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WO1997031635A1 - Methods of treating or preventing sleep apnea - Google Patents

Methods of treating or preventing sleep apnea Download PDF

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Publication number
WO1997031635A1
WO1997031635A1 PCT/US1997/003113 US9703113W WO9731635A1 WO 1997031635 A1 WO1997031635 A1 WO 1997031635A1 US 9703113 W US9703113 W US 9703113W WO 9731635 A1 WO9731635 A1 WO 9731635A1
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WO
WIPO (PCT)
Prior art keywords
benzimidazole
ethoxy
trimethoxyphenyl
benzyl
dimethylamino
Prior art date
Application number
PCT/US1997/003113
Other languages
French (fr)
Inventor
Bruce D. Gitter
Smriti Iyengar
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to US09/142,026 priority Critical patent/US6030992A/en
Priority to AU21390/97A priority patent/AU2139097A/en
Publication of WO1997031635A1 publication Critical patent/WO1997031635A1/en

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Classifications

    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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

  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • the mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as
  • NK-1, NK-2, and NK-3 are present in a variety of organs.
  • Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra. Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches. see, e.g.. S.L. Shepheard, et al.. British Journal of Pharmacology. 108:11-20 (1993); S.M. Moussaoui, et al.. European Journal of Pharmacology.
  • Sleep apnea is a condition in which apnea coours during sleep without subjective symptom. It is more prevailing in male middle- and old-aged persons in their forties and fifties. Approximately one per 100 persons is reported to suffer from this condition. In sleep apena there is repeated many times in sleep a sequence of 20-40 seconds apnea, about 10-20 seconds pneusis, and 20-40 seconds apnea. For example, during a 6.5 hour sleep, approximately 400 occurrences of apnea may occur.
  • sleep apnea there occur phenomena, such as daytime sleepiness, loss of energy or appetite, swelling in the lower part of the body, and shortness of breath. Increase in leukocyte number, development of polycythemia, and even cardiomegaly are associated with severe instances of sleep apnea. Sleep apnea is observed not only in adults of middle or advanced age, but also in infants, and may be an indirect cause of hypertension, cardiac insufficiency, and arrhythmia, possibly being a leading cause of sudden infant death syndrome.
  • SIDS Sudden Infant Death Syndrome
  • R 1 is hydrogen, C 1 -C 12 alkyl, Ci-C ⁇ alkoxy, phenyl, C 3 -C 8 cycloalkyl, naphthyl, heterocyclic, unsaturated heterocyclic, phenyl-(C ⁇ -C6 alkylidenyl)-, naphthyl-(C ⁇ -C 6 alkylidenyl)-, heterocyclic-(C ⁇ -C 6 alkylidenyl)-, unsaturated heterocyclic-(C ⁇ -C6 alkylidenyl)-, phenyl-(C ⁇ -C6 alkoxy)-, naphthyl-(C ⁇ -C6 alkoxy)-, heterocyclic-(C ⁇ -C6 alkoxy)-, or unsaturated heterocyclic-(C ⁇ -C6 alkoxy)-,
  • any one of which phenyl, naphthyl, heterocyclic, C 3 - C ⁇ cycloalkyl, or unsaturated heterocyclic groups may be optionally substituted with one, two, or three moieties independently selected from group consisting of heterocyclic-(C ⁇ -C 6 alkylidenyl)-, unsaturated heterocyclic-(C ⁇ -C6 alkylidenyl)-, hydroxy, halo, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, trifluoromethyl, nitro, amino, cyano, Ci-C ⁇ alkylamino, and Ci-C ⁇ alkylthio;
  • R 2 is hydrogen, C 1 -C 12 alkyl, Ci-C ⁇ alkoxy, phenyl, C 3 -C 8 cycloalkyl, naphthyl, heterocyclic, unsaturated heterocyclic, phenyl-(C ⁇ -C ⁇ alkylidenyl)-, naphthyl-(C ⁇ -Ce alkylidenyl)-, heterocyclic-(C ⁇ -C 6 alkylidenyl)-, unsaturated heterocyclic-(C ⁇ -C ⁇ alkylidenyl)-, phenyMCi-C ⁇ alkoxy)-, naphthyl-(C ⁇ -C 6 alkoxy)-, heterocyclic-(C ⁇ -C6 alkoxy)-, or unsaturated heterocyclic-(C ⁇ -C 6 alkoxy)-,
  • C ⁇ cycloalkyl, or unsaturated heterocyclic groups may be optionally substituted with one, two, or three moieties independenly selected from group consisting of phenyl-(C ⁇ -C 6 alkylidenyl)-, naphthyl-(C ⁇ -C6 alkylidenyl)-, heterocyclic-(C ⁇ -C 6 alkylidenyl)-, unsaturated heterocyclic-(C ⁇ -C 6 alkylidenyl)-, phenyl- (Ci-C ⁇ alkoxy)-, naphthyHCi-C ⁇ alkoxy)-, heterocyclic-(C ⁇ -C 6 alkoxy)-, or unsaturated heterocyclic-(C ⁇ -C6 alkoxy)-, hydroxy, halo, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, trifluoromethyl, nitro, amino, cyano, Ci-C ⁇ alkylamino, and Ci-C ⁇ alkylthio;
  • R 3 is hydrogen, nitro, Ci-C ⁇ alkanoyl, amino, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, C3-C 8 cycloalkyl, heterocyclic, unsaturated heterocyclic, halo, Ci-C ⁇ alkylthio, hydroxy-(C ⁇ -C6 alkylidenyl)-, hydroxy-(C ⁇ -C6 alkylidenyDamino-, R R 5 N-,
  • R 4 R ⁇ N-(C ⁇ -C 6 alkylidenyl)-, R 4 R5N-(C ⁇ -C 6 alkoxy)-, hydroxy- (Ci-C ⁇ alkyl)-, heterocyclic-(C ⁇ -C6 alkoxy)-, amino(C ⁇ -C6 alkylidenyl)-, or trifluoromethyl,
  • R 4 and R 5 are independently selected from the group consisting of Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, CI-C ⁇ alkanoyl, aryl, heterocyclic, unsaturated heterocyclic, aryKCi-C ⁇ alkylidenyl)-, heterocyclic(C ⁇ - C ⁇ alkylidenyl)-, unsaturated heterocyclic(C ⁇ -C 6 alkylidenyl)-, and hydrogen or R 4 and R 5 combine to form C3-C 8 cycloalkyl,
  • alkyl or alkoxy groups may be substituted with one or more halo, amino, or nitro, and
  • any one of which aryl, unsaturated heterocyclic, or heterocyclic groups may be substituted with one, two, or three moieties independenly selected from group consisting of hydroxy, halo, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, trifluoromethyl, nitro, amino, cyano, C 3 -C 8 cycloalkyl, Ci-C ⁇ alkylamino, and Ci-C ⁇ alkylthio; with the proviso that not more than one of R 1 and R 2 may be hydrogen;
  • Ci-C ⁇ alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • C 1 -C6 alkyl includes within its definition the term “C 1 -C3 alkyl”.
  • Halo represents chloro, fluoro, bromo or iodo.
  • haloformate refers to an ester of a haloformic acid, this compound having the formula
  • X is halo
  • R d is Ci-C ⁇ alkyl.
  • Preferred haloformates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein R ⁇ * is C3-C6 alkyl are especially preferred. Most preferred is isobutylchloroformate.
  • the term "unsaturated heterocycle” represents a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which has one or more double bonds and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quarternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the unsaturated heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure.
  • heterocycles and unsaturated heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, t
  • Ci-C ⁇ alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical Ci-C ⁇ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, f-butoxy, pentoxy and the like.
  • the term "Ci-C ⁇ alkoxy” includes within its definition the term “C 1 -C4 alkoxy”.
  • C2-C 6 alkanoyl represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety.
  • Typical C2-C 6 alkanoyl groups include acetyl, propanoyl, isopropanoyl, butanoyl, £-butanoyl, pentanoyl, hexanoyl, 3- methylpentanoyl and the like.
  • C 3 -C 8 cycloalkyl represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms which is unsubstituted.
  • Typical C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • hydroxy-protecting groups refers to substitents of the hydroxy group commonly employed to block or protect the hydroxy functionality while reacting other functional groups on the compound. Examples of such hydroxy-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl,
  • the compounds prepared in the processes of the present invention have an asymmetric center.
  • the compounds produced in the present invention may occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. Processes for preparing such asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • the prefix "D” is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • this invention includes methods employing the pharmaceutically acceptable salts of the compounds defined by Formula I.
  • a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non- toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic arid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic arid, hydroiodic acid, sulfuric arid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic arid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic arid, hydroiodic acid, sulfuric arid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic arid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylprop
  • Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • This invention further encompasses methods employing the pharmaceutically acceptable solvates of the compounds of Formula I.
  • Many of the compounds of Formula I can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • the compounds of the present invention are derivatives of benzimidazole which are named and numbered according to the Ring Index, The American Chemical Society, as follows.
  • R 1 is phenyl, naphthyl, heterocyclic, unsubstituted heterocyclic, or substituted derivatives thereof;
  • R 2 is phenyl, heterocyclic, unsaturated heterocyclic, phenyKCi-C ⁇ alkylidenyl)-, heterocyclic(C ⁇ -C6 alkylidenyl)-, unsaturated heterocyclic(C ⁇ -C 6 alkylidenyl)-, or substituted derivatives thereof;
  • R 3 is R 4 R 5 N-(C ⁇ -C 6 alkylidenyl)-, C ⁇ -C 6 alkanoyl, , C 1 -C4 alkoxy, imidazole, amino-(C ⁇ -C6 alkylidenyl), hydroxy-(C ⁇ -C6 alkylidenyDamino-, heterocyclic-(C ⁇ -C6 alkoxy)-, R 4 R 5 N-(C ⁇ -C6 alkoxy)-, or hydroxy;
  • R 3 is at the 5 or 6 position of the benzimidazole.
  • R 1 is phenyl or naphthyl substituted with one or more electron donating, lipophilic substituents
  • R 2 is substituted benzyl or substituted phenyl
  • R 3 is R R 5 N-(C ⁇ -C 6 alkylidenyl)-, heterocyclic-(C ⁇ -C 6 alkoxy)-, R 4 R 5 N-(C ⁇ -C6 alkoxy)-, or unsaturated heterocyclic(C ⁇ -C6 alkylidenyl)-;
  • R 3 is at the 6 position of the benzimidazole.
  • the compounds of Formula I can be prepared by processes known in the literature. See, e.g.. G.W.H. Cheeseman and R.F. Cookson, THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, (A. Weissberger, et al.. eds. 1979).
  • the usual process for the preparation of the compounds of Formula I is by cyclization of an appropriately substituted o-phenylenediamine such as the one depicted in Formula III
  • Suitable solvents include ethanol, isopropanol, gladal acetic add, benzene, toluene, chlorobenzene, glycol, ethylene glycol, dimethyl ether, diethyl ether, dimethylformamide, chloroform, ethyl acetate, and the like.
  • a condensation agent such as phosphorous oxychloride, thionyl chloride, p-toluenesulfonic add, hydrochloric add, sulfuric add, phosphoric acid, polyphosphoric add, phosphorous pentoxide, methanesulfonyl hydroxide, methanesulfonyl chloride, and the like.
  • the cyclization reaction may also optionally be performed in the presence of a base such as sodium hydroxide, sodium mesylate, or potassium tert-butylate.
  • the keto benzimidazole reactants can be prepared from acetanilide by a Friedel-Crafts acylation with the appropriate derivative of C2-C 6 alkanoic add.
  • the resulting 4-keto acetanilide is nitrated to give a 2-nitro-4-ketoacetanilide.
  • the acetanilide is hydrolyzed to give a 2-mtro-4-ketoaniline, which can then be catalytically hydrogenated to yield a 4-keto-o-phenylenediamine which can then be ring closed to provide the 5 or 6-substituted benzimidazole.
  • Those compounds of Formula III wherein R 3 is a substituted alkyl or alkylidenyl may be prepared by means of a Friedel- Crafts alkylation with the appropriate derivative of the R 3 moiety using standard procedures, usually employing an alkyl halide or an olefin in the presence of a catalyst such as aluminum chloride, aluminum bromide or another Lewis acid.
  • a catalyst such as aluminum chloride, aluminum bromide or another Lewis acid.
  • those compounds of Formula I in which R 2 is alkyl or substituted alkyl may be produced by alkylation of an aromatic amine with alkyl halide or tosylate, or the like, in the presence of a suitable base, such as trialkylamine, potassium carbonate, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
  • a suitable base such as trialkylamine, potassium carbonate, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
  • Cyclization of this substituted phenylenediamine is then performed as described sunra. followed by cleavage of the ester group protecting the hydroxy group at the 6-position of the benzimidazole.
  • Suitable cyclization catalysts include phosphorous oxychloride, thionyl chloride, phosphorous pentoxide, phosphorous pentachloride, and other like strong dehydrating agents.
  • a preferred method of cleaving this ester is by incubation of the intermediate in a basic solution, such as IN sodium hydroxide, or a weaker base such as potassium carbonate.
  • a basic solution such as IN sodium hydroxide, or a weaker base such as potassium carbonate.
  • the hydroxy group at the 6- position is then substituted using an alkyl or aryl halide, resulting in a compound of Formula I.
  • compounds of Formula I substituted at the 5-position of the benzimidazole can be prepared as described above by employing 3-amino-4-nitrophenol as the starting material instead of the 3-nitro-4-aminophenol shown supra.
  • Those compounds of Formula I wherein R 2 is alkyl or substituted alkyl may alternatively be prepared by the direct alkylation of a benzimidazole wherein the nitrogen at the 1-position is substituted with a hydrogen.
  • This type of alkylation is usually performed by the reaction of the benzimidazole with an alkyl halide in the presence of a strong base, such as sodium hydride.
  • This reaction is usually performed in a polar aprotic solvent, such as N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, hexamethylphosphoric triamide, and the like.
  • NMR nuclear magnetic resonance spectrum
  • IR infrared absorption spectrum
  • MS mass as determined by mass spectrometry
  • N-phenyl-o-phenylenediamine (10 mmol, 1.84 grams) was added to diethyl ether (100 ml) and stirred at room temperature as benzoyl chloride (10 mmol, 1.41 g) was added dropwise (a predpitate formed after about one half of the benzoyl chloride was added). After addition of the benzoyl chloride, the solution was stirred at room temperature for about 15 minutes. The reaction mixture was partitioned between aqueous sodium hydroxide and diethyl ether. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined and dried over magnesium sulfate.
  • the reaction mixture was partitioned with IN sodium hydroxide.
  • the diethyl ether layer was removed and the aqueous layer extracted with ethyl acetate (4 x 150 ml).
  • the organic layers were combined, dried over potassium carbonate, filtered, and concentrated in vacuo to yield 3.72 grams (>99%) of a dark red/brown solid.
  • the crude product could be used as is or could be further purified. In the further purification the crude product was triturated in diethyl ether and filtered to yield an off-white solid, mp 169-171°C.
  • the titled intermediate was prepared essentially as described in Journal of Medidnal Chemistry, 18:319 (1975).
  • a solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and m-methoxybenzoic add (1.52 g, 10 mmol) was stirred at room temperature in methylene chloride (80 ml).
  • N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (2.97 g) was added dropwise and the reaction was refluxed for about 16 hours.
  • Additional N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoUne was added and the reaction was refluxed for an additional 18 hours.
  • reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with chloroform (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 1.18 grams (>99%).
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (75 ml) was stirred at room temperature as 4- nitrobenzoylchloride (1.86 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. A predpitate quickly formed. The reaction was stirred overnight.
  • reaction mixture was partitioned with 1 N sodium hydroxide and the organic layer removed.
  • the aqueous layer (pH ⁇ 14) was extracted with ethyl acetate (3 x 100 ml).
  • the organic layers were combined, washed with saturated sodium chloride, dried over potassium carbonate, filtered and concentrated in vacuo.
  • reaction mixture was cooled and partitioned with 1 N sodium hydroxide (pH ⁇ 14).
  • the organic layer was separated and the aqueous layer was extracted with chloroform (3 x 100 ml).
  • the organic layers were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.50 grams of a yellow/green solid.
  • the reaction product was purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent. MS 316(M+), mp 175-177°C. Analysis for C19H 1 3N 3 O2: Theory: C, 72.37; H, 4.15; N, 13.33.
  • reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1 to 4:1) solution as eluent, yielding 1.89 grams (62%) of a light yellow solid. MS 339(M + ), mp 99-101°C.
  • the reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The product was purified by trituration with diethyl ether to yield 2.19 g (65.7%) of a yellow solid, mp 127-129°C. A solution of the intermediate prepared above (2.9 g, 8.7 mmol) in chloroform (85 ml) was stirred at room temperature was phosphorous oxychloride (in 35 ml chloroform) was added dropwise.
  • reaction mixture was partitioned with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with chloroform (3 x 120 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.50 grams of a brown/green solid.
  • reaction product was further purified by chromatography to yield 2.31 grams (77%) of a light pink solid. MS 339, 341, mp l62-164°C.
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 4- (trifluoromethyDbenzoyl chloride (2.09 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
  • reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, washed with a sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a brown/black solid.
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) was stirred at room temperature in diethyl ether (85 ml) as naphthoyl chloride (10 mmol, 1.91 g) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
  • the reaction mixture was alkalinized with IN sodium hydroxide. The organic layer was removed. The aqueous layer (pH ⁇ 14) was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown solid (3.91 g, >99%).
  • the solid was triturated with diethyl ether and the remaining solid was collected by vacuum filtration.
  • the reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as eluent. mp 147-149°C.
  • the reaction mixture was alkalinized with IN sodium hydroxide.
  • the organic layer was removed and the aqueous layer was extracted with chloroform (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.38 grams (>99%) of a brown solid.
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 3,5- dimethylbenzoyl chloride (2.00 g, 1.84 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with ethyl acetate (3 x 100 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.46 grams of a red/brown oil which solidified upon standing.
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 3,4- dimethoxybenzoyl chloride (2.01 g, 10 mmol) in 40 ml of diethyl ether was added dropwise. The reaction mixture was then stirred overnight at room temperature.
  • reaction mixture was then alkalinized with IN sodium hydroxide.
  • the organic layer was removed and the aqueous layer was extracted with diethyl ether (3 x 150 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.11 grams.
  • This intermediate was further purified by chromatography using a hexanes/ethyl acetate solution as the eluent, followed by trituration with hexanes to yield a white crystalline solid, mp 159-160°C.
  • a solution of the intermediate prepared supra (3.11 g, 8.9 mmol) in chloroform (30 ml) was stirred at room temperature as phosphorous oxychloride (1.40 g, 9 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was then refluxed overnight. The reaction mixture was partitioned with IN sodium hydroxide.
  • the organic fraction was removed and the aqueous phase was extracted with methylene chloride (3 x 150 ml). The organic fractions were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a brown oil which solidified upon standing.
  • the crude product was partitioned between IN hydrochloric add and a hexanes/ethyl acetate (1:1) solution.
  • the aqueous layer was removed and the organic layer was extracted with IN hydrochloric add (3 x 100 ml).
  • the aqueous fractions were combined and alkalinized to pH 14 with sodium hydroxide. This basified solution was extracted with ethyl acetate (5 x 100 ml).
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 3,4,5- trimethoxybenzoyl chloride (2.31 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. The reaction mixture was then stirred overnight at room temperature. The solvents were then removed in vacuo leaving N- [(3,4,5-trimethoxyphenyl)carbonyl]-N'-phenyl-phenylenediamine.
  • reaction mixture was partitioned with IN sodium hydroxide and the organic layer removed.
  • the aqueous fraction was further extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • reaction product was further purified by chromatography to yield 2.64 grams (82.1%) of a light pink solid. MS 335, 337, mp 183-185°C.
  • the reaction mixture was alkalinized with IN sodium hydroxide.
  • the organic layer was removed and the aqueous fraction was extracted with ethyl acetate (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.18 grams of a red/brown solid.
  • the intermediate was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as the eluent to yield a yellow solid, mp 143-145°C.
  • reaction mixture was partitioned with IN sodium hydroxide and the organic layer removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield a red/brown oil which solidified upon standing.
  • reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as the eluent. The fractions were combined, the solvents removed in vacuo and the resulting oil was triturated with diethyl ether. The title product was recystallized from diethyl ether/hexanes to yield 1.54 grams (63%). MS 285(M+) Analysis for C 2 0H 16 N2:
  • the reaction mixture was then alkalinized with IN sodium hydroxide.
  • the organic layer was removed and the aqueous fraction was extracted with ethyl acetate (3 x 150 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.12 grams of a gray/brown solid.
  • the intermediate was further purified by chromatography. mp 129-130°C.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • the reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent. The product was recrystallized from hexanes to yield 0.97 grams (41.1%) of a white solid. MS 285(M+), mp 69-71°C. Analysis for C2 0 H 1 6N2:
  • reaction mixture was partitioned with IN sodium hydroxide. The organic fraction was removed and the aqueous layer was extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 3.31 grams of a red/black oily gum.
  • the reaction mixture was alkalinized wtih IN sodium hydroxide.
  • the organic layer was removed and the aqueous fraction was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
  • reaction mixture was alkalinized with IN sodium hydroxide.
  • the organic fraction was removed and the aqueous phase was extracted with ethyl acetate (3 x 150 ml).
  • the organic fractions were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.81 grams of a brown solid.
  • the reaction product was further purified by chromatography to yield N-phenyl-N'-cyclohexylcarbonyl- phenylenediamine as a yellow solid.
  • reaction mixture was alkalinized with IN sodium hydroxide.
  • the organic layer was removed and the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • methylene chloride (3 x 150 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.81 grams of a black/red oil which solidified upon standing.
