- MACROCYCLIC ANTAGONISTS OF THE MOTILIN RECEPTOR FOR TREATMENT OF GASTROINTESTINAL DYSMOTILITY DISORDERS
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The present invention provides conformationally-defined macrocyclic compounds that bind to and/or are functional modulators of the motilin receptor including subtypes, isoforms and/or variants thereof. These macrocyclic compounds, at a minimum, possess adequate pharmacological properties to be useful as therapeutics for a range of disease indications. In particular, these compounds are useful for treatment and prevention of disorders characterized by hypermotilinemia and/or gastrointestinal hypermotility, including, but not limited to, diarrhea, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease, other types of diarrhea, dyspepsia, irritable bowel syndrome, chemotherapy-induced nausea and vomiting (emesis) and post-operative nausea and vomiting and functional gastrointestinal disorders. In addition, the compounds possess utility for the treatment of diseases and disorders characterized by poor stomach or intestinal absorption, such as short bowel syndrome, celiac disease and cachexia. The compounds also have use for the treatment of inflammatory diseases and disorders of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease and pancreatitis. Accordingly, methods of treating such disorders and pharmaceutical compositions including compounds of the present invention are also provided.
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Page/Page column 57
(2010/04/30)
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- A spectroscopic study of the reduction of geometrically restrained viologens
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A small series of N,N′-dimethyl-4,4′-bipyridinium dication derivatives (commonly known as viologens) has been synthesized and fully characterized; a short dialkoxy tether attached at the 3,3′-positions is used to alter the central dihedral angle. These angles were determined by both single-crystal X-ray diffraction and by computational studies made for the dication, radical cation, and neutral species in a solvent reservoir. The dihedral angle derived for the dication controls the first reduction potential, whereas the geometry of the resultant π-radical cation determines the magnitude of the second reduction potential. The optical absorption spectra recorded for the various species, and especially those of the radical cations, and the EPR spectral parameters of the π-radical cations also depend on the molecular geometry. In particular, the central dihedral angle influences the spin density distribution around the aromatic nucleus and, by way of comparison to the parent viologen, it has been possible to resolve the angle dependence from the inherent inductive effect of the strap. These results are considered in terms of the degree of electronic communication between the two aromatic rings, as controlled by the length of the tether.
- Benniston, Andrew C.,Harriman, Anthony,Li, Peiyi,Rostron, James P.,Harrington, Ross W.,Clegg, William
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p. 7838 - 7851
(2008/04/01)
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- New approaches to bicylic vinyl heterocycles from propargylic acetals
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(Chemical Equation Presented) The paper describes further studies on the intramolecular carbolithiation of propargylic acetals with aryllithiums leading to 2-vinylbenzofurans and 3-vinylfuropyridines. Attempts to extend the cascade to [4.4.0] binuclear he
- Le Strat, Frederic,Harrowven, David C.,Maddaluno, Jacques
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p. 489 - 498
(2007/10/03)
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- Fused pyridine derivatives
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The present provides a condensed pyridine compound (I) represented by the following formula: (wherein, R2represents ring A represents benzene ring, pyridine ring, thiophene ring or furan ring; and B represents its pharmaceutically acceptable salt or hydrates thereof, which is a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating or preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
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- Synthesis of two conformationally constrained analogues of the minor tobacco alkaloid anabasine.
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The anabasine analogues spiro[4-azaindan-1,2'-piperidine] (7) and spiro[6-azaindan-1,2'-piperidine] (8) have been prepared. A series of palladium-catalyzed reactions, where an intramolecular cyclization constituted a key reaction, were utilized for the pr
- Lindstroem,Ripa,Hallberg
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p. 2291 - 2293
(2007/10/03)
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- Furopyridine, thienopyridine pyrrolopyridine useful in controlling chemical synaptic transmission
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Novel heterocyclic ether compounds having the formula: STR1 wherein A, m, R, X, Y1, Y2 and Y3 are specifically defined, which are useful in selectively controlling chemical synaptic transmission; therapeutically-effective pharmaceutical compositions thereof; and use of said compositions to selectively control synaptic transmission in mammals.
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