acid (1 g, 3 mmol) in toluene (10 mL). The mixture was refluxed under argon for 1.5 h and concentrated to provide 2-(2- chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carbonyl chloride, which was used in the next step without purification. JHNMR (300 MHz, CD2C12) δ 8.40 (s, 1H), 7.69-7.09 (m, 8H).
[079] Step 2. Triethylamine (1.46 mL, 10.45 mmol) was added to a suspension of 4- piperidinone trifluoroacetate (0.76 g, 3.58 mmol) in CH2C12 (10 mL) and a solution of 2-(2- chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carbonyl chloride in CH C12 (5 mL) was added. The mixture was stirred at rt under argon for 17 h, diluted with CH2C12 (50 mL), washed with water (2 x 50 mL), dried over MgS04, and concentrated to give l-{[2-(2-chlorophenyl)-l-(4- chlorophenyl)-l /-imidazol-4-yl]carbonyl}-4-piperidinone as a yellow solid (0.96 g, 77 %). MS (Electrospray) 414 (MH+), !H NMR (300 MHz, CD2C12) δ 7.80 (s, 1H), 7.37-7.20 (m, 6H), 7.06- 7.00 (m, 6H), 4.47 (br, 2H), 3.92 (br, 2H), 2.46 (t, 4H).
[080] Example 14 5-Butyl-2-('2-cMorophenyl)-l-(4-chlorophenyl)-N-fl-piperidinylVlg-irnidazole-4-carboxamide
Figure imgf000026_0002
[081] Step 1. To a solution of 5-butyl-2-(2-chlorophenyl)-l-(4-chlorophenyl)-liϊ-imidazole-4- carboxylic acid (438 mg, 1.12 mmol) in dry toluene (3 mL), at rt was added thionyl chloride (401 μL, 3.4 mmol). The solution was stirred overnight at rt, and then heated at 110°C for 5 h. The resulting reaction was cooled to rt, and the solvents evaporated, to give 5-butyl-2-(2- chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carbonyl chloride (455 mg, 100%), which was used in the next step without purification. LC-MS m/z 407 (MH+), retention time 3.62 min (method 2).
[082] Step 2. To a solution of 5-butyl-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4- carbonyl chloride (227 mg, 0.56 mmol) in CH2C12 (5 mL), were added 1-aminopiperidine (113 mg, 1.12 mmol) and Et3N (234 μL, 1.68 mmol). The solution was stirred overnight at rt, and then the solvents were evaporated under reduced pressure. The residue was purified by preparative reversed-phase HPLC, using 20 to 100% MeCN in water as gradient, to provide 125 mg (48 %) of 5-butyl-2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-( 1 -piperidinyl)- 1 ϊ-imidazole-4-carboxaιrιide as a white powder. !H ΝMR (400 MHz, CDC13) δ 7.49-7.27 (m, 8 H), 2.93 (t, 2 H), 2.82 (bs, 4 H), 1.77-1.71 (m, 4 H), 1.46-1.37 (m, 4 H), 1.25-1.20 (2 H), 0.79 (t, 3 H). LC-MS m/z 471.33 (MH4), retention time 2.88 min (method 2).
[083] Example 15 Preparation of N-exo-bicyclor2.2.11hept-2-yl-2-(2-chlorophenyl')-l-(4-chlorophenyl)-lJ!-r- imidazole-4-carboxamide
Figure imgf000027_0001
[084] Step 1. 2-(2-Chlorophenyl)-l-(4-chlorophenyl)-lJHr-imidazole-4-carboxylic acid (1.5 g, 4.5 mmol) was dissolved in dichloromethane (40 mL). l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 946 mg, 4.95 mmol) and triethylamine (500 mg, 4.95 mmol) were added followed by pentafluorophenol (815 mg, 4.37 mmol). The mixture was stirred at rt under argon for one hour before it was washed with 5% HCI, sodium bicarbonate solution, and then brine. The organic layer was dried (MgS0 ), filtered, and concentrated to give the crude product (1.26 g) which was chromatographed over silica gel (20% EtOAc in hexanes) to afford pentafluorophenyl 2-(2-chlorophenyl)-l-(4-chlorophenyl)-lflr-imidazole-4-carboxylate (0.73 g, 32% yield): LC-MS m/z 499.0 (MET), retention time 3.93 min (method 1).
[085] Step 2. The pentafluorophenol ester (60 mg, 0.12 mmol) and exo-norbornylamine (40 mg,
0.36 mmol) were dissolved in dichloromethane (2 mL), treated with triethylamine (49 mg, 0.48 mmol), and stirred at rt overnight. The mixture was then washed with 5% aqueous HCI, sodium bicarbonate solution and brine, dried (MgS0 ), filtered, and concentrated. Pure N-exo- bicyclo[2.2.1]hept-2-yl-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carboxarnide was thus obtained (30 mg, 59% yield): LC-MS m/z 426.1 (MET4"), retention time 3.49 min (method 1).
[086] Example 16 Preparation of N-f r2-(2-chlorophenyl")-l-('4-chlorophenyl")-lH-imidazol-4-vncarbonyll-4- (trifluoromethyl) benzenesαlfonamide
Figure imgf000028_0001
[087] In a 20-mL screw-cap vial, 250 mg (0.75 mmol) 2-(2-chlorophenyl)-l-(4-chlorophenyl)- lH-imidazole-4-carboxylic acid, 18.3 mg DMAP (0.15 mmol), 1.25 g PS-Carbodiimide (1.5 mmol) (polystyrene-supported cyclohexylcarbodiimide ,Argonaut Technologies Inc., San Carlos, CA), 169 mg α,α, -trifluoro-p-toluenesulfonamide (0.75 mmol), and 12 mL dichloromethane were added, and the reaction mixture was mixed by orbital shaking at rt overnight. The reaction mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 2 mL MeOH and purified by preparative HPLC to give 39.3 mg of N-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-liϊ-imidazol-4- yl]carbonyl}-4-(trifluoromethyl)benzenesulfonamide (beige solid, 10% yield). XH ΝMR (400 MHz, CD3COCD3) δ 8.25 (d, 2 H), 7.85 (s, 1 H), 7.75 (s, 2H), 7.20-7.40 (m, 6 H), 6.95 (t, 2 H); LC-MS m/z 540 (MH+), retention time 3.36 min (method 2).
[088] Example 17 Preparation of l-{ r2-(2-chlorophenyl)-l-(4-chlorophenγl')-l -'-imidazol-4-vncarbonyli-4-r4- fluorophenyl)-4-piperidinol
Figure imgf000028_0002
[089] A solution of 1 -{ [2-(2-chlorophenyl)-l -(4-chlorophenyl)-l -imidazol-4-yl]carbonyl}-4- piperidinone (0.1 g, 0.24 mmol, prepared as described in Example 13) in THF (4 mL) was added dropwise to a solution of 4-fluorophenylmagnesium bromide (0.6 mL, 0.60 mL) at -78°C. The mixture was stirred at -78°C for 2 h then allowed to warm up to 30°C. Saturated NH4C1 (3 mL) was added slowly followed by water (3 mL). The mixture was extracted with ethyl acetate (3 x 20 mL) and dried over MgS04. The product (0.056 g, 46 %) was isolated by column (50 % ethyl acetate in hexane). MS (Electrospray) 510.1 (M)+; T1NMR (300 MHz, CD2C12) δ 7.81 (s, 1H), 7.50-7.24 (m, 8H), 7.10-6.98 (m, 4H), 5.33-5.17 (m, 1H), 4.74-4.57 (m, 1H), 3.68 (t, 1H), 3.31 (t, 1H), 2.15 (br, 2H), 1.83 (d, 2H).
[090] Examplel8
Preparation of l-( r2-(2-cMorophenyl -l-(4-chlorophenylVli?-irnidazol-4-yl1 carbonyl l-4-(2-furyl")- 4-piperidinol
Figure imgf000029_0001
[091] BuLi (0.875 mL, 1.40 mmol, 1 M solution in THF) was added slowly to a solution of furan (0.106 mL, 1.45 mmol) in THF (2 mL) at -78°C, and the mixture was stirred at -78°C for 1 h. A solution of l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-li;-r-imidazol-4-yl]carbonyl}-4- piperidinone (0.3 g, 0.68 mmol) in THF (1 mL) was added slowly. The mixture was stirred at -78°C for 2 h and saturated NHtCl (3 mL) and water added. The mixture was extracted with ethyl acetate (3 x 20 mL) and dried over MgS04. The product (0.142 g, 61 %) was isolated by column (ethyl acetate). MS (Electrospray) 482 (M)+; *H NMR (300 MHz, CD2C12) δ.7.85 (s, 1H), 7.51- 7.31 (m, VH), 7.10-6.98 (m, 4H), 7.17-7.10 (m, 2H), 6.39 (s, 1H), 6.29 (s, 1H), 4.68 (br, 1H), 4.28 (br, 1H), 3.94 (br, 1H), 3.57 (br, 1H), 2.26-1.91 (m, 4H).
