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Patent Issued for Isoxazoles / O-Pyridines with Ethyl and Ethenyl Linker

The patent's inventors are Buettelmann, Bernd (Schopfheim, DE); Lucas, Matthew C. (Verona, NJ); Thomas, Andrew (Binningen, CH).

This patent was filed on February 17, 2010 and was cleared and issued on March 5, 2013.

From the background information supplied by the inventors, news correspondents obtained the following quote: "Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA A receptors, which are members of the ligand-gated ion channel superfamily and (2) GABA B receptors, which are members of the G-protein linked receptor family. The GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of .alpha., .beta. and .gamma. subunits.

"Presently a total number of 21 subunits of the GABA A receptor have been cloned and sequenced. Three types of subunits (.alpha., .beta. and .gamma.) are required for the construction of recombinant GABA A receptors which most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA A receptors obtained from mammalian brain cells. There is strong evidence that the benzodiazepine binding site lies between the .alpha. and .gamma. subunits. Among the recombinant GABA A receptors, .alpha.1.beta.2.gamma.2 mimics many effects of the classical type-I BzR subtypes, whereas .alpha.2.beta.2.gamma.2, .alpha.3.beta.2.gamma.2 and .alpha.5.beta.2.gamma.2 ion channels are termed type-II BzR.

"It has been shown by McNamara and Skelton in Psychobiology, 1993, 21:101-108 that the benzodiazepine receptor inverse agonist .beta.-CCM enhance spatial learning in the Morris watermaze. However, .beta.-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans. In addition, these compounds are non-selective within the GABA A receptor subunits, whereas a GABA A .alpha.5 receptor partial or full inverse agonist which is relatively free of activity at GABA A .alpha.1 and/or .alpha.2 and/or .alpha.3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity. It is also possible to use GABA A .alpha.5 inverse agonists which are not free of activity at GABA A .alpha.1 and/or .alpha.2 and/or .alpha.3 receptor binding sites but which are functionally selective for .alpha.5 containing subunits. However, inverse agonists which are selective for GABA A .alpha.5 subunits and are relatively free of activity at GABA A .alpha.1, .alpha.2 and .alpha.3 receptor binding sites are preferred.

"Literature has been published to establish the link between GABA A .alpha.5 subunits and the treatment of various diseases of the Central Nervous System, like Neuroscience Letts., 2005, 381, 108-13, Neuropsychobiology, 2001, 43(3), 141-44, Amer. J. Med. Genetics, 2004, 131B, 51-9, Autism 2007, 11(2): 135-47, Investigacion Clinica, 2007, 48, 529-41, Nature Neuroscience, 2007, 10, 411-13, Neuroscience Letts., 2008, 433, 22-7 and Cell 2008, 135, 549-60."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "The present invention provides isoxazole-pyridines having affinity and selectivity for GABA A .alpha.5 receptor, their manufacture, pharmaceutical compositions containing them and their use as pharmaceuticals.

"In particular, the present invention provides isoxazole-pyridines of formula I

"##STR00002## wherein L is --CH.sub.2--CH.sub.2-- or --CH.dbd.CH--; R.sup.1 is lower-alkyl or aryl, wherein lower-alkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro, cyano, hydroxy, lower-alkoxy and fluoro-lower-alkoxy, and wherein aryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, hydroxy, lower-alkyl, fluoro-lower-alkyl, cyano-lower-alkyl, hydroxy-lower-alkyl, lower-alkyl-C(O)OH, lower-alkyl-C(O)O-lower-alkyl, lower-alkyl-CO--NH.sub.2, lower-alkyl-CO--N(H, lower-alkyl), lower-alkyl-CO--N(lower-alkyl).sub.2, lower-alkyl-N(H, lower-alkyl), lower-alkyl-N(lower-alkyl).sub.2, lower-alkoxy-lower-alkyl, CO-lower-alkyl, COOH, COO-lower-alkyl, CONH.sub.2, CON(H, lower-alkyl), CON(lower-alkyl).sub.2, NH.sub.2, N(H, lower-alkyl), N(lower-alkyl).sub.2, lower-alkoxy, fluoro-lower-alkoxy, SO.sub.2-lower-alkyl, SO.sub.2--NH.sub.2, SO.sub.2--N(H, lower-alkyl), SO.sub.2--N(lower-alkyl).sub.2, cycloalkyl, phenyloxy and phenyl; R.sup.2 is lower-alkyl optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro, cyano, hydroxy, lower-alkoxy and fluoro-lower-alkoxy; R.sup.3 is --O--R.sup.4 or N(R.sup.5,R.sup.6); R.sup.4 is hydrogen or lower-alkyl; R.sup.5 is hydrogen or lower-alkyl; and R.sup.6 is lower-alkyl, hydroxy-lower-alkyl or heterocyclyl, or wherein R.sup.5 and R.sup.6 are bound together and with the Nitrogen atom to which they are attached form a heterocyclyl; or a pharmaceutically acceptable salt or ester thereof.

"The compounds of present invention are preferably inverse agonists of GABA A .alpha.5.

"The present invention provides compounds of formula I per se and their pharmaceutically acceptable salts and esters, pharmaceutical compositions containing them, the preparation of the above-mentioned compounds and compositions, and the use of the above-mentioned compounds in the treatment or prevention of diseases related to the GABA A .alpha.5 receptor.

"The compounds of present invention and their pharmaceutically acceptable salts and esters can be used, alone or in combination with other drugs, as cognitive enhancers or for the treatment or prevention of acute and/or chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive/compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder, neuropathic pain, stroke and attentional disorders."

For the URL and additional information on this patent, see: Buettelmann, Bernd; Lucas, Matthew C.; Thomas, Andrew. Isoxazoles / O-Pyridines with Ethyl and Ethenyl Linker. U.S. Patent Number 8389550, filed February 17, 2010, and issued March 5, 2013. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&p=78&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=3895&f=G&l=50&co1=AND&d=PTXT&s1=20130305.PD.&OS=ISD/20130305&RS=ISD/20130305

Keywords for this news article include: Pharmaceutical Companies, Neuroscience, Hoffmann-La Roche Inc., F. Hoffmann-LaRoche Ltd..

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