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Patent Issued for Process for the Preparation of Protected L-Alanine Derivatives

May 12, 2014



By a News Reporter-Staff News Editor at Gastroenterology Week -- From Alexandria, Virginia, NewsRx journalists report that a patent by the inventors Anzalone, Luigi (West Chester, PA); Feibush, Penina (Ambler, PA); Villani, Frank J. (Perkasie, PA), filed on October 27, 2009, was published online on April 29, 2014 (see also Janssen Pharmaceutica, N.V.).

The patent's assignee for patent number 8710256 is Janssen Pharmaceutica, N.V. (Beerse, BE).

News editors obtained the following quote from the background information supplied by the inventors: "The opioid receptors were identified in the mid-1970's, and were quickly categorized into three sub-sets of receptors (mu, delta and kappa). More recently the original three types of receptors have been further divided into sub-types. Also known is that the family of opioid receptors are members of the G-protein coupled receptor (GPCR) super-family. More physiologically pertinent are the well established facts that opioid receptors are found throughout the central and peripheral nervous system of many mammalian species, including humans, and that modulation of the respective receptors can elicit numerous, albeit different, biological effects, both desirable and undesirable (D. S. Fries, 'Analgesics', in Principles of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269; J. V. Aldrich, 'Analgesics', Burger's Medicinal Chemistry and Drug Discovery, 5.sup.th Edition, Volume 3: Therapeutic Agents, John Wiley & Sons, Inc., 1996, pp. 321-441). In the most current literature, the likelihood of heterodimerization of the sub-classes of opioid receptors has been reported, with respective physiological responses yet undetermined (Pierre J. M. Riviere and Jean-Louis Junien, 'Opioid receptors: Targets for new gastrointestinal drug development', Drug Development 2000, pp. 203-238).

"Biological effects identified for opioid modulators have led to many useful medicinal agents. Most significant are the many centrally acting mu opioid agonist modulators marketed as analgesic agents to attenuate pain (e.g., morphine), as well as peripherally acting mu agonists to regulate motility (e.g., loperamide). Currently, clinical studies are continuing to evaluate medicinal utility of selective delta, mu, and kappa modulators, as well as compounds possessing combined sub-type modulation. It is envisioned such explorations may lead to agents with new utilities, or agents with minimized adverse side effects relative to currently available agents (examples of side effects for morphine includes constipation, respiratory depression, and addiction potential). Some new GI areas where selective or mixed opioid modulators are currently being evaluated includes potential treatment for various diarrheic syndromes, motility disorders (post-operative ileus, constipation), and visceral pain (post operative pain, irritable bowel syndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere and Jean-Louis Junien, 'Opioid receptors: Targets for new gastrointestinal drug development' Drug Development, 2000, pp. 203-238).

"Around the same time the opioid receptors were identified, the enkephalins were identified as a set of endogenous opioid ligands (D. S. Fries, 'Analgesics', in Principles of Medicinal Chemistry, 4th ed.; W. O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncating the original pentapeptide enkephalins to simplified dipeptides yielded a series of compounds that maintained opioid activity (Schiller, P. WO 96/06855). However one potential drawback cited for such compounds is the likelihood of their inherent instability (P. W. Schiller et al., Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

"More recently, a series of opioid pseudopeptides containing heteroaromatic or heteroaliphatic nuclei were disclosed, however this series is reported showing a different functional profile than that described in the Schiller works. (L. H. Lazarus et al., Peptides 2000, 21, pp. 1663-1671)

"Additionally, works around morphine related structures were reported by Wentland, et al, where carboxamido morphine derivatives and it's analogs were prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 623-626). Wentland found that substitution for the phenol moiety of the morphine related structures with a primary carboxamide led anywhere from equal activities up to 40 fold reduced activities, depending on the opioid receptor and the carboxamide. It was also revealed that any additional N-substitutions on the carboxamide significantly diminished the desired binding activity.

"Opioid receptor modulators, agonists or antagonists are useful in the treatment and prevention of various mammalian disease states, for example pain and gastrointestinal disorders, such as, diarrheic syndromes, motility disorders, including post-operative ileus and constipation, and visceral pain, including post-operative pain, irritable bowel syndrome, and inflammatory bowel disorders.