[092] Example 19 Preparation of t-butyl 2-hydroxyimino-3-oκobutanoate
Figure imgf000029_0002
[093] t-Butyl acetoacetate (5.0 g, 31.6 mmol) was dissolved in acetic acid (4.5 mL), cooled by an ice water bath, and treated with sodium nitrite (2.45 g, 35.5 mmol) in water (5.5 mL) while the internal temperature was kept at <10°C (see, e.g., U.S. Patent No. 4,743,586). After the addition was complete, the mixture was stirred at rt for 30 minutes before water (16 mL) was added. After 2 h, extraction with ether (3 x 25 mL), which was washed with water (10 mL), sodium bicarbonate solution (3 x 10 mL), and water (20 mL), gave t-butyl 2-hydroxyimino-3-oxobutanoate as a white solid (5.52 g, 93%): !H NMR (300 MHz, CDC13) δ 8.61 (s, 1H), 2.39 (s, 3H), 1.58 (s, 9H).
[094] Example 20 Preparation of t-Butyl 2-(2-chlorophenyl)-5-methyl-lff-imidazole-4-carboxylate
Figure imgf000030_0001
[095] t-Butyl 2-hydroxyimino-3-oxobutanoate (0.50 g, 2.67 mmol) was mixed with 2- chlorobenzylamine (0.34 mL, 2.82 mmol) in anhydrous acetonitrile (lO mL), and heated at reflux for 3 h. Upon cooling, the suspension was filtered, and the filtered material was washed with a small amount of acetonitrile to afford a white soUd (0.379 g). The filtrate was concentrated and the residue chromatographed over silica gel (25% EtOAc in hexane) to give t-butyl 2-(2- chlorophenyl)-5-methyl-lH-imidazole-4-carboxylate as a yellow foam (0.262 g, 82% combined yield): Ti NMR (300 MHz, CDC13) δ 10.43 (br, 1H), 8.29 (m, 1H), 7.38 (m, 3H), 2.52 (s, 3H), 1.60 (s, 9H).
[096] Example 21
Preparation of t-Butyl 2-(2-chlorophenyl)-5-methyl-l-('4-nitrophenyl)-lH-imidazole-4-carboxylate
Figure imgf000030_0002
[097] t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate (70 mg, 0.24 mmol) was mixed with 4-fluoro-l -nitrobenzene (27 μL, 0.25 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry DMF and heated at 120°C for 4 h. The mixture was diluted with water and filtered to give a yellow solid which was chromatographed over silica gel (40% EtOAc in hexane) to afford a yellow solid (72 mg, 73%): JH NMR (300 MHz, CDClj)δ 8.20 (m, 2H), 7.51 (m, 1H), 7.25 (m,
5H), 2.45 (s, 3H), 1.66 (s, 9H). [098] Example 22 Preparation of 2-(2-chloropherιyl -5-methyl-l-(4-nitrophenyl)-lic-'-imidazole-4-carbox:ylic acid
Figure imgf000031_0001
[099] t-Butyl 2-(2-chloropherιyl)-5-methyl-l-(4-nitrophenyl)-lH-irrιidazole-4-carboxylate (69 mg, 0.17 mmol) was dissolved in dry dichloromethane (2 mL) and treated dropwise with trifluoroacetic acid (2 mL). After stirring at rt for 2 h, the solution was concentrated to give 2-(2- chlorophenyl)-5-methyl-l-(4-nitrophenyl)-lfl"-imidazole-4-carboxylic acid as a yellow foam, which was used without purification in the preparation of Example 23.
[100] Example 23 Preparation of N-cyclohexyl-2-('2-chlorophenyl')-5-methyl-l-(4-nitrophenyl)-liJr-imidazole-4- carboxamide
Figure imgf000031_0002
[101 ] The carboxylic acid obtained from Example 22 was dissolved in dry dichloromethane (3 mL), cooled by an ice water bath, and treated with l-(3-dimethylamino)propyl-3- ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol) and dimethylaminopyridine (46 mg, 0.38 mmol). The mixture was stirred at rt for 1 h before cyclohexylamine (23 μL, 0.20 mmol) was added. The solution was stirred overnight, diluted with dichloromethane, washed with water and ammonium chloride solution, dried (sodium sulfate), and filtered. The filtrate was concentrated to afford a yellow oil (70 mg) which was chromatographed over silica gel (35% EtOAc in hexane) to give N-cyclohexyl-2-(2-chlorophenyl)-5-methyl-l-(4-nitrophenyl)-lH-irmdazole-4-carboxamide as a yellow solid (50 mg, 67%): mp 217-220°C; !H ΝMR (300 MHz, CDC13) δ 8.20 (d, 2H), 7.41 (m, IH), 7.25 (m, 5H), 7.12 (m, lH), 3.95 (m, IH), 2.55 (s, 3H), 2.00 (m, 2H), 1.75 (m, 2H), 1.61 (m, IH), 1.30 (m, 5H); LC-MS m/z 439.2 (MH+), retention time 3.41 min (method 1).
[102] Example 24 Preparation of tert-butyl l-(4-chlorobenzyl -2-('2-chloropheny -5-methyl-l -'-imidazole-4- carboxylate
Figure imgf000032_0001
[103] t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate (70 mg, 0.24 mmol) was mixed with 4-chlorobenzyl bromide (50 mg, 0.24 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry acetonitrile (3 mL) and heated at reflux overnight. The next day, additional 4- chlorobenzyl bromide (10 mg, O.05 mmol) was added, and the reaction mixture was again heated at reflux overnight. The next day, water was added to the cooled mixture, which was subsequently extracted with EtOAc. The extract was washed with aqueous NaCl, dried (NaS0 ), filtered, and concentrated to give a colorless oil (113 mg). It was chromatographed over silica gel (25% EtOAc in hexane) to afford tert-butyl 1 -(4-chlorobenzyl)-2-(2-chlorophenyl)-5-methyl-lH-imidazole-4- carboxylate as a white foam (61 mg, 61% yield): H NMR (300 MHz, CDC13) δ 7.48 (d, IH), 7.40 (m, IH), 7.27 (m, 2H), 7.17 (d, 2H), 6.78 (d, 2H), 5.33 (br, 2H), 2.55 (s, 3H), 1.50 (s, 9H); LC-MS m/z 417.1 (Mlf), retention time 3.23 min (method 1).
[104] Example 25 Preparation of ethyl 5-bromo-l-(4-chloroρhenyl')-2-(2,4-dimethylphenyl)-lH-imidazole-4- carboxylate
Figure imgf000033_0001
[105] Ethyl l-(4-chlorophenyl)-2-(2,4-dimethylphenyl)-lH-imidazole-4-carboxylate (1.23 g, 3.47 mmol) was dissolved in EtOH (15 mL) and treated with N-bromosuccinimide (1.25 g, 7.02 mmol). The solution was stirred at rt for 3 h. Water was added. Extraction with dichloromethane, which was then washed with ΝaCl solution, gave an orange solid (1.94 g). Purification by chromatography over silica gel (20% EtOAc in hexane) afforded a light tan solid (1.028 g, 68%): lR ΝMR (300 MHz, CDC13) δ 7.35 (d, 2H), 7.03 (d, 2H), 7.00 (m, IH), 6.86 (m, 2H), 4.44 (q, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.43 (t, 3H); LC-MS m/z 433.1 (MH+), retention time 3.84 min (method 1).
[106] Example 26 Preparation of ethyl l-(4-chlorophenyl)-5-methyl-2-('2,4-dimethylphenyl')-l fl-imidazole^- carboxylate
Figure imgf000033_0002
[107] Ethyl 5-bromo-l-(4-chlorophenyl)-2-(2,4-dirnethylphenyl)-lH-imidazole-4-carboxylate (430 mg, 0.99 mmol) was dissolved in dry DMF (5 mL) in a pressure tube and treated with tetramethyltin (1.3 mL, 9.38 mmol), palladium acetate (9 mg, 0.04 mmol), and tri-(o- tolyl)phosphine (26 mg, 0.085 mmol). The mixture was heated at 110°C for 15 minutes. After the mixture was cooled to rt, water was added (25 mL). The mixture was extracted with dichloromethane (2 x 25 mL), and the organic phase was washed with water, dried (Na2S04), filtered, and concentrated, to give a light brown oil (436 mg). Purification by chromatography over silica gel (33% EtOAc in hexane) afforded ethyl l-(4-chloroplιenyl)-5-methyl-2-(2,4- dimethylphenyl)-l#-imidazole-4-carboxylate as a white foam (338 mg, 93% yield): :H NMR (300 MHz, CDC13) δ 7.30 (d, 2H), 7.00 (m, 3H), 6.85 (m, 2H), 4.41 (q, 2H), 2.42 (s, 3H), 2.23 (s, 3H), 2.06 (s, 3H), 1.41 (t, 3H).
[108] Example 27
Preparation of 5-bromo-2-('2-chlorophenyl)-l-(4-chlorophenyl)-N- π-piperidinyl)-l#-imidazole-4- carboxamide
Figure imgf000034_0001
[109] Step 1. A solution of 2-(2-chlorophenyl)-l-(4-chlorophen5 )-lH-imidazole-4-carboxylic acid (50 mg, 0.15 mmol) and N-bromosuccinimide (88 mg, 0.49 mmol) in dimethylformamide (5 mL) was stirred at 75°C for 3 days. The solution was purified by preparative HPLC to give 5- bromo-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carhoxylic acid as a white solid (30.7 mg, 50%). LC-MS m/z 411.2 (MH*), retention time 2.70 min (method 2).
