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Talaglumetad hydrochloride

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Chemical structure for Talaglumetad hydrochloride (USAN)

Talaglumetad hydrochloride
Formula
C11H16N2O5. HCl
Exact mass
292.0826
Mol weight
292.7161
CAS: 441765-97-5
441765-98-6 (free base)
IUPAC Name: (1R,4S,5S,6S)-4-[[(2S)-2-aminopropanoyl]amino]bicyclo[3.1.0]hexane-4,6-dicarboxylic acid hydrochloride
Synonyms: Talaglumetad HCl, Talaglumetad hydrochloride, LY 544344 hydrochloride,
UNII-X30300EU7I,  D09008, 441765-97-5,
Bicyclo(310)hexane-2,6-dicarboxylic acid, 2-(((2S)-2-amino-1-oxopropyl)amino)-, monohydrochloride, (1S,2S,5R,6S)-
(1S,2S,5R,6S)-2-(L-Alanylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride
(1S,2S,5R,6S)-2-[2(S)-Aminopropionamido]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride

Treatment of anxiety and stress disorders [metabotropic glutamate [mGlu] agonist]

Talaglumetad hydrochloride, a prodrug of the type II metabotropic glutamate receptor agonist eglumetad, reached phase III clinical studies for the treatment of anxiety at Lilly.

Compound Structure

  • In recent years, with the repeated cloning of glutamate receptor genes, it has become clear that there are surprisingly many subtypes of glutamate receptors. At present, glutamate receptors are broadly classified into two types: the “ionotropic type”, in which the receptor has an ion channel structure, and the “metabotropic type”, in which the receptor is coupled to G-proteins (Science, 258, 597-603, 1992). Ionotropic receptors are classified pharmacologically into three types: N-methyl-D-asparaginic acid (NMDA), α-amino-3-hydroxy-5-methyl isoxazole-4-propionate AMPA), and kynate (Science, 258, 597-603, 1992). Metabotropic receptors are classified into eight types, type 1 through type 8 (J. Neurosci., 13, 1372-1378, 1993; Neuropharmacol., 34, 1-26, 1995).
  • The metabotropic glutamate receptors are classified pharmacologically into three groups. Of these, group 2 (mGluR2/mGluR3) bind with adenylcyclase, and inhibit the accumulation of the Forskolin stimulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmacol. Sci., 14, 13 (1993)), which suggests that compounds that act on group 2 metabotropic glutamate receptors should be useful for the treatment or prevention of acute and chronic psychiatric and neurological disorders. As a substance that acts on group 2 metabotropic glutamate receptors, (+)-(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid has been disclosed in Japanese Unexamined Patent Publication, No. Hei 8-188561 [1996].
  • Fluorine atoms tend to be strongly electron-attractive and to confer high fat solubility, and compounds into which fluorine atoms are introduced greatly change their physical properties. Thus introducing fluorine atoms might greatly affect the absorbability, metabolic stability, and pharmacological effects of a compound. But it is by no means easy to introduce fluorine atoms. In fact, Japanese Unexamined Patent Publication No. Hei 8-188561 [1996] does not even discuss the introduction of fluorine atoms into (+)-(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

 

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Process development of (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2′,5′-dioxo-2,4′-imidazolidine]-6-carboxylic acid, (R)-alpha-methylbenzenemethanamine salt (LSN344309)
Org Process Res Dev 2006, 10(1): 28

http://pubs.acs.org/doi/abs/10.1021/op049829e

LY544344 hydrochloride 6 is Talaglumetad

 

Abstract Image

Process development and a pilot-plant process for the synthesis of 4 and its resolution to obtain (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2‘,5‘-dioxo-2,4‘-imidazolidine]-6-carboxylic acid, (R)-α-methylbenzenemethanamine salt (5) are described. Starting from the inexpensive raw 2-cyclopenten-1-one and sulfur ylide 1 the racemic bicyclo keto ester 2 was synthesized. Reaction of 2 with potassium cyanide and ammonium carbonate under Bücherer−Berg’s reaction conditions affords racemic 3 in 80% yield. Hydrolysis of 3 followed by the resolution with (R)-(+)-α-methylbenzylamine gave 4 in excellent yield and purity under optimized conditions. The improvement of the original discovery process to accommodate safety and environmental requirements for scale-up in manufacturing facilities is also discussed.

LY544344 hydrochloride 6 is a new chemical entity under investigation by Eli Lilly & Company as a potential treatment of neurological or psychiatric disorders related to the mammalian central nervous system (CNS)

Figure

Scheme 1.  Original process for the synthesis of LSN344309 an intermediate of Talaglumetad

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Journal of Medicinal Chemistry (2005), 48(16), 5305-5320

http://pubs.acs.org/doi/full/10.1021/jm050235r

Figure

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WO 2002055485

OR;

http://www.google.im/patents/US20040138304?cl=un

 

 

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http://www.google.com/patents/EP1052246A1?cl=en

Figure 00090001

 

 

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REFERENCES

New approaches in the development of orally bioavailable selective group 2 metabotropic glutamate receptor agonists
Drugs Fut 2002, 27(Suppl. A): Abst C39

Utility of influx transporters to enhance oral bioavailability
241st ACS Natl Meet (March 27-30, Anaheim) 2011, Abst MEDI 163

The intestinal absorption of a prodrug of the mGlu2/3 receptor agonist LY354740 is mediated by PEPT1: In situ rat intestinal perfusion studies
J Pharm Sci 2010, 99(3): 1574

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist
J Med Chem 2005, 48(16): 5305

An efficient synthesis of LY544344.HCl: A prodrug of mGluR2 agonist LY354740
Tetrahedron Lett 2005, 46(43): 7299

Pharmacodynamics of a novel anxiolytic (LY544344)
24th CINP Congr (June 20-24, Paris) 2004, Abst P02.269

 

 

WO2000004010A1 * Jul 14, 1999 Jan 27, 2000 Stephen Richard Baker Bicyclohexane derivatives
EP0696577A1 * Aug 11, 1995 Feb 14, 1996 Eli Lilly And Company Synthetic excitatory amino acids
EP1052246A1 * Jan 27, 1999 Nov 15, 2000 Taisho Pharmaceutical Co. Ltd Fluorine-containing amino acid derivatives

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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