  • the reaction product was further purified by partitioning between IN hydrochloric add and an ethyl acetate/hexanes (1:1) solution.
  • the aqueous layer was alkalinized to pH 10 using IN sodium hydroxide.
  • the aqueous fraction was then extracted with ethyl acetate (4 x 250 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 1.47 grams (76%) of a light yellow solid.
  • MS 277(M+) mp 99-101°C. Analysis for C 19 H20N 2 :
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer removed.
  • the aqueous phase was extrated with ethyl acetate (3 x 100 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.2 grams (>99%) of a gray/brown solid.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous fraction was extracted with ethyl acetate (3 x 100 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent. Trituration with hexanes and subsequent filtration yielded a white solid, mp 118-120°C.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • the reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1 to 4:1) solution as the eluent to yield a pale yellow oil.
  • the product was triturated with hexanes to yield a light yellow solid.
  • MS 285(M+) mp 99-101°C. Analysis for C20H16N2:
  • the reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as eluent.
  • the reaction product was recrystallized from hexanes. mp 178-180°C.
  • the intermediate prepared above (2.65 g, 8.3 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous fraction was extracted with ethyl acetate (3 x 100 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as the eluent.
  • the product was recrystallized from hexanes to yield a white solid. mp l41-143°C.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • N,N-dimethylformamide (anhydrous, 20 ml) was stirred at room temperature under nitrogen atmosphere. Two equivalents of sodium hydride in 60% dispersion (0.40 g, 10 mmol) was quickly added and the reaction mixture was allowed to stir under nitrogen. N-(2- chloroethyDpiperidinyl (10 mmol) in anhydrous N,N- dimethylformamide (12 ml) was added dropwise by syringe to the stirring mixture. The reaction mixture was stirred overnight at room temperature.
  • reaction mixture was partitioned between acetic add and ethyl acetate. The organic layer was discarded and the aqueous phase was extracted with diethyl ether (5 x 75 ml). All organic fractions were discarded.
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and 4-chloro-3-nit ⁇ o-benzoic add (2.07 g, 10 mmol) in anhydrous tetrahydrofuran was stirred at room temperature as N-ethoxycarbonyl- 2-ethoxy-l,2-dihydroquinoline (3.71 g, 15 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred at room temperature for about 72 hours.
  • reaction mixture was alkalinized with IN sodium hydroxide.
  • aqueous layer was extracted with ethyl acetate (4 x 100 ml).
  • the organic fractions were combined, dried over potassium carbonate, filtered, and the solvents removed in vacuo to yield the crude product.
  • the reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent.
  • the intermediate prepared above (3.00 g, 8.4 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • reaction mixture was partitioned between acetic add and ethyl acetate. The organic layer was discarded and the aqueous phase was extracted with diethyl ether (5 x 75 ml). All organic fractions were discarded.
  • aqueous phase was alkalinized with 2N sodium hydroxide. This solution was then extracted with diethyl ether (4 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a doudy oil.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous fraction was extracted with ethyl acetate (3 x 100 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • the reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent. The product was recrystallized from hexanes to yield a white solid.
  • the intermediate prepared above in chloroform was stirred at room temperature as an equimolar amount of phosphorous oxychloride in chloroform was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • reaction product was further purified by trituration in diethyl ether. Recrystallization from ethyl acetate yielded a white solid which was homogeneous on thin layer chromatography. mp 150-152°C.
  • the intermediate prepared above in chloroform was stirred at room temperature as an equimolar amount of phosphorous oxychloride in chloroform was added dropwise. The reaction mixture was refluxed overnight.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as an equimolar amount of hexanoyl chloride in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
  • the reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous fraction was extracted with ethyl acetate (3 x 100 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
  • the reaction product was further purified by trituration in diethyl ether. Recrystallization from ethyl acetate yielded a white solid which was homogeneous on thin layer chromatography.
  • reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methylene chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
  • the reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as eluent to yield 1.82 grams (69.2%) as a red oil.
  • the red oil was stirred in a 2N hydrochloric add/ethanol (1:1) solution for ten minutes.
  • the ethaol was removed in vacuo to yield 2.1 grams of a brown/green solid.
  • the title product was recrystallized from an ethyl acetate/ethanol (1:1) solution.
  • N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as an equimolar amount of 2-trifluoromethylbenzoyl chloride in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
  • the reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous fraction was extracted with ethyl acetate (3 x 100 ml).
  • the organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
  • reaction product was further purified by trituration in diethyl ether to yield a white solid which was homogeneous on thin layer chromatography. mp 161-162°C.
  • the intermediate prepared above in chloroform was stirred at room temperature as an equimolar amount of phosphorous oxychloride in chloroform was added dropwise.
  • the reaction mixture was refluxed overnight.
  • the reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed.
  • the aqueous layer was extracted with methyl ne chloride (3 x 150 ml).
  • the organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown mixture of oil and solid.
  • reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as eluent followed by trituration in diethyl ether to yield 1.07 grams (37.2%). Recrystallization from hexanes yielded white crystals, homogeneous on thin layer chromatography. MS 338, mp 142-144°C. Analysis for C2 0 H13F 3 N2: Theory: C, 71.00; H, 3.87; N, 8.28. Found: C, 70.70; H, 3.97; N, 8.12.
  • Example 52 Synthesis of l-(2,6-dicMorobenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
  • the title compound was prepared essentially as described in Example 40, supra, except that 2,6-dichlorobenzyl bromide (0.81 g, 4.10 mmol) was employed instead of the 3-chlorobenzyl bromide, mp 157°C.
  • Example fifi Synthesis of l-(4-methylbenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
  • the title compound was prepared essentially as described in Example 40, sjipxa, except that 4-methylbenzyl bromide (0.45 g, 2.23 mmol) was employed instead of the 3-chlorobenzyl bromide.
  • the intermediate 2-(3-methylphenyl)-benrimidazole was prepared by first mixing reacting l-amino-2-nitrobenzene (8.50 g, 61.54 mmol) with toluene (180 ml) and heating to 100°C. To this mixture was then added 20 ml of N,N-diethylaniline and the reaction vessel was placed under a nitrogen atmosphere. To this solution was then added 3- methylbenzoyl chloride (24 ml, 132 mmol) and this mixture was then stirred overnight. After stirring, the reaction mixture was neutralized by the addition of 300 ml of IN hydrochloric acid and 300 ml of ethyl acetate. This was then stirred for about 30 minutes.
  • the substituted 1,2-phenylenediamine (1.01 g, 4.46 mmol) was then cydized using phosphorous oxychloride (1.01 g, 6.6 mmol) as described supra to produce 2-(3-methylphenyl)benrimidazole.
  • Example 65 l-(3-Methoxybenzyl)-2-(3-methylphenyl)benzimidazole. Oil at room temperature. NMR, IR, MS 328. Analysis for C22H20N2O: Theory: C, 80.46; H, 6.14; N, 8.53.
  • This compound was prepared by first synthesizing l-(3- methoxybenzyl)-2-(3-methylphenyl)benzimidazole as described in Example 65, supra. With an amount of the compound of Example 65 (4.31 g, 13.12 mmol) in glarial acetic add (50 ml) and hydrobromic add (300 ml of a 48% w/v in acetic add solution). This mixture was stirred for 2 hours while warming to reflux. The mixture was then stirred at reflux for about three hours.
  • the title compound was prepared by first reacting 4-amino- 3-nitrophenol (25.0 g, 162.2 mmol) with 3,4,5-trimethoxybenzoyl chloride (112 g, 485.6 mmol) in N,N-diethylaniline (69 ml) and toluene (500 ml). The reaction mixture was stirred and the temperature was raised to 100°C. The solution was maintained at this temperature for about 6 hours as a yellow predpitate formed. The reaction mixture was then partitioned between IN hydrochloric add (250 ml) and ethyl acetate (250 ml).
  • a benzyl group was then substituted on the nitro group by reacting the above intermediate (10 g, 18.4 mmol) with benzaldehyde (6 ml) in N,N-din ⁇ ethylformamide (100 ml) under a hydrogen atmosphere (60°C at 60 p.s.i.) with 6.0 g of a palladium on activated carbon catalyst.
  • the benzimidazole ring was closed using phosphorous oxychloride in chloroform as described supra.
  • the ester on the 6- hydroxy group of the benzimidazole was removed by incubating the intermediate in IN sodium hydroxide (500 ml) and tetrahydrofuran (500 ml). This solution was stirred overnight, followed by addification with a suffirient amount of 1 N hydrochloric add to reduce the pH to 1.0. This solution was then washed with ethyl acetate (2 x 500 ml). The organic fractions were combined, dried over magnesium sulfate, and the solvents removed in vacuo to yield a brownish/red solid. The title compound was further purified by flash chromatography to yield a grayish solid. MS 390. Analysis for C23H22N2O4 • HCl: Theory: C, 64.71; H, 5.43; N, 6.56.
  • the title compound was prepared by reacting the compound of Example 76, supra. (0.45 g, 1.0 mmol) with 4-(piperdin-l-yl)piperidine (2.0 g, 11.9 mmol) in the presence of the base N,N- diisopropylethylamine, tetra-n-butylammonium iodide and acetonitrile at 80°C. After incubating overnight at 80°C the reaction was washed with water (2 x 500 ml), followed by a wash with a saturated sodium chloride solution (1 x 500 ml). The organic phase was then dried over potassium carbonate and the solvents were removed in vacuo to yield a light brown oil.
  • the title compound was prepared by reacting the compound of Example 70, supra. 0.45 g, 1.15 mmol) with l-methyl-2- dimethylaminoethyl chloride (1.82 g, 11.51 mmol) and potassium chloride (3.18 g, 23.01 mmol) in 100 ml of acetone. The reactants were admixed and then heated to reflux overnight.
  • reaction mixure was addified by adding 500 ml of IN hydrochloric add and then washed with ethyl acetate (2 x 250 ml). The aqueous layer was then basified and extracted with ethyl acetate (500 ml). The organic fractions were combined and washed with a saturated sodium chloride solution and dried over potassium carbonate. The solvents were removed in vacuo to yield a yellow oil which was triturated with hexanes, forming a white solid. This was further purified by crystallizing from 10:1 hexanes:ethanol to yield the desired title product. IR, NMR, MS 475, 476, mp 93°C.
  • Example 85 sjipxa, except that 2-(N,N-dimethylamino)propyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride, mp 74°C, NMR, IR, MS 399, 400.
  • the title compound was prepared by first adding morpholine (1.02 g, 11.77 mmol) and the compound of Example 97, supra. (0.39 g, 1.00 mmol) to 125 ml of acetonitrile while stirring under nitrogen purge. To this mixture is then added diisopropylethyl aniline (1.51 ml, 8.67 mmol) dropwise. This reaction mixture is then allowed to stir overnight.
  • the title compound was prepared by first reacting 3,4,5- trimethoxybenzoyl chloride (112.0 g, 485.6 mmol) with 4-amino-3- nitrophenol (25.0 g, 162.2 mmol) in N,N-diethylaniline (69 ml) and toluene (500 ml). This reaction mixture was heated to 100°C and maintained at that temperature for about 6 hours. The intermediate ester of 4-(3,4,5-trimethoxyphenylcarbonylamino)-3-nitrophenol was purified essentially as described in Example 69, supra.
  • Example 120 The title compound was prepared essentially as described in Example 106 except that the compound of Example 120 was reacted with 3-(N,N-dimethylamino)propyl chloride, mp 74°C, NMR, IR, MS
  • the title compound was prepared essentially as described above except that the compound of Example 120 was reacted with 1- methyl-2-(N,N-dimethylamino)ethyl chloride, yielding the title product as an oil.
  • Example 115 The title compound was prepared essentially as described in Example 115 except that the compound of Example 126 was reacted with 2-(piperidin-l-yl)ethyl chloride, mp 107°C, NMR, IR, MS 503, 505. Analysis for C2sH 3 oBrN 3 O:
  • Example 117 The title compound was prepared essentially as described in Example 117 except that the compound of Example 126 was reacted with 2-(N,N-dimethylamino)ethyl chloride, mp 71°C, NMR, IR, MS 464, 466. Analysis for C 2 5H2 ⁇ BrN 3 ⁇ :
  • the title compound was prepared essentially as described above except that the compound of Example 126 was reacted with 1- methyl-2-(N,N-dimethylamino)ethyl chloride.
  • Example 138 The following compounds were prepared essentially as described supra, except that the compound of Example 138 was employed as a starting material.
  • Example 138
  • Example 142 l-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- dimethylamino)propoxy]benzimidazole. MS 491, 493. Analysis for C27H3oBrN 3 ⁇ : Theory: C, 65.85; H, 6.14; N, 8.53.
  • the title compound was prepared by first reacting 1-chloro- 3,4-dinitrobenzene (100 g, 0.50 mole) with aniline (140 ml, 1.54 moles) in ethanol (95%, 550 ml). This reaction mixture was stirred at room temperature for about 72 hours. The resulting l-chloro-3-phenylamino- 4-nitrobenzene was purified by first filtering the orange crystals, followed by washing with hexanes. The crystals were then dried at 80°C for about 4 hours. Additional product was recovered from the hexanes filtrate by recrystallizing from ethanol.
  • the l-chloro-3-phenylamino-4-nitrobenzene was then reacted with two molar equivalents of sodium methoxide, the sodium methoxide being prepared essentially as described in Kottenhahn, et al.. Journal of Organic Chemistry. 28:3114 (1963).
  • Metallic sodium 5.0 g, 217 mmol
  • methanol 400 ml
  • the l-chloro-3-phenylamino-4- nitrobenzene was added and the red-orange solution was heated to reflux and maintained at that temperature overnight.
  • the gold crystals of l-methoxy-3-phenylamino-4-nitrobenzene were recovered by filtration, washed with water (2 liters) and dried in vacuo.
  • the nitro group of the above-described intermediate was then reduce to an amino group by catalytic hydrogenation using a palladium on activated carbon catalyst, essentially as previously described, resulting in 3-phenylamino-4-methoxyaniline with was then reacted with 3,4-dimethylbenzoyl chloride as previously described.
  • This intermediate was then cyclized to the corresponding benzimidazole with phosphorous oxychloride as previously described to yield l-phenyl-2-(3,4- dimethylphenyl)-6-methoxybenrimidazole.
  • a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e.g.. J. Jukic, et al.. Life Sdences.49:1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medidnal Chemistry. 36:1654-1661 (1993); N. Rouissi, s s , Biochemical and Biophysical
  • Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al.. Journal of Immunology. 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 10 6 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125 I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at
  • the IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London). 251:443-444 (1974); Proceedings of the National Academy of Sdences (USA). 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 ⁇ g/ml gentamirin sulfate and 10% fetal calf serum.
  • reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Spedfic binding of labeled substance P was determined in the presence of 20 nM uniabeled ligand.
  • the CHO-hNK-2R cells a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm 2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum.
  • minimal essential medium alpha modification
  • the gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al.. Journal of Biological Chemistry.265:20455-20462 (1990).
  • 30 confluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of
  • the protein concentration of this preparation was 2 mg/ml.
  • CHO-hNK-2R membrane preparation For the receptor binding assay, one 4-ml aliquot of the CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 ⁇ g/ml chymostatin. A 200 ⁇ l volume of the homogenate (40 ⁇ g protein) was used per sample.
  • the radioactive ligand was [ 125 I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol.
  • the ligand was prepared in assay buffer at 20 nCi per 100 ⁇ l; the final concentration in the assay was 20 pM.
  • Non-sperific binding was determined using 1 ⁇ M eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
  • DMSO dimethylsulfoxide
  • IC50 IC50 determinations.
  • the order of additions for incubation was 190 or 195 ⁇ l assay buffer, 200 ⁇ l homogenate, 10 or 5 ⁇ l sample in DMSO, 100 ⁇ l radioactive ligand.
  • the samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 m polystyrene tubes and counted in a gamma counter.
  • the compounds of Formula I are useful in treating sleep apnea.
  • the effectiveness of a compound employed in the present invention may be demonstrated using standard techniques.
  • the patients who have been diagnosed with sleep apnea are given soft capsules, each containing 10 mg of (R)-3-(lH-indol-3-yl)-l-[N- (2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin-l-yl)piperidin-l- yl)acetyl)amino]propane dihydrochloride trihydrate at a dose of one capsule after supper for period of days. Clinical symptoms of the patients are observed, and apnea index (times/hour) are also measured before and after administration.
  • compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usually mixed with an exdpient, diluted by an exdpient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the exdpient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • exdpients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calrium phosphate, alginates, tragacanth, gelatin, calrium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical exdpient.
  • the active compounds are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especially preferred.
  • the amount of the compound actually administered will be determined by a physidan, in the light of the relevant drcumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • Quantity Ingredient (mg/tahlet)
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. - 102 -
  • Capsules each containing 40 mg of medicament are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient(s) is passed through a No. 60 mesh
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as follows:
  • the active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium dtrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • 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.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

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Abstract

This invention provides methods for the treatment or prevention of sleep apnea in a mammal which comprise administering to a mammal in need thereof an effective amount of a substituted benzimidazole, or a pharmaceutically acceptable salt or solvate thereof.

Description

Title
METHODS OF TREATING OR PREVENTING SLEEP APNEA
Background of the Invention
Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early
1970 s.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin α), and neurokinin B (also known as neuromedin K and neurokinin β). See. J.E.
Maggio, Peptides. 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues. The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as
NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra. Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches. see, e.g.. S.L. Shepheard, et al.. British Journal of Pharmacology. 108:11-20 (1993); S.M. Moussaoui, et al.. European Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, et al.. British Journal of Pharmacology. 112:920-924 (1994). In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non- peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in United States Patent 5,328,927, issued July 12, 1994; United States Patent 5,360,820, issued November 1, 1994; United States Patent 5,344,830, issued September 6, 1994; United States Patent 5,331,089, issued July 19, 1994; European Patent Publication 591,040 Al, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994;
Patent Cooperation Treaty publication WO 94/04494, published March 3, 1994; and Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993.
Sleep apnea is a condition in which apnea coours during sleep without subjective symptom. It is more prevailing in male middle- and old-aged persons in their forties and fifties. Approximately one per 100 persons is reported to suffer from this condition. In sleep apena there is repeated many times in sleep a sequence of 20-40 seconds apnea, about 10-20 seconds pneusis, and 20-40 seconds apnea. For example, during a 6.5 hour sleep, approximately 400 occurrences of apnea may occur.
As a result of sleep apnea there occur phenomena, such as daytime sleepiness, loss of energy or appetite, swelling in the lower part of the body, and shortness of breath. Increase in leukocyte number, development of polycythemia, and even cardiomegaly are associated with severe instances of sleep apnea. Sleep apnea is observed not only in adults of middle or advanced age, but also in infants, and may be an indirect cause of hypertension, cardiac insufficiency, and arrhythmia, possibly being a leading cause of sudden infant death syndrome.
Several thousand apparently healthy infants (children under the age of one year) die each year in the United States from Sudden Infant Death Syndrome (SIDS). Deaths from SIDS have been estimated at 7,000 to 10,000 per year. The occurrence of SIDS in a given family can be particularly devastating emotionally because, in general, there is no warning that the infant is at risk and the parent or care giver has no knowledge of any problem until he or she discovers an unconscious or deceased infant thought to be safely sleeping in its crib.
Therapies currently adopted for sleep apnea include bodyweight reduction, pressure application through the nose, surgical operation, and the use of a drug, such as acetazolamide. United States Patent 5,422,374, issued June 6, 1995, describes the use of ubidecarenone to treat sleep apnea. United States Patent 5,356,934, issued October 18, 1994, describes the use of serotonin agonists, most preferably (R)- fluoxetine, to treat sleep apnea. Both of these patents are herein incorporated by reference. Because of the current dissatisfaction of the currently marketed treatments for sleep apnea within the affected population, there exists a need for a more efficacious and safe treatment.
