The present invention relates to the field of prodrugs of chemotherapeutic agents and method of use thereof

Ashton, Paul

Crooks, Peter A.

Cynkowska, Grazyna

Cynkowski, Tadeusz

Guo, Hong

English

University of Kentucky

University of KentuckyUKnowledgePharmaceutical Sciences Faculty Patents Pharmaceutical Sciences5-8-2007Permeable, Water Soluble, Non-Irritating Prodrugsof Chemotherapeutic Agents with OxaalkanoicAcidsPeter A. CrooksUniversity of Kentucky, pcrooks@uky.eduTadeusz CynkowskiUniversity of KentuckyGrazyna CynkowskaUniversity of KentuckyHong GuoPaul AshtonRight click to open a feedback form in a new tab to let us know how this document benefits you.Follow this and additional works at: https://uknowledge.uky.edu/ps_patentsPart of the Pharmacy and Pharmaceutical Sciences CommonsThis Patent is brought to you for free and open access by the Pharmaceutical Sciences at UKnowledge. It has been accepted for inclusion inPharmaceutical Sciences Faculty Patents by an authorized administrator of UKnowledge. For more information, please contactUKnowledge@lsv.uky.edu.Recommended CitationCrooks, Peter A.; Cynkowski, Tadeusz; Cynkowska, Grazyna; Guo, Hong; and Ashton, Paul, "Permeable, Water Soluble, Non-Irritating Prodrugs of Chemotherapeutic Agents with Oxaalkanoic Acids" (2007). Pharmaceutical Sciences Faculty Patents. 56.https://uknowledge.uky.edu/ps_patents/56United States Patent US007214710B2 (12) (10) Patent N0.: US 7,214,710 B2 Crooks et al. (45) Date of Patent: *May 8, 2007 (54) PERMEABLE, WATER SOLUBLE, 5,482,965 A 1/1996 Rajadhyaksha NON-IRRITATING PRODRUGS OF 5,501,863 A 3/ 1996 Rossling et al. CHEMOTHERAPEUTIC AGENTS WITH 5,578,637 A 11/1996 Lai et a1. OXAALKANOIC ACIDS 5,614,549 A 3/ 1997 Greenwald et al. 5,650,510 A 7/1997 Webb, II et al. (75) Inventors: Peter A. Crooks, Lexington, KY (US); 5,654,466 A 8/1997 Stuk et al. Tadeusz Cynkowski, Lexington, KY 5,681,964 A 10/1997 Ashton et al. (US); Grazyna CynkoWska, Lexington, 5,707,984 A 1/1998 Tjoeng et al. KY (US); Hong Guo, Belmont, MA 5,712,400 A 1/1998 Leanna et al. (US); Paul Ashton, WatertoWn, MA 5,714,148 A 2/1998 Burke et al. (US) 5,847,003 A * 12/1998 Ptchelintsev et al. ..... .. 514/532 5,880,131 A 3/1999 Greenwald et al. (73) Assignee: University of Kentucky Research 5,918,568 A 7/1999 Gjerlov Foundation, Lexington, KY (US) 6,110,908 A 55/2000 Guthery ( * ) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. CA 1 148 165 3/1981 This patent is subject to a terminal dis- EP 0 357 495 3/1990 Claimen EP 0 494 370 B1 11/1991 EP 0 540 751 A1 5/1992 (21) Appl. N0.: 10/851,096 WO WO96/22303 1/1996 WO WO00/77020 A1 6/2000 (22) Filed: May 24, 2004 (65) Prior Publication Data OTHER PUBLICATIONS (62) (60) (51) (52) (58) (56) US 2004/0214784 A1 Oct. 28, 2004 Related US. Application Data Division of application No. 09/565,079, ?led on May 4, 2000, noW Pat. No. 6,765,019. Provisional application No. 60/132,803, ?led on May 6, 1999. Int. Cl. A61K 31/215 (2006.01) US. Cl. ...................... .. 514/529; 514/506; 546/48; 546/301; 536/26 Field of Classi?cation Search .............. .. 514/529, 514/506; 546/48, 71, 301; 536/26 See application ?le for complete search history. References Cited U.S. PATENT DOCUMENTS 4,009,283 A 2/1977 Herr et al. 4,053,638 A 10/1977 Litch?eld et al. 4,083,974 A 4/1978 Turi 4,206,220 A 6/1980 Sloan 4,412,994 A 11/1983 Sloan 4,439,451 A 3/1984 Coleman 4,443,476 A 4/1984 Lomen 4,473,584 A 9/1984 Heckler 4,477,468 A 10/1984 Heckler 4,489,080 A 12/1984 Lomen 4,613,505 A 9/1986 MiZushima et al. 4,767,751 A 8/1988 Davis 4,786,495 A 11/1988 Bird et al. 4,897,417 A 1/1990 Patil et al. 4,935,508 A 6/1990 Kamachi et al. 4,937,253 A 6/1990 Gleason et al. 4,990,499 A 2/1991 Gupta et al. 5,196,438 A 3/1993 Martin et al. Cynkowski et aliNovel prodrug ester forms of hydroxyl-contain ing drugs. Mono- and dicarboxylic oxa acids conjugatesiBook of Abstracts, 211th ACS National Meeting, New Orleans, LA, Mar. 24-28 1996, MEDI-029 Publisher: American Chemical Society. Monkhouse et aliTransdermal Drug DeliveryiProblems and Promises 0 Drug Development and Industrial Pharmacy, 14(2&3), 1983-209 (1988). Stoughton et al.iAZone® : A New Non-toxic Enhancer of Cuta neous Penetration -Drug Development and Industrial Pharmacy, ((4), 723-744 (1983). Wells et aliMutagenicity and Cytotoxicity of N-Methyl-2-pyr rolidinone and 4-(Methylamino)butanoic Acid in Salmonella/ Microsome AssayiJournal of Applied Toxicology, vol. 8(2), 135 139 (1988). Akhter et aliAbsorption through human skin of ibuprofen an d?ubiprofen; effect of doese variation, deposited drug ?lms, occlu sion and the penetration enhancer N-methyl-2-pyrrolidoneiJ. Pharm. Pharmacol. 1985, 37: 27-37. Hoelgaard, et aliVehicle effect on topical drug delivery IV. Effect of N-methylpyrrolidone and polar lips on percutaneous drug transpoitilnternational Journal of Pharmaceutics, 43 (1988) 233 240. Bennett, et al.4OptimiZation of bioavailiability of topical steriods: non-occluded penetration enhancers under thermodynamic controliJ. Pharm. Pharmacol. 1985, 37: 298-304. (Continued) Primary ExamineriDavid Lukton (74) Attorney, Agent, or F irmiMcDermott Will & Emery LLP (57) ABSTRACT The present invention relates to the ?eld of prodrugs of chemotherapeutic agents and method of use thereof. 2 Claims, 23 Drawing Sheets US 7,214,710 B2 Page 2 OTHER PUBLICATIONS Sasaki et aliEnhancing effect of pyrrolidone derivatives on transdermal drug delivery. IiInternational Journal of Pharmaceutics, 44 (1988) 15-24. Cynkowski et aliNovel prodrug ester forms of hydroxyl-containg drugs. Mono- and dicarboxylic oxa acids conjugatesiBook of Abstracts, 211th ACS National Meeting, New Orleans, Mar. 24-28 1996, MEDI-029 Publisher: American Chemical Society. FlynniMechanism of Percutaneous Absorption from Physicochemical EvidenceiUniversity of Michigan College of Pharmacy, pp. 17-42. Wells et aliDisposition and Metabolism of Double-Labeled [3H and 14C] N-Methyl-Z-Pyrrolidinone in the Rativol. 16, No. 2, 1988 The American Society for Pharmacology and Experimental Thera peutics. Barry, et aliOptimiZation of Bioavailability of Topical Steroids: Penetration Enhancers Under Occlusionivol. 82, No. 1, The Jour nal of Investigation Dermatology, 82:49-52, 1984. Sugibayashi, et aliElfect of Several Penetration Enhancers on the Percutaneous Absorption of Indomethacin in Hairless Rats4Chem. Pharm. Bull. 36(4)1519-1528 (1988). Chromey et aliToxicity of N-Methyl-2-pyrrolidone (NMP): Teratogenic, subchronic and Two-Year Inhalation StudiesiFundamental and Applied Toxicology 9, 222-235 (1987). Cynkowska et aliStructure-stability study of novel anti-HIV prodrugs of Zalcitabine With acids, oxa acids and aminooxa acid derivativesiBook of Abstracts, 217th ACS National Meeting, Anaheim, Calif., Mar. 21-25 , 1999, MEDI-170 Publisher: Ameri can Chemical Society. Cynkowski, et aliSynthesis and properties of novel codrugs of protease inhibitors With reverse transcriptase inhibitorsiBook of Abstracts, 217th ACS National Meeting, Anaheim, CA, Mar. 21-25, 1999, MEDI-171, PublisheriAmerican Chemical Society. Cynkowska, et aliSynthesis and propertis of biolabile prodrugs of Zidovudine With polyoxa acids and short chain polyethylene glycolsiAbstracts of Papers American Chemical Society, (1998) V0. 215, No. 1-2, pp. MEDI 36. Cynkowska, et aliSynthesis and properties of biolabile prodrugs of didanosine With polyoxa acids, amino acids and short chain polyethylene glycolsiBook of Abstracts, 216th ACS National Meeting, Boston, Aug. 23-27, 1998, MEDI-347 Publisher: Ameri can Chemical Society. Greenwald, et al.4Camptothecