Granted Patent
B2
US 12,392,781 · App. 18/559,031 · Granted Aug 19, 2025
Deuterated indole heptamethine cyanine dyes
Assignee:
University of Notre Dame du Lac
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Abstract
Described are deuterated indole heptamethine cyanine dyes, aqueous formulations including the deuterated dyes, and methods of using the dyes and formulations for diagnosing and treating abnormal tissue, assessing tissue perfusion, determining cardiac output, determining hepatic function, or ophthalmic angiography.
Claims (14)
1. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof,
wherein:
D is deuterium;
A is a 6- to 12-membered arene, wherein A is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C 1-4 alkyl, —OC 1-4 alkyl, C 1-2 haloalkyl, —OC 1-2 haloalkyl, halogen, —CN, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —YO n − , —YO n H, and —YO n M;
L 1 is a C 1-10 hydrocarbon chain;
Y is sulfur or carbon;
n is 2, 3, or 4; and M is an alkali metal cation.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is sulfur.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 3.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
Assignments (2)
CONFIRMATORY LICENSE
Recorded Jan 19, 2024
From: UNIVERSITY OF NOTRE DAME
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066356/0099 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 3, 2023
From: SMITH, BRADLEY D.; LI, DONG-HAO
To: UNIVERSITY OF NOTRE DAME DU LAC
Reel/Frame 065458/0803 →
Continuity (4)
Provisional Application
63246708
· Sep 21, 2021
Provisional Application
63219826
· Jul 8, 2021
Provisional Application
63184059
· May 4, 2021
References Cited (59)
US 4569589A
· Neufeld
· 1986
[cited by applicant]
US 8110597B2
· Taniguchi et al.
· 2012
[cited by applicant]
US 8628753B2
· Murthy
· 2014
[cited by examiner]
US 20040156782A1
· Alam et al.
· 2004
[cited by applicant]
US 20060051315A1
· Scaria et al.
· 2006
[cited by applicant]
US 20140105826A1
· Murthy
· 2014
[cited by examiner]
EP 2579027B1
· 2019
[cited by applicant]
WO 2001043781A1
· 2001
[cited by applicant]
WO 03057259A2
· 2003
[cited by applicant]
WO 2020240514A1
· 2020
[cited by applicant]
Ruttger et al., Isomerization and Dimerization of Indocyanine Green and a Related Heptamethine Dye, European Journal of Organic Chemistry, 2019, 30, 4791-4796. (Year: 2019).
[cited by examiner]
Ruttger et al., and Supporting Information, Isomerization and Dimerization of Indocyanine Green and a Related Heptamethine Dye, European Journal of Organic Chemistry, European Journal of Organic Chemistry, 2019, 30, 1-1…
[cited by examiner]
Lipowska et al., A Highly Selective Hydrogen-Deuterium Exchange in Indolium Heptamethine Cyanines, J. Heterocyclic Chemistry, 1993, 30, 1177-1180. (Year: 1993).
[cited by examiner]
Janekova et al., Deuteration of Heptamethine Cyanine Dyes Enhances Their Emission Efficiency, Chemical Communication, 2024, 60, 1000-1003. (Year: 2024).
[cited by examiner]
Biotechne, ICG-d7, Tocris, 2025, 1-3. Obtained online at: https://www.tocris.com/products/icg-d7_7749#product-details on Jan. 8, 2025. (Year: 2025).
[cited by examiner]
Kumar et al., Salt Selection in Drug Development, Pharmaceutical Technology, 2008, 32(3), 1-21. (Year: 2008).
[cited by examiner]
Li et al., Deuterated Indocyanine Green (ICG) with Extended Aqueous Storage Shelf-Life: Chemical and Clinical Implications, Chemistry—A European Journal, 2021, 27, 14535-14542. (Year: 2021).
[cited by examiner]
Li et al., Deuterated Indocyanine Green (ICG) with Extended Aqueous Storage Shelf-Life: Chemical and Clinical Implications, Supporting Information, Chemistry—A European Journal, 2021, 27, 1-37. (Year: 2021).
[cited by examiner]
Wang et al., Self-Assembled Hydrophobin for Producing Water-Soluble and Membrane-Permeable Fluorescent Dye, Scientific Reports, 2016, 6(23061), 1-11. (Year: 2016).
[cited by examiner]
Matikonda et al., Impact of Cyanine Conformational Restraint in the Near-Infrared Range, The Journal of Organic Chemistry, 2020, 85, 5907-5915. (Year: 2020).
[cited by examiner]
International Search Report and Written Opinion mailed in International Patent Application No. PCT/US2022/023799 (Jun. 24, 2022).
[cited by applicant]
Sun et al., “Research progress of near-infrared fluorescence probes based on indole heptamethine cyanine dyes in vivo and in vitro”, BMC Chemistry, vol. 14, pp. 1-28 (Mar. 30, 2020).
[cited by applicant]
Li et al., “Deuterated Indocyanine Green (ICG) with Extended Aqueous Storage Shelf Life: Chemical and Clinical Implications”, Chemistry, vol. 27, pp. 14535-14542 (Sep. 24, 2021).
[cited by applicant]
Becher et al., “Derivatives and Reactions of Glutaconaldehyde-IX”, Tetrahedron 1979, 35, pp. 1523-1530.
[cited by applicant]
Berezin et al., “Rational Approach to Select Small Peptide Molecular Probes Labeled with Fluorescent Cyanine Dyes for in Vivo Optical Imagine”, Biochemistry 2011, 50, pp. 2691-2700.
[cited by applicant]
Berlepsch et al., “H-Aggregates of an Indocyanine Cy5 Dye: Transition from Strong to Weak Molecular Coupling”, J. Phys. Chem. B 2015, 119, pp. 11900-11909.
[cited by applicant]
De Valk et al., “First-in-Human Assessment of CRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma”, Clin. Cancer Res., 2020, vol. 26, No. 15, pp. 3990-3998.
[cited by applicant]
Desmettre et al., “Fluorescence Properties and Metabolic Features of Indocyanine Green (ICG) as Related to Angiography”, Surv. Ophthalmol., 2000, vol. 45, No. 1, pp. 15-27.
[cited by applicant]
Grimm et al., “A General Method to Improve Fluorophores Using Deuterated Auxochromes”, JACS Au, 2021, vol. 1, No. 5, pp. 690-696.
[cited by applicant]
Hernot et al., Latest Developments in Molecular Tracers for Fluorescence Image-Guided Cancer Surgery. Lancet Oncol. 2019, 20 (7), e354-e367.
[cited by applicant]
Hibbert et al., “The death of the Job plot, transparency, open science and online tools, uncertainty estimation methods and other developments in supramolecular chemistry data analysis”, Chem. Commun. 2016, 52, pp. 1279…
[cited by applicant]
International Preliminary Report on Patenability for Application No. PCT/US2022/023799 dated Oct. 24, 2023 (5 pages).
[cited by applicant]
Kolmakov et al., “Red-Emitting Rhodamine Dyes for Fluorescence Microscopy and Nanoscopy”, Chem. A Eur. J., 2010, vol. 16, No. 1, pp. 158-166.
[cited by applicant]
Kuthan et al., “Prepartion of 1-Phenyldihydropyridines Polydeuterated in Their Heterocyclic Ring”, Collect. Czechoslov. Chem. Commun. 1982, 47, pp. 3283-3287.
[cited by applicant]
Kuzmin et al., “Complex formation of albumin with tricarbocyanine dyes containing phosphonate groups”, Photochem. Photobiol. Sci. 2016, 15, pp. 1377-1384.
[cited by applicant]
Li et al., “Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near-Infrared Fluorescence Imaging”, Angew. Chem. Int. Ed, 2020, vol. 59, pp. 12154-12161.