Sιιττ,ττiflrv of the Invention
This invention provides methods for the treatment or prevention of sleep apnea in a mammal which comprise administering to a mammal in need thereof an effective amount of a compound of Formula I
Figure imgf000005_0001
wherein:
R1 is hydrogen, C1-C12 alkyl, Ci-Cβ alkoxy, phenyl, C3-C8 cycloalkyl, naphthyl, heterocyclic, unsaturated heterocyclic, phenyl-(Cι-C6 alkylidenyl)-, naphthyl-(Cι-C6 alkylidenyl)-, heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-C6 alkylidenyl)-, phenyl-(Cι-C6 alkoxy)-, naphthyl-(Cι-C6 alkoxy)-, heterocyclic-(Cι-C6 alkoxy)-, or unsaturated heterocyclic-(Cι-C6 alkoxy)-,
any one of which phenyl, naphthyl, heterocyclic, C3- Cβ cycloalkyl, or unsaturated heterocyclic groups may be optionally substituted with one, two, or three moieties independently selected from group consisting of heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-C6 alkylidenyl)-, hydroxy, halo, Ci-Cβ alkyl, Ci-Cβ alkoxy, trifluoromethyl, nitro, amino, cyano, Ci-Cβ alkylamino, and Ci-Cβ alkylthio;
R2 is hydrogen, C1-C12 alkyl, Ci-Cβ alkoxy, phenyl, C3-C8 cycloalkyl, naphthyl, heterocyclic, unsaturated heterocyclic, phenyl-(Cι-Cβ alkylidenyl)-, naphthyl-(Cι-Ce alkylidenyl)-, heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-Cβ alkylidenyl)-, phenyMCi-Cβ alkoxy)-, naphthyl-(Cχ-C6 alkoxy)-, heterocyclic-(Cι-C6 alkoxy)-, or unsaturated heterocyclic-(Cι-C6 alkoxy)-,
any one of which phenyl, naphthyl, heterocyclic, C3-
Cβ cycloalkyl, or unsaturated heterocyclic groups may be optionally substituted with one, two, or three moieties independenly selected from group consisting of phenyl-(Cι-C6 alkylidenyl)-, naphthyl-(Cι-C6 alkylidenyl)-, heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-C6 alkylidenyl)-, phenyl- (Ci-Cβ alkoxy)-, naphthyHCi-Cβ alkoxy)-, heterocyclic-(Cι-C6 alkoxy)-, or unsaturated heterocyclic-(Cι-C6 alkoxy)-, hydroxy, halo, Ci-Cβ alkyl, Ci-Cβ alkoxy, trifluoromethyl, nitro, amino, cyano, Ci-Cβ alkylamino, and Ci-Cβ alkylthio;
R3 is hydrogen, nitro, Ci-Cβ alkanoyl, amino, Ci-Cβ alkyl, Ci-Cβ alkoxy, C3-C8 cycloalkyl, heterocyclic, unsaturated heterocyclic, halo, Ci-Cβ alkylthio, hydroxy-(Cι-C6 alkylidenyl)-, hydroxy-(Cι-C6 alkylidenyDamino-, R R5N-,
R4RδN-(Cι-C6 alkylidenyl)-, R4R5N-(Cι-C6 alkoxy)-, hydroxy- (Ci-Cβ alkyl)-, heterocyclic-(Cι-C6 alkoxy)-, amino(Cι-C6 alkylidenyl)-, or trifluoromethyl,
where R4 and R5 are independently selected from the group consisting of Ci-Cβ alkyl, Ci-Cβ alkoxy, CI-CΘ alkanoyl, aryl, heterocyclic, unsaturated heterocyclic, aryKCi-Cβ alkylidenyl)-, heterocyclic(Cι- Cβ alkylidenyl)-, unsaturated heterocyclic(Cι-C6 alkylidenyl)-, and hydrogen or R4 and R5 combine to form C3-C8 cycloalkyl,
any one of which alkyl or alkoxy groups may be substituted with one or more halo, amino, or nitro, and
any one of which aryl, unsaturated heterocyclic, or heterocyclic groups may be substituted with one, two, or three moieties independenly selected from group consisting of hydroxy, halo, Ci-Cβ alkyl, Ci-Cβ alkoxy, trifluoromethyl, nitro, amino, cyano, C3-C8 cycloalkyl, Ci-Cβ alkylamino, and Ci-Cβ alkylthio; with the proviso that not more than one of R1 and R2 may be hydrogen;
or a pharmaceutically acceptable salt or solvate thereof, in combination with another analgesic whose primary mechanism of action is not as a tachykinin receptor antagonist.
Detailed Description and Preferred Embodiments
The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example "°C" refers to degrees Celsius; "N" refers to normal or normality; "mol" refers to mole or moles; "mmol" refers to millimole or millimoles; "g" refers to gram or grams; "kg" refers to kilogram or kilograms; "L" refers to liter or liters; "ml" means milliliter or milliliters; "M" refers to molar or molarity; "MS" refers to mass spectrometry; and "NMR" refers to nuclear magnetic resonance spectroscopy.
As used herein, the term "Ci-Cβ alkyl" refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term "C1-C6 alkyl" includes within its definition the term "C1-C3 alkyl".
"Halo" represents chloro, fluoro, bromo or iodo. The term "haloformate" as used herein refers to an ester of a haloformic acid, this compound having the formula
0 II
X— C,
V
0- d
wherein X is halo, and Rd is Ci-Cβ alkyl. Preferred haloformates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein R<* is C3-C6 alkyl are especially preferred. Most preferred is isobutylchloroformate. The term "unsaturated heterocycle" represents a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which has one or more double bonds and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quarternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The unsaturated heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure.
Examples of such heterocycles and unsaturated heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl-sulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. "Ci-Cβ alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical Ci-Cβ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, f-butoxy, pentoxy and the like. The term "Ci-Cβ alkoxy" includes within its definition the term "C1-C4 alkoxy".
"C2-C6 alkanoyl" represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety. Typical C2-C6 alkanoyl groups include acetyl, propanoyl, isopropanoyl, butanoyl, £-butanoyl, pentanoyl, hexanoyl, 3- methylpentanoyl and the like.
"C3-C8 cycloalkyl" represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms which is unsubstituted. Typical C3-C8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "hydroxy-protecting groups" as used herein refers to substitents of the hydroxy group commonly employed to block or protect the hydroxy functionality while reacting other functional groups on the compound. Examples of such hydroxy-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, 2,2-dichloro-l,l- difiuoroethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, Ci- Ce alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, i-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, adamantoate and tetrahydropyranyl. Further examples of these groups may be found in T. W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, (1991) at Chapter 3.
The compounds prepared in the processes of the present invention have an asymmetric center. As a consequence of this chiral center, the compounds produced in the present invention may occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. Processes for preparing such asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in NOMENCLATURE OF ORGANIC COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al.. eds., 1974) at pages 103-120.
In addition to the (R)-(S) system, the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix "D" is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
As noted supra, this invention includes methods employing the pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantially non- toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic arid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic arid, hydroiodic acid, sulfuric arid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic arid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
This invention further encompasses methods employing the pharmaceutically acceptable solvates of the compounds of Formula I. Many of the compounds of Formula I can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
The compounds of the present invention are derivatives of benzimidazole which are named and numbered according to the Ring Index, The American Chemical Society, as follows.
Figure imgf000012_0001
The preferred methods of this invention employ those compounds of Formula I wherein: a) R1 is phenyl, naphthyl, heterocyclic, unsubstituted heterocyclic, or substituted derivatives thereof;
b) R2 is phenyl, heterocyclic, unsaturated heterocyclic, phenyKCi-Cβ alkylidenyl)-, heterocyclic(Cι-C6 alkylidenyl)-, unsaturated heterocyclic(Cι-C6 alkylidenyl)-, or substituted derivatives thereof;
c) R3 is R4R5N-(Cι-C6 alkylidenyl)-, Cι-C6 alkanoyl, , C1-C4 alkoxy, imidazole, amino-(Cι-C6 alkylidenyl), hydroxy-(Cι-C6 alkylidenyDamino-, heterocyclic-(Cι-C6 alkoxy)-, R4R5N-(Cι-C6 alkoxy)-, or hydroxy;
d) R3 is at the 5 or 6 position of the benzimidazole.
The especially preferred methods of this invention employ those compounds of Formula I wherein:
a) R1 is phenyl or naphthyl substituted with one or more electron donating, lipophilic substituents;
b) R2 is substituted benzyl or substituted phenyl;
c) R3 is R R5N-(Cι-C6 alkylidenyl)-, heterocyclic-(Cι-C6 alkoxy)-, R4R5N-(Cι-C6 alkoxy)-, or unsaturated heterocyclic(Cι-C6 alkylidenyl)-; and
d) R3 is at the 6 position of the benzimidazole.
The steps of this synthesis are described in European Patent Application Publication 694,535, to be published January 31, 1996.
The compounds of Formula I can be prepared by processes known in the literature. See, e.g.. G.W.H. Cheeseman and R.F. Cookson, THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, (A. Weissberger, et al.. eds. 1979). The usual process for the preparation of the compounds of Formula I is by cyclization of an appropriately substituted o-phenylenediamine such as the one depicted in Formula III
Figure imgf000014_0001
in a solvent or solvent mixture. It is generally preferred that the solvent or solvent mixture be heated, preferably to the boiling point of the solvent. Suitable solvents include ethanol, isopropanol, gladal acetic add, benzene, toluene, chlorobenzene, glycol, ethylene glycol, dimethyl ether, diethyl ether, dimethylformamide, chloroform, ethyl acetate, and the like. It is generally preferred to add a condensation agent such as phosphorous oxychloride, thionyl chloride, p-toluenesulfonic add, hydrochloric add, sulfuric add, phosphoric acid, polyphosphoric add, phosphorous pentoxide, methanesulfonyl hydroxide, methanesulfonyl chloride, and the like. The cyclization reaction may also optionally be performed in the presence of a base such as sodium hydroxide, sodium mesylate, or potassium tert-butylate.
In those compounds in which R2 is phenyl a derivative of N- phenyl-o-phenylenediamine was used as the starting material for the cyclization reaction. The examples infra provide sufficient guidance in the preparation of those compounds of Formula I wherein R3 is hydrogen.
Those compounds of Formula I wherein R3 is not hydrogen, can be prepared by methods taught in the literature. For example, the compounds of this invention wherein R3 is C2-C6 alkanoyl can be prepared from the appropriate keto o-phenylenediamine of the formula
( C1 -C5 alkyl
Figure imgf000014_0002
by methods known in the benzimidazole art such as the procedures described in U.S. Patent 4,401,817, issued August 30, 1983, which is herein incorporated by reference. The method of preparation involves the ammonolysis and reduction of a 4-halo-3-nitrophenyl ketone which is prepared by the Friedel-Crafts reaction of either a 4-halo-3- nitrobenzoyl chloride with an appropriate hydrocarbon or a halobenzene with an appropriate add chloride followed by aromatic nitration.
Alternatively, the keto benzimidazole reactants can be prepared from acetanilide by a Friedel-Crafts acylation with the appropriate derivative of C2-C6 alkanoic add. The resulting 4-keto acetanilide is nitrated to give a 2-nitro-4-ketoacetanilide. The acetanilide is hydrolyzed to give a 2-mtro-4-ketoaniline, which can then be catalytically hydrogenated to yield a 4-keto-o-phenylenediamine which can then be ring closed to provide the 5 or 6-substituted benzimidazole. Those compounds of Formula III wherein R3 is a substituted alkyl or alkylidenyl may be prepared by means of a Friedel- Crafts alkylation with the appropriate derivative of the R3 moiety using standard procedures, usually employing an alkyl halide or an olefin in the presence of a catalyst such as aluminum chloride, aluminum bromide or another Lewis acid.
An alternative strategy for preparing those compounds of Formula I wherein R3 is Ci-Cβ alkoxy, R4R5N-(Cι-C6 alkoxy)-, or heterocyclic-(Cι-C6 alkoxy)-, or a substituted derivative thereof, involves first reacting a 3-nitro-4-aminophenol with an acyl halide in the presence of a base
Figure imgf000015_0001
R1 0
to get substitution of the primary amine as well as substitution of the hydroxy group, the ester moiety serving as a hydroxy-protecting group for subsequent reactions. In the next step of this synthesis the nitro - 14 -
group is then reduced to an amino group, usually by catalytic hydrogenation .
Figure imgf000016_0001
The primary amine of the above compound is then substituted, usually using an aldehyde, such as benzaldehyde or a substituted derivative thereof, followed by hydrogenation, if necessary. In an alternative embodiment, those compounds of Formula I in which R2 is alkyl or substituted alkyl may be produced by alkylation of an aromatic amine with alkyl halide or tosylate, or the like, in the presence of a suitable base, such as trialkylamine, potassium carbonate, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
Figure imgf000016_0002
Cyclization of this substituted phenylenediamine is then performed as described sunra. followed by cleavage of the ester group protecting the hydroxy group at the 6-position of the benzimidazole. Suitable cyclization catalysts include phosphorous oxychloride, thionyl chloride, phosphorous pentoxide, phosphorous pentachloride, and other like strong dehydrating agents.
Figure imgf000017_0001
A preferred method of cleaving this ester is by incubation of the intermediate in a basic solution, such as IN sodium hydroxide, or a weaker base such as potassium carbonate. The hydroxy group at the 6- position is then substituted using an alkyl or aryl halide, resulting in a compound of Formula I.
alkyl or aryl halide
Figure imgf000017_0002
Figure imgf000017_0003
The skilled artisan understands that compounds of Formula I substituted at the 5-position of the benzimidazole can be prepared as described above by employing 3-amino-4-nitrophenol as the starting material instead of the 3-nitro-4-aminophenol shown supra. Those compounds of Formula I wherein R2 is alkyl or substituted alkyl may alternatively be prepared by the direct alkylation of a benzimidazole wherein the nitrogen at the 1-position is substituted with a hydrogen. This type of alkylation is usually performed by the reaction of the benzimidazole with an alkyl halide in the presence of a strong base, such as sodium hydride. This reaction is usually performed in a polar aprotic solvent, such as N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, hexamethylphosphoric triamide, and the like.
The following examples further illustrate the preparation of the compounds of Formula I. The examples are illustrative only and are not intended to limit the scope of the invention in any way. The designations "NMR", "IR", and "MS" in an example indicate that the nuclear magnetic resonance spectrum (NMR), the infrared absorption spectrum (IR), or the mass as determined by mass spectrometry (MS) were consistent with the desired compound.
Exam l 1
Synthesis of 1,2-diphenylbenzimidazole
N-phenyl-o-phenylenediamine (10 mmol, 1.84 grams) was added to diethyl ether (100 ml) and stirred at room temperature as benzoyl chloride (10 mmol, 1.41 g) was added dropwise (a predpitate formed after about one half of the benzoyl chloride was added). After addition of the benzoyl chloride, the solution was stirred at room temperature for about 15 minutes. The reaction mixture was partitioned between aqueous sodium hydroxide and diethyl ether. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined and dried over magnesium sulfate. The magnesium sulfate was filtered out and the solvent removed in vacuo to yield a red/brown solid (2.88 g, 99.8%) which was suitable for use in the cydization reaction. NMR, mp 136-137°C. A solution of the intermediate synthesized supra (2.5 g, 8.6 mmol) and phosphorous pentoxide/methanesulfonyl chloride (1:10) (30 ml) was heated at 100°C for about one hour. The reaction mixture was then stirred with ice as 5N sodium hydroxide was added to raise the pH to 14. This mixture was then partitioned with ethyl acetate in a separation funnel. The ethyl acetate layer was removed and the aqueous layer was washed with ethyl acetate (3 x 100 ml). The organic layers were combined and dried over potassium carbonate overnight. The solution was filtered and the solvent removed in vacuo to yield 2.2 grams (94.6%) of crude product. The product was purified by chromatography using a hexanes/ethyl acetate (4:1) solution as the eluent to yield 1.98 grams (85.2%) of the pure title product. NMR, MS 27KM+), mp 108-110°C. Analysis for C19H14N2:
Theory: C, 84.42; H, 5.22; N, 10.36. Found: C, 84.72; H, 5.27; N, 10.35. Eyflm le 2
Synthesis of l-phenyl-2-(4-methoxyphenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (10 mmol, 1.84 g) in 100 ml diethyl ether was stirred at room temperature as p-anisoyl chloride (1 mmol, 1.71 g) was added dropwise. The resulting mixture was stirred at room temperature for about 96 hours. A preripitate formed before half of the anisoyl chloride/diethyl ether was added.
The resulting reaction mixture was partitioned with IN sodium hydroxide and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined and dried over potassium carbonate overnight, filtered, and the solvents were removed in vacuo. This yielded 3.57 grams of a dark brown crude product. Further purification could be performed by way of recrystallization from methylene chloride to yield a homogenous spot as determined by chromatography. mp 147-149°C.
A solution of the intermediate prepared fiup a (3.19 g, 10 mmol) in 35 ml phosphorous pentoxide/methanesulfonyl chloride (1:10) was stirred at 100°C for about 2.5 hours. The resulting reaction mixture was poured over ice and stirred as aqueous sodium hydroxide was added. The final solution had a pH of 14. This solution was partitioned with ethyl acetate. The ethyl acetate layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined and washed with saturated sodium chloride. This was then dried over potassium carbonate, filtered, concentrated in vacuo to yield a brown/dark red crude product.
This crude product was purified by chromatography using hexanes/ethyl acetate (9:1) as eluent to yield 1.38 grams of the title product. NMR, MS 30KM+), mp 105-107°C. Analysis for C20H 16N2O :
Theory: C, 79.98; H, 5.37; N, 9.33. Found: C, 79.77; H, 5.38; N, 9.11.
F.yam lp 3
Synthesis of l-phenyl-2-phenylmethylbenzimidazole The title intermediate was synthesized in substantial accordance with Journal of Medirinal Chemistry. 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (10 mmol, 1.84 g) and 2-ethoxy- l-ethoxycarbonyl-l,2-dihydroquinoline (12 mmol, 2.97 g) was stirred in methylene chloride (60 ml) at room temperature. Phenylacetic add (10 mmol, 1.36 g) in methylene chloride (30 ml) was added via dropping funnel and stirred at room temperature over a drying tube overnight. The resulting reaction mixture was partitioned with 6N sodium hydroxide. The methylene chloride layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100). The organic fractions were combined, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 5.28 grams of a dark red brown crude product.
The crude product was recrystallized from ethyl acetate and then diethyl ether to yield a white crystalline product (1.77 g, 58.5%) of the title product, mp 108-110°C.
A portion of the intermediate synthesized supra (1.35 g, 4.5 mmol) and 30 ml of phosphorous pentoxide/methane sulfonyl hydroxide (1:10) were stirred at 100 °C for about 6 hours. The resulting reaction mixture was poured over ice and neutralized with aqueous sodium hydroxide (to pH 14). The aqueous layer was partitioned with ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate (4 x 200 ml). The organic layers were combined, dried over potassium carbonate, and filtered. The solvent was removed in vacuo and the crude dark red/brown product was purified by chromatography using hexanes/ethyl acetate (9:1) as the eluent. MS 285(M+), mp 106-
108°C
Analysis for C20H16N2O:
Theory: C, 84.48; H, 5.67; N, 9.85. Found: C, 84.75; H, 5.78; N, 9.93.
Exam le 4
Synthesis of l-phenyl-2-(3-chlorophenyl)benzimidazole A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (80 ml) was stirred at room temperature as 3- chlorobenzoylchloride (1.95 g, 11 mmol) in diethyl ether (30 ml) was added dropwise. Predpitate formed almost immediately after total addition of the 3-chlorobenzoylchloride. The resulting reaction mixture was stirred at room temperature for about 3 hours. The reaction mixture was partitioned with aqueous sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 120 ml). The organic layers were combined, dried over potassium carbonate, and filtered. The solvent was removed in vacuo to yield 3.5 grams of the desired intermediate. Further purification could be performed using thin layer chromatography with hexanes/ethyl acetate (9:1) as the eluent. mp 133- 134°C, NMR.
A solution of the intermediate prepared supra (2.50 g, 7.7 mmol) and 40 ml phosphorous pentoxide/methane sulfonyl hydroxide (1:10) was stirred at 100°C for about 16 hours. This reaction mixture was then poured over ice and alkalinized with 5N sodium hydroxide (until pH = 14). This aqueous solution was then extracted with ethyl acetate (5 x 150 ml). The organic layers were combined and dried over potassium carbonate, filtered, and concentrated in vacuo to yield 2.2 grams of crude red/brown product.
This crude product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as the eluent. MS 305, 307, mp 107-109°C. Analysis for C19H13CIN2: Theory: C, 74.88; H, 4.30; N, 9.19.
Found: C, 74.68; H, 4.47; N, 9.25.
Eτam lp fi
Synthesis of l-phenyl-2-(4-chlorophenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (80 ml) was stirred at room temperature as 4- chlorobenzoylchloride (1.95 g, 11 mmol) in diethyl ether (30 ml) was added dropwise. Predpitate formed almost immediately after total addition of the 4-chlorobenzoylchloride. After total addition of the 4- chlorobenzoylchloride, the resulting reaction mixture was stirred at room temperature for about 17 hours.
The reaction mixture was partitioned with IN sodium hydroxide. The diethyl ether layer was removed and the aqueous layer extracted with ethyl acetate (4 x 150 ml). The organic layers were combined, dried over potassium carbonate, filtered, and concentrated in vacuo to yield 3.72 grams (>99%) of a dark red/brown solid. The crude product could be used as is or could be further purified. In the further purification the crude product was triturated in diethyl ether and filtered to yield an off-white solid, mp 169-171°C.
A portion of the intermediate synthesized above (crude, 2.84 g) was stirred in phosphorous pentoxide/methanesulfonyl hydroxide (1:10, 40 ml) at 100°C for about 16 hours. The reaction mixture was poured over ice and alkalinized with 5N sodium hydroxide (pH=14). The aqueous layer was extracted with ethyl acetate (5 x 150 ml). The combined organic fractions were dried over potassium carbonate, filtered, and concentrated in vacuo to yield 2.52 grams of crude title product. Further purification could be accomplished by chromatography to yield a solid yellow crystal. MS 305, 307, mp 139- 141°C.
Analysis for C19H13CIN2:
Theory: C, 74.88; H, 4.30; N, 9.19. Found: C, 74.97; H, 4.33; N, 9.21.
Example 6
Synthesis of l-phenyl-2-(3-methoxyphenyl)ben.rimidazole
The titled intermediate was prepared essentially as described in Journal of Medidnal Chemistry, 18:319 (1975). A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and m-methoxybenzoic add (1.52 g, 10 mmol) was stirred at room temperature in methylene chloride (80 ml). N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (2.97 g) was added dropwise and the reaction was refluxed for about 16 hours. Additional N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoUne was added and the reaction was refluxed for an additional 18 hours. The reaction mixture was partitioned with IN sodium hydroxide. The organic layer (pH ~ 14) was extracted with ethyl acetate (3 x 150 ml). The combined organic fractions were dried over potassium carbonate, filtered and concentrated in vacuo. Crude red oil was purified by chromatography using hexanes/ethyl acetate (9:1) as the eluent. White solid crystallized out of several fractions, mp 118-120°C.
A solution of the intermediate prepared above (1.08 g, 3.4 mmol) in chloroform (85 ml) was stirred at room temperature as phosphorous oxychloride (0.52 g, 3.4 mmol) in chloroform (35 ml) was added dropwise. The reaction mixture was then refluxed overnight.
The reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with chloroform (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 1.18 grams (>99%).
