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(12) United States Patent (10) Patent No.: US 9,302,982 B2 Christian (45) Date of Patent: *Apr

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(12) United States Patent (10) Patent No.: US 9,302,982 B2 Christian (45) Date of Patent: *Apr US009302982B2 (12) United States Patent (10) Patent No.: US 9,302,982 B2 Christian (45) Date of Patent: *Apr. 5, 2016 (54) PHARMACEUTICAL DOPAMINE 6,339,064 B1 1/2002 McDevitt et al. GIYCOCONJUGATECOMPOSITIONS AND 355 R. 393 Eas 51462 METHODS OF THEIR PREPARATION AND 8,352.752 B2 8/2012 Christian ........................ 514.42 USE 9,023,818 B2 5/2015 Christian 2006/0189547 A1 8, 2006 Christian (75) Inventor: Samuel T. Christian, Alabaster, AL (US) FOREIGN PATENT DOCUMENTS (73) Assignee: GLYCON LLC, Riverside, AL (US) WO 9728174 8, 1997 WO 9905089 2, 1999 (*) Notice: Subject to any disclaimer, the term of this WO O197244 12/2001 patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 255 days. This patent is Subject to a terminal dis- Thomas et al., “Parkinson's Disease” Human Molecular Genetics claimer. (2007) vol. 16 reviss 2, pp. R183-R194.* Rao et al., “Parkinson's Disease:Diagnosis and Treatment” American Family Physician (2006) vol. 74 No. 2 pp. 2046-2054.* (21) Appl. No.: 13/551,131 “Remington: The Science and Practice of Pharmacy, 20' edition”, (22) Filed: Jul. 17, 2012 iamsEdited A by Wii Alfonso M. pp.R. Gennaro,218, publishedity. 2000 by Lippincott PP Will O O Czarnocki et al., "Enantioselective Synthesis of (R)-(-) Laudanosine (65) Prior Publication Data and (R)-(-) Glaucine from E. Acid', E.A. Asym US 2013/0203855A1 Aug. 8, 2013 metry, vol. 7, No. 9, Sep. 1996, pp. 2711-2720. Doherty, “The Synthesis of Glyconyl Peptides”,Journal of Biologi Related U.S. Application Data cal Chemistry, vol. 201(2), May 1953, pp. 857-866. Fernandez et al., “Synthesis and biological studies of glycosyl (63) Continuation-in-part of application No. 1 1/965,444, dopamine deriviatives”. Carbohyd. Res. vol. 327, 2000, pp. 353-365. filed on Dec. 27, 2007, now Pat. No. 8,252,752, which Glinsky et al., “Inhibition of colony formation in agarose of meta is a continuation of application No. 10/625,645, filed static human breast carcinoma and melanoma cells by Synthetic on Jul. 22, 2003, now Pat. No. 7,345,031, application glycoamine analogs”. Clin. Exp. Metastasis, vol. 14(3), May 1996, No. 13/551,131, which is a continuation-in-part of pp. 253-267. application No. 12/913,543, filed on Oct. 27, 2010, Haavik et al., "Tyrosine hydroxylase and Parkinson's disease'. now Pat. No. 9.023.818, which is a continuation of Molecular Neurobiology, vol. 16, No. 3, Jun. 1998, pp. 285-309. application No. 1 1/343 266 filed on Jan. 30, 2006 Jakaset al. “Synthesis and 13C NMR investigation of novel Amadori now abandoned,s which is a continuation of application opioidcompounds peptide, (1-amino leucine—enkephalin'. -1-deoxy-D-fructose J. Chem. derivatives) Soc., Perkin related Trans. to the No. 09/547.501, filed on Apr. 12, 2000, now vol. 2, DOI 10.1039/P29960000789, 1996, pp. 789-794. abandoned. Jiang et al., “Dopaminergic properties and experimental anti Parkinsonian effects . Clin. Neuropharmacol vol. 27, No. 2, (51) Int. Cl. 2004, 63-73. A6 IK3I/7008 (2006.01) Knoerzer et al., “Dopaminergic Benzoaphenanthridines: Resolu A 6LX3L/7032 (2006.01) tion and Pharmacological Evaluation of the Enantiomers of C7H5/04 (2006.01) Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist'. C7H 5/18 (2006.01) Journal of Medicinal Chemistry, vol. 37 No. 15, Jul. 1994, pp. 2453 C07C 235/08 (2006.01) iRoberto et al., “Giycoconjugates of amines: alkylation of pri A6 IK 47/48 (2006.01) marv and second amines Russ. Chem. Bull vol 47. No. 6 iss. A6 IK3I/704 (2006.01) s: Hisplay v w w K-1 - w C07H 17/00 (2006.01) Likhoshersfov et al., “Synthesis of N-chloroacetyi-B- (52) U.S. Cl. glycopyranosylamines, derivatives of monosaccharides and CPC ............. C07C 235/08 (2013.01); A61 K3I/704 lactose.”. Russ. Chern. B1 vol: 45, 1996, pp. 1760-1763. (2013.01); A61K47/48092 (2013.01); C07H Maher et al., “Substrate specificity and kinetic parameters of 5/04 (2013.01); C07H 1700 (2013.01) GLUT3". Biochem. J. vol.315, 1996, pp. 827-831. (58) Field of Classification Search (Continued) CPC. C07H 15/2013; C07H5/06; A61K31/7032: A61K 3.1 F7008 See application file for complete search history. Primary Examiner — Eric Olson (74) Attorney, Agent, or Firm — Kilpatrick Townsend & (56) References Cited Stockton LLP U.S. PATENT DOCUMENTS (57) ABSTRACT 3,929,813 A 12/1975 Higuchi 3,962.447 A 6/1976 Higuchi et al. Hydrophilic transportable N-linked glycosyl dopaminergic 4,032,676 A 6, 1977 Heins et al. prodrug compounds and methods of their use. 4,190,672 A 2, 1980 Fahn 5,380,837 A 1/1995 Nakada et al. 5,639,737 A 6, 1997 Rubin 9 Claims, 22 Drawing Sheets U.S. Patent Apr. 5, 2016 Sheet 1 of 22 US 9,302,982 B2 360- P=0.6349 340 320 500 280 260 240 220 200 180 160 140 120 P=0.0066 100 80 60 40 20 Z Before(n=2 2 ) AfterNoC ( r 6) AfterMPTP(n=18) FG 1 U.S. Patent Apr. 5, 2016 Sheet 3 of 22 US 9,302,982 B2 O Before IPX-750 IPX-750 St week 700 IPX-750 2nd week ZIPX-750 3rd week NY IPX-750 4th week as 500 3. , N soto 3.WN NN i 200 WN NZN % SNN Z 3.3 t SN WN | 2NZN3N t NZN MPTP+NoCI(n=6) MPTP-IPX-750 MPTP-IPX-750 (20mg/kg)(n=6) (80mg/kg)(n=6) Roto-Rod test for different time of IPX-750 treatment FIG.3 U.S. Patent Apr. 5, 2016 US 9,302,982 B2 700 O After MPP After treotment of IPX-750 600 WOsh-Out 1st Week ZZ Wosh-out 2nd week 500 ? 500 200 100 <> N N` MPTP+PX-750 MPTP+IPX-750 (20mg/kg)(n=6) (80mg/kg)(n=6) FIG.4 U.S. Patent Apr. 5, 2016 Sheet 5 of 22 US 9,302,982 B2 6-OHDA+ 6-OHDA+ 6-OHDA 6-OHDA+ Apomorphine 0.9% NgC PX-750 IPX-750 (80mg/kg) (200mg/kg) Acute effects of IPX-750 FIG.5 U.S. Patent Apr. 5, 2016 Sheet 6 of 22 US 9,302,982 B2 is NZNZ W 2 N N r" as cry co - to r- in CN " . any led Sapko u000 U.S. Patent Apr. 5, 2016 Sheet 7 of 22 US 9,302,982 B2 is is is 55 E E2 E . ÉS 33 3 SSS3 -s a N. N. N. N. x:it a is s 33s is a g a set is is is is is ww. SS is a a r sSS s SSSSSSSSSSSSSSSSSSS SXSS s s XXX RSSSSSSSSSSSSSSSSSSS Xs deRys SS SSSSs SSSSSSSSSSS N sExx s XXXXXXSSSS s : wa + HE Š& eaw –2aÉs • 2 - al a &YsS E . &Si; s SES ZZZZZZZZZZZZZZZ N S. 2 S se S S S S 3 g S S S se c was saw was was views (SPU003S) au PO1-Dog U.S. Patent Apr. 5, 2016 Sheet 8 of 22 US 9,302,982 B2 OThe lost treatment 120 1st week wash-out 2nd week wosh-out 3rd week WOsh-out OO 80 k (spu008S)ºupou-0308 60 40 O N N```` Hetero HetN Ø>s oC (PX-750 20mg/kg) RotO-rod T t with IPX-750 (20mg/kg)/0.9% NoC in heterozygous/WT Mice FIG.8 U.S. Patent Apr. 5, 2016 Sheet 9 of 22 US 9,302,982 B2 U.S. Patent Apr. 5, 2016 Sheet 12 of 22 US 9,302,982 B2 |Gipons]fra U.S. Patent Apr. 5, 2016 Sheet 13 of 22 US 9,302,982 B2 Spl Cenotoxic Compounds. Spl cnd GLUT1 mRNA e.g. eioposide, cisplotin, -radiation decrease after myogenesis Myobicsts-kiyotubes Differentition Repressor re cities Sp1 Repressor. FO Cell cycle plO7 RelA of NFy -27Rip to -J.3%ip Housekeeping - Eoholicer-fi) -ette to -2dio is -33bp to -99bp Growth Factors e.g. insulin, Serum, PDGF, Oncogene products IkB Phosphorylation (inhibitory subunit of NFkB) Doponine-induced Apoptosis Inlommctory Cytokines c.g. IL-1, THF-, a FN- 7 FIG. 1 OA U.S. Patent Apr. 5, 2016 Sheet 14 of 22 US 9,302,982 B2 yPTP Insecticides: e.g., -- Rolenone, 02/03 Agonists pyrethroids, Alpha-Synuclein chlorpyrifos, + permethrin Growth foctors e.g. Scrum, PDCF, l C2/03 Receptor Activotion Oncogene products Kurr1 mRNA Down-Regulation and Blocks Nurri Nuclear Trorislocation ove CLU RNA f +16.7Kbp to +1.8Kbp Enhancer-2E2) in intron 2 Guti ni 3 tip at 2.18%ip to 24Kip 80kDo cylosolic protein tronscribed from 3'UTR of CLUI in recction to hypoxic C or tumorigenesis, i.e., an pge \ mRNA stabilizer protein P53, HPTF Targeted Endonucleose Stabilized Sensitive it rRNA Ubiquinotor WHL Pro PI3K/AKT Gut frMA Closes, Signaling ProteoSome Clucose Degradation deprivation Hific A inctive Hypoxie: Ferroprotein Sensor Co2t Fe2+ chelotion OH-pyridinones Growth Fociors: e.g. insulin, IGF-1 FIG. 1 OB U.S. Patent Apr. 5, 2016 Sheet 15 of 22 US 9,302,982 B2 jossaJdeu-c) U.S. Patent Apr. 5, 2016 Sheet 16 of 22 US 9,302,982 B2 (01-6'0E005) uchopp1783 OXd10/pub(01-6(9.3935) |dS U.S. Patent Apr. 5, 2016 Sheet 18 of 22 US 9,302,982 B2 U.S. Patent Apr. 5, 2016 Sheet 19 of 22 US 9,302,982 B2 |-5H$ &### U.S. Patent Apr. 5, 2016 Sheet 20 of 22 US 9,302,982 B2 udsoqd-90 U.S. Patent US 9,302,982 B2 30 U.S.
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