[110] Step 2. As described previously for Example 14, 5-bromo-2-(2-chlorophenyl)-l-(4- chlorophenyl)-liϊ-imidazole-4-carboxylic acid was converted to 5-bromo-2-(2-chlorophenyl)-l- (4-chlorophenyl)-N-(l-piperidinyl)-lflr-imidazole-4-carboxamide. LC-MS m/z 493.0 (MH+), retention time 2.63 min (method 2). XH ΝMR (CD2C12, 400 MHz) δ 7.29 (m, 6H, Ph), 7.05 (m, 2H, Ph), 3.68 (m, 3H, piperidine), 3.36 (m, 2H, piperidine), 1.88 (no, 3H, piperidine), 1.57 (m, 2H, piperidine).
[111] Example 28 Ethyl 5-chloro-2-(2-chlorophenyl)-l-(4-chlorophenyl')-lJi'-imidazole-4-carboxylate
Figure imgf000035_0001
[112] To a solution of ethyl 2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-iτnidazole-4-carboxylate (270 mg, 0.75 mmol) in CH2C12 (5 mL) was added S02Cι2 (1.6 mL, 20 mmol). The mixture was heated at reflux overnight, and diluted with water. The organic layer was dried over MgS0 , filtered, and concentrated. The residue was purified by flash chromatography over silica gel (33% EtOAc in hexane) to give ethyl 5-chloro-2-(2-chlorophenyl)-l-(4-chlorophLenyl)-l -imidazole-4- carboxylate (60 mg) in 20% yield as a white solid: LC-MS m/z 395.0 (Mrl+), retention time 3.45 min (method 1). This intermediate, which is an example of Formula (X) in Scheme 2, was converted into 5-chloro-2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-(l-piperidinyl)-lJfϊ-imidazole-4- carboxamide (Table entry 21).
[113] Example 29 Preparation of Σ- Σ-chlorophenvD-l-^-chlorophenylVΝ-methoxy-Ν-methyl-lH-imidazole^- carboxamide
Figure imgf000035_0002
[114] A solution of 2-(2-chlorophenyl)-l-(4-chlorophenyl)-liϊ-imidazole-4-carbonyl chloride (4.71 g, 13.4 mmol, prepared by the method described in Example 13, step 1) in 10 mL dichloromethane was added to a solution of N, -dimethylhydroxyamine hydrochloride (1.44 g, 14.7 mmol) and triethylamine (5.6 mL, 40.2 mmol) in 60 mL dichloromet-hane in an ice water bath under argon with stirring. The bath was removed upon completion of addition. Stirring was continued for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na S04 and concentrated down under reduced pressure. The crude product was purified on siUca gel, eluting with ethyl acetate to yield 2-(2-chlorophenyl)-l~(4- chlorophenyl)-N-methoxy-N-methyl-lH-imidazole-4-carboxamide as an off-white solid. (4.20 g, 83%): Rf = 0.22 (ethyl acetate).
[115] Example 30 Preparation of r2-("2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl1(4-fluoroplienyl')- methanone
Figure imgf000036_0001
[116] To a solution of 2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-methoxy-N-methyl- 1 H- imidazole-4-carboxamide (50.0 mg, 0.133 mmol) in 1.5 mL THF was added a 1.0 M solution of 4- fluorophenylmagnesium bromide (0.27 mL, 0.27 mmol) under argon at rt with stirring. The resultant mixture was stirred for 30 minutes and a saturated aqueous solution of ΝH4CI vas added. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO.-j. and concentrated down in vacuo. The crude product was purified on HPLC to give [2-(2- chlorophenyl)-l-(4-chlorophenyl)-l-ct-imidazol-4-yl](4-fluorophenyl)-methanone as a solid (38.0 mg, 69%): Rf = 0.58 (1: 1 ethyl acetate / hexanes).
[117] Example 31 Preparation of r2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-l^-"-imidazol-4-vn(2-'thienyl)- methanone
Figure imgf000036_0002
[118] To a solution of 2-bromothiophene (0.22 g, 1.36 mmol) in 2 mL THF was added 0.84 mL of a 1.6 M solution of BuLi in hexane under argon at -78°C with stirring. The stirring was continued for 1 h. To this was added a solution of l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-5- ethyl-lJΪ-imidazol-4-yl]carbonyl}-4-piperidinone in 2 mL THF. The resultant mixture was stirred and gradually allowed to warm up to rt overnight. The reaction was quenched with saturated aqueous NILC1 and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude product was purified by HPLC to yield [2-(2-chlorophenyl)-l-(4- chlorophenyl)-5-ethyl-l -'-imidazol-4-yl](2-thienyl)-methanone as a solid (60 mg, 31%): Rf = 0.13 (1:5 ethyl acetate / hexanes).
[119] Example 32 Preparation of 2-(2-chlorophenyl)-l-(4-chlorophenyl -li[-"-imidazole-4-carboxaldehvde
Figure imgf000037_0001
[120] To a solution of ethyl 2-(2-chlorophenyl)-l-(4-chlorophenyl)-l -imidazole-4-carbo_xylate (200 mg, 0.51 mmol) in toluene (10 mL) at -78°C was added DIBAH (2.0 mL) in toluene dropwise. The resulting solution was stirred at rt, quenched with IN HCI (0.5 mL). The organic layer was washed with IN HCI (5 mL), dried over MgS04, filtered, and concentrated. The residue was purified by flash chromatography (50% EtOAc in hexane) to give the product (62 mg, 3 8% yield). LC-MS m/z 317.0 (Mrf), retention time: 2.75 min (method 1).
[121] Example 33 Preparation of N-{ r2-(2-chlorophenyl)-l-(4-chlorophenyl)-l g-imidazoM-yllmethyll-N- cyclohexylamine
Figure imgf000038_0001
[122] To a solution of 2-(2-chlorophenyl)-l-(4-chlorophenyl)-lJf-'-imidazole-4-carboxaldehyde (62 mg, 0.20 mmol) in methanol (7 mL) was added cyclohexylamine (58 μL, 0.5 mmol). The mixture was stirred overnight, and cooled to 4°C. ΝaBH (40 mg, 1.1 mmol) was added. The mixture was stirred at rt for 1 h, and concentrated. The residue was dissolved in CH2C12, washed with brine, dried over MgS04, filtered, and concentrated. The residue was purified by preparative TLC (50% EtOAc in hexane) to give N-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-liϊ-imidazol-4- yl]methyl}-N-cyclohexylamine (65 mg, 81% yield): LC-MS /z (400.7 MH+), retention time 2.32 min (method 1).
[123] Example 34 Preparation of l-{ ri-(4-chlorophenyl')-2-(2.4-dichlorophenyl')-l g-imidazol-4-yl1methyll-4-(4- methylphenvDpiperazine
Figure imgf000038_0002
[124] To a suspension of lithium aluminum hydride (21 mg, 0.54 mmol) in THF (2 mL), l-(4- methylphenyl)piperazine hydrochloride (32 mg, 0.13 mmol) was added. After 10 minutes, a solution of ethyl 2-(2,4-dichlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carboxylate (39 mg,
0.1 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred for 10 minutes, and diluted by water. The organic layer was dried over MgS04, filtered, and concentrated. The residue was purified by HPLC (YMC-packed Pro C18 20 x 150 mm column, 10-90% CH3CN in H 0/TFA, 25 mL/min) to give the product l-{[l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-l#- irnidazol-4-yl]methyl}-4-(4-methylphenyl)-piperazine (1.4 mg, 2% yield): LC-MS m/z 511.1 (MH+), retention time 2.94 min (method 1). !H NMR (300 MHz, CDC13) δ: 2.29 (3H, s), 3.42- 3.49 (8H, br), 4.39 (2H, s), 6.85- 7.41 (11H, m), 7.54 (IH, s).
Other Procedures
[125] In certain cases, the products and intermediates prepared by the experimental methods described in Examples 1-34 were converted into additional products, by applying the appropriate additional chemical steps. These additional examples are described below.
