NARONAPRIDE

NARONAPRIDE

860174-12-5

Average: 537.1

C₂₇H₄₁ClN₄O₅

ATI 7505 / ATI-7505

(3R)-1-azabicyclo[2.2.2]octan-3-yl 6-[(3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl]hexanoate

 860174-12-5 (free base)   860169-57-9 (HCl)

Naronapride (free base), also known as ATI-7505, is a highly selective, high-affinity 5-HT(4) receptor agonist for gastrointestinal motility disorders. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

Investigated for use/treatment in gastroesophageal reflux disease (GERD) and gastroparesis.

Renexxion , presumed to have been spun-out from Armetheon , under license from ARYx Therapeutics is developing naronapride (ATI-7505; phase 2 clinical in February 2020), an analog of the gastroprokinetic 5-HT 4 agonist cisapride identified using ARYx’s RetroMetabolic platform technology (ARM), for the oral treatment of upper GI disorders. In September 2018, this was still the case . PATENT

WO2005068461

NEW PATENT

WO-2020096911

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020096911&tab=PCTDESCRIPTION&_cid=P21-KANOVN-53661-1

Process for preparing trihydrate salt of naronapride  hydrochloride as 5-HT 4 receptor agonist useful for treating gastrointestinal disorders such as dyspepsia, gastroparesis, constipation, post-operative ileus. Appears to be the first filing from the assignee and the inventors on this compound,

In some aspects, provided herein is a method of making a trihydrate form of (3S, 4R, 3’R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-l-yl]-hexanoic acid l-azabicyclo[2.2.2]oct-3’-yl ester di-hydrochloride salt, which has the following formula:

Example 5: NMR Characterization of the Trihydrate

[0282] ^-Nuclear Magnetic Resonance Spectroscopy (‘H-NMR) : Approximately 6 mg of the trihydrate was dissolved in in 1 g of deuterated solvent (dimethylsulfoxide (DMSO)-C45 99.9% d, with 0.05% v/v tetramethyl silane (TMS)). A Varian Gemini 300 MHz FT-NMR spectrometer was used to obtain the ¾-NMK spectrum. A list of the peaks is provided in Table 1 below. A representative ‘H-NMR spectrum is provided in FIG. 6.

Table 1. ‘H-NMR peak list for trihydrate

[0283] ¹³ C-Nuclear Magnetic Resonance Spectroscopy ( ¹³C-NMR ): Approximately 46 mg of the trihydrate was dissolved in 1 mL of deuterated solvent (deuterium oxide, Aldrich, 99.9% D, TPAS 0.75%). The ¹³C-NMR spectrum was obtained using a Varian Gemini 300 MHz FT-NMR spectrometer. A list of the peaks is provided in Table 2 below. A representative ¹³C-NMR spectrum is provided in FIG. 7.

Table 2. ¹³C-NMR peak list for trihydrate

PATENT

US10570127 claiming composition (eg tablet) comprising a trihydrate form of naronapride.

REFERENCES

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4: Shin A, Camilleri M, Kolar G, Erwin P, West CP, Murad MH. Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014 Feb;39(3):239-53. doi: 10.1111/apt.12571. Epub 2013 Dec 5. Review. PubMed PMID: 24308797.

5: Stevens JE, Jones KL, Rayner CK, Horowitz M. Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives. Expert Opin Pharmacother. 2013 Jun;14(9):1171-86. doi: 10.1517/14656566.2013.795948. Epub 2013 May 11. Review. PubMed PMID: 23663133.

6: Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy BE, Müller-Lissner S, Quigley EM, Schuurkes J, De Maeyer JH, Stanghellini V. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012 Apr;35(7):745-67. doi: 10.1111/j.1365-2036.2012.05011.x. Epub 2012 Feb 22. Review. PubMed PMID: 22356640; PubMed Central PMCID: PMC3491670.

7: Hoffman JM, Tyler K, MacEachern SJ, Balemba OB, Johnson AC, Brooks EM, Zhao H, Swain GM, Moses PL, Galligan JJ, Sharkey KA, Greenwood-Van Meerveld B, Mawe GM. Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology. 2012 Apr;142(4):844-854.e4. doi: 10.1053/j.gastro.2011.12.041. Epub 2012 Jan 4. PubMed PMID: 22226658; PubMed Central PMCID: PMC3477545.

8: Bowersox SS, Lightning LK, Rao S, Palme M, Ellis D, Coleman R, Davies AM, Kumaraswamy P, Druzgala P. Metabolism and pharmacokinetics of naronapride (ATI-7505), a serotonin 5-HT(4) receptor agonist for gastrointestinal motility disorders. Drug Metab Dispos. 2011 Jul;39(7):1170-80. doi: 10.1124/dmd.110.037564. Epub 2011 Mar 29. PubMed PMID: 21447732.

9: Tack J. Current and future therapies for chronic constipation. Best Pract Res Clin Gastroenterol. 2011 Feb;25(1):151-8. doi: 10.1016/j.bpg.2011.01.005. Review. PubMed PMID: 21382586.

10: Manabe N, Wong BS, Camilleri M. New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders. Expert Opin Investig Drugs. 2010 Jun;19(6):765-75. doi: 10.1517/13543784.2010.482927. Review. PubMed PMID: 20408739.

11: Sanger GJ. Translating 5-HT receptor pharmacology. Neurogastroenterol Motil. 2009 Dec;21(12):1235-8. doi: 10.1111/j.1365-2982.2009.01425.x. Review. PubMed PMID: 19906028.

12: Vakil N. New pharmacological agents for the treatment of gastroesophageal reflux disease. Rev Gastroenterol Disord. 2008 Spring;8(2):117-22. Review. PubMed PMID: 18641594.

13: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. PubMed PMID: 17805439.

14: Camilleri M, Vazquez-Roque MI, Burton D, Ford T, McKinzie S, Zinsmeister AR, Druzgala P. Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans. Neurogastroenterol Motil. 2007 Jan;19(1):30-8. PubMed PMID: 17187586.

////////////NARONAPRIDE, ATI 7505, ATI 7505,PHASE 2

CO[C@H]1CN(CCCCCC(=O)O[C@H]2CN3CCC2CC3)CC[C@H]1NC(=O)C1=C(OC)C=C(N)C(Cl)=C1