[cited by applicant]
Lipowska et al., “A Highly Selective Hydrogen-Deuterium Exchange in Indolium Heptamethine Cyanines”, J. Heterocyclic Chem, 1993, vol. 30, pp. 1177-1180.
[cited by applicant]
Mindt et al., “Stability and Degradation of Indocyanine Green in Plasma, Aqueous Solution and Whole Blood”, Photochem. Photobiol. Sci., 2018, vol. 17, No. 9, pp. 1189-1196.
[cited by applicant]
Nani et al., “Reactive species involved in the regioselective photooxidation of heptamethine cyanines”, Chem. Sci. 2015, 6, pp. 6556-6563.
[cited by applicant]
Norcott et al., “Using 2H Labelling to improve the NMR detectability of pyridine and its derivatives by SABRE”, Magn Reson Chem, 2018, vol. 56, pp. 663-671.
[cited by applicant]
Okoh et al., “Promising Near-Infrared Non-Targeted Probes: Benzothiazole Heptamethine Cyanine Dyes”, J. Sulfur Chem., 2014, vol. 35, No. 1, pp. 42-56.
[cited by applicant]
Pirali et al., “Applications of Deuterium in Medicinal Chemistry”, J. Med. Chem., 2019, vol. 62, pp. 5276-5297.
[cited by applicant]
Reinhart et al., “Indocyanine Green: Historical Context, Current Applications, and Future Considerations”, Surg. Innov., 2016, vol. 23, No. 2, pp. 166-175.
[cited by applicant]
Rüttger et al. “Isomerization and Dimerization of Indocyanine Green and a Related Heptamethine Dye” Eur. J. Org. Chem., 2019, pp. 4791-4796.
[cited by applicant]
Stackova et al., “Approach to a Substituted Heptamethine Cyanine Chain by the Ring Opening of Zincke Salts”, J. Am. Chem. Soc., 2019, vol. 141, No. 17, pp. 7155-7162.
[cited by applicant]
Thordarson, “Determining association constants from titration experiments in supramolecular chemistry”, Chem. Soc. Rev. 2011, 40, pp. 1305-1323.
[cited by applicant]
Toronto Research Chemicals, Product No. I697003 <https://www.trc-canada.com/product-detail/?1697003>, 3 pages.
[cited by applicant]
Urbitsch et al., “A Modular Enantioselective Synthesis of Resolvins D3, E1, and Hybrids”, Org. Lett. 2020, 22, pp. 1510-1515.
[cited by applicant]
Van den Berg et al. “Concomitant radio- and fluorescence-guided sentinel lymph node biopsy in squamous cell carcinoma of the oral cavity using ICG-99mTc-nanocolloid,” Eur. J. Nucl. Med. Mol. Imaging, 2012, vol. 39, pp. …
[cited by applicant]
Van Manen et al., “A Practical Guide for the Use of Indocyanine Green and Methylene Blue in Fluorescence-Guided Abdominal Surgery”, J. Surg. Oncol., 2018, vol. 118, No. 2, pp. 283-300.
[cited by applicant]
Xia et al. “Gallium-68-Labelled Indocyanine Green as a Potential Liver Reserve Imaging Agent” Contrast Media Mol Imaging, 2019, pp. 1-8.
[cited by applicant]
Yau et al., “Deuteration of Indole and N-Methylindole by Raney Nickel Catalysis”, J. Label. Compd. Radiopharm. Off. J. Int. Isot. Soc., 1999, vol. 42, No. 7, pp. 709-714.
[cited by applicant]
Zincke et al., “Ueber Dinitrophenylpyridiniumchlorid und dessen Umwandlungsproducte”, Justus Liebigs Ann. Chem. 1904, 333, pp. 296-345.
[cited by applicant]
European Patent Office. Extended European Search Report for Application No. 22799267.4, dated Dec. 9, 2024 (8 pages).
[cited by applicant]