[126] Example 35 l-(4-chlorophenyl')-2-f2,4-dichlorophenyl)-N-r('lR.2R)-2-hvdroxycvclohexyl1-lH-imidazole-4- carboxamide
Figure imgf000039_0001
[127] To a solution of N-[(1R, 2R)-2-(benzyloxy)cyclohexyl]-l-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-lH-imidazole-4-carboxamide (Table entry 278, prepared according to the procedures described in Examples 13 and 14) (100 mg, 0.18 mmol) in CH2C12 (2 mL), TMSI (iodotrimethylsilane) (60 μL, 0.42 mmol) was added. The mixture was stirred at rt overnight, and diluted with water. The organic layer was dried over MgS0 , filtered, and concentrated. The residue was purified by preparative TLC (EtOAc) to afford l-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-N-[(lR,2R)-2-hydroxycyclohexyl]-lict-imidazole-4-carboxamide (56 mg, 67% yield) as a yeUow solid: LC-MS m/z 464.3 (MH+), retention time 3.19 min (method 1); Rf = 0.67 (EtOAc); XH ΝMR (300 MHz, CDC13) δ 1.16-1.30 (4H, m), 1.66-1.69 (2H, m), 1.98-2.02 (2H, m), 3.37-3.39 (IH, m), 3.70-3.80 (IH, m), 3.99-4.06 (IH, m), 6.96- 7.37 (8H, m), 7.78 (IH, s). [128] Example 36 l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-r(lS. 2S -2-hvdroxycvclopentvn-li?-imidazole-4- carboxamide
Figure imgf000040_0001
[129] To a solution of N-[(1S, 2S)-2-(benzyloxy)cyclopentyl]-l-(4-chlorophenyl)-2-(2,4- dichlorophenyl)-lH-imidazole-4-carboxamide (Table entry 282, prepared according to the procedures described in Examples 13 and 14) (119 mg, 0.22 mmol) in CH2C12 (4 mL), TMSI (0.2 mL, 1.4 mmol) was added. The mixture was stirred at rt overnight, and diluted by water. The organic layer was dried over MgS0 , filtered, and concentrated. The residue was purified by preparative TLC (EtOAc) to afford l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-[(lS, 2S)-2- hydroxycyclopentyl]-lH-imidazole-4-carboxamide (80 mg, 82% yield) as a white foam: LC-MS m/z 450.0 (MIT"), retention time 3.24 min (method 1); Rf = 0.45 (50% EtOAc in hexane); !H ΝMR (300 MHz, CDC13) δ 1.22-2.24 (6H, m), 3.97-4.15 (2H, m), 7.03-7.42 (7H, m), 7.86 (IH, s).
[130] Example 37 2-('2-chlorophenyl')-l-f4-chlorophenyl)-N-(4-piperidinyl)-lJi/'-imidazole-4-carboxamide
Figure imgf000040_0002
[131] To a solution of ethyl 4-({[2-(2-chlorophenyl)-l-(4-chlorophenyl)-liε-'-imidazol-4- yl]carbonyl}amino)-l-piperidinecarboxylate (Table entry 221) (0.595 g, 1.221 mmol) in CH2C12 (10 mL) was added TMSI (0.176 mL, 2.7 mmol). The mixture was heated at reflux for 3 h, diluted by methanol, and concentrated. The residue was dissolved in methanol and NaOMe (0.62 mmol) was added. The mixture was concentrated and purified by flash chromatography (2M NH3 in methanol : EtOAc = 15: 85) to afford the product 2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-(4- piperidinyl)-l#-imidazole-4-carboxamide (180 mg, 36% yield): LC-MS m/z 415.3 (MH+), retention time 2.22 min (method 1); Rf = 0.25 (1:1 EtOAc/2M NH3 in MeOH). *H NMR (300 MHz, CDC13) δ 1.35-1.51 (2H, m), 1.91-2.15 (3H, br), 2.63-2.78 (2H, m), 3.03-3.09 (2H, m), 3.97- 4.15 (IH, m), 6.96-7.52 (8H, m), 7.81 (IH, s).
[132] Example 38 2-(2-Chlorophenyl)-l-("4-chlorophenyl)-N-ri-f2-pyridinylV4-piperidinyn-l -imidazole-4- carboxanύde
Figure imgf000041_0001
[133] A flask was charged with 2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-(4-piperidinyl)- 1 H- imidazole-4-carboxamide (Example 37) (100 mg, 0.24 mmol), 2-bromopyridine (0.55 mg, 0.22 mmol), Pd2(dba)3 (38 mg, 0.24 mmol), BIΝAP (1.18 mg, 0.0019 mmol), ΝaOtBu (33.6 mg, 0.35 mmol), and toluene (2 mL). The reaction mixture was heated at reflux overnight, cooled to rt, and diluted with CH2C12. The solid was filtered off. The solvent was evaporated. The residue was purified by flash chromatography (33% EtOAc in hexane) to give the product 2-(2-chldrophenyl)- l-(4-chlorophenyl)-N-[l-(2-pyridinyl)-4-piperidinyl]-li -imidazole-4-carboxamide (55 mg, 47% yield): LC-MS m/z 492.1 (MH+), retention time 2.47 min (method 1); Rf = 0.33 (50% EtOAc in hexane). [134] Example 39 2-(2-chlorophenvD- 1 -(4-chlorophenvD-N-(l -methyl-4-piperidinyl)- lff-imidazole-4-carboxamide
Figure imgf000042_0001
[135] To a solution of 2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-(4-piperidinyl)- l -imidazole-4- carboxamide (Example 37) (80 mg, 0.2 mmol) in CH2C12 (6 mL) was added CH3I (28.4 mg, 0.2 mmol) and Et3Ν (0.031 mL, 0.22 mmol). The reaction mixture was heated at reflux for 5 h, cooled to rt, and washed with brine. The organic layer was dried over MgS0 , filtered, and concentrated. The residue was purified by flash chromatography (2M NH3 in methanol : EtOAc = 1 : 10) to afford the product 2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-(l -methyl-4-piperidinyl)- l#~imidazole-4- carboxamide (24 mg, 28% yield): LC-MS m/z 429.1 (MH+), retention time 2.27 min (method 1); Rf = 0.31 (EtOAc: 2M ΝH3 in MeOH = 9:1).
[136] Example 40
2-(2-chlorophenvD- 1 -(4-chlorophenyl)-N-rtrans-2-(2-hvdroxyethoxy)cyclohexyll- 1 jjr-imidazole-4- carboxamide
Figure imgf000042_0002
[137] To a solution of 2-{ [trans-2-({ [2-(2-chlorophenyl)-l-(4-chlorophenyl)-l#-imidazol-4- yl]carbonyl}amino)cyclohexyl]oxy}-ethyl acetate (Table entry 286) (31 mg, 0.06 mmol) in THF (7 mL) and water (0.7 mL) was added ΝaBHU (5 mg, 0.13 mmol) portionwise over 1 h with the temperature kept below 20°C. The mixture was stirred at rt overnight, cooled to 5°C, treated with acetone (1 mL), and then concentrated. The residue was dissolved in CH2C12 and washed with brine. The organic layer was dried over MgS04, filtered, and concentrated. The residue was purified by flash chromatography (2.5% methanol in EtOAc) to give the product 2-(2- chlorophenyl)- 1 -(4-chlorophenyl)-N-[( IR, 2S)-2-(2-hydroxyethoxy)cyclohexyl]- liϊ-imidazole-4- carboxamide (7.5 mg, 26% yield): LC-MS m/z (474.8 MW), retention time 2.91 min (method 1); Rf = 0.17 (EtOAc).
[138] Example 41 2-(2-chlorophenyl -l-r4-chlorophenyl*)-N-rtrans-2-methoxycvclohexyll-lit-"-imidazole-4- carboxamide
Figure imgf000043_0001
[139] A flask was charged with 2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[trans-2- hydroxycyclohexyl]-12ϊ-imidazole-4-carboxaπιide (Table entry 336) (35 mg, 0.1 mmol), benzene (3 mL), 50% aqueous ΝaOH (2.5 mL), and Bu4ΝHS04 (17 mg). While the mixture was stirred vigorously at 10°C, CH3I (19 μL, 0.3 mmol) was added dropwise rapidly. The mixture was stirred for another 30 minutes, and diluted with water (5 mL) and hexane (10 mL). The organic layer was dried over MgS04, filtered, and concentrated. The residue was purified by flash chromatography (75% EtOAc in hexane) to give the product 2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lR,2S)-2- methoxycyclohexyll-lH-iπudazole-4-carboxamide (23 mg, 63% yield): LC-MS m/z 444.2 (MH+), retention time 3.24 min (method 1).
[140] Example 42 4- { r2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4-yll carbonyl } thiomorpholine 1 -oxide
Figure imgf000044_0001
[141] To a solution of 4-{ [2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-iιnidazol-4-yl]caι-bonyl} thiomorpholine (Table entry 176) (30 mg, 0.072 mmol) in acetone (2 mL), was added 30% aqueous H202 (0.09 mmol). The resulting solution was stirred at rt for 36 h, diluted with water, neutralized with NaHC03, and extracted with CH2C12. The organic layer was dried over MgS04, filtered, and concentrated. The residue was purified by flash chromatography (20% MeOH in EtOAc) to give the product 4-{ [2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4- yl]carbonyl}thiomorpholine 1 -oxide (17 mg, 54% yield): LC-MS m/z 434.5 (MIT), retention time 2.55 min (method 1); Rf = 0.47 (17% EtOAc in hexane).
