- A facile and scaleable synthesis of ABT-239, a benzofuranoid H3 antagonist
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A facile and scaleable synthesis of a potent and selective histamine H 3 receptor antagonist, ABT-239 (1), was developed starting from commercially available 4′-hydroxy-biphenyl-4-carbonitrile (2). The synthesis comprised four chemical steps and a salt formation step with an overall yield of 40%. A highly selective monoiodination of a phenol was developed and used to prepare iodophenol (3b) in near quantitative yield using NIS in AcOH in the presence of a small amount of H2SO4. A Pd-catalyzed cross coupling reaction of the iodophenols (3b) with butyn-3-ol (4a) provided benzofuran (5) in one step in >80% yield, en route to 1. The new process required no chromatographic purification throughout the synthesis and was successfully demonstrated on scale-up to prepare 1.7 kg of the target ABT-239 (1).
- Pu, Yu-Ming,Grieme, Timothy,Gupta, Ashok,Plata, Daniel,Bhatia, Ashok V.,Cowart, Marlon,Ku, Yi-Yin
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- An efficient and convergent synthesis of the potent and selective H3 antagonist ABT-239
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An efficient and convergent process for the preparation of a potent and selective H3 receptor antagonist, ABT-239, 1A was accomplished with an overall yield of 64%. The key step in the synthesis is a Sonogashira coupling/cyclization reaction of 1-but-3-ynyl-2-(R)-methylpyrrolidine (9) with 4′-hydroxy-3′-iodo-biphenyl-4-carbonitrile (3). Additionally, the key amine component 2-(R)-methylpyrrolidine (7) was effectively synthesized from the readily available Boc-l-prolinol with a simple catalytical hydrogenolysis as the key step. This column chromatography-free process is highlighted by several simple work-up and purification procedures and is amendable to the large-scale preparation of 1A.
- Ku, Yi-Yin,Pu, Yu-Ming,Grieme, Tim,Sharma, Padam,Bhatia, Ashok V.,Cowart, Marlon
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p. 4584 - 4589
(2007/10/03)
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- 4-(2-[2-(2(R)-Methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention
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H3 receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H 3 receptors, with Ki values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in particular, 4-(2-[2-(2(R)- methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H3 receptor antagonism and excellent pharmacokinetic and metabolic properties across species, with full efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg. Furthermore, this compound did not stimulate locomotor activity and showed high selectivity for the induction of behavioral efficacy versus central nervous system based side effects. The potency and selectivity of this compound and of analogues from this class support the potential of H3 receptor antagonists for the treatment of cognitive dysfunction.
- Cowart, Marlon,Faghih, Ramin,Curtis, Michael P.,Gfesser, Gregory A.,Bennani, Youssef L.,Black, Lawrence A.,Pan, Liping,Marsh, Kennan C.,Sullivan, James P.,Esbenshade, Timothy A.,Fox, Gerard B.,Hancock, Arthur A.
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- PROCESS FOR PREPARING AMINE-SUBSTITUTED BENZOFURANS
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The present invention relates to processes for preparing amine substituted benzofurans, and more particularly 4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile, and salts thereof. Compounds prepared by the processes of the invention have demonstrated activity as histamine-3 receptor ligands.
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- A new class of potent non-imidazole H3 antagonists: 2-Aminoethylbenzofurans
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2-Aminoethylbenzofurans constitute a new class of H3 antagonists that are more rotationally constrained than most previously reported H3 antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.
- Cowart, Marlon,Pratt, John K.,Stewart, Andrew O.,Bennani, Youssef L.,Esbenshade, Timothy A.,Hancock, Arthur A.
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p. 689 - 693
(2007/10/03)
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- Histamine-3 receptor ligands for diabetic conditions
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The invention relates to a method of treating a diabetic condition by administering a therapeutically effective amount of a histamine-3 receptor antagonist, including benzofuran and benzopyran derivatives of formula (I), aminoalkoxybiphenylcarboxamide compounds of formula (III), and aminoetherbiphenyl compounds of formula (IV) as described herein.
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- Histamine-3 receptor ligands for diabetes conditions
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The invention relates to a method of treating a diabetic condition by administering a therapeutically effective amount of a histamine-3 receptor antagonist, including benzofuran and benzopyran derivatives of formula (I), aminoalkoxybiphenylcarboxamide compounds of formula (III), and aminoetherbiphenyl compounds of formula (IV) as described herein.
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- Novel amines as histamine-3 receptor ligands and their therapeutic applications
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Compounds of formula (I) or a pharmaceutically acceptable salts or prodrug thereof which are useful for the modulation of the histamine-3 receptors in mammals and which are useful for the treatment of disorders ameliorated by histamine-3 receptor ligands.
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- Novel amines as histamine-3 receptor ligands and their therapeutic applications
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Compounds of formula (I) or a pharmaceutically acceptable salts or prodrug thereof which are useful for the modulation of the histamine-3 receptors in mammals and which are useful for the treatment of disorders ameliorated by histamine-3 receptor ligands.
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