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as eluent. MS 30KM+), mp 110-111°C. Analysis for C20H16N2O:
Theory: C, 79.98; H, 5.37; N, 9.33. Found: C, 79.72; H, 5.49; N, 9.39.
Example 7
Synthesis of l-phenyl-2-(4-nitrophenyl)benzimidazole l-phenylamine-2-[(4-nitrophenyl)carbonylamino]benzene
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (75 ml) was stirred at room temperature as 4- nitrobenzoylchloride (1.86 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. A predpitate quickly formed. The reaction was stirred overnight.
The reaction mixture was partitioned with 1 N sodium hydroxide and the organic layer removed. The aqueous layer (pH ~ 14) was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, washed with saturated sodium chloride, dried over potassium carbonate, filtered and concentrated in vacuo.
The resulting crude product was triturated with diethyl ether and filtered to yield 2.48 grams of an orange/brown product was homogenous by chromatography. mp 169-171°C.
A solution of the above-prepared intermediate (2.48 g, 7.4 mmol) in chloroform (80 ml) was stirred at room temperature as phosphorous oxychloride (1.13 g, 7.4 mmol) in chloroform (35 ml) was added dropwise. After constant addition the reaction mixture was refluxed overnight.
The reaction mixture was cooled and partitioned with 1 N sodium hydroxide (pH ~ 14). The organic layer was separated and the aqueous layer was extracted with chloroform (3 x 100 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.50 grams of a yellow/green solid. The reaction product was purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent. MS 316(M+), mp 175-177°C. Analysis for C19H13N3O2: Theory: C, 72.37; H, 4.15; N, 13.33.
Found: C, 72.67; H, 4.16; N, 13.30.
Example
Synthesis of l-(4-chlorophenyl)-2-phenylbenzimidazole
A solution of N-(4-chlorophenyl)-l,2-phenylenediamine (2.19 g, 10 mmol) in diethyl ether (75 ml) was stirred at room temperature as benzoyl chloride (1.41 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. A predpitate quickly formed. The reaction mixture was stirred overnight and partitioned with IN sodium hydroxide.
The organic layer was removed and the aqueous layer (pH ~ 14) was extracted with ethyl acetate (3 x 150 ml). The organic layers were combined, washed with saturated sodium chloride, dried over potassium carbonate, filtered and removed in vacuo. The crude product was triturated in diethyl ether to yield 1.84 grams (57%) of a white solid which was chromatographically homogenous, mp 158-160°C. A solution of the intermediate prepared fiajn a (.33 g, 7.2 mmol) in chloroform (80 ml) was stirred at room temperature as phosphorous oxychloride (1.10 g, 7.2 mmol) in chloroform (30 ml) was added dropwise. After the addition was complete the reaction mixture was refluxed overnight. The reaction mixture was alkalinized to pH = 14 with IN sodium hydroxide and separated.
The aqueous layer was extracted with chloroform (3 x 10 ml). The organic layers were combined, washed with a saturated sodium chloride, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.45 grams of a red/brown oil which solidified upon setting at room temperature. The product was purified by chromatography using a hexanes/ethyl acetate (4:1) as eluent. MS 305, 307, mp 122-123°C. Analysis for C19H13CIN2: Theory: C, 74.88; H, 4.30; N, 9.19.
Found: C, 75.18; H, 4.30; N, 9.15.
Example 9
Synthesis of l-phenyl-2-(3-trifluoromethylphenyl)-benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (80 ml) was stirred at room temperature as m- trifluorormethylbenzoyl chloride (2.09 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. The reaction mixture was stirred overnight. The reaction mixture was partitioned with IN sodium hydroxide (pH ~ 14) and the organic layer removed. The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a dark red brown oil which solidified upon standing at room temperature. The reaction product was purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent.
A solution of the intermediate prepared above (3.20 g, 9.0 mmol) in chloroform (85 ml) was stirred at room temperature as phosphorous oxychloride (1.78 g, 9 mmol) in chloroform (35 ml) was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with chloroform (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.00 grams of a yellow/brown oil which solidified upon standing.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1 to 4:1) solution as eluent, yielding 1.89 grams (62%) of a light yellow solid. MS 339(M+), mp 99-101°C.
Analysis for C20H13F3N2:
Theory: C, 71.00; H, 3.87; N, 8.28. Found: C, 71.21; H, 4.07; N, 8.42.
Example 10
Synthesis of l-phenyl-2-(3-nitrophenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (80 ml) was stirred at room temperature as 3- nitrobenzoyl chloride (1.86 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The product was purified by trituration with diethyl ether to yield 2.19 g (65.7%) of a yellow solid, mp 127-129°C. A solution of the intermediate prepared above (2.9 g, 8.7 mmol) in chloroform (85 ml) was stirred at room temperature was phosphorous oxychloride (in 35 ml chloroform) was added dropwise.
The reaction mixture was then refluxed overnight.
The reaction mixture was partitioned with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with chloroform (3 x 120 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.50 grams of a brown/green solid.
The reaction product was further purified using thin layer chromatography with a hexanes/ethyl acetate (9:1 to 4:1) solution as eluent. MS 316(M+), mp 166-168°C. Analysis for C19H13N3O2:
Theory: C, 72.37; H, 4.16; N, 13.33. Found: C, 72.54; H, 4.27; N, 13.55.
Example 11
Synthesis of l-(4-chlorophenyl)-2-(4-chlorophenyl)-benzimidazole
A solution of N-(4-chlorophenyl)-l,2-phenylenediamine (2.19 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as
4-chlorobenzoyl chloride (1.75 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer (pH ~
14) was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a crude red/brown solid. The reaction product was purified by trituration with diethyl ether to yield 2.91 grams (81.5%) of an off-white solid which was chromatographically homogeneous, mp 180-181°C.
A solution of the intermediate prepared above (3.16 g, 8.8 mmol) in chloroform (90 ml) was stirred at room temperature as phosphorous oxychloride (1.36 g, 8.8 mmol) in chloroform (35 ml) was added dropwise. The reaction mixture was then refluxed overnight. The mixture was partitioned with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with chloroform (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.83 grams of a gray/brown solid.
The reaction product was further purified by chromatography to yield 2.31 grams (77%) of a light pink solid. MS 339, 341, mp l62-164°C.
Analysis for C19H12CI2N2:
Theory: C, 67.27; H, 3.57; N, 8.30. Found: C, 67.45; H, 3.72; N, 8.36.
Example 12
Synthesis of l-phenyl-2-(4-trifluoromethylphenyl)-benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 4- (trifluoromethyDbenzoyl chloride (2.09 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was partitioned with IN sodium hydroxide. The organic layer was removed and the aqueous layer extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, washed with a sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a brown/black solid.
The crude product was triturated with diethyl ether and vacuum filtered to yield 2.56 grams (72%) of a yellow solid which was homogeneous on thin layer chromatography. mp 143-145°C.
A solution of the intermediate prepared above (3.25 g, 9.1 mmol) in chloroform (85 ml) was stirred at room temperature as phosphorous oxychloride in chloroform (35 ml) was added dropwise. The reaction mixture was partitioned with IN sodium hydroxide.
The organic layer was removed and the aqueous layer was extracted with chloroform (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil which solidified upon standing. The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1 to 4:1) solution as eluent. Yield: 2.39 grams (77.6%) of a light yellow solid. MS 339(M+), mp 133-135°C. Analysis for C20H13F3N2:
Theory: C, 71.00; H, 3.87; N, 8.28. Found: C, 71.28; H, 3.99; N, 8.46.
Example 13
Synthesis of l-phenyl-2-(2-naphthyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) was stirred at room temperature in diethyl ether (85 ml) as naphthoyl chloride (10 mmol, 1.91 g) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide. The organic layer was removed. The aqueous layer (pH ~ 14) was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown solid (3.91 g, >99%).
The solid was triturated with diethyl ether and the remaining solid was collected by vacuum filtration. The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as eluent. mp 147-149°C.
A solution of the intermediate prepared above (2.4 g, 7.1 mmol) in chloroform (85 ml) was stirred at room temperature as phosphorous oxychloride (1.1 g, 7.1 mmol) in chloroform (35 ml) was added dropwise. After the addition the reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with chloroform (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.38 grams (>99%) of a brown solid.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate solution as the eluent to yield 1.91 grams (84%) of a light yellow solid. MS 321(M+), mp 169-170°C. Analysis for C23H16N2:
Theory: C, 86.22; H, 5.03; N, 8.04. Found: C, 86.21; H, 5.24; N, 8.61.
Example 14
Synthesis of l-phenyl-2-(3,5-dimethoxyphenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 3,5- dimethylbenzoyl chloride (2.00 g, 1.84 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.46 grams of a red/brown oil which solidified upon standing.
Further purification of the title intermediate was achieved by chromatography. mp 107-109°C.
A solution of the crude product of the reaction above (2.3 g, 6.6 mmol) in chloroform (85 ml) was stirred at room temperature as phosphorous oxychloride (1.01 g, 6.6 mmol) in chloroform (25 ml) was added dropwise. The reaction mixture was then refluxed overnight. The reaction mixture was alkalinized with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with methylene chloride (3 x 100 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil which solidified upon standing. Further purification of the reaction product was accomplished by chromatography, employing a hexanes/ethyl acetate mixture as the eluent to yield 1.91 grams (87.6%) of a light yellow solid. MS 33KM+), mp 98-99°C. Analysis for C21H18N2O2:
Theory: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.17; H, 5.60; N, 8.51.
Exam le 15
Synthesis of l-phenyl-2-(3,4-dimethoxyphenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 3,4- dimethoxybenzoyl chloride (2.01 g, 10 mmol) in 40 ml of diethyl ether was added dropwise. The reaction mixture was then stirred overnight at room temperature.
The reaction mixture was then alkalinized with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with diethyl ether (3 x 150 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.11 grams.
This intermediate was further purified by chromatography using a hexanes/ethyl acetate solution as the eluent, followed by trituration with hexanes to yield a white crystalline solid, mp 159-160°C. A solution of the intermediate prepared supra (3.11 g, 8.9 mmol) in chloroform (30 ml) was stirred at room temperature as phosphorous oxychloride (1.40 g, 9 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was then refluxed overnight. The reaction mixture was partitioned with IN sodium hydroxide.
The organic fraction was removed and the aqueous phase was extracted with methylene chloride (3 x 150 ml). The organic fractions were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a brown oil which solidified upon standing. The crude product was partitioned between IN hydrochloric add and a hexanes/ethyl acetate (1:1) solution. The aqueous layer was removed and the organic layer was extracted with IN hydrochloric add (3 x 100 ml). The aqueous fractions were combined and alkalinized to pH 14 with sodium hydroxide. This basified solution was extracted with ethyl acetate (5 x 100 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 1.70 grams (57.8%) of a pink solid. MS 331(M+), mp 114-115°C. Analysis for C21H18N2O2:
Theory: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.31; H, 5.63; N, 8.53.
fi ample 16
Synthesis of l-phenyl-2-(3,4,5-trimethoxyphenyl)-benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 3,4,5- trimethoxybenzoyl chloride (2.31 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. The reaction mixture was then stirred overnight at room temperature. The solvents were then removed in vacuo leaving N- [(3,4,5-trimethoxyphenyl)carbonyl]-N'-phenyl-phenylenediamine.
The crude intermediate (3.6 g, 9.5 mmol) in chloroform (100 ml) was stirred at room temperature as phosphorous oxychloride (1.5 g, 9.5 mmol) in chloroform (20 ml) was added dropwise. The reaction mixture was then stirred at room temperature for about 72 hours.
The reaction mixture was partitioned between IN hydrochloric add and ethyl acetate. The organic phase was discarded and the aqueous phase was alkalinized with IN sodium hydroxide. The aqueous solution was then extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined and dried over potassium carbonate. The solvents were removed in vacuo to yield the title product as a white solid (2.08 g, 61%). MS 36KM+), mp 139-141°C. Analysis for C22H20N2O3: Theory: C, 73.32; H, 5.59; N, 7.77.
Found: C, 73.17; H, 5.71; N, 7.72. Eγaτnp1ft 17
Synthesis of l-(4-chlorophenyl)-2-(4-methoxyphenyl)-benzimidazole A solution of N-(4-chlorophenyl)-l,2-phenylenediamine (2.13 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as p-anisoyl chloride (1.71 g, 10 mmol) in diethyl ether (45 ml) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned with IN sodium hydroxide. The orgnaic layer was removed and the aqueous fraction was extracted with ethyl acetate (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.6 grams of a brown/pink solid. The desired intermediate was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent to yield a light pink solid, mp 162-164°C.
The intermediate prepared above (3.40 grams, 9.6 mmol) was dissolved in chloroform (90 ml). This solution was stirred at room temperature as phosphorous oxychloride in chloroform (40 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was partitioned with IN sodium hydroxide and the organic layer removed. The aqueous fraction was further extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography to yield 2.64 grams (82.1%) of a light pink solid. MS 335, 337, mp 183-185°C.
Analysis for C20H15CIN2O:
Theory: C, 71.75; H, 4.52; N, 8.37. Found: C, 71.67; H, 4.77; N, 8.59.
Example 18 Synthesis of l-phenyl-2-(4-methylphenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as p- toluoyl chloride (1.60 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide. The organic layer was removed and the aqueous fraction was extracted with ethyl acetate (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.18 grams of a red/brown solid.
The intermediate was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as the eluent to yield a yellow solid, mp 143-145°C.
The intermediate prepared above (2.63 g, 8.6 mmol) was dissolved in chloroform (85 ml). This solution was stirred at room temperature as phosphorous oxychloride (1.35 g, 8.6 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was partitioned with IN sodium hydroxide and the organic layer removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield a red/brown oil which solidified upon standing.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as the eluent. The fractions were combined, the solvents removed in vacuo and the resulting oil was triturated with diethyl ether. The title product was recystallized from diethyl ether/hexanes to yield 1.54 grams (63%). MS 285(M+) Analysis for C20H16N2:
Theory: C, 84.48; H, 5.67; N, 9.85. Found: C, 85.60; H, 5.94; N, 10.45. Ex npl lfl
Synthesis of l-phenyl-2-(3-methylphenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as m- toluoyl chloride (1.55, 10 mmol) in diethyl ether (30 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight.
The reaction mixture was then alkalinized with IN sodium hydroxide. The organic layer was removed and the aqueous fraction was extracted with ethyl acetate (3 x 150 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.12 grams of a gray/brown solid. The intermediate was further purified by chromatography. mp 129-130°C.
The intermediate prepared above (2.5 g, 8.3 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.30 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent. The product was recrystallized from hexanes to yield 0.97 grams (41.1%) of a white solid. MS 285(M+), mp 69-71°C. Analysis for C20H16N2:
Theory: C, 84.48; H, 5.67; N, 9.85. Found: C, 84.48; H, 5.72; N, 9.80.
Examnle 20
Synthesis of l-phenyl-2-(4-cyanophenyl)benzimidazole A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (100 ml) was stirred at room temperature as 4- cyanobenzoyl chloride (1.66 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was partitioned with IN sodium hydroxide. The organic fraction was removed and the aqueous layer was extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 3.31 grams of a red/black oily gum.
This oily gum (2.8 g, 8.9 mmol) was dissolved in chloroform (90 ml). This solution was stirred as phosphorous oxychloride (1.40 g, 9.0 mmol) in chloroform (35 ml) was added dropwise. This reaction mixture was refluxed overnight.
The reaction mixture was alkalinized wtih IN sodium hydroxide. The organic layer was removed and the aqueous fraction was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate solution as eluent. The title product then was recystallized from ethyl acetate to yield a white solid. MS 296(M+), mp 182-184°C. Analysis for C20H13N3:
Theory: C, 81.34; H, 4.44; N, 14.23. Found: C, 81.55; H, 4.50; N, 14.47.
Example 21
Synthesis of l-phenyl-2-cyclohexylbenzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as cyclohexanecarbonyl chloride (1.46 grams, 10 mmol) in diethyl ether (3 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight.
The reaction mixture was alkalinized with IN sodium hydroxide. The organic fraction was removed and the aqueous phase was extracted with ethyl acetate (3 x 150 ml). The organic fractions were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.81 grams of a brown solid. The reaction product was further purified by chromatography to yield N-phenyl-N'-cyclohexylcarbonyl- phenylenediamine as a yellow solid.
The intermediate prepared above (2.0 g, 7 mmol) was dissolved in chloroform (80 ml). This solution was stirred at room temperature as phosphorous oxychloride (1.05 g, 7 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide. The organic layer was removed and the aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.81 grams of a black/red oil which solidified upon standing.
The reaction product was further purified by partitioning between IN hydrochloric add and an ethyl acetate/hexanes (1:1) solution. The aqueous layer was alkalinized to pH 10 using IN sodium hydroxide. The aqueous fraction was then extracted with ethyl acetate (4 x 250 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered and the solvents were removed in vacuo to yield 1.47 grams (76%) of a light yellow solid. MS 277(M+), mp 99-101°C. Analysis for C19H20N2:
Theory: C, 82.57; H, 7.29; N, 10.14. Found: C, 82.33; H, 7.45; N, 10.21.
Example 22 Synthesis of l-phenyl-2-(2-chlorophenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 2- chlorobenzoyl chloride (1.76 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer removed. The aqueous phase was extrated with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.2 grams (>99%) of a gray/brown solid.
The crude product prepared supra (2.7 g, 8.4 mmol) was dissolved in chloroform (95 ml). This solution was stirred at room temperature as phosphorous oxychloride (1.3 g, 8.5 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight and then partitioned with IN sodium hydroxide.
The organic layer was removed and the aqueous phase was extracted with methylene chloride (3 x 150 ml). The combined organic layers were washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The crude product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as the eluent. The recovered product was triturated in hexanes and filtered to yield 1.31 grams (51.2%) of a light yellow solid. MS 305, 307, mp 146-148°C. Analysis for C19H13CIN2:
Theory: C, 74.88; H, 4.30; N, 9.19. Found: C, 75.16; H, 4.31; N, 9.21.
Example 23
Synthesis of l-phenyl-2-(2-methylphenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as o- toluoyl chloride (1.55 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent. Trituration with hexanes and subsequent filtration yielded a white solid, mp 118-120°C.
The intermediate prepared above (2.52 g, 8.3 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1 to 4:1) solution as the eluent to yield a pale yellow oil. The product was triturated with hexanes to yield a light yellow solid. MS 285(M+), mp 99-101°C. Analysis for C20H16N2:
Theory: C, 84.48; H, 5.67; N, 9.85. Found: C, 84.48; H, 5.72; N, 9.80.
Example 24
Synthesis of l-phenyl-2-(2-methoxyphenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 2- methoxybenzoyl chloride (1.55 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as eluent. The reaction product was recrystallized from hexanes. mp 178-180°C. The intermediate prepared above (2.65 g, 8.3 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent to yield 1.64 grams (65.7%) of the title product as a white solid. MS 30KM+), mp 159-160°C. Analysis for C20H16N2O:
Theory: C, 79.98; H, 5.37; N, 9.33. Found: C, 80.01; H, 5.36; N, 9.40.
Ex m le 9.5
Synthesis of l-phenyl-2-(3-cyanophenyl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 3- cyanobenzoyl chloride (1.66 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as the eluent. The product was recrystallized from hexanes to yield a white solid. mp l41-143°C.
The intermediate prepared above (2.63 g, 8.3 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1 to 4:1) solution as eluent. The title product was recrystallized from hexanes and ethyl acetate. MS 296(M+), mp 153-154°C. Analysis for C20H13N3:
Theory: C, 81.34; H, 4.44; N, 14.23. Found: C, 81.60; H, 4.45; N, 14.38.
Example 26
Synthesis of l-dimethylaminoethyl-2-phenylbenzimidazole dihydrochloride
A solution of 2-phenylbenzimidazole (0.97 g, 5 mmol) in N,N-dimethylformamide (anhydrous, 20 ml) was stirred at room temperature under nitrogen atmosphere. Two equivalents of sodium hydride in 60% dispersion (0.40 g, 10 mmol) was quickly added and the reaction mixture was allowed to stir under nitrogen. N,N- Dimethylaminoethyl bromide hydrobromide (1.16 g, 5 mmol) in anhydrous N,N-dimethylformamide (12 ml) was added dropwise by syringe to the stirring mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between acetic add and ethyl acetate. The organic layer was discarded and the aqueous phase was extracted with diethyl ether (5 x 75 ml). All organic fractions were discarded. The aqueous phase was alkalinized with 2N sodium hydroxide. This solution was then extracted with diethyl ether (4 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 1.11 grams of a cloudy oil. The crude product was stirred with 2N hydrochloric add in ethanol. The solvents were removed in vacuo to yield 1.16 (66.8%) grams of the title product as a white solid. MS 309, mp 228-231°C Analysis for C17H19N3 • 2 HCl:
Theory: C, 60.36; H, 6.26; N, 12.42. Found: C, 60.09; H, 6.22; N, 12.18.
Example 27
Synthesis of l-phenyl-2-(3,4-dichlorophenyl)benzimidazole A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 3,4- dichlorobenzoyl chloride (2.10 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as the eluent. The product was recrystallized from hexanes to yield a white solid, mp 146-147°C.
The intermediate prepared above (3.00 g, 8.4 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent. The title product was recrystallized from hexanes and ethyl acetate as a white solid. MS 339, 341, mp 144-146°C. Analysis for C19H12CI2N2:
Theory: C, 67.27; H, 3.57; N, 8.26. Found: C, 67.53; H, 3.61; N, 8.13.