[142] Example 43 N-rdS.2S")-2-(benzyloxy cvclohexyll-5-bromo-2-f2-chlorophenyl)-l-(4-chlorophenyl)-l -'- imidazole-4-carboxamide
Figure imgf000044_0002
[143] A solution of N-[(lS,2S)-2-(benzyloxy)cyclohexyl]-2-(2-chlorophenyl)-l-(4- chlorophenyl)-lH-imidazole-4-carboxamide (Table entry 276) (198 mg, 0.380 mmol) and N- bromosuccinimide (88 mg, 0.49 mmol) in dimethylformamide (5 mL) was stirred at 75°C for 3 days. The solution was purified by preparative HPLC to give N-[(lS,2S)-2- (benzyloxy)cyclohexyl]-5-bromo-2-(2-chlorophenyl)-l-(4-chlorophenyl)-liϊ-imidazole-4- carboxamide as a white solid (196 mg, 86%). LC-MS m/z 598.1 (MH+), retention time 3.72 min (method 2).
[144] Example 44
5-Bromo-2-(2-chlorophenylVl-(4-chlorophenyl -N-r(lS,2S -2-hvdroxycvclohexyl1-lg-imidazole- 4-carboxamide
Figure imgf000045_0001
[145] As described previously for Example 35, N-[(lS,2S)-2-(benzyloxy)cyclohexyl]-5-bromo- 2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazole-4-carboxamide (Example 43) was de- benzylated by treatment with iodotrimethylsilane to give 5-bromo-2-(2-chlorophenyl)-l-(4- chlorophenyl)-N-[(lS,2S)-2-hydroxycyclohexyl]-l -imidazole-4-carboxamide. LC-MS m/z 508.1 (MH+), retention time 2.96 min (method 2). H ΝMR (CD2C12, 400 MHz) δ 7.43 (d, IH, Ph), 7.27 (m, 5H, Ph), 7.06 (m, 2H, Ph), 3.70 (m, IH, CHOH), 3.44 (m, IH, CHΝ), 1.95 (m, 2H, cyclohexane), 1.64 (m, 2H, cyclohexane), 1.24 (m, 4H, cyclohexane).
[146] Example 45 l-(4-Aininophenyl -2-f2-chlorophenylV5-methyl-N-(l-piperidinyl)-liJ-imidazole-4-carboxamide
Figure imgf000045_0002
[147] A sample of 2-(2-chlorophenyl)-5-methyl-l-(4-nitrophenyl)-N-(l-piperidinyl)-lH- imidazole-4-carboxamide (Table entry 41) (111 mg, 0.25 mmol) was added as a suspension in ethanol (5 mL) to Degussa-type palladium on carbon (10% by weight, 12 mg). The mixture was hydrogenated at atmospheric pressure and rt for 2 h. Filtration of the mixture through Celite and concentration of the filtrate gave l-(4-aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(l- piperidinyl)-l#-imidazole-4-carboxamide as a yellow foam (104 mg, 100%). This material was used without purification for the preparation of compounds of the invention, such as Example 46.
[148] Example 46 2-(2-chlorophenyl -l-(4-{ r(ethylamino')carbonyl1aminolphenyl')-5-methyl-N-(l-piperidinyl')-lH- imidazole-4-carboxamide trifluoroacetate
Figure imgf000046_0001
[149] l-(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-(l-piperidinyl)-lic-'-imidazole-4- carboxamide (Example 45) (52 mg, 0.13 mmol) was dissolved in dry dichloromethane (2 mL) and added to ethyl isocyanate (20 μL, 0.25 mmol). The solution was stirred at rt for 6 h before more ethyl isocyanate (30 μL, 0.38 mmol) was added. After stirring overnight, the mixture was heated at reflux for 1 h. The solvent was evaporated to give a yellow solid which was chromatographed over silica gel (3% MeOH in EtOAc) to afford semi-pure product (21 mg). This material was further purified by HPLC (YMC-packed Pro C18 15 x 200 mm column, 30-90% CH3CΝ in H20/TFA, 20 mL/min.) to give 2-(2-chlorophenyl)-l-(4-{ [(ethylamino)carbonyl]amino}phenyl)-5- methyl-N-(l-piperidinyl)-l /'-imidazole-4-carboxamide trifluoroacetate as a white solid (12 mg, 13% yield): LC-MS /z 481.4 (MH+), retention time 2.35 min (method 1).
[150] Example 47 l-r4-(acetylarnino)phenyl]-2-(2-chlorophenyl)-5-methyl-N-('l-piperidinyl)-lH-imidazole-4- carboxamide
Figure imgf000047_0001
[151] 1 -(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-( 1 -piperidinyl)- lH-imidazole-4- carboxamide (Example 45) (51 mg, 0.12 mmol) was dissolved in dry dichloromethane (2 mL) and treated with acetic anhydride (14 μL, 0.15 mmol) dropwise. The solution was stirred at rt for 4 h, and then the solvent was evaporated to give an amber oil. It was purified by HPLC (YMC-packed Pro C18 15 x 200 mm column, 30-90% CH3CΝ in HzO/TFA, 20 mL/min.) to afford an off-white soUd (13 mg, 15%): LC-MS m/z 452.3 (MH+), retention time 2.31 min (method 1).
[152] Example 48 2-(2-Chlorophenyl)-5-methyl-l-|4-f(methylsulfonyl)aminolphenyll-N-('l-piperidinyl)-lH- imidazole-4-carboxamide trifluoroacetate
Figure imgf000047_0002
[153] 1 -(4-Aminophenyl)-2-(2-chlorophenyl)-5-methyl-N-( 1 -piperidinyl)- lH-imidazole-4- carboxamide (Example 45) (52 mg, 0.13 mmol) was dissolved in dry dichloromethane (2 mL), cooled by an ice water bath, and the mixture was then treated with methanesulfonyl chloride (12 μL, 0.16 mmol) and triethylamine (21 μL, 0.15 mmoL). The solution was stirred at rt overnight, and then the solvent was evaporated. The residue was purified by HPLC (YMC-packed Pro C18 15 x 200 mm column, 30-90% CH3CN in H20/TFA, 20 mL/min.) to afford a light tan solid (21 mg, 27%): LC-MS m/z 488.4 (MH+), retention time 2.29 min (method 1).
[154] Example 49 l-i ri-('4-Chlorophenyl-)-2-(2-methylphenyl)-lJJr-imidazol-4-yllcarbonyl)-4-phenyl-L2.3.6- tetrahvdropyridine
Figure imgf000048_0001
[155] A 30-mg sample of l-{ [2-(2-methylphenyl)-l-(4-chlorophenyl)-lir -imidazol-4- yl]carbonyl}-4-phenyl-4-piperidinol (Table entry 414), was dissolved in 20 mL dichloromethane, and then 5 mL 2M HCI in ether was added to the solution. Evaporation of the solvent at high temperature (ca. 70°C, 16 hr) in a multiple sample evaporator (Gene Vac) gave l-{[l-(4- chlorophenyl)-2-(2-methylphenyl)-lH-imidazol-4-yl]carbonyl}-4-phenyl-l,2,3,6- tetraliydropyridine (yellow soUd). *H NMR (400 MHz, CD3COCD3) δ 8.31 (s, IH), 7.05-7.35 (m, 13 H), 6.05 (s, 1 H), 4.2 (m, 2 H), 3.85 (m, 2H), 2.5 (m, 2H), 2.0 (s, 3H); LC-MS m/z 454 (MH+), retention time 2.92 min (method 2).
Preparation of Intermediates
[156] Experimental procedures for the preparation of chemical reagents that are not commercially available are described below.
[157] Intermediate A Ethyl 3-bromo-2-oxobutanoate
Figure imgf000048_0002
[158] This bromo pyruvate was prepared by oxidative bromination of the corresponding hydroxyesters, by the procedure described by Plouvier et al., (Heterocycles 32:693-701, 1991). In a similar manner, ethyl 3-bromo-2-oxopentanoate and ethyl 3-bromo-2-oxohexanoate were prepared. [159] Intermediate B Ethyl 3-bromo-3-cyclopropyl-2-oxopropanoate
Figure imgf000049_0001
[160] The procedure was similar to that reported in the literature (see, e.g., J. Org. Chem. 37, 505-506, 1972).
[161 ] Step 1. To a solution of BF3.Et20 (57.5 mL, 0.454 mmol) in CHC13 (180 mL) heated at reflux was added dropwise, over a 1-h period, a solution of 1 ,3-propanedithiol (22.7 mL, 0.227 mmol), followed by ethyl diethoxyacetate (40 g, 0.227 mmol) in CHC13 (40 mL). The resulting mixture was heated for 30 minutes, and then cooled to rt. The cooled solution was washed 2 times with water, once with saturated aqueous NaHC03, and then re-washed with water. The combined organic phases were dried over MgS04, then evaporated to give 41 g (94%) of ethyl 1,3-dithiane- 2-carboxylate as a yellow oil, which was used in the next step without purification. *H NMR (CDC13): δ 4.24 (2H, q, J = 7.2 Hz), 4.17 (IH, s), 3.46-3.39 (2H, m), 2.64-2.58 (2H, m), 2.18-2.01 (2H, m), 1.30 C3H, t, J = 7.2 Hz).
[162] Step 2. To a suspension of NaH (95 %, 2.8 g, 111 mmol) in dry toluene (120 mL) stirring at 0°C was dropwise added, over 10 minutes, a solution of bromomethylcyclopropane (15 g, 111 mmol), and ethyl l,3-dithiane-2-carboxylate (17.77 g, 92.58 mmol) in dry DMF (40 mL). The ice bath was removed and the solution was stirred overnight at rt. Water was added to the solution and the phases were separated. The organic phase was dried over MgS04, then evaporated to give 19.6 g (50%) of ethyl 2-(cyclopropylmethyl)-l,3-dithiane-2-carboxylate, which was used in the next step without purification. H NMR (CDC13): δ 4.26 (2H, q, J = 7.2 Hz), 3.30-3.23 (2H, m), 2.69-2.64 (2H, m), 2.16-2.11 (IH, m), 1.96 (2H, d, J = 6.8 Hz), 1.91-1.81 (IH, m), 1.34 (3H, t, J = 7.2 Hz), 0.93-O.86 (IH, m), 0.52-0.47 (2H, m), 0.20-0.16 (2H, m).
[163] Step 3. A solution of ethyl 2-(cyclopropylmethyl)-l,3-dithiane-2-carboxylate (19.6 g, 79.67 mmol) in CH3CN (20 mL) was slowly added, over 30 minutes, to a well-stirred suspension of NBS (N-bromosuccinimide) in CH3CN (210 mL) and water (55 rriL). After the mixture was stirred for 1 h, the resulting red solution was poured into an ice-cold CH2θ2-Hexane solution (1:1 500 mL). The resulting mixture was washed with saturated aqueous NaHS03 and water. The colorless organic phase was carefully washed with saturated aqueous K2C03 and water. The organic phase was dried over MgS04, then evaporated to give 6.88 g (55%) of ethyl 3- cyclopropyl-2-oxopropanoate as a yellow oil. XH NMR (CDC13): δ 4.29 (2H, q, J = 8 Hz), 2.71 (2H, d, J = 9 Hz), 1.35 (3H, t, J = 8 Hz), 1.05-0.98 (IH, m), 0.59-0.54 (2H, m), 0.17-0.14 (2H, m).
[164] Step 4. To a solution of ethyl 3-cyclopropyl-2-oxopropanoate (4.75g, 30.44 mmol) in CC14 (60 mL) at rt was added NBS (5.96 g 33.49 mmol). The resulting mixture was heated at reflux overnight, then cooled, filtered, and evaporated to provide ethyl 3-bromo-3-cyclopropyl-2- oxopropanoate; rH NMR (CDC13): δ 4.46-4.32 (3H, m), 1.41 (3H, t, J = 8 Hz), 0.96-0.86 (IH, m), 0.55-0.50 (2H, m), 0.07-0.03 (2H, m). This compound was used without purification for the preparation of compounds of the invention such as l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l- piperidinyl)-5-cyclopropyl-lH-imidazole-4-carboxamide hydrochloride (Table entry 22). In a similar manner, ethyl 3-bromo-3-cyclobutyl-2-oxopropanoate and ethyl 3-bromo-3-isobutyl-2- oxopropanoate were prepared.
[165] Intermediate C Ethyl 3-bromo-2-oxoheptanoate Br O
O [166] Step 1. To a suspension of Lil (23.61 g, 176.44 mmol) in THF (200 mL) at rt was slowly added Cu2Br2 (25.30 g, 88.22 mmol). A vigorous exothermic reaction occurred, and the mixture was then cooled to -78°C. Pentylrnagnesium bromide (2M, 36.76 mL, 88.22 mmol) was slowly added at -78°C, and followed soon after by ethyl chloro(oxo)acetate (lOg, 73.52 mmol) . The resulting solution was stirred 10 minutes at -78°C, then quenched by dropwise addition of water. The mixture was allowed to warm to rt, and then the organic phase was separated, dried (MgS04), and evaporated. Purification by flash chromatography using 9: 1 hexane/EtOAc as eluant gave ethyl 2-oxoheptanoate as a colorless oil (3.0 g, 23%). lR NMR (400 MHz, CDC13) δ 4.33-4.21 (m, 2 H), 2.82 (m, 2 H), 1.63-1.59 (m, 2 H), 1.63-11.19 (m, p H), 0.9-0.83 (m, 3 H): LC-MS m/z 279.21 (MH+), retention time 2.42 min (method 2).
[167] Step 2. To a cold solution of ethyl 2-oxoheptanoate (2 g, 11.62 mmol) in AcOH (20 mL), was added Br2 (596 μL, 11.62 mmol). The mixture was stirred 20 minutes at 0°C, then the mixture was allowed to warm to rt. After the mixture was stirred for 3 h, water and CH2C12 were added. The organic phase was separated, dried (MgS04), and evaporated to give crude ethyl 3-bromo-2- oxoheptanoate as a dark oil; ]H N-MR (400 MHz, CDC13) δ 5.05-5.01 (m, 1 H), 4.45-4.20 (m, 2 H), 2.18-1.94 (m, 2 H), 1.74-1.57 ( , 2 H), 1.48-1.17 (m, 5 H), 0.95-0.82 (m, 3 H). This compound was used without purification for the preparation of compounds of the invention such as 1 -(4-chlorophenyl)-2-(2-chlorophenyl)-N-( 1 -piperidinyl)-5-butyl- 1 H-imidazole-4-carboxamide hydrochloride (Table entry 20).
[168] Intermediate D 4-Piperidinone trifluoroacetate
Figure imgf000051_0001
H TFA
[169] A suspension of t-butyl 4-oxo-l -piperidine carboxylate (10 g, 0.05 mol) in trifluoroacetic acid (10 mL) was stirred rt overnight and concentrated to give a pale yellow solid (11.26 g, crude). MS (Electron spray) 100 (MH+), free amine; *H NMR (300 MHz, CD3OD) δ 3.27-3.12 (m, 4H), 2.01-1.86 (m, 4H).
[170] Intermediate E trarts-l -Amino-2-hydroxyindan
Figure imgf000051_0002
[171] This compound was prepared as described by Thompson et al., (J. Med. Chem. 35:1685- 1701, 1992). To 1 liter of 12 N NH4OH cooled to 0°C was added 50 g (0.235 mol) of 2-bromo-l- indanol. After stirring for 30 minutes , the mixture was allowed to warm, and then stirred for 24 hours. The mixture was concentrated under reduced pressure to remove excess ammonia and then allowed to stand open at rt overnight. The mixture was made basic (pH >10) by addition of 20% KOH, cooled in an ice bath, and filtered. After the residue was dried in a vacuum oven at 60°C overnight, the desired product was obtained as a tan solid (24 g, 69%).
[172] Intermediate F cis- 1 -Hydroxy-2-aminoindan
Figure imgf000051_0003
[173] Following the procedure described in TetrahecLron: Asymmetry 7: 1559-1562, 1996, trans- 2-bromo-l-indanol (500 mg, 2.35 mmol) was dissolved in DMF (5 mL) and sodium azide (305 mg, 4.69 mmol) was added dropwise. The mixture was stirred at rt for 1 h, and then heated to 70°C and stirred for an additional 18 h. The mixture was cooled, water was added, and extracted with ether. The ether was removed and the crude (412 mg) was dissolved in THF (15 mL). This solution was added to Pd/C (41 mg) and stirred under hydrogen at rt for 3 days. The reaction mixture was filtered and the filtrate was concentrated down to provide the desired product, which was used without purification.
[174] Intermediate G trans- 1 - Amino-2-hydroxy- 1 ,2, 3 ,4-tetrahydronaphthalene
Figure imgf000052_0001
[175] This compound was prepared from dihydronaphthalene according to the procedures described by Bellucci et al., (Tetrahedron: Asymmetry 8:895-902, 1997).
[176] Intermediate H trαw5-(2R,3R')-3-r('2.4-Dimethoxybenzyl amino1-l,2,3,4-tetrahydro-2-naphthalenol
Figure imgf000052_0002
[177] This compound was prepared by following the procedure described by Efange et al, (J. Med. Chem. 40:3905-3914, 1997).
[178] Intermediate E dS.2R.3S.4RV3-Amino-1.7J-trimethΥlbicyclor2.2.11heptan-2-ol
Figure imgf000052_0003
[179] This compound, and its enantiomer, were obtained by LiAlH-t reduction of the respective camphorquinone 3-oximes, by the procedure described by Ga_wley and Zhang, (J. Org. Chem. 61:8103-8112, 1996).
[180] Intermediate J Ethyl r(trans-2-aminoc vclohexylloxyl acetate
Figure imgf000053_0001
[181] To a solution of trans-2-amino-cyclohexanol hydrochloride (455 mg, 3.0 mmol) in THF (7 mL) was added sodium hydride (78 mg, 3.25 mmol) under argon. The mixture was stirred at rt for 12 h before ethyl bromoacetate (500 mg, 3.0 mmol) was added, and the solution was stirred at rt for another 12 h. After filtration, the solution was concentrated and the residue taken up in CH2C12 and washed with brine. The organic layer was separated and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate) to afford the desired product (51 mg, 8.5% yield): LC-MS m/z 202.2 (MH+), retention time 0.73 min (method 1); Rf = 0.23 (ethyl acetate).
