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WO2005099705A2 - Preparation de derives imidazoles et leurs procedes d'utilisation - Google Patents

Preparation de derives imidazoles et leurs procedes d'utilisation 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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Prior art keywords
chlorophenyl
alkyl
imidazole
phenyl
carboxamide
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WO2005099705A3 (fr
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Stephen J. Gardell
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Bayer Pharmaceuticals Corp
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Bayer Pharmaceuticals Corp
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    • 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

La présente invention a trait à des composés imidazoles utiles pour favoriser la désaccoutumance au tabac et le maintien d'abstinence.
PCT/US2005/008904 2004-03-24 2005-03-18 Preparation de derives imidazoles et leurs procedes d'utilisation Ceased WO2005099705A2 (fr)

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WO2017157735A1 (fr) 2016-03-15 2017-09-21 Bayer Cropscience Aktiengesellschaft Sulfonylamides substitués pour lutter contre les ravageurs
WO2018083288A1 (fr) 2016-11-07 2018-05-11 Bayer Aktiengesellschaft Sulfonylamides substitués pour la lutte contre les ravageurs
US10258624B2 (en) 2014-10-06 2019-04-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
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US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
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CA2182851A1 (fr) * 1995-08-15 1997-02-16 August Masaru Watanabe Methode de traitement d'un etat resultant de l'arret de la consommation abusive de drogues

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US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
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JP7106532B2 (ja) 2016-11-07 2022-07-26 バイエル・アクチエンゲゼルシヤフト 害虫を防除するための置換スルホニルアミド類
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US10820591B2 (en) 2016-11-07 2020-11-03 Bayer Aktiengesellschaft Substituted sulfonyl amides for controlling animal pests
JP2019534276A (ja) * 2016-11-07 2019-11-28 バイエル・アクチエンゲゼルシヤフト 害虫を防除するための置換スルホニルアミド類
CN110191639A (zh) * 2016-11-07 2019-08-30 拜耳公司 用于防治动物害虫的取代的磺酰胺
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US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
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US12350262B2 (en) 2017-07-17 2025-07-08 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11155533B2 (en) 2017-10-19 2021-10-26 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US12415798B2 (en) 2017-12-08 2025-09-16 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
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