Example 28
Synthesis of l-(piperidin-l-ylethyl)-2-phenylbenzimidazole dihydrochloride A solution of 2-phenylbenzimidazole (0.97 g, 5 mmol) in
N,N-dimethylformamide (anhydrous, 20 ml) was stirred at room temperature under nitrogen atmosphere. Two equivalents of sodium hydride in 60% dispersion (0.40 g, 10 mmol) was quickly added and the reaction mixture was allowed to stir under nitrogen. N-(2- chloroethyDpiperidinyl (10 mmol) in anhydrous N,N- dimethylformamide (12 ml) was added dropwise by syringe to the stirring mixture. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was partitioned between acetic add and ethyl acetate. The organic layer was discarded and the aqueous phase was extracted with diethyl ether (5 x 75 ml). All organic fractions were discarded.
The aqueous phase was alkalinized with 2N sodium hydroxide. This solution was then extracted with diethyl ether (4 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 1.11 grams of a cloudy oil. This was then stirred in 2N hydrochloric acid in ethanol. The solvents were removed in vacuo, yielding the crude product, which was recrystallized twice from an ethyl acetate/ethanol solution. The solvents were removed in vacuo to yield 0.95 grams (50.2%) of the title product as a white solid. MS 306 Analysis for C20H23N3 • 2 HCl:
Theory: C, 63.49; H, 6.66; N, 11.11. Found: C, 63.33; H, 6.64; N, 10.92.
Example 29
Synthesis of l-phenyl-2-(4-hydroxyphenyl)benzimidazole A solution of l-phenyl-2-(4- methoxyphenyl)benzimidazole(0.60 g, 2.0 mmol) in hydrobromic add (6 ml) and acetic add (6 ml) was refluxed for 40 hours. The reaction mixture was extracted with diethyl ether (5 x 150 ml) at a pH of 3-5. The organic solvents were discarded. The aqueous phase was alkalinized to pH 8-9 and extracted with ethyl acetate (5 x 150 ml). The organic fractions were combined and dried over potassium carbonate, then filtered and the solvents were removed in vacuo to yield a white solid.
The solid was triturated in diethyl ether and filtered to yield 0.25 grams of the desired product. Analysis for C19H14N2O • 0.5 H2O:
Theory: C, 77.27; H, 5.12; N, 9.48. Found: C, 77.56; H, 4.96; N, 9.39.
Example 30
Synthesis of l-phenyl-2-(3-nitro-4-chlorophenyl)-benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and 4-chloro-3-nitτo-benzoic add (2.07 g, 10 mmol) in anhydrous tetrahydrofuran was stirred at room temperature as N-ethoxycarbonyl- 2-ethoxy-l,2-dihydroquinoline (3.71 g, 15 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred at room temperature for about 72 hours.
The reaction mixture was alkalinized with IN sodium hydroxide. The aqueous layer was extracted with ethyl acetate (4 x 100 ml). The organic fractions were combined, dried over potassium carbonate, filtered, and the solvents removed in vacuo to yield the crude product.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (4:1) solution as eluent. The intermediate prepared above (3.00 g, 8.4 mmol) in chloroform (95 ml) was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4 mmol) in chloroform (30 ml) was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (9:1) solution as eluent. The title product was recrystallized from fractions with ethyl acetate as a white solid. MS 349, 351, mp 179-182°C. Analysis for C19H12CIN3O2:
Theory: C, 65.24; H, 3.46; N, 12.01. Found: C, 65.50; H, 3.51; N, 12.06.
Example 3?
Synthesis of l-[2-(morpholin-4-yl)ethyl]-2-phenylbenzimidazole dihydrochloride
A solution of 2-phenylbenzimidazole (0.97 g, 5 mmol) in N,N-dimethylformamide (anhydrous, 20 ml) was stirred at 60°C under nitrogen atmosphere. Two equivalents of sodium hydride in 60% dispersion (0.40 g, 10 mmol) was quickly added and the reaction mixture was allowed to stir under nitrogen. N-(2-chloroethyl)morpholine (0.93 g, 5 mmol) in anhydrous N,N-dimethylformamide (12 ml) was added dropwise by syringe to the stirring mixture. The reaction mixture was stirred overnight at 60°C.
The reaction mixture was partitioned between acetic add and ethyl acetate. The organic layer was discarded and the aqueous phase was extracted with diethyl ether (5 x 75 ml). All organic fractions were discarded.
The aqueous phase was alkalinized with 2N sodium hydroxide. This solution was then extracted with diethyl ether (4 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a doudy oil.
The crude product was mixed with a 2N hydrochloric add/ethanol (1:1) solution. The solvents were removed in vacuo to yield 1.52 grams (40%) of a white solid. MS 308. Analysis for C19H21N3O • 2 HCl • EtOH:
Theory: C, 59.16; H, 6.86; N, 9.85. Found: C, 59.20; H, 6.85; N, 9.89.
Example 32
Synthesis of l-phenyl-2-propylbenzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in tetrahydrofuran (90 ml) was stirred at room temperature under a nitrogen atmosphere as butanoyl chloride (1.28 g, 12 mmol) in tetrahydrofuran (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent. The product was recrystallized from hexanes to yield a white solid. The intermediate prepared above in chloroform was stirred at room temperature as an equimolar amount of phosphorous oxychloride in chloroform was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as eluent. The title product was recrystallized from hexanes and ethyl acetate as a white solid, yielding 1.55 grams (66%). MS 237, mp 53-55°C. Analysis for C16H16N2: Theory: C, 81.32; H, 6.82; N, 11.85.
Found: C, 81.06; H, 6.69; N, 12.02.
FfXλ Ple 3
Synthesis of l-phenyl-2-(thien-2-yl)benzimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature under a nitrogen atmosphere as an equimolar amount of 2- chlorocarbonylthiophene in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
The reaction product was further purified by trituration in diethyl ether. Recrystallization from ethyl acetate yielded a white solid which was homogeneous on thin layer chromatography. mp 150-152°C. The intermediate prepared above in chloroform was stirred at room temperature as an equimolar amount of phosphorous oxychloride in chloroform was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as eluent. The title product was recrystallized from hexanes and ethyl acetate as clear crystals. The solvent was removed in vacuo, yielding 1.70 grams (64%). MS 277, mp 118-120°C. Analysis for C17H12N2S:
Theory: C, 73.62; H, 4.72; N, 10.10. Found: C, 73.84; H, 4.48; N, 10.30.
Ex m le 34
Synthesis of l-phenyl-2-(3-hyo *oxyphenyl)benziιnidazole A solution of l-phenyl-2-(3-methoxyphenyl)benzimidazole
(0.20 g, 0.67 mmol) and hydrobromic add (4 ml) and acetic add (4 ml) was refluxed for 48 hours. The reaction mixture was cooled and extracted with diethyl ether (5 x 150 ml) at pH 3-5. The organic fractions were discarded. The aqueous phase was alkalinized to pH 8-9 and extracted with ethyl acetate (5 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo to yield a white solid. The solid was triturated with an ethyl acetate/diethyl ether mixture. The reaction product was further purified by chromatography to yield 0.17 grams (88.6%) of a white solid. MS
287(M+), mp 245-247°C. Analysis for C19H14N2O • 2 H2O:
Theory: C, 78.71; H, 5.01; N, 9.66. Found: C, 78.79; H, 5.16; N, 9.70. Example 35
Synthesis of l-phenyl-2-pentylbenzimidazole hydrochloride
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as an equimolar amount of hexanoyl chloride in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil. The reaction product was further purified by trituration in diethyl ether. Recrystallization from ethyl acetate yielded a white solid which was homogeneous on thin layer chromatography.
The intermediate prepared above in chloroform was stirred at room temperature as an equimolar amount of phosphorous oxychloride in chloroform was added dropwise. The reaction mixture was refluxed overnight.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as eluent to yield 1.82 grams (69.2%) as a red oil. The red oil was stirred in a 2N hydrochloric add/ethanol (1:1) solution for ten minutes. The ethaol was removed in vacuo to yield 2.1 grams of a brown/green solid. The title product was recrystallized from an ethyl acetate/ethanol (1:1) solution.
The solvent was removed in vacuo, yielding 1.56 grams (51.9%) of the title product as a white solid. MS 265(M+), mp 202-205°C.
Analysis for C18H20N2 • HCl: Theory: C, 71.87; H, 7.04; N, 9.31. Found: C, 72.02; H, 7.23; N, 9.05.
Example 36
Synthesis of l-phenyl-2-(2-trifluoromethylphenyl)-benrimidazole
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as an equimolar amount of 2-trifluoromethylbenzoyl chloride in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature.
The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown oil.
The reaction product was further purified by trituration in diethyl ether to yield a white solid which was homogeneous on thin layer chromatography. mp 161-162°C.
The intermediate prepared above in chloroform was stirred at room temperature as an equimolar amount of phosphorous oxychloride in chloroform was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was alkalinized with IN sodium hydroxide and the organic layer was removed. The aqueous layer was extracted with methyl ne chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a red/brown mixture of oil and solid.
The reaction product was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as eluent followed by trituration in diethyl ether to yield 1.07 grams (37.2%). Recrystallization from hexanes yielded white crystals, homogeneous on thin layer chromatography. MS 338, mp 142-144°C. Analysis for C20H13F3N2: Theory: C, 71.00; H, 3.87; N, 8.28. Found: C, 70.70; H, 3.97; N, 8.12.
Example 37
Synthesis of l-benz l-2-(3,4,5-trimethoxyphenyl)-benzimidazole
A solution of o-phenylenediamine dihydrochloride (3.62 g, 20 mmol), 3,4,5-trimethoxybenzaldehyde (3.92 g, 20 mmol) and triethylamine (2.02 g, 20 moles) in nitrobenzene (100 mis) was heated at 150°C for 32 hours. The majority of the nitrobenzene was distilled off by vacuum distillation (60°C pot temperature, 0.1 mm Hg). The crude product was partitioned between IN sodium hydroxide and ethyl acetate. The ethyl acetate fraction was removed and the aqueous phase was extracted with ethyl acetate (3 x 100 ml).
The organic fractions were combined, washed with brine, dried over sodium sulfate, filtered, and the solvents were removed in vacuo to yield a red brown oil which was purified by column chromatography using a hexanes/ethyl acetate (1:1) solution as the eluting solvent to yield the intermediate 2-(3,4,5- trimethoxyphenyDbenzimidazole. NMR
The intermediate prepared above (0.91 g, 3.2 mmol) and sodium hydride (0.26 g, 6.4 mmol) in N,N-dimethylformamide (25 ml) were stirred at room temperature as benzyl bromide (0.60 g, 6.4 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes and then heated to 120°C where it was maintained for seven days. Additional sodium hydride and benzymbromide were added as needed force the reaction forward.
The crude product was partitioned between water and ethyl acetate, followed by an add base workup in a separatory funnel. The organic layers were washed with brine, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. MS 375(M+) Analysis for C23H22N2O3:
Theory: C, 73.78; H, 5.92; N, 7.48. Found: C, 73.99; H, 5.95; N, 7.19. Exa ples 38 and 39
Synthesis of l-phenylmethyl-2-(3,4,5-trimethoxyphenyl)-5- methoxybenzimidazole (Example 38) and l-phenylmethyl-2-(3,4,5- trimethoxyphenyl)-6-methoxybenzimidazole (Example 39)
This synthesis was performed essentially as described in Example 37 except for the substitution of 4-methoxy-o-phenylenediamine in place of the o-phenylenediamine employed there. This resulted in a mixture of the regioisomers of the title products which could be separated using common techniques.
Example 38: MS 404, Analysis for C24H24N2O4:
Theory: C, 71.27; H, 5.98; N, 6.92.
Found: C, 71.07; H, 6.16; N, 6.89.
Example 39: MS 404, Analysis for C24H24N2O4: Theory: C, 71.27; H, 5.98; N, 6.93.
Found: C, 71.24; H, 6.11; N, 6.97.
Example 40 Synthesis of l-(3-chlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole
An amount of 2-(3,4,5-trimethoxyphenyl)-benzimidazole (1.05 g, 3.69 mmol), prepared as described in Example 37, supra, was added to a three-neck flask with a stir bar. The contents of the flask were placed under nitrogen atmosphere and 50 ml of N,N- dimethylformamide was added by syringe. This mixture was then allowed to stir. Sodium hydride (60%, 0.41 g, 4.10 mmol) was then added to the reaction mixture and the resulting mixture was stirred for about 30 minutes.
The resulting grayish mixture was then placed into an oil bath and 3-chlorobenzyl bromide (0.60 ml, 4.10 mmol) was added. The temperature of the solution was then raised to 60°C and the solution was allowed to stir overnight.
The solution was then removed from the oil bath and allowed to cool to room temperature. Ethyl acetate (150 ml) was then added to the reaction mixture. This organic solution was extracted with water (3 x 150 ml), followed by 25 ml of diethyl ether. The organic phase was then washed with a saturated sodium chloride solution.
The organic solution was reduced in vacuo to yield a yellow oil. To this oil ethanol (50 ml) and hexanes (20 ml) were added. The yellow solution was cooled and allowed to crystallize. The crystals were recovered by filtration and then washed with 20 ml of hexanes. The liquors were reduced in vacuo and allowed to crystallize to yield a total of
1.05 grams of the title product. MS 409, 411, mp 83°C. Analysis for C23H21CIN2O3: Theory: C, 67.56; H, 5.18; N, 6.85.
Found: C, 67.82; H, 5.21; N, 6.64.
Exam le 41 Synthesis of l-(2-chlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole
The title product was prepared essentially as described in Example 40, supra, except that 2-chlorobenzyl bromide (0.50 ml, 4.19 mmol) was employed instead of the 3-chlorobenzyl bromide, to yield 1.13 g (80%). MS 409, 411, mp 173.5°C. Analysis for C23H21CIN2O3:
Theory: C, 67.56; H, 5.18; N, 6.85. Found: C, 67.33; H, 5.21; N, 6.60.
Example 42 Synthesis of l-(4-chlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 4-chlorobenzyl bromide (0.75 g, 4.03 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 409, 411, mp l69°C.
Analysis for C23H21CIN2O3:
Theory: C, 67.56; H, 5.18; N, 6.85. Found: C, 68.07; H, 5.34; N, 6.46.
Example 43 - 52 -
Synthesis of l-(2-methylbenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, sjipxa, except that α-bromo-o-xylene (0.55 g, 4.10 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 389, mp 140.5°C. Analysis for C24H24N2O3:
Theory: C, 74.21; H, 6.23; N, 7.21. Found: C, 73.92; H, 6.25; N, 7.05.
Example 44 Synthesis of l-(3-methylbenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that α-bromo-m-xylene (0.55 g, 4.10 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 389, mp 78°C. Analysis for C24H24N2O3: Theory: C, 74.21; H, 6.23; N, 7.21.
Found: C, 73.96; H, 6.34; N, 7.01.
Example 45 Synthesis of l-(3-methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 3-methoxybenzyl chloride (0.60 ml, 4.13 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 405, mp 127°C.
Analysis for C24H24N2O4:
Theory: C, 71.27; H, 5.98; N, 6.93. Found: C, 71.21; H, 6.04; N, 6.98.
Example 4fi Synthesis of l-(4-methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 4-methoxybenzyl chloride (0.60 ml, 4.13 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 405, mp 110.5°C. Analysis for C24H24N2O4:
Theory: C, 71.27; H, 5.98; N, 6.93. Found: C, 71.01; H, 6.01; N, 7.08.
Example 47
Synthesis of l-(2-methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, sunra. except that 2-methoxybenzyl chloride (50% 1.26 ml, 4.13 mmol) was employed instead of the 3-chlorobenzyl bromide. This reaction was performed at room temperature and allowed to stir for about six hours. MS 405, mp 136°C.
Analysis for C24H24N2O4:
Theory: C, 71.27; H, 5.98; N, 6.93. Found: C, 71.47; H, 6.13; N, 6.92.
Example 48
Synthesis of l-(2-fluorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole
The title compound was prepared essentially as described in Example 40, sunra. except that 2-fluorobenzyl bromide (0.48 ml, 4.33 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 392, mp
153.5°C.
Analysis for C23H21FN2O3:
Theory: C, 70.40; H, 5.39; N, 7.14. Found: C, 70.15; H, 5.37; N, 7.14.
Example 49 Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 2-trifluoromethylbenzyl bromide (0.48 ml, 4.33 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 442, mp 144°C. Analysis for C24H21F3N2O3:
Theory: C, 65.15; H, 4.78; N, 6.33. Found: C, 65.18; H, 4.75; N, 6.28.
Example 50 Synthesis of l-(2-iodobenzyl)-2-(3,4,5-trimethoxvphenyl)-benrimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 2-iodobenzyl bromide (1.0 ml, 4.33 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 500, mp
179°C.
Analysis for C23H21IN2O3: Theory: C, 55.21; H, 4.23; N, 5.60.
Found: C, 55.26; H, 4.27; N, 5.71.
Example K1
Synthesis of l-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 2-bromobenzyl bromide (1.0 ml, 4.33 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 452, 454, mp 152°C. Analysis for C23H2iBrN2θ3:
Theory: C, 60.94; H, 4.67; N, 6.18. Found: C, 61.18; H, 4.62; N, 6.09.
Example 52 Synthesis of l-(2,6-dicMorobenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole The title compound was prepared essentially as described in Example 40, supra, except that 2,6-dichlorobenzyl bromide (0.81 g, 4.10 mmol) was employed instead of the 3-chlorobenzyl bromide, mp 157°C. MS 443, 445, NMR, IR. Analysis for C23H20CI2N2O3:
Theory: C, 62.31; H, 4.55; N, 6.32. Found: C, 62.84; H, 4.57; N, 6.31.
Example 53
Synthesis of l-(3,4-dichlorobenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 3,4-dichlorobenzyl bromide (0.90 g, 4.45 mmol) was employed instead of the 3-chlorobenzyl bromide, mp 145°C, MS 443, 445, NMR, IR. Analysis for C23H20CI2N2O3:
Theory: C, 62.31; H, 4.55; N, 6.32. Found: C, 62.35; H, 4.65; N, 6.17.
Example 54 Synthesis of l-(2,4-dichlorobenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole
The title compound was prepared essentially as described in Example 40, supra, except that 2,4-dichlorobenzyl bromide (0.45 g, 2.23 mmol) was employed instead of the 3-chlorobenzyl bromide, mp 186°C. MS 443, 445, NMR, IR. Analysis for C23H20CI2N2O3:
Theory: C, 62.31; H, 4.55; N, 6.32. Found: C, 62.22; H, 4.65; N, 6.34.
Example fifi Synthesis of l-(4-methylbenzyl)-2-(3,4,5-trimethoxyphenyl)- benzimidazole The title compound was prepared essentially as described in Example 40, sjipxa, except that 4-methylbenzyl bromide (0.45 g, 2.23 mmol) was employed instead of the 3-chlorobenzyl bromide. MS 389, mp 84.5°C.
Analysis for C24H24N2O3:
Theory: C, 74.21; H, 6.23; N, 7.21. Found: C, 73.91; H, 6.23; N, 6.98.
Example 56
Synthesis of l-(2-chlorobenzyl)-2-(3-methylphenyl)-benzimidazole
The intermediate 2-(3-methylphenyl)-benrimidazole was prepared by first mixing reacting l-amino-2-nitrobenzene (8.50 g, 61.54 mmol) with toluene (180 ml) and heating to 100°C. To this mixture was then added 20 ml of N,N-diethylaniline and the reaction vessel was placed under a nitrogen atmosphere. To this solution was then added 3- methylbenzoyl chloride (24 ml, 132 mmol) and this mixture was then stirred overnight. After stirring, the reaction mixture was neutralized by the addition of 300 ml of IN hydrochloric acid and 300 ml of ethyl acetate. This was then stirred for about 30 minutes. The organic phase was then removed and washed with water, followed by drying over magnesium sulfate and reduction in vacuo, yielding yellow crystals of the intermediate l-[(3-methylphenyl)carbonylamino]-2-nitrobenzene. The nitro group of the above intermediate was then reduced by catalytic hydrogenation employing a palladium on activated carbon catalyst resulting in the substituted 1,2-phenylenediamine.
The substituted 1,2-phenylenediamine (1.01 g, 4.46 mmol) was then cydized using phosphorous oxychloride (1.01 g, 6.6 mmol) as described supra to produce 2-(3-methylphenyl)benrimidazole.
The title compound was then produced by reacting the 2-(3- methylphenyDbenzimidazole (0.75 g, 3.60 mmol) with 2-chlorobenzyl chloride (0.50 ml, 4.19 mmol) essentially as described in Example 40, supra. MS 332, 334, mp 117°C. Analysis for C21H17CIN2: Theory: C, 75.78; H, 5.15; N, 8.42. Found: C, 75.99; H, 5.24; N, 8.43.
The following compounds were synthesized essentially as described in Example 56 by reacting 2-(3-methylphenyl)benzimidazole with the appropriately substituted benzyl halide.
Example 57 l-(3-Chlorobenzyl)-2-(3-methylphenyl)benzimidazole. MS 332, 334, mp 90°C.
Analysis for C21H17CIN2:
Theory: C, 75.78; H, 5.15; N, 8.42. Found: C, 75.51; H, 5.20; N, 8.56.
Example 58 l-(4-Chlorobenzyl)-2-(3-methylphenyl)benzimidazole. MS 332, 334, mp 108.5°C. Analysis for C21H17CIN2:
Theory: C, 75.78; H, 5.15; N, 8.42. Found: C, 75.55; H, 5.29; N, 8.37.
Example 60 l-(2-Bromobenzyl)-2-(3-methylphenyl)benzimidazole. MS 376, 378, mp 134°C. Analysis for C2iHi7BrN2:
Theory: C, 66.85; H, 4.54; N, 7.42. Found: C, 67.13; H, 4.60; N, 7.34.
