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WO1997031635A1 - Procedes de traitement ou de prevention de l'apnee du sommeil - Google Patents

Procedes de traitement ou de prevention de l'apnee du sommeil 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
English (en)
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/fr

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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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédés de traitement ou de prévention de l'apnée du sommeil chez un mammifère, consistant à lui administrer une quantité efficac d'un benzimidazole substitué ou un sel ou un solvate de celui-ci acceptable du point de vue pharmaceutique.
PCT/US1997/003113 1996-03-01 1997-02-26 Procedes de traitement ou de prevention de l'apnee du sommeil WO1997031635A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/142,026 US6030992A (en) 1997-02-26 1997-02-26 Methods of treating or preventing sleep apnea
AU21390/97A AU2139097A (en) 1996-03-01 1997-02-26 Methods of treating or preventing sleep apnea

Applications Claiming Priority (2)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050398A2 (fr) * 1999-02-24 2000-08-31 F. Hoffmann-La Roche Ag Derives de pyridinyl et de phenyle
WO2002059088A1 (fr) * 2001-01-23 2002-08-01 Wyeth Derives de 1-aryl-ou 1-alkylsulfonylbenzazole utilises en tant que ligands de 5-hydroxytryptamine-6
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 (fr) 2011-03-31 2012-10-04 Bayer Pharma Aktiengesellschaft Benzimidazoles substitués
US8435988B2 (en) 2010-10-06 2013-05-07 Glaxosmithkline Llc Benzimidazole derivatives as P13 kinase inhibitors
US8703760B2 (en) 2009-12-18 2014-04-22 Mitsubishi Tanabe Pharma Corporation Antiplatelet agent
US11891382B2 (en) 2017-04-26 2024-02-06 Basilea Pharmaceutica International AG Processes for the preparation of furazanobenzimidazoles and crystalline forms thereof

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

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050398A3 (fr) * 1999-02-24 2001-04-05 Hoffmann La Roche Derives de pyridinyl et de phenyle
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
WO2000050398A2 (fr) * 1999-02-24 2000-08-31 F. Hoffmann-La Roche Ag Derives de pyridinyl et de phenyle
US7541358B2 (en) 2001-01-23 2009-06-02 Wyeth 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
WO2002059088A1 (fr) * 2001-01-23 2002-08-01 Wyeth Derives de 1-aryl-ou 1-alkylsulfonylbenzazole utilises en tant que ligands de 5-hydroxytryptamine-6
US6509357B1 (en) 2001-01-23 2003-01-21 Wyeth 1-aryl or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US6710069B2 (en) 2001-01-23 2004-03-23 Wyeth 1-aryl- or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
US6919354B2 (en) 2001-01-23 2005-07-19 Wyeth 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
AU2002251811B2 (en) * 2001-01-23 2007-06-21 Wyeth 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 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
US7807697B2 (en) 2003-05-07 2010-10-05 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US7358263B2 (en) 2003-05-07 2008-04-15 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US7094790B2 (en) 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US8106088B2 (en) 2003-05-07 2012-01-31 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US9533983B2 (en) 2009-12-18 2017-01-03 Mitsubishi Tanabe Pharma Corporation Antiplatelet agent
US8703760B2 (en) 2009-12-18 2014-04-22 Mitsubishi Tanabe Pharma Corporation Antiplatelet agent
KR20140072220A (ko) 2009-12-18 2014-06-12 미쓰비시 타나베 파마 코퍼레이션 신규 항혈소판약
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8674090B2 (en) 2010-10-06 2014-03-18 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8541411B2 (en) 2010-10-06 2013-09-24 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8435988B2 (en) 2010-10-06 2013-05-07 Glaxosmithkline Llc Benzimidazole derivatives as P13 kinase inhibitors
US9156797B2 (en) 2010-10-06 2015-10-13 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9872860B2 (en) 2010-10-06 2018-01-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10314845B2 (en) 2010-10-06 2019-06-11 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10660898B2 (en) 2010-10-06 2020-05-26 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
WO2012130905A1 (fr) 2011-03-31 2012-10-04 Bayer Pharma Aktiengesellschaft Benzimidazoles substitués
US11891382B2 (en) 2017-04-26 2024-02-06 Basilea Pharmaceutica International AG Processes for the preparation of furazanobenzimidazoles and crystalline forms thereof

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