[182] Intermediate K r(2S)-l-Amino-2-piperidinyllna.ethanol
Figure imgf000053_0002
[183] [(2S)-l-Amino-2-piperidinyl]methanol was prepared according to the method described by Rosling et al., (Heterocycles 95-106, 1997). In a similar manner were prepared [(2R)-l-amino-2- piperidinyl]-methanol, [(2S)-l-amino-2-pyrrolidinyl]methanol, and [(2R)-l-amino-2- pyrrolidinyljmethanol. [184] Intermediate L 3-Methylisonicotinonitrile
Figure imgf000054_0001
[185] This nitrile was synthesized the procedure described by van den Eϊaak et al., ( J. Heterocycl. Chem. 18:1349-1352, 1981.
Summary of Examples
[186] Using appropriate starting materials and the experimental procedures described above for Examples 1-49 and Intermediates A-L, the following compounds in Tables 1-18 were prepared. It will be understood by those skilled in the art that some minor modifications to the referenced procedures may have been made, but such modifications do not significantly affect the results of the preparation.
[187] LC-MS characterization of compounds, as listed in the tables, was carried out by using the instrumentation and methods set forth above.
Table 1
Figure imgf000055_0001
Figure imgf000055_0002
54
Figure imgf000056_0001
Figure imgf000057_0001
56
Figure imgf000058_0001
57
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Table 1 Synthesis
Entry MS m/z TLC Rf HPLC HPLC R1 R2 R3 R4 IUPAC name Method of No. [MH+] (solvent) RT (min) method Ex. No.
1 ,2-diphenyl-N-(1 -piperidinyl)-1 H- 53 Ph Ph H 1 -piperidinyl 347.2 3.50 1 13,14 imidazole-4-carboxamide
Table 2
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000066_0001
65
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Table 3
Figure imgf000070_0001
Figure imgf000070_0002
Figure imgf000071_0001
Table 3 HPLC Synthesis
Entry MS m/z HPLC R1 Z IUPAC name TLC Rf (solvent) RT Method of No. R2 [MH+] method (min.) Ex. No.
1 -(4-chlorophenyI)-2-(2- 0.62 (25% 2M ethylphenyl)-N-(4-methyl-1 - 84 2-Et-Ph 4-CI-Ph NMe 424.3 NH3/MeOH in 2.28 1 13,14 piperazinyl)-1 H-imidazole-4- EtOAc) carboxamide
Table 4
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000074_0001
Table 5
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000076_0002
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
77
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000081_0002
Figure imgf000083_0001
Figure imgf000084_0001
Table s HPLC Synthesis
Entry MS m/z TLC Rf HPLC R1 R2 R3 R6 R7 IUPAC name RT Method of No. [MH+] (solvent) method (min) Ex. No.
N'-(3-chloro-4-fluorophenyl)-2- 2-Me- (2-methylphenyl)-1-(4- 140 4-CI-Ph H 3-CI-4-F-Ph H 455 3.78 2 10,11,12 Ph chlorophenyl)-1 H-imidazole-4- carbohydrazide hydrochloride
Table 6
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
68
Figure imgf000090_0001
89
Table 7
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Table 8
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000096_0001
Figure imgf000097_0002
Figure imgf000097_0001
Figure imgf000098_0002
Figure imgf000098_0001
Figure imgf000099_0001
Table 9
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0002
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000107_0002
Figure imgf000107_0003
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0002
Figure imgf000110_0001
Figure imgf000111_0002
Figure imgf000111_0001
Figure imgf000112_0002
Figure imgf000112_0001
Figure imgf000113_0002
Figure imgf000113_0001
Figure imgf000114_0002
Figure imgf000114_0001
Figure imgf000115_0002
Figure imgf000115_0001
Figure imgf000116_0002
Figure imgf000116_0001
Table 10 MS HPLC Synthesis
Entry TLC Rf HPLC R1 R2 RT Method of No. R3 n R13 IUPAC name m/z (solvent) method [MH+] (min) Ex. No.
1-{[2-(2-chlorophenyl)-5-methyl-1-(4- 0.35 (67% 4-N02- 275 2-CI-Ph Me 1 3-CF3-Ph nitrophenyl)-1 H-imidazoI-4-yI]carbonyl}-4- 570 EtOAc in 3.64 1 8 Ph [3-(trifluoromethyl)phenyl]piperazine hexane)
Figure imgf000117_0001
Table 11
Figure imgf000118_0001
Figure imgf000118_0003
Figure imgf000118_0002
Figure imgf000119_0002
Figure imgf000119_0001
Figure imgf000120_0002
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000121_0002
Figure imgf000122_0002
Figure imgf000122_0001
Table 12
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000131_0002
Figure imgf000132_0001
Figure imgf000133_0001
Table 13
Figure imgf000134_0001
Figure imgf000134_0003
Figure imgf000134_0002
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000139_0002
Figure imgf000140_0001
Figure imgf000140_0002
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Table 14
Figure imgf000149_0001
Figure imgf000149_0002
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Table 15
Figure imgf000154_0001
Figure imgf000154_0002
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000157_0002
Table 17
Figure imgf000158_0001
Figure imgf000158_0002
Figure imgf000159_0001
Table 18
Figure imgf000160_0001
Figure imgf000160_0002
Figure imgf000161_0001
Figure imgf000162_0001
Methods of Use
[188] As used herein, various terms are defined below.
[189] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.
[190] The term "subject" as used herein includes mammals (e.g., humans and animals).
[191] The term "treatment" includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
[192] The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat a diabetic condition and/or disorder. Such administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner.
[193] The phrase "therapeutically effective" means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
[194] The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product.
[195] The compounds of the present invention are useful in promoting smoking cessation and maintaining abstinence. In addition, these compounds are useful to treat nicotine addiction.
[196] The compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of smoking cessation. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.
[197] The compounds of the invention may be administered in combination with other pharmacotherapies utilized for nicotine dependence. For example, these compounds may be co- administered with nicotine replacement therapy (NRT) such as nicotine gum, nicotine patch, nicotine spray, nicotine lozenge, nicotine inhaler, and the like. The compounds of the present invention may also be administered in combination with a nicotinic receptor modulator (e.g., Varenicline).
[198] The compounds of the present invention may also be used in combination with antidepressant agents such as bupropion (e.g., Zyban®).
[199] Compounds of the invention may also be used in methods of the invention in combination with anti-obesity drugs. Anti-obesity drugs include β-3 agonists; CB-1 antagonists; neuropeptide Y5 inhibitors; appetite suppressants, such as, for example, sibutramine (Meridia); and lipase inhibitors, such as, for example, orlistat (Xenical).
[200] Compounds of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, β-blockers and ACE inhibitors. Examples of additional anti- hypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e. g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual Ϊ EP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
[201] Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the invention in combination with nicotine replacement therapy and an anti-obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
[202] Based on well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
[203] The total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
[204] Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
[205] The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds described herein may be administered with a pharmaceutically- acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
[206] For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
[207] In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
[208] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
[209] The pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums, (2) naturally occurring phosphatides, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, and (4) condensation products of partial esters. The emulsions may also contain sweetening and flavoring agents. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil; or in a mineral oil. The oily suspensions may contain a thickening agent. The suspensions may also contain one or more preservatives; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
[210] Syrups and elixirs may be formulated with sweetening agents. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
[211 ] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent, or emulsifying agent and other pharmaceutical adjuvants.
[212] The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
[213] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents; dispersing or wetting agents.
[214] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
[215] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such material are, for example, cocoa butter and polyethylene glycol.
[216] Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[21 ] Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release. Such foπnulations can be comprised of synthetic polymers or copolymers. Such formulations allow for injection, inhalation, nasal or oral administration. The construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., U.S. Patent No. 6, 706,289, incorporated herein by reference).
[218] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical deUvery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable deUvery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference.
[219] The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generaUy referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
[220] The compounds described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-obesity, or with known nicotine replacement therapeutics or other indication agents, and the like, as well as with admixtures and combinations thereof.
[221] The compounds described herein may also be utilized, in free base form or in compositions, in research and diagnostics, or as analytical reference standards, and the like. Therefore, the present invention includes compositions which are comprised of an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried. An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.
[222] Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20th edition, 2000).
[223] It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.
Evaluation of Biological Activity
[224] hi order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.
[225] Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for smoking cessation, the following assays may be used.
In vivo Studies
[226] An intravenous nicotine self-administration model or place preference model may be used to assess the effects of a test compound on nicotine dependence (see, e.g., Vastola, et al. Physiol. Behav. 77:107-114, 2002; Brower, et al., Brain Res. 930:12-20, 2002).
Place Preference
[227] Sprague-Dawley rats are used in this study (Vastola, et al., 2002). Animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. Conditioning and testing are conducted in a chamber divided into two compartments with a door separating the two compartments. Behavior of the animals is recorded by video camera.
[228] Animals are habituated to the injection procedure for several days. The animals are then placed into the test chamber and given free access to both compartments. The initial preference for a particular compartment is determined. For the conditioning trials, animals are injected with nicotine and restricted to the nonpreferred compartment, or the animals are injected with saline and restricted to the preferred compartment. On test day, the door separating the compartments is removed, the animal is placed in the center of the chamber and allowed to move freely between compartments. Time spent in each compartment is scored. Preferential occupancy of the nicotine compartment follows from the conditioned reinforcing effects of nicotine.