Example 61 l-(2-Iodobenzyl)-2-(3-methylphenyl)benzimidazole. MS 424, 425, mp 129°C. Analysis for C21H17IN2 • 0.1 hexanes:
Theory: C, 59.93; H, 4.28; N, 6.47. Found: C, 60.20; H, 4.12; N, 6.87.
Example 62 l-(2,6-Dichlorobenzyl)-2-(3-methylphenyl)benzimidazole. mp 148°C, NMR, IR, MS 366, 368. Analysis for C21H16CI2N2 • 0.1 hexanes:
Theory: C, 69.02; H, 4.67; N, 7.45. Found: C, 69.25; H, 4.42; N, 7.21.
Example 63 l-(2,4-Dichlorobenzyl)-2-(3-methylphenyl)benzimidazole. mp 161°C, MS 366, 368, IR, NMR. Analysis for C2 ιH 16CI2N2 :
Theory: C, 68.68; H, 4.39; N, 7.63. Found: C, 68.48; H, 4.61; N, 7.70.
Example 64 l-(3,4-Dichlorobenzyl)-2-(3-methylphenyl)benzimidazole. mp 85.5°C, MS 366, 368, IR, NMR. Analysis for C21H16CI2N2:
Theory: C, 68.68; H, 4.39; N, 7.63. Found: C, 68.88; H, 4.41; N, 7.50.
Example 65 l-(3-Methoxybenzyl)-2-(3-methylphenyl)benzimidazole. Oil at room temperature. NMR, IR, MS 328. Analysis for C22H20N2O: Theory: C, 80.46; H, 6.14; N, 8.53.
Found: C, 81.39; H, 6.70; N, 8.23.
Example fifi l-(4-Methoxybenzyl)-2-(3-methylphenyl)benzimidazole. mp 91°C, NMR, IR, MS 328. Analysis for C22H20 2O:
Theory: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.68; H, 6.31; N, 8.63.
Example 67 Synthesis of l-(3-hydroxybenzyl)-2-(3-methylphenyl)benzimidazole hydrobromide.
This compound was prepared by first synthesizing l-(3- methoxybenzyl)-2-(3-methylphenyl)benzimidazole as described in Example 65, supra. With an amount of the compound of Example 65 (4.31 g, 13.12 mmol) in glarial acetic add (50 ml) and hydrobromic add (300 ml of a 48% w/v in acetic add solution). This mixture was stirred for 2 hours while warming to reflux. The mixture was then stirred at reflux for about three hours.
The reaction mixture was then allowed to cool to room temperature after which time the reaction mixture was partitioned between water (1 liter) and methylene chloride, followed by extraction with methylene chloride (3 x 500 ml). The organic fractions were combined and dried over magnesium sulfate. After reducing the volume of the organic solvents in vacuo, the organic fraction was washed with water (3 x 250 ml) to remove residual hydrobromic add. The orgnaic phases were combined and dried in vacuo to yield a gray solid which was washed with diethyl ether (2 x 250 ml) and dried in a vacuum oven. NMR, IR, MS 314, mp 235°C. Analysis for C21H18N2O • HBr:
Theory: C, 63.81; H, 4.84; N, 7.09. Found: C, 64.45; H, 5.02; N, 7.23.
Ffxample fiQ
Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-(hydroxy)- benzimidazole hydrochloride.
The title compound was prepared by first reacting 4-amino- 3-nitrophenol (25.0 g, 162.2 mmol) with 3,4,5-trimethoxybenzoyl chloride (112 g, 485.6 mmol) in N,N-diethylaniline (69 ml) and toluene (500 ml). The reaction mixture was stirred and the temperature was raised to 100°C. The solution was maintained at this temperature for about 6 hours as a yellow predpitate formed. The reaction mixture was then partitioned between IN hydrochloric add (250 ml) and ethyl acetate (250 ml). The crystals were then removed by filtration and washed with ethyl acetate (300 ml) and water (300 ml) to yield the intermediate l-(3,4,5- trimethoxy)benzyl ester of 4-(3,4,5-trimethoxyphenylcarbonylamino)-2- nitrophenol.
A benzyl group was then substituted on the nitro group by reacting the above intermediate (10 g, 18.4 mmol) with benzaldehyde (6 ml) in N,N-dinιethylformamide (100 ml) under a hydrogen atmosphere (60°C at 60 p.s.i.) with 6.0 g of a palladium on activated carbon catalyst.
The benzimidazole ring was closed using phosphorous oxychloride in chloroform as described supra. The ester on the 6- hydroxy group of the benzimidazole was removed by incubating the intermediate in IN sodium hydroxide (500 ml) and tetrahydrofuran (500 ml). This solution was stirred overnight, followed by addification with a suffirient amount of 1 N hydrochloric add to reduce the pH to 1.0. This solution was then washed with ethyl acetate (2 x 500 ml). The organic fractions were combined, dried over magnesium sulfate, and the solvents removed in vacuo to yield a brownish/red solid. The title compound was further purified by flash chromatography to yield a grayish solid. MS 390. Analysis for C23H22N2O4 • HCl: Theory: C, 64.71; H, 5.43; N, 6.56.
Found: C, 65.12; H, 5.40; N, 6.63.
Example 70
Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4- morpholinyl)ethoxy]benzimidazole.
The title compound was prepared by reacting the compound of Example 69, supra. (0.23 g, 0.59 mmol) with 4-(2- chloroethyDmorpholine hydrochloride (1.10 g, 5.91 mmol) and potassium carbonate (1.63 g, 11.80 mmol) in acetone. The reaction conditions employed were essentially as described for previous alkylations. MS 503. Analysis for C29H33N3O5:
Theory: C, 69.17; H, 6.60; N, 8.34. Found: C, 69.10; H, 6.70; N, 8.42. Example 71
Synthesis of 1 -benzyl- 2-(3,4,5-trimethoxyphenyl)-6-[2-(l- piperidinyl)ethoxy]benzimidazole.
The title compound was prepared essentially as described in Example 70 except that l-(2-chloroethyl)piperidine hydrochloride was employed in place of 4-(2-chloroethyl)morpholine hydrochloride. MS 501. Analysis for C30H35N3O4:
Theory: C, 71.83; H, 7.03; N, 8,38. Found: C, 71.95; H, 7.27; N, 8.17.
Example 72 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(l- pyrroldinyl)ethoxy]benzimidazole.
The title compound was prepared essentially as described in Example 70 except that l-(2-chloroethyl)pyrrolidine hydrochloride was employed in place of 4-(2-chloroethyl)morpholine hydrochloride. MS 488. Analysis for C29H33N3O4: Theory: C, 71.44; H, 6.82; N, 8.62.
Found: C, 71.61; H, 7.05; N, 8.87.
Example 73 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(l- hexamethyleneiminyl)ethoxy]benzimidazole.
The title compound was prepared essentially as described in Example 70 except that l-(2-chloroethyl)hexamethyleneimine hydrochloride was employed in place of 4-(2-chloroethyl)morpholine hydrochloride. NMR, IR, MS 515, mp 122.5°C. Analysis for C31H37N3O4:
Theory: C, 72.21; H, 7.23; N, 8.15. Found: C, 72.18; H, 7.19; N, 8.42.
Example 74 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[3-(l- piperidinyl )propoxy]benzimidazol e .
The title compound was prepared essentially as described in Example 70 except that l-(3-chloropropyl)piperidine hydrochloride was employed in place of 4-(2-chloroethyl)morpholine hydrochloride. mp 92°C, NMR, IR, MS 515. Analysis for C31H37N3O4:
Theory: C, 72.21; H, 7.23; N, 8.15. Found: C, 72.50; H, 7.26; N, 7.90.
Example 75
Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-(3- chloropropoxy)benzimidazole.
The title compound was prepared essentially as described in Example 70 except that l-chloro-3-iodopropane was employed in place of 4-(2-chloroethyl)morpholine hydrochloride. mp 118.5°C, MS 466, 468,
NMR, IR. Analysis for C26H27CIN2O4 • 0.5 H20:
Theory: C, 65.61; H, 5.93; N, 5.89. Found: C, 65.92; H, 5.74; N, 5.91.
Example 76 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-(2- chloroethoxy)benzimidazole.
The title compound was prepared essentially as described in Example 70 except that l-bromo-2-chloroethane was employed in place of 4-(2-chloroethyl)morpholine hydrochloride. IR, NMR, MS 452,
454, mp 129°C.
Analysis for C25H25CIN2O4:
Theory: C, 66.30; H, 5.56; N, 6.19. Found: C, 67.33; H, 5.41; N, 6.61.
Example 77 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-[4-(piperidin-l- yl )piperdin- l-yl]ethoxy]benzimidazole .
The title compound was prepared by reacting the compound of Example 76, supra. (0.45 g, 1.0 mmol) with 4-(piperdin-l-yl)piperidine (2.0 g, 11.9 mmol) in the presence of the base N,N- diisopropylethylamine, tetra-n-butylammonium iodide and acetonitrile at 80°C. After incubating overnight at 80°C the reaction was washed with water (2 x 500 ml), followed by a wash with a saturated sodium chloride solution (1 x 500 ml). The organic phase was then dried over potassium carbonate and the solvents were removed in vacuo to yield a light brown oil. The desired product was purified by chromatography and triturated with diethyl ether to yield a light brown powder, which was removed by filtration and washed with diethyl ether to yield the purified title compound. MS 584, 585, NMR, IR, mp 143°C. Analysis for C35H44N4O4:
Theory: C, 71.89; H, 7.58; N, 9.58. Found: C, 72.11; H, 7.62; N, 9.67.
Example 78
Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[l-methyl-2-(N,N- dimethylamino)]ethoxy]benzimidazole.
The title compound was prepared by reacting the compound of Example 70, supra. 0.45 g, 1.15 mmol) with l-methyl-2- dimethylaminoethyl chloride (1.82 g, 11.51 mmol) and potassium chloride (3.18 g, 23.01 mmol) in 100 ml of acetone. The reactants were admixed and then heated to reflux overnight.
After the overnight incubation the reaction mixure was addified by adding 500 ml of IN hydrochloric add and then washed with ethyl acetate (2 x 250 ml). The aqueous layer was then basified and extracted with ethyl acetate (500 ml). The organic fractions were combined and washed with a saturated sodium chloride solution and dried over potassium carbonate. The solvents were removed in vacuo to yield a yellow oil which was triturated with hexanes, forming a white solid. This was further purified by crystallizing from 10:1 hexanes:ethanol to yield the desired title product. IR, NMR, MS 475, 476, mp 93°C.
Analysis for C28H33N3O4:
Theory: C, 70.71; H, 6.99; N, 8.84. Found: C, 70.93; H, 7.01; N, 8.92.
Example 79 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole.
The title compound was prepared essentially as described in Example 78, supra, except that 2-dimethylaminoethyl chloride was employed in place of the l-methyl-2-dimethylaminoethyl chloride. IR, NMR, MS 461, mp 108°C. Analysis for C27H31N3O4 • 0.1 hexanes:
Theory: C, 70.51; H, 6.95; N, 8.94. Found: C, 70.98; H, 6.60; N, 8.62.
Example «0 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole.
The title compound was prepared essentially as described in Example 78, supra, except that 3-dimethylaminopropyl chloride was employed in place of the l-methyl-2-dimethylaminoethyl chloride. IR, NMR, MS 475, mp 112°C. Analysis for C28H33N3O4:
Theory: C, 70.71; H, 6.99; N, 8.83. Found: C, 70.42; H, 6.97; N, 8.68.
Example ftl Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]benzimidazole.
The title compound was prepared essentially as described in Example 78, supra, except that 2-diisopropylaminoethyl chloride was employed in place of the l-methyl-2-dimethylaminoethyl chloride. IR, NMR, MS 517, 518, mp 101°C. Analysis for C31H39N3O4:
Theory: C, 71.93; H, 7.59; N, 8.12. Found: C, 71.91; H, 7.76; N, 7.98.
Example 83 Synthesis of l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4-methyl-l- piperazinyl)ethoxy]benzimidazole.
The title compound was prepared essentially as described in Example 77, supra, employing the compound of Example 76, except that 1-methylpiperazine was employed in place of the 4-(piperdin-l- yDpiperidine. IR, NMR, MS 517, mp 113°C. Analysis for C30H36N4O4 • 0.5 H2O:
Theory: C, 68.55; H, 7.09; N, 10.66. Found: C, 68.83; H, 7.19; N, 10.98.
Example 84
Synthesis of l-benzyl-2-(3-methylphenyl)-6-hydroxybenzimidazole
The title compound was prepared essentially as described in Example 69, supra, except that 3-methylbenzoyl chloride (18.8 g, 121.6 mmol) was employed instead of the 3,4,5-trimethoxybenzoyl chloride. MS 314 Analysis for C21H18N2O:
Theory: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.10; H, 5.85; N, 8.81.
Example 85
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(l- piperidinyl)ethoxy]benzimidazole The title compound was synthesized by reacting the compound of Example 84, supra. (0.25 g, 0.79 mmol) with 2-(piperdinyl- l-yl)ethyl chloride (17.46 g, 7.9 mmol) in the presence of potassium carbonate (2.20 g, 15.9 mmol) and acetone (150 ml). These contents were added to a flask and refluxed overnight.
After the overnight incubation, the reaction mixture was quenched by adding 0.5 N hydrochloric add (300 ml) and was washed with ethyl acetate (300 ml). The aqueous layer was basified with IN sodium hydroxide until the pH=10. This aqueous layer was extracted with ethyl acetate (300 ml). The organic fractions were combined and the solvent volume was reduced in vacuo, leaving a yellow oil. Diethyl ether and hexanes were added to this oil and it was then placed at -20°C until crystals of the title product formed, which were then harvested by filtration. MS 425, 426. Analysis for C28H31N3O:
Theory: C, 79.03; H, 7.34; N, 9.87. Found: C, 78.75; H, 7.47; N, 10.09.
Example 8fi
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(l- pyrrolidinyl)ethoxy]benzimidazole.
The title product was prepared essentially as described in Example 85, supra, except that l-(2-chloroethyl)pyrrolidine hydrochloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 411. Analysis for C27H29N3O:
Theory: C, 78.80; H, 7.10; N, 10.21. Found: C, 78.85; H, 7.14; N, 10.08.
Example 87
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(4- morpholinyl)ethoxy]benzimidazole The title product was prepared essentially as described in Example 85, supra, except that 4-(2-chloroethyl)morpholine hydrochloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 427. Analysis for C27H29N3O2:
Theory: C, 75.85; H, 6.84; N, 9.83. Found: C, 75.75; H, 6.89; N, 9.88.
Example 88
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole
The title product was prepared essentially as described in Example 85, supra, except that 2-(N,N-dimethylamino)ethyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 385. Analysis for C25H27N3O:
Theory: C, 77.89; H, 7.06; N, 10.90. Found: C, 77.88; H, 7.14; N, 10.74.
Example 89
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(N,N- dibenzylamino)ethoxy]benzimidazole
The title product was prepared essentially as described in Example 85, supra, except that 2-(N,N-dibenzylamino)ethyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 537. Analysis for C37H35N3O: Theory: C, 82.65; H, 6.56; N, 7.82.
Found: C, 82.47; H, 6.73; N, 7.81.
Example 90
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(N-phenyl-N- ethylamino)ethoxy]benzimidazole The title product was prepared essentially as described in Example 85, s ιp a> except that 2-(N-benzyl-N-ethylamino)ethyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 461, 462.
Analysis for C31H31N3O:
Theory: C, 80.66; H, 6.77; N, 9.10. Found: C, 80.37; H, 6.81; N, 8.98.
Example 31
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(N,N- isopropylamino)ethoxy]benzimidazole
The title product was prepared essentially as described in
Example 85, supra, except that 2-(N,N-diisopropylamino)ethyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 441. Analysis for C29H35N3O:
Theory: C, 78.87; H, 7.99; N, 5.51. Found: C, 79.07; H, 8.12; N, 5.60.
Example 92
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(hexamethyleneimin- 1- yl)ethoxy]benzimidazole
The title product was prepared essentially as described in Example 85, supra, except that 2-(hexamethyleneimin-l-yl)ethyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 439.
Analysis for C29H33N3O:
Theory: C, 79.23; H, 7.57; N, 9.56. Found: C, 79.45; H, 7.72; N, 9.66.
Example 93 Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(N,N-diethylamino)ethoxy]- benzimidazole
The title product was prepared essentially as described in Example 85, supra, except that 2-(N,N-diethylamino)ethyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 413, 414. Analysis for C27H31N3O • 0.25 H2O:
Theory: C, 77.57; H, 7.59; N, 10.05. Found: C, 77.60; H, 7.42; N, 9.74.
Example 94
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole
The title product was prepared essentially as described in Example 85, supra, except that 3-(N,N-dimethylamino)propyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride. MS 399. Analysis for C26H29N3O: Theory: C, 78.16; H, 7.32; N, 10.52.
Found: C, 77.93; H, 7.32; N, 10.25.
Example 95
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[3-(piperdin- l-yl)propoxy]- benzimidazole.
The title product was prepared essentially as described in Example 85, supra, except that 3-(piperidin-l-yl)propyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride, mp 84°C, MS 439, NMR, IR. Analysis for C29H33N3O:
Theory: C, 79.23; H, 7.57; N, 9.55. Found: C, 79.39; H, 7.59; N, 9.59.
Example 96 Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(N,N- dimethylamino)propoxy]-benzimidazole
The title product was prepared essentially as described in
Example 85, sjipxa, except that 2-(N,N-dimethylamino)propyl chloride was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride, mp 74°C, NMR, IR, MS 399, 400. Analysis for C26H29N3O: Theory: C, 78.16; H, 7.32; N, 10.52.
Found: C, 79.58; H, 7.44; N, 10.49.
Example 97
Synthesis of l-benzyl-2-(3-methylphenyl)-6-(3-chloropropoxy)- benzimidazole
The title product was prepared essentially as described in Example 85, supra, except that 3-chloropropyl iodide was employed instead of the 2-(piperdinyl-l-yl)ethyl chloride, mp 97°C, NMR, IR, MS 390, 391. Analysis for C24H23CIN2O:
Theory: C, 73.74; H, 5.93; N, 7.17. Found: C, 73.61; H, 5.94; N, 7.39.
Example 98
Synthesis of l-benzyl-2-(3-methylphenyl)-6-(2-chloroethoxy>- benzimidazole
The title product was prepared essentially as described in Example 85, supra, except that 2-chloroethyl bromide was employed instead of the 2-(piρerdinyl-l-yl)ethyl chloride, mp 88°C, MS 376, 378, NMR, IR. Analysis for C23H21CIN2O:
Theory: C, 73.30; H, 5.62; N, 7.43. Found: C, 73.04; H, 5.67; N, 7.65.
EvflTTiple 99
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[3-(morpholin-4- yl)propoxy)benzimidazole.
The title compound was prepared by first adding morpholine (1.02 g, 11.77 mmol) and the compound of Example 97, supra. (0.39 g, 1.00 mmol) to 125 ml of acetonitrile while stirring under nitrogen purge. To this mixture is then added diisopropylethyl aniline (1.51 ml, 8.67 mmol) dropwise. This reaction mixture is then allowed to stir overnight.
After the overnight stirring, additional diisopropyl aniline (1.00 ml) is added and the mixture is then heated to 60°C and maintained at this temperature for about 3 days. The reaction mixture was then washed with water (3 x 250 ml) and the solvents were removed in vacuo, resulting in a yellow oil.
The yellow oil was further purified by chromatography using ethyl acetate, followed by removal of the solvents in vacuo, and trituration with hexanes to afford yellow crystals. NMR, MS 441, IR, mp
120°C.
Analysis for C28H31N3O2:
Theory: C, 76.16; H, 7.08; N, 9.52. Found: C, 76.39; H, 7.26; N, 9.54.
Example 100
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[3-(pyrrolidin-l- yl)propoxy)benzimidazole
The title compound was prepared essentially as described in Example 99, supra, except that pyrrolidine was employed in place of morpholine. mp 120°C, NMR, IR, MS 425. Analysis for C28H31N3O:
Theory: C, 79.03; H, 7.34; N, 9.87. Found: C, 79.22; H, 7.39; N, 9.83.
Example 101
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[3-(hexamethyleneimin-l- yl)propoxy)benzimidazole
The title compound was prepared essentially as described in Example 99, sμpra. except that hexamethyleneimine was employed in place of morpholine. mp 69.5°C, NMR, IR, MS 453, 454. Analysis for C30H35N3O:
Theory: C, 79.43; H, 7.78; N, 9.26. Found: C, 79.60; H, 7.88; N, 9.28.
Example Q?
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[3-(heptamethyleneimin-l- yl)propoxy)benzimidazole
The title compound was by reacting the compound of
Example 97, supra. (0.39 g, 1.00 mmol) with heptamethyleneimine (10 g, 88.3 mmol) in the presence of N,N-diisopropylethylamine (2 ml) and acetonitrile (5 ml). This reaction mixture was raised to 80°C and allowed to stir at that temperature overnight. The compound was purified essentially as described in Example 99, supra. NMR, MS 467, mp 77°C. Analysis for C31H37N3O:
Theory: C, 79.62; H, 7.97; N, 8.98. Found: C, 79.50; H, 7.99; N, 8.99.
Example 1Q3
Synthesis of l-benzyl-2-(3-methylphenyl)-6-[2-(4-methyl-piperazin-l- yl )ethoxy]benzimidazole The title compound was prepared by reacting the compound of Example 98, supra. (1.89 g, 5.01 mmol) with 1-methyl-piperazine (65 ml) in the presence of N,N-diisopropylethyl amine (4 ml) and N,N- dimethylformamide (100 ml) under nitrogen atmosphere. This reaction mixture was heated to 50°C and stirred overnight at that temperature. The compound was purified essentially as described in Example 99, sjipxa. NMR, IR, MS 440, 441, mp 91°C. Analysis for C28H32N4O:
Theory: C, 76.33; H, 7.32; N, 12.72. Found: C, 76.19; H, 7.15; N, 12.96.
Example 104
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6- hydroxybenzimidazole
The title compound was prepared by first reacting 3,4,5- trimethoxybenzoyl chloride (112.0 g, 485.6 mmol) with 4-amino-3- nitrophenol (25.0 g, 162.2 mmol) in N,N-diethylaniline (69 ml) and toluene (500 ml). This reaction mixture was heated to 100°C and maintained at that temperature for about 6 hours. The intermediate ester of 4-(3,4,5-trimethoxyphenylcarbonylamino)-3-nitrophenol was purified essentially as described in Example 69, supra.
The nitro moiety of the above-described intermediate was reduced to an amino group by catalytic hydrogenation using a palladium on activated carbon catalyst as described previously. This primary amino group was then alkylated by reacting with 2- trifluoromethylbenzyl bromide in the presence of N,N-diisopropylethyl amine and tetrahydrofuran. This mixture was allowed to reflux overnight
The reaction mixture was then washed with water (5 x 500 ml) followed by a wash with saturated sodium chloride (500 ml). The organic phase was dried over potassium carbonate, and the solvents were removed in vacuo, leaving a brown solid. Following trituration in diethyl ether a gray solid formed. The benzimidazole ring was closed using phosphorous oxychloride in chloroform as previously described. The protecting ester on the 6-hydroxy of the benzimidazole ring was removed by incubating the protected compound in IN sodium hydroxide in tetrahydrofuran to cleave this group, leaving the title compound. NMR, IR, MS 458, mp 191°C. Analysis for C24H21F3N2O4:
Theory: C, 62.88; H, 4.62; N, 6.11. Found: C, 62.89; H, 4.88; N, 5.90.
Example I PS
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2- (piperidin-l-yl)ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 104 with l-(2-chloroethyl)piperidine hydrochloride essentially as previously described, mp 167°C, NMR, IR, MS 570. Analysis for C31H34F3N3O4: Theory: C, 65.37; H, 6.02; N, 7.38.
Found: C, 65.40; H, 6.02; N, 7.41.
Example 106
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2- (N,N-dimethylamino)propoxy]-benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-dimethylamino)propyl chloride essentially as previously described, mp 163°C, NMR, IR, MS 543, 544. Analysis for C29H32F3N3O4:
Theory: C, 64.08; H, 5.93; N, 7.73. Found: C, 64.00; H, 5.86; N, 7.68.
Example 1Q7 Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2- (N,N-dimethylamino)ethoxy]-benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-dimethylamino)ethyl chloride essentially as previously described, mp 151°C, NMR, IR, MS 529. Analysis for C28H30F3N3O4:
Theory: C, 63.51; H, 5.71; N, 7.94. Found: C, 63.79; H, 5.57; N, 8.02.
Example 108
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3- (N,N-dimethylamino)propoxy]-benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 3-(N,N-dimethylamino)propyl chloride essentially as previously described, mp 142°C, NMR, IR, MS 543. Analysis for C29H32F3N3O4: Theory: C, 64.08; H, 5.93; N, 7.73.
Found: C, 64.33; H, 5.78; N, 7.47.
Example 109
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3- (piperidin- 1-yl )propoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 3-(piperidin-l-yl)propyl chloride essentially as previously described, mp 138°C, IR, NMR, MS. 584 Analysis for C32H36F3N3O4:
Theory: C, 65.85; H, 6.22; N, 7.20. Found: C, 65.74; H, 6.07; N, 7.35.
Example UQ Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2- (hexamethyleneimin-l-yl)ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 2-(hexamethyleneimin-l-yl)ethyl chloride essentially as previously described, mp 156°C, IR, NMR, MS 583, 584. Analysis for C32H36F3N3O4:
Theory: C, 65.85; H, 6.22; N, 7.20. Found: C, 65.59; H, 5.98; N, 7.33.
Example 11 1
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2- (pyrrolidin-l-yl)ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 2-(pyrrolidin-l-yl)ethyl chloride essentially as previously described, mp 143°C, NMR, IR, MS 555. Analysis for C30H32F3N3O4: Theory: C, 64.85; H, 5.80; N, 7.56.
Found: C, 64.93; H, 5.87; N, 7.54.
Example 112
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2- (morpholin-4-yl)ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 2-(morpholin-4-yl)ethyl chloride essentially as previously described, mp 175°C, NMR, IR, MS 572. Analysis for C30H32F3N3O5:
Theory: C, 63.04; H, 5.64; N, 7.35. Found: C, 62.82; H, 5.74; N, 7.38.
Example 113 Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2- (N,N-diisopropylamino)ethoxy]-benzimidazole
The title compound was prepared by reacting the compound of Example 104 with 2-(N,N-diisopropylamino)ethyl chloride essentially as previously described, mp 184°C, MS 585, NMR, IR. Analysis for C32H38F3N3O4:
Theory: C, 65.63; H, 6.54; N, 7.18. Found: C, 65.67; H, 6.42; N, 7.35.
Example 114
Synthesis of l-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6- hydroxybenzimidazole
The title compound was prepared essentially as described in Example 104 except that 2-bromobenzyl bromide was employed in place of 2-trifluoromethylbenzyl bromide, mp 208°C, NMR, IR, MS 468,
470. Analysis for C23H2iBrN2θ4:
Theory: C, 58.86; H, 4.51; N, 5.97. Found: C, 58.61; H, 4.81; N, 6.12.
Example 115
Synthesis of l-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(piperidin- 1-yl )ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 114 with 2-(piperidin-l-yl)ethyl chloride essentially as previously described, mp 145°C, NMR, MS 579, 581, IR. Analysis for C3oH34BrN3θ4:
Theory: C, 62.07; H, 5.90; N, 7.24. Found: C, 61.86; H, 5.91; N, 7.08.
Example 116 Synthesis of l-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- dimethylamino)propoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-dimethylamino)propyl chloride essentially as previously described, mp 152°C, NMR, IR, MS 553, 555. Analysis for C2βH32BrN3θ4:
Theory: C, 60.65; H, 5.82; N, 7.58. Found: C, 60.85; H, 5.77; N, 7.44.
Example 117
Synthesis of l-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- dimethylamino )ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-dimethylamino)ethyl chloride essentially as previously described, mp 152°C, NMR, IR, MS 539, 541. Analysis for C27H3nBrN3θ4:
Theory: C, 60.00; H, 5.59; N, 7.77. Found: C, 59.83; H, 5.63; N, 7.54.
Example 118
Synthesis of l-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 114 with 3-(N,N-dimethylamino)propyl chloride essentially as previously described, mp 141°C, NMR, IR, MS 553, 555. Analysis for C2δH32BrN3θ4:
Theory: C, 60.65; H, 5.82; N, 7.58. Found: C, 60.49; H, 6.03; N, 7.34.
Example 119 Synthesis of l-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-diisopropylamino)ethyl chloride essentially as previously described. MS 595, 597. Analysis for C3iH3sBrN3θ4:
Theory: C, 62.41; H, 6.42; N, 7.04. Found: C, 62.48; H, 6.48; N, 7.03.
Example 120
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6- hydroxybenzimidazole
The title compound was prepared essentially as described in Example 104, supra, except that 3-methylbenzoyl chloride was employed instead of 3,4,5-trimethoxybenzoyl chloride, mp 233°C, MS 382, IR, NMR.
Analysis for C22H17F3N2O:
Theory: C, 69.10; H, 4.48; N, 7.33. Found: C, 69.40; H, 4.49; N, 7.27.
Example 121
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2- (piperidinyl-l-yl)ethoxy]benzimidazole
The title compound was prepared essentially as described in Example 105 except that the compound of Example 120 was reacted with 2-(piperidin-l-yl)ethyl chloride, mp 114°C, NMR, IR, MS 493. Analysis for C29H30F3N3O:
Theory: C, 70.57; H, 6.13; N, 8.51. Found: C, 70.77; H, 6.22; N, 8.50. Example 122
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole
The title compound was prepared essentially as described in Example 107 except that the compound of Example 120 was reacted with 2-(N,N-dimethylamino)ethyl chloride, mp 93°C, NMR, IR, MS 453. Analysis for C26H26F3N3O: Theory: C, 68.86; H, 5.78; N, 9.26.
Found: C, 69.12; H, 5.79; N, 9.34.
Example 123
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]-benzimidazole
The title compound was prepared essentially as described in Example 113 except that the compound of Example 120 was reacted with 2-(N,N-diisopropylamino)ethyl chloride. MS 510. Analysis for C30H34F3N3O:
Theory: C, 70.71; H, 6.72; N, 8.25. Found: C, 70.48; H, 6.59; N, 8.26.
Example 124
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole
The title compound was prepared essentially as described in Example 106 except that the compound of Example 120 was reacted with 3-(N,N-dimethylamino)propyl chloride, mp 74°C, NMR, IR, MS
468.
Analysis for C27H28F3N3O: Theory: C, 69.36; H, 6.04; N, 8.99.
Found: C, 69.52; H, 6.10; N, 9.03. Example 125
Synthesis of l-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[l-methyl- 2-(N,N-dimethylamino)ethoxy]-benzimidazole
The title compound was prepared essentially as described above except that the compound of Example 120 was reacted with 1- methyl-2-(N,N-dimethylamino)ethyl chloride, yielding the title product as an oil.
Example 126
Synthesis of l-(2-bromobenzyl)-2-(3-methylphenyl)-6- hydroxybenzimidazole
The title compound was prepared essentially as described in Example 114, supra, except that 3-methylbenzoyl chloride was employed instead of 3,4,5-trimethoxybenzoyl chloride, mp 218°C, NMR, IR, MS 392, 394.
Analysis for C2iHi7BrN2θ:
Theory: C, 64.13; H, 4.36; N, 7.12. Found: C, 64.23; H, 4.51; N, 6.93.
Example 127
Synthesis of l-(2-bromobenzyl)-2-(3-methylphenyl)-6-[2-(piperidinyl- 1- yl)ethoxy]benzimidazole
The title compound was prepared essentially as described in Example 115 except that the compound of Example 126 was reacted with 2-(piperidin-l-yl)ethyl chloride, mp 107°C, NMR, IR, MS 503, 505. Analysis for C2sH3oBrN3O:
Theory: C, 66.67; H, 5.99; N, 8.33. Found: C, 66.97; H, 6.12; N, 8.19. Example 128
Synthesis of l-(2-bromobenzyl)-2-(3-methylphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole
The title compound was prepared essentially as described in Example 117 except that the compound of Example 126 was reacted with 2-(N,N-dimethylamino)ethyl chloride, mp 71°C, NMR, IR, MS 464, 466. Analysis for C25H2βBrN3θ:
Theory: C, 64.66; H, 5.64; N, 9.05. Found: C, 64.58; H, 5.58; N, 9.04.
Example 130
Synthesis of l-(2-bromobenzyl)-2-(3-methylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole
The title compound was prepared essentially as described in Example 116 except that the compound of Example 126 was reacted with 3-(N,N-dimethylamino)propyl chloride. MS 479. Analysis for C26H2sBrN3O:
Theory: C, 65.27; H, 5.90; N, 8.78. Found: C, 64.99; H, 5.85; N, 8.66.
Example 131
Synthesis of l-(2-bromobenzyl)-2-(3-methylphenyl)-6-[l-methyl-2-(N,N- dimethylamino)ethoxy]benzimidazole
The title compound was prepared essentially as described above except that the compound of Example 126 was reacted with 1- methyl-2-(N,N-dimethylamino)ethyl chloride.
Example 132 Synthesis of l-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6- hydroxybenzimidazole
The title compound was prepared essentially as described in Example 104 except that 3,4,dimethylbenzoyl chloride was employed instead of 3,4,5-trimethoxybenzoyl chloride, mp 178°C, NMR, IR, MS
396.
Analysis for C23H19F3N2O:
Theory: C, 69.69; H, 4.83; N, 7.07. Found: C, 69.40; H, 4.87; N, 6.90.
The following compounds were prepared essentially as described supra, except that the compound of Example 132 was employed as a starting material.
Example 133
l-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(piperidin-l- yl)ethoxy]benzimidazole. mp 131°C, NMR, MS 507, IR. Analysis for C30H32F3N3O:
Theory: C, 70.99; H, 6.35; N, 8.28. Found: C, 70.70; H, 6.23; N, 8.42.
Example 134
l-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole. mp 87°C, MS 467, NMR, IR. Analysis for C27H28F3N3O:
Theory: C, 69.36; H, 6.04; N, 8.99. Found: C, 69.42; H, 6.01; N, 8.91.
Example 135
l-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]benzimidazole. mp 121°C, NMR, IR, MS 524. Analysis for C31H36F3N3O: - 84 -
Theory: C, 71.11; H, 6.93; N, 8.03. Found: C, 71.34; H, 6.96; N, 8.26.
Example 136
l-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- dimethylamino)propoxy]benzimidazole.
MS 481.
Analysis for C28H30F3N3O: Theory: C, 69.84; H, 6.28; N, 8.73.
Found: C, 70.24; H, 6.33; N, 8.55.
Example 136A
l-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[l- methyl-2-(N,N- dimethylamino)ethoxy]benrimidazole MS 481. Analysis for C28H30F3N3O:
Theory: C, 69.84; H, 6.28; N, 8.73. Found: C, 69.61; H, 6.35; N, 8.50.
Example 137
l-(2-bromomethylbenzyl)-2-(3,4-diuιιethylphenyl)-6-hydroxybenzimidazole
The title compound was prepared essentially as described in Example 114, supra, except that 3,4-dimethylbenzoyl chloride was employed instead of 3,4,5-trimethoxybenzoyl chloride, mp 213°C, MS
406, 408, NMR, IR. Analysis for C22Hi9BrN2θ:
Theory: C, 64.56; H, 5.17; N, 6.84 Found: C, 64.76; H, 4.95; N, 6.62.
The following compounds were prepared essentially as described supra, except that the compound of Example 138 was employed as a starting material. Example 138
l-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole Analysis for C27H3nBrN3θ:
Theory: C, 65.85; H, 6.14; N, 8.53. Found: C, 66.12; H, 6.20; N, 8.49.
Example 139
l-(2-bromobenzyl)-2-(3 ,4-dimethylphenyl)-6-[2-(piperidin- 1- yl)ethoxy]benzimidazole. mp 137°C, NMR, IR, MS 517, 519. Analysis for C29H32BrN3θ: Theory: C, 67.18; H, 6.72; N, 8.10.
Found: C, 67.45; H, 6.30; N, 8.01.
Example 140
l-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole. mp 102°C, IR, NMR, MS 478,
479, 480.
Analysis for C2βH28BrN3θ:
Theory: C, 65.27; H, 5.90; N, 8.78. Found: C, 65.43; H, 5.88; N, 8.75.
Example 141
l-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]benzimidazole
MS 533, 535.
Analysis for C3oH3eBrN3O:
Theory: C, 67.41; H, 6.79; N, 7.86. Found: C, 67.36; H, 6.60; N, 7.93.
Example 142 l-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- dimethylamino)propoxy]benzimidazole. MS 491, 493. Analysis for C27H3oBrN3θ: Theory: C, 65.85; H, 6.14; N, 8.53.
Found: C, 66.07; H, 6.18; N, 8.54.
Example 142A
l-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[ l-methyl-2-(N,N- dimethylamino)ethoxy]benzimidazole. MS 491, 493. Analysis for C27H3oBrN3θ:
Theory: C, 65.85; H, 6.14; N, 8.53. Found: C, 65.74; H, 6.20; N, 8.32.
Example 143
l-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole. MS 491, 493. Analysis for C11H14N2O4S:
Theory: C, 65.85; H, 6.14; N, 8.53. Found: C, 66.12; H, 6.20; N, 8.49.
Example 145
l-(2-bromomethylbenzyl)-2-(3,5-dimethylphenyl)-6-hydroxybenzimidazole
The title compound was prepared essentially as described in Example 114, supra, except that 3,5-dimethylbenzoyl chloride was employed instead of 3,4,5-trimethoxybenzoyl chloride, mp 213°C, MS 406, 408, NMR, IR. Analysis for C22Hi9BrN2θ:
Theory: C, 64.88; H, 4.70; N, 6.88. Found: C, 64.74; H, 4.80; N, 7.01. The following compounds were prepared essentially as described supra, except that the compound of Example 145 was employed as a starting material.
Example 146
l-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(piperidin-l- yl )ethoxy]benzimidazole IR, NMR, MS 517, 519, mp 112°C. Analysis for C29H32BrN3 • 0.5 H2O:
Theory: C, 66.03; H, 6.31; N, 7.97. Found: C, 66.17; H, 6.50; N, 7.46.
Example 147
l-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole
MS 477, 479.
Analysis for C2&H28BrN3θ • H2O: Theory: C, 62.90; H, 6.09; N, 8.46.
Found: C, 63.09; H, 5.95; N, 8.45.
Example 148
l-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[l-methyl-2-(N,N- dimethylamino)ethoxy]benzimidazole. mp 78°C, NMR, IR, MS 491, 493. Analysis for C27H3nBrN3θ :
Theory: C, 65.85; H, 6.14; N, 8.53. Found: C, 66.05; H, 6.15; N, 8.80.
Example 149
l-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]benzimidazole MS 534, 536.
Analysis for C3oH36BrN3O: Theoiy: C, 67.41; H, 6.79; N, 7.86. Found: C, 67.34; H, 6.87; N, 7.62.
Example 150
l-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole. MS 491, 493. Analysis for C27H3oBrN3θ:
Theory: C, 65.85; H, 6.14; N, 8.53. Found: C, 65.68; H, 6.19; N, 8.53.
Example 151
l-phenyl-2-[3-[2-(piperidin-l-yl)ethoxy]phenyl]-benzimidazole
The title compound was prepared by reacting the compound of Example 34 with 2-(piperdin-l-yl)ethyl chloride in acetone and potassium carbonate as previously described, mp 68°C, IR, NMR, MS
397. Analysis for C26H27N3O:
Theory: C, 78.56; H, 6.85; N, 10.57. Found: C, 78.41; H, 6.90; N, 10.45.
Example 152
l-phenyl-2-[4-[2-(piperidin-l-yl)ethoxy]phenyl]-benzimidazole
The title compound was prepared by reacting the compound of Example 29 with 2-(piperdin-l-yl)ethyl chloride in acetone and potassium carbonate as previously described, mp 107°C, NMR, MS 397. Analysis for C26H27N3O:
Theory: C, 78.56; H, 6.85; N, 10.57. Found: C, 78.79; H, 7.12; N, 10.51.
Example 153 l-phenyl-2-[4-[3-(piperidin-l-yl)propoxy]phenyl]-benzimidazole
The title compound was prepared by reacting the compound of Example 29 with 3-(piperdin-l-yl)propyl chloride in acetone and potassium carbonate as previously described, mp 86°C, NMR, MS 412. Analysis for C27H29N3O:
Theory: C, 78.80; H, 7.10; N, 10.21. Found: C, 79.01; H, 7.18; N, 10.20.
Example 1 S4
Synthesis of l-phenyl-2-(3,4-dimethylphenyl)-6-hydroxybenzimidazole
The title compound was prepared by first reacting 1-chloro- 3,4-dinitrobenzene (100 g, 0.50 mole) with aniline (140 ml, 1.54 moles) in ethanol (95%, 550 ml). This reaction mixture was stirred at room temperature for about 72 hours. The resulting l-chloro-3-phenylamino- 4-nitrobenzene was purified by first filtering the orange crystals, followed by washing with hexanes. The crystals were then dried at 80°C for about 4 hours. Additional product was recovered from the hexanes filtrate by recrystallizing from ethanol.
The l-chloro-3-phenylamino-4-nitrobenzene was then reacted with two molar equivalents of sodium methoxide, the sodium methoxide being prepared essentially as described in Kottenhahn, et al.. Journal of Organic Chemistry. 28:3114 (1963). Metallic sodium (5.0 g, 217 mmol) was added slowly to methanol (400 ml). After all of the sodium had gone into solution, the l-chloro-3-phenylamino-4- nitrobenzene was added and the red-orange solution was heated to reflux and maintained at that temperature overnight. The gold crystals of l-methoxy-3-phenylamino-4-nitrobenzene were recovered by filtration, washed with water (2 liters) and dried in vacuo.
The nitro group of the above-described intermediate was then reduce to an amino group by catalytic hydrogenation using a palladium on activated carbon catalyst, essentially as previously described, resulting in 3-phenylamino-4-methoxyaniline with was then reacted with 3,4-dimethylbenzoyl chloride as previously described. This intermediate was then cyclized to the corresponding benzimidazole with phosphorous oxychloride as previously described to yield l-phenyl-2-(3,4- dimethylphenyl)-6-methoxybenrimidazole.
This intermediate was then reacted with hydrobromic add (48%) and gladal acetic add under nitrogen atmosphere to cleave the methoxy group from the 6-position of the benzimidazole. The resulting title compound was purified by adding the reaction mixture to one liter of water and extracting with methylene chloride (3 x 500 ml). The organic fractions were combined, dried over magnesium sulfate and the solvents were removed in vacuo to yield reddish solid crystals. The crystals were washed with water (3 x 250 ml) to remove excess hydrobromic add and then dried, followed by washing with diethyl ether (2 x 250 ml) and drying in vacuo. mp 251°C, IR, NMR, MS 314. Analysis for C21H18N2O: Theory: C, 80.23; H, 5.77; N, 8,91.
Found: C, 79.98; H, 5.77; N, 8.94.