"Breslin, H. J., et al., in U.S. Patent Publication 2005/0203143 A1, published Sep. 15, 2005, which is herein expressly incorporated by reference in its entirety, disclose opioid receptor modulators, pharmaceutical compositions including such modulators, and methods of treatment using such modulators. The present invention is directed to processes for the preparation of intermediates useful in the synthesis of the opioid receptor modulators as described in U.S. Patent Publication 2005/0203143 A1."

As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "The present invention is directed to a process for the preparation of compounds of formula (I)

"##STR00001##

"wherein

"PG.sup.1 is a nitrogen protecting group;

"R.sup.0 is selected from the group consisting of hydrogen, C.sub.1-4alkyl and benzyl;

"R.sup.6 is selected from the group consisting of hydrogen and C.sub.1-6alkyl;

"R.sup.4 is aryl or heteroaryl; wherein the aryl or heteroaryl is optionally substituted with one to five substituents independently selected from the group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, arylC.sub.1-6alkoxy, arylC.sub.1-6alkylcarbonyloxy, heteroarylC.sub.1-6alkylcarbonyloxy, heteroaryl, hydroxy, halogen, aminosulfonyl, formylamino, aminocarbonyl, C.sub.1-6alkylaminocarbonyl, di(C.sub.1-6alkyl)aminocarbonyl, heterocyclylcarbonyl, carboxy, and cyano; wherein the C.sub.1-6alkyl is optionally substituted with amino, C.sub.1-6alkylamino, or (C.sub.1-6alkyl).sub.2amino; and wherein the aryl portion of arylC.sub.1-6alkylcarbonyloxy is optionally substituted with one to four substituents independently selected from the group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, cyano, amino and hydroxy;

"and pharmaceutically acceptable enantiomers, pharmaceutically acceptable diastereomers, pharmaceutically acceptable racemates and pharmaceutically acceptable salts thereof; comprising, consisting of and/or consisting essentially of

"##STR00002##

"reacting a compound of formula (X), wherein PG.sup.1 is a nitrogen protecting group, with zinc; in the presence of a source of iodine; in a first organic solvent or a mixture of organic solvents, wherein the first organic solvent is non-reactive to the source iodine; to yield the corresponding compound of formula (XI);

"##STR00003##

"reacting the compound of formula (XI) with a compound of formula (XII), wherein LG.sup.1 is a leaving group; in the presence of a palladium catalyst and phosphine ligand system; in a second organic solvent or a mixture of organic solvents; to yield the corresponding compound of formula (I).

"The present invention is further directed to a process for the preparation of a compound of formula (I-B)

"##STR00004##

"comprising, consisting of and/or consisting essentially of

"##STR00005##

"reacting a compound of formula (X-B) with zinc; in the presence of a source of iodine; in a first organic solvent or mixture a mixture of organic solvents, wherein the first organic solvent is non-reactive to the source iodine; to yield the corresponding compound of formula (XI-B);

"##STR00006##

"reacting the compound of formula (XI-B) with a compound of formula (XII-B); in the presence of a palladium catalyst and phosphine ligand system; in a second organic solvent or a mixture of organic solvents; to yield the corresponding compound of formula (I-B).

"The present invention is further directed to a process for the preparation of a compound of formula (II-B)

"##STR00007##

"or a pharmaceutically acceptable salt thereof; comprising, consisting of and/or consisting essentially of

"##STR00008##

"reacting a compound of formula (I-B) with an oxidizing agent; in the presence of an inorganic base; in a third organic solvent; to yield the corresponding compound of formula (II-B).

"The present invention is further directed to a product prepared according to any of the processes described herein. Preferably, the compounds prepared according to the processes of the present invention are substantially pure."

For additional information on this patent, see: Anzalone, Luigi; Feibush, Penina; Villani, Frank J.. Process for the Preparation of Protected L-Alanine Derivatives. U.S. Patent Number 8710256, filed October 27, 2009, and published online on April 29, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=80&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=3960&f=G&l=50&co1=AND&d=PTXT&s1=20140429.PD.&OS=ISD/20140429&RS=ISD/20140429

Keywords for this news article include: Iodine, Alanine, Halogens, Chemicals, Neurology, Analgesics, Amino Acids, Therapeutics, mu Receptors, Pain Medicine, delta Receptors, kappa Receptors, Gastroenterology, Opioid Receptors, Membrane Proteins, Medicinal Chemistry, Neuropeptide Receptors, Janssen Pharmaceutica N.V., G-Protein-Coupled Receptors.

Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC


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Source: Gastroenterology Week


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