Self-administration
[229] Self-administration in animals is a predictor of a compound's abuse potential in humans. Modifications to this procedure may also be used to identify compounds that prevent or block the reinforcing properties of drugs that have abuse potential. A compound that extinguishes the self- administration of a drug may prevent that drug's abuse or its dependence.
[230] Sprague-Dawley rats are used in this study. Initially, animals are housed in a temperature- controlled, 12h/12h illumination cycle with ad libitum access to food and water. The animals are then implanted with jugular catheters which exit through the animal's back, and each animal is placed in an individual operant chamber (Brower, et al., 2002). The catheters are connected to a computer-driven syringe pump which is located outside of the chamber. The chamber contains two levers with a green light located above each lever. The light is illuminated when nicotine is available.
[231] In a self-administration test, animals are placed in the operant chambers and the levers are randomly designated as an active and inactive lever. Each response on the active lever produces an infusion of nicotine. Presses on the inactive lever have no effect, but are also recorded. Animals are then trained to self-administer nicotine over a set period of time by having drug access during each daily session. Illumination of the chamber house light signals the beginning of the session and the availabiUty of nicotine. When the session ends, the house light is turned off. Initially, a nicotine infusion occurs with every press of the active lever. Once lever-pressing behavior has been established, the number of presses to produce a nicotine infusion is increased. After stable nicotine self-administration is obtained, the effect of a test compound on the nicotine- reinforced behavior may be evaluated. Administration of this test compound prior to the session can either potentiate, extinguish, or produce no change to the self-administrating behavior. Tests are conducted every two days, and the order of the administration of the test compound doses is controlled.
[232] The structures, materials, compositions, and methods described herein are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.

Claims

ClaimsWhat is claimed:
1. A method for promoting smoking cessation comprising administering to a subject in need thereof an effective amount of a compound of Formula (I)
Figure imgf000171_0001
( l ) wherein
R1 and R2 are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (Cι-C6)alkyl, ( - C6)alkoxy, trifluoromethyl, cyano, nitro, (Cι-C6)alkyl sulfonyl, (Cι-C6)alkyl sulfonyl- amino, (Cι-C6)alkyl carbonyl-a ino, (Cι-C6)alkyl amino-carbonyl-amino, or phenyl,
(C2-C6)alkyl, cyclohexyl optionally substituted with (C1-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, or with one or more fluorine,
1-naphthyl or 2-naphthyl optionally substituted with halogen, (C1-C6)alkyl, (Ci- C6)alkoxy, trifluoromethyl, or cyano, benzyl optionally substituted on the phenyl ring with one or more halogen, (Cι-Ce)alkyl, ( -Cβ) alkoxy, trifluoromethyl, or cyano, a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine, ( -C^alkyl, (C1-C6)alkoxy, trifluoromethyl, or cyano, and a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, nitro, or phenyl;
R3 is hydrogen, (C!-C6)aιkyl, benzyl, chloro, or bromo;
Figure imgf000172_0001
where R4is hydrogen or (Cι-C6)alkyl;
R5 is selected from (C2-C9)alkyl or (C7-Cn)bicycloalkyl, each of which may optionally be substituted with one or more phenyl, hydroxy, benzyloxy, (Ci- ) alkoxy,
Figure imgf000172_0002
amino, bis[(C1-C3)alkyl]-amino, 1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-l,4- benzodioxin-2-yl, hydroxy-substituted (C1-C6)alkyl, or fluorine, benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Cι-C6)alkyl, and optionally substituted on the phenyl ring with one or more halogen, (Cι-C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro, piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, each of which may optionally be substituted on the nitrogen atom of the piperidine or pyrrolidine ring with ( - C6)alkyl, hydroxy-substituted (Cι-C6)alkyl, (Cι-C3)alkoxy-substituted (Q- C3)alkyl, benzyl, or phenyl optionally substituted with one or more of ( - C6)alkyl, (Cι-C6)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, nitro, or halogen,
-NR6R7 where R is hydrogen or (C1-C6)alkyl;
R7 is (Cι-C9)alkyl; or phenyl optionally substituted with one or more of ( -Q alkyl, hydroxy-substituted (Cι-C6)alkyl, (Cι-C3)alkoxy- substituted (Cι-C3)alkyl, phenyl, hydroxy, benzyloxy, (Cι-C6)alkoxy, trifluoromethyl, cyano, nitro, or a halogen atom, or
R6 and R7, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more (Cι-C6)alkyl, (Ci- C6)alkoxy, hydroxy-substituted (Cι-C3)alkyl, (Cι-C3)alkoxy-substituted (Cι-C3)alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine; or
R4 and R5, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (Cι-C6)alkyl, (Cι-C6)alkoxy, ( - C6)alkyl-amino, bis[(Cι-C3)alkyι]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (Cι-C6)alkyl, phenyl-substituted (Cι-C6)alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (C1-C6)alkyl, hydroxy, benzyloxy, ( - C6)alkoxy, trifluoromethyl, cyano, nitro, or halogen;
or
Figure imgf000173_0001
where R10 is (Cι-C9)alkyl optionally substituted with one or more phenyl, hydroxy, benzyloxy, ( -C6)alkoxy, or a fluorine atom, or phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, ( -C^alkoxy, or halogen;
and pharmaceutical salts and esters thereof.
2. The method of claim 1, wherein the compound is selected from l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yljcarbonyl}-4-(4- fluorophenyl)-4-piperidinol; 1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl]carbonyl } -4-(4- chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-[3- (trifluromethyl)phenyl]-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(4- trifluoromethoxyphenyl)-4-piperidinol; 1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl] carbonyl } -4-(3- fluorophenyl)-4-piperidinol;
1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-5-ethyl- 1 H-imidazol-4- yl]carbonyl}-4-(3-chlorophenyl)-4-piperidinol;
1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4-yl]carbonyl } -4-(3 - fluoro-4-chlorophenyl)-4-piperidinol;
1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4-yl]carbonyl }-4- [3 -
(trifluoromethoxy)phenyι]-4-piperidinol;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[l-(2-pyridinyl)-4-piperidinyl]-lH- imidazole-4-carboxamide;
[2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4- yl](cyclohexyl)methanone;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-(4-pyridinyl)-lH-imidazole-4- carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[2-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[3-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
N'-[2-chloro-4-(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4- chlorophenyl)-lH-imidazole-4-carbohydrazide;
2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N'-[4-chloro-2-
(trifluoromethyl)phenyl]-lH-imidazole-4-carbohydrazide;
N'-(4-chloro-2-methylphenyl)-2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H- imidazole-4-carbohydrazide;
N'-(2,4-dichlorophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;
N'-[2,4-bis(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4-chlorophenyl)- lH-imidazole-4-carbohydrazide;
N'-(2-chloro-4-cyanophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-(2,4-dichlorophenyl)-5-methyl- lH-imidazole-4-carbohydrazide; l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(l-piperidinyl)-lH-imidazole-
4-carboxamide;
1 -(4-chlorophenyl)-2-(2-chlorophenyl)-N-( 1 -piperidinyl)- 1 H-imidazole-4- carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-butyl-lH- imidazole-4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide;
1 -(4-chlorophenyl)-2-(2-chlorophenyl)-N-( 1 -piperidinyl)-5-methyl- 1 H- imidazole-4-carboxamide;
1 -(4-isopropylphenyl)-2-(2-chlorophenyl)-N-( 1 -piperidinyl)-5-ethyl- 1 H- imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-hexahydrocyclopenta[c]pyrrol-
2(1 H)-yl- 1 H-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;
2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-N-[( 1 S,2S)-2-hydroxycyclohexyl]- lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]-
1 H-imidazole-4-carboxamide;
2-(2-chlorophenyl)- 1 -(4-chlorophenyl)-5-ethyl-N-[(l S,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;
2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-propyl-N-[(lS,2S)-2- hydroxycyclohexyl] - 1 H-imidazole-4-carboxamide; l-(4-bromophenyl)~2-(2-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lR,2R)-2- hydroxycyclohexyl] - 1 H-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(cis)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;
4-(4- { [ 1 -(4-chlorophenyl)-2-(2,4-dichlorophenyl)- 1 H-imidazol-4- yljcarbonyl } - 1 -piperazinyl)benzonitrile; and
4-(4- { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl]carbonyl } - 1 - piperazinyl)benzonitrile.
3. The method of claim 1 or 2, further comprising administering nicotine replacement therapy in combination with the compound.
4. The method of claim 1 or 2, further comprising administering a nicotinic receptor modulator in combination with the compound.
5. The method of claim 1 or 2, further comprising administering an anti-obesity agent in combination with the compound.
6. The method of claim 1 or 2, further comprising administering an anti-hypertensive agent in combination with the compound.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more nicotine replacement therapies.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more nicotinic receptor modulators.
9. A method for promoting smoking cessation comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 8 or 9.
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