Example ^ fi
l-phenyl-2-(3 ,4-dimethylphenyl )-6-[2-(piperidin- 1- yl )ethoxy]benzimidazole
The title compound was prepared by reacting the compound of Example 154, supra, with 2-(piperidin-l-yl)ethyl chloride as previously described. NMR, IR, MS 425, mp 111°C. Analysis for C28H31N3O • 0.5 H2O:
Theory: C, 77.39; H, 7.42; N, 9.67. Found: C, 77.38; H, 7.24; N, 10.36.
The following compounds were prepared essentially as described above:
Example 1 6
l-Benzyl-2-phenylbenzimidazole Examnle 157
l-(l-Diethylaminopent-4-yl)-2-(3-nitrophenyl)benzimidazole
Example 158
l-(l-Diethylaminopent-4-yl)-2-(4-methoxyphenyl)-benzimidazole
Example 159
l-(l-Dimethylaminoethyl)-2-phenylbenzimidazole
Example 160
l-( l-Dimethylaminopropyl)-2-benzylbenzimidazole
Example 161
l-(4-chlorophenylmethyl)-2-(4-chlorophenylmethyl)-benzimidazole. mp 89-90°C.
Example 162
l-phenyl-2-(4-chlorophenyl)-6-methoxybenzimidazole. mp 171-172.5°C.
Example 163
l-phenyl-2-(4-chlorophenyl)-5-(l-ethylaminoethyl)-benzimidazole, (Z)-2- butenedioic add salt, mp 228°C.
Example 164
l-phenyl-2-(4-chlorophenyl)-6-chlorobenzimidazole. mp 210-212°C.
Example 165 l-phenyl-2-(4-chlorophenyl)-6-(imidazol-l-yl)benzimidazole. mp 223°C.
Example 166
l-phenyl-2-(4-chlorophenyl)-5-nitrobenzimidazole. mp 194°C.
Example 167
l-phenyl-2-(4-chlorophenyl)-6-hydroxyethylamino-benzimidazole . mp 225°C.
Example 168
l-phenyl-2-(4-chlorophenyl)-5-( l-aminoethyl)benzimidazole, (Z)-2- butenedioic add salt, mp 206°C.
Example 169
l-phenyl-2-(4-chlorophenyl)-6-(N-isopropylcarbonyl-N- butylamino)benzimidazole. bp 213-220°C.
Example 170
l-phenyl-2-(4-chlorophenyl)-5-acetylbenzimidazole. mp 159°C.
Example 171
l-phenyl-2-(4-chlorophenyl)-5-(2-hydroxyethyl)benzimidazole. mp 165°C.
Example 172
l-phenyl-2-(4-chlorophenyl)-6-[2-(piperidin-l-yl)ethoxy]benzimidazole. mp 138-140.
Example 173 l-phenyl-2-(4-chlorophenyl)-6-[3-(N,N-dimethylamino)- propoxy]benzimidazole. mp 126°C.
Example 174
l-phenyl-2-(4-hydroxyphenyl)-6-hydroxybenzimidazole, hydrochloride . mp 212°C.
The other compounds of Formula I may be prepared essentially as described above, employing corresponding starting materials.
The biological efficacy of a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites. Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e.g.. J. Jukic, et al.. Life Sdences.49:1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medidnal Chemistry. 36:1654-1661 (1993); N. Rouissi, s s , Biochemical and Biophysical
Resear h Communications, 176:894-901 (1991).
NK-1 Receptor Binding Assay
Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al.. Journal of Immunology. 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 106 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at
4°C.
The IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London). 251:443-444 (1974); Proceedings of the National Academy of Sdences (USA). 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 μg/ml gentamirin sulfate and 10% fetal calf serum.
The reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Spedfic binding of labeled substance P was determined in the presence of 20 nM uniabeled ligand.
Many of the compounds employed in the methods of the present invention are also effective antagonists of the NK-2 receptor.
NK-2 Receptor Binding Assay
The CHO-hNK-2R cells, a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al.. Journal of Biological Chemistry.265:20455-20462 (1990). For preparation of membranes, 30 confluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of
Dulbecco's phosphate buffered saline (PBS) without calrium and magnesium, followed by addition of 10 ml of enzyme-free cell dissociation solution (PBS-based, from Spedalty Media, Inc.). After an additional 15 minutes, the dissociated cells were pooled and centrifuged at 1,000 RPM for 10 minutes in a clinical centrifuge. Membranes were prepared by homogenization of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA-14® rotor. The pellets were washed once using the above procedure, and the final pellets were resuspended in 100-120 ml 50 mM
Tris buffer, pH 7.4, and 4 ml aliquots stored frozen at -70°C. The protein concentration of this preparation was 2 mg/ml.
For the receptor binding assay, one 4-ml aliquot of the CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 μg/ml chymostatin. A 200 μl volume of the homogenate (40 μg protein) was used per sample. The radioactive ligand was [125I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol. The ligand was prepared in assay buffer at 20 nCi per 100 μl; the final concentration in the assay was 20 pM. Non-sperific binding was determined using 1 μM eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
All samples and standards were added to the incubation in 10 μl dimethylsulfoxide (DMSO) for screening (single dose) or in 5 μl DMSO for IC50 determinations. The order of additions for incubation was 190 or 195 μl assay buffer, 200 μl homogenate, 10 or 5 μl sample in DMSO, 100 μl radioactive ligand. The samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 m polystyrene tubes and counted in a gamma counter.
The compounds of Formula I are useful in treating sleep apnea. The effectiveness of a compound employed in the present invention may be demonstrated using standard techniques. United States Patent 5,422,374, issued June 6, 1995, the entire contents of which are herein incorporated by reference, describes a typical study to examine the effectiveness of a compound in treating sleep apnea.
Sleep Study Example 1
Ten patients of sleep apnea are given a soft capsule containing 10 mg of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl )acetylamino]-2-[N-( 2-(4-(piperidin- 1 -yl )piperi din- 1 - yl)acetyl)amino]propane dihydrochloride trihydrate before bed.
Observation of the patients during sleep reveals no apneic symptoms.
Moreover, no feelings of mailaise in daytime are observed. Sleep Study Example 2
The patients who have been diagnosed with sleep apnea are given soft capsules, each containing 10 mg of (R)-3-(lH-indol-3-yl)-l-[N- (2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin-l-yl)piperidin-l- yl)acetyl)amino]propane dihydrochloride trihydrate at a dose of one capsule after supper for period of days. Clinical symptoms of the patients are observed, and apnea index (times/hour) are also measured before and after administration.
While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
In making the compositions employed in the present invention the active ingredient is usually mixed with an exdpient, diluted by an exdpient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the exdpient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable exdpients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calrium phosphate, alginates, tragacanth, gelatin, calrium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical exdpient.
The active compounds are generally effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physidan, in the light of the relevant drcumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
Formulation Preparation 1
Hard gelatin capsules containing the following ingredients are prepared:
Quantity Ingredient (mg/capsule) Active Ingredient(s) 30.0
Starch 305.0
Magnesium stearate 5.0
The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
Formulation Preparation 2
A tablet formula is prepared using the ingredients below:
Quantity
Ingredient (mg/tablet)
Active Ingredient(s) 25.0
Cellulose, microcrystalline 200.0
Colloidal silicon dioxide 10.0
Stearic add 5.0
The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3
A dry powder inhaler formulation is prepared containing the following components:
Ingredient. Weight %
Active Ingredient(s) 5
Lactose 95
The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Formulation Preparation 4
Tablets, each containing 30 mg of active ingredient, are prepared as follows:
Quantity Ingredient (mg/tahlet)
Active Ingredient(s) 30.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone (as 10% solution in water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1.0 mg
Total 120 mg
The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. - 102 -
Formulation Preparation 5
Capsules, each containing 40 mg of medicament are made as follows:
Quantity
Ingredient (mg/capsule)
Active Ingredient(s) 40.0 mg
Starch 109.0 mg
Magnesium stearate 1.0 mg
Total 150.0 mg
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Preparation 6
Suppositories, each containing 25 mg of active ingredient are made as follows:
Ingredient Amoun
Active Ingredient(s) 25 mg
Saturated fatty add glycerides to 2,000 mg
The active ingredient(s) is passed through a No. 60 mesh
U.S. sieve and suspended in the saturated fatty add glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capadty and allowed to cool. Formulation Preparation 7
Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:
Ingredient Amount
Active Ingredient(s) 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10.0 mg
Flavor and Color q.v.
Purified water to 5.0 ml
The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
Formulation Preparation 8
Capsules, each containing 15 mg of medicament, are made as follows:
Quantity
Ingredient (mg/capsuie)
Active Ingredient(s) 15.0 mg
Starch 407.0 mg
Magnesium stearate 3.0 mg
Total 425.0 mg
The active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9
An intravenous formulation may be prepared as follows:
Ingredient Quantity
Active Ingredient(s) 250.0 mg
Isotonic saline 1000 ml
Formulation Preparation 10
A topical formulation may be prepared as follows:
Ingredient Quantity
Active Ingredient(s) 1-10 g
Emulsifying Wax 30 g
Liquid Paraffin 20 g
White Soft Paraffin to 100 g
The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Formulation Preparation 11
Sublingual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as follows:
Quantity ingredient Per Tablet
Active Ingredient(s) 10.0 mg
Glycerol 210.5 mg
Water 143.0 mg
Sodium Citrate 4.5 mg
Polyvinyl Alcohol 26.5 mg
Polyvinylpyrrolidone 15.5 mg
Total 410.0 mg
The glycerol, water, sodium dtrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C. When the polymers have gone into solution, the solution is cooled to about 50-55°C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
Another preferred 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 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of biological factors to spedfic anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

Claims

We Claim:
1. A method for the treatment or prevention of sleep apnea in a mammal which comprise administering to a mammal in need thereof an effective amount of a compound of the formula
Figure imgf000110_0001
wherein:
R1 is hydrogen, C1-C12 alkyl, Ci-Cβ alkoxy, phenyl, C3-C8 cycloalkyl, naphthyl, heterocyclic, unsaturated heterocyclic, phenyl-(Cι-C6 alkylidenyl)-, naphthyl-(Cι-C6 alkylidenyl)-, heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-C6 alkylidenyl)-, phenyl-(Cι-C6 alkoxy)-, naphthyl-(Cι-Cβ alkoxy)-, heterocydic-(Cι-C6 alkoxy)-, or unsaturated heterocyclic-(Cι-C6 alkoxy)-,
any one of which phenyl, naphthyl, heterocyclic, C3- Cβ cycloalkyl, or unsaturated heterocyclic groups may be optionally substituted with one, two, or three moieties independently selected from group consisting of heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-C6 alkylidenyl)-, hydroxy, halo, Ci-Cβ alkyl, Ci-Cβ alkoxy, trifluoromethyl, nitro, amino, cyano, Ci-Cβ alkylamino, and Ci-Cβ alkylthio;
R2 is hydrogen, C1-C12 alkyl, C1-C6 alkoxy, phenyl, C3-C8 cycloalkyl, naphthyl, heterocyclic, unsaturated heterocyclic, phenyMCi-Cβ alkylidenyl)-, naphthyl-(Cι-C6 alkylidenyl)-, heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-C6 alkylidenyl)-, phenyl-(Cι-C6 alkoxy)-, naphthyl-(Cι-C6 alkoxy)-, heterocyclic-(Cι-C6 alkoxy)-, or unsaturated heterocyclic-(Cι-C6 alkoxy)-,
any one of which phenyl, naphthyl, heterocyclic, C3-
Cβ cycloalkyl, or unsaturated heterocyclic groups may be optionally substituted with one, two, or three moieties independenly selected from group consisting of phenyl-(Cι-C6 alkylidenyl)-, naphthyl-(Cι-C6 alkylidenyl)-, heterocyclic-(Cι-C6 alkylidenyl)-, unsaturated heterocyclic-(Cι-C6 alkylidenyl)-, phenyl- (Ci-Cβ alkoxy)-, naphthyl-(Cι-C6 alkoxy)-, heterocyclic-(Cι-C6 alkoxy)-, or unsaturated heterocyclic-(Cι-C6 alkoxy)-, hydroxy, halo, Ci-Cβ alkyl, Ci-Cβ alkoxy, trifluoromethyl, nitro, amino, cyano, C±-CQ alkylamino, and Ci-Cβ alkylthio;
R3 is hydrogen, nitro, CI-CQ alkanoyl, amino, Ci-Cβ alkyl, Ci-Cβ alkoxy, C3-C8 cycloalkyl, heterocyclic, unsaturated heterocyclic, halo, Ci-Cβ alkylthio, hydroxy-(Cι-C6 alkyhdenyl)-, hydroxy-(Cι-C6 alkylidenyDamino-, R R5N-, R4R5N-(Cι-C6 alkylidenyl)-, R R5N-(Cι-C6 alkoxy)-, hydroxy- (Ci-Cβ alkyl)-, heterocyclic-(Cι-C6 alkoxy)-, amino(Cι-C6 alkylidenyl)-, or trifluoromethyl,
where R4 and R5 are independently selected from the group consisting of Ci-Cβ alkyl, Ci-Cβ alkoxy, Ci-Cβ alkanoyl, aryl, heterocyclic, unsaturated heterocyclic, aryKCi-Cβ alkylidenyl)-, heterocyclic(Cι- Cβ alkylidenyl)-, unsaturated heterocyclic(Cι-C6 alkylidenyl)-, and hydrogen or R4 and R5 combine to form C3-C8 cycloalkyl, any one of which alkyl or alkoxy groups may be substituted with one or more halo, amino, or nitro, and
any one of which aryl, unsaturated heterocyclic, or heterocyclic groups may be substituted with one, two, or three moieties independenly selected from group consisting of hydroxy, halo, Ci-Cβ alkyl, Ci-Cβ alkoxy, trifluoromethyl, nitro, amino, cyano, C3-C8 cycloalkyl, Ci-Cβ alkylamino, and Ci-Cβ alkylthio;
with the proviso that not more than one of R1 and R2 may be hydrogen;
or a pharmaceutically acceptable salt or solvate thereof.
2. A method as claimed in Claim 1 employing employing l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4- morpholinyl)ethoxy]benzimidazole, l-benzyl-2-(3,4,5-trimethoxyphenyl)- 6-[2-( l-piperidinyl)ethoxy]benzimidazole, l-benzyl-2-(3,4,5- trimethoxyphenyl)-6-[2-(l-pyrroldinyl)ethoxylbenzimidazole, l-benzyl-2- (3,4,5-trimethoxyphenyl)-6-[2-( 1- hexamethyleneinιinyl)ethoxy]benzimidazole, l-benzyl-2-(3,4,5- trimethoxyphenyl)-6-[3-(l-piperidinyl)propoxy]benzimidazole, l-benzyl-2- (3,4,5-trimethoxyphenyl)-6-[2-[4-(piperidin-l-yl)piperdin-l- yl]ethoxy]benzimidazole, l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4- methyl-l-piperazinyl)ethoxy]benzimidazole, l-benzyl-2-(3-methylphenyl)- 6-[2-(l-pyrrolidinyl)ethoxy]benzimidazole, l-benzyl-2-(3-methylphenyl)-6- [3-(piperdin-l-yl)propoxy]-benzimidazole, l-benzyl-2-(3-methylphenyl)-6- [3-(morpholin-4-yl)propoxy)benzimidazole, l-benzyl-2-(3-methylphenyl)- 6-[3-(pyrrolidin-l-yl)propoxy)benzimidazole, l-benzyl-2-(3-methylphenyl)- 6-[3-(hexamethyleneimin-l-yl)propoxy)benzimidazole, l-benzyl-2-(3- methylphenyl )-6- [3 -(heptamethyleneimin- 1-yl )propoxy )benzimidazole , 1 - benzyl-2-(3-methylphenyl)-6-[2-(4-methyl-piperazin-l- yl)ethoxy]benzimidazole, l-(2-trifluoromethylbenzyl)-2-(3,4,5- trimethoxyphenyl)-6-[2-(piperidin- l-yl)ethoxy]benzimidazole, l-(2- trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(piperidin-l- yl)propoxy]benzimidazole, l-(2-trifluoromethylbenzyl)-2-(3,4,5- trimethoxyphenyl)-6-[2-(hexamethyleneimin-l-yl)ethoxy]benzimidazole, l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(pyrrolidin-l- yl)ethoxy]benzimidazole, l-(2-trifluoromethylbenzyl)-2-(3,4,5- trimethoxyphenyl)-6-[2-(morpholin-4-yl)ethoxy]benzimidazole, l-(2- bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(piperidin-l- yl)ethoxy]benzimidazole, l-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)- 6-[2-(piperidinyl-l-yl)ethoxy]benzimidazole, l-(2-bromobenzyl)-2-(3- methylphenyl)-6-[2-(piperidinyl- l-yl)ethoxy]benzimidazole, l-(2- trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(piperidin-l- yl)ethoxy]benzimidazole, l-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2- (piperidin-l-yl)ethoxy]benzimidazole, or l-(2-bromobenzyl)-2-(3,5- dimethylphenyl)-6-[2-(piperidin-l-yl)ethoxy]benzimidazole, or a pharmaceutically acceptable salt or solvate thereof.
3. A method as claimed in Claim 1 employing employing l-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[ l-methyl-2-(N,N- dimethylamino)]ethoxy]benzimidazole, l-benzyl-2-(3,4,5- trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole, 1- benzyl-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole, l-benzyl-2-(3,4,5- trimethoxyphenyl)-6-[2-(N,N-d isopropylamino)ethoxy]benzimidazole, 1- benzyl-2-(3-methylphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole, l-benzyl-2-(3-methylphenyl)-6-[2- (N,N-diethylamino)ethoxy]-benzimidazole, l-benzyl-2-(3-methylphenyl)-
6-[3-(N,N-dimethylamino)propoxy]benzimidazole, l-benzyl-2-(3- methylphenyl)-6-[2-(N,N-isopropylamino)ethoxy]benzimidazole, 1- benzyl-2-(3-methylphenyl)-6-[2-(N,N- dibenzylamino)ethoxy]benzimidazole, l-benzyl-2-(3-methylphenyl)-6-[3- (N,N-dimethylamino)propoxy]benzimidazole , 1-benzyl- 2-(3- methylphenyl)-6-[2-(N,N-dimethylamino)propoxy]-benzimidazole, l-(2- trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- dimethylamino)propoxy]-benzimidazole, l-(2-trifluoromethylbenzyl)-2- (3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]- benzimidazole, l-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6- [3-(N,N-dimethylamino)propoxy]-benzimidazole, l-(2- trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]-benzimidazole, l-(2-bromobenzyl)-2-(3,4,5- trimethoxyphenyl)-6-[2-(N,N-dimethylamino)propoxy]benzimidazole, 1- (2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- dimethylamino)ethoxy]benzimidazole, l-(2-bromobenzyl)-2-(3,4,5- trimethoxyphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole, 1- (2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]benzimidazole, l-(2-trifluoromethylbenzyl)-2-(3- methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole, l-(2- trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole, l-(2-bromobenzyl)-2-(3- methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole, l-(2- bromobenzyl)-2-(3-methylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole, l-(2-trifluoromethylbenzyl)-2- (3,4-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole, 1- (2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- diisopropylamino)ethoxy]benzimidazole, l-(2-bromobenzyl)-2-(3,4- dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole, l-(2- bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N- dϋsopropylamino)ethoxy]benzimidazole, l-(2-bromobenzyl )-2-(3 ,4- dimethylphenyl)-6-[l-methyl-2-(N,N- dimethylamino)ethoxy]benzimidazole, l-(2-bromobenzyl)-2-(3,5- dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole, l-(2- bromobenzyl)-2-(3,5-dimethylphenyl)-6-[l-methyl-2-(N,N- dimethylamino )ethoxy]benzimidazole , l-(2-bromobenzyl )-2-(3 ,5- dimethylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole, or 1- (2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[3-(N,N- dimethylamino)propoxy]benzimidazole, or a pharmaceutically acceptable salt or solvate thereof.
4. A compound as described in any one of Claims 1 to 3, for use in treating or preventing sleep apnea.
5. A pharmaceutical formulation containing, as an active ingredient, a compound as described in any one of Claims 1 to 3, adapted for use in the treatment or prevention of sleep apnea.
6. The use of a compound as described in any one of
Claims 1 to 3, for the manufacture of a medicament for the treatment or prevention of sleep apnea.
PCT/US1997/003113 1996-03-01 1997-02-26 Methods of treating or preventing sleep apnea WO1997031635A1 (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050398A2 (en) * 1999-02-24 2000-08-31 F. Hoffmann-La Roche Ag Phenyl- and pyridinyl derivatives as neurokinin 1 antagonists
WO2002059088A1 (en) * 2001-01-23 2002-08-01 Wyeth 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US7094790B2 (en) 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US7271180B2 (en) 2001-01-23 2007-09-18 Wyeth 1-Aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US7547804B2 (en) 2002-07-15 2009-06-16 Myriad Genetics, Inc. Compounds, compositions, and methods employing same
WO2012130905A1 (en) 2011-03-31 2012-10-04 Bayer Pharma Aktiengesellschaft Substituted benzimidazoles
US8435988B2 (en) 2010-10-06 2013-05-07 Glaxosmithkline Llc Benzimidazole derivatives as P13 kinase inhibitors
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5356934A (en) * 1990-03-29 1994-10-18 Eli Lilly And Company Selected serotonin subtype receptor agonist to treat sleep apnea

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5356934A (en) * 1990-03-29 1994-10-18 Eli Lilly And Company Selected serotonin subtype receptor agonist to treat sleep apnea

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US6407111B1 (en) 1999-02-24 2002-06-18 Hoffmann-La Roche Inc. Phenyl substituted pyridine and benzene derivatives
US6596773B2 (en) 1999-02-24 2003-07-22 Hoffmann-La Roche Inc. Phenyl substituted pyridine and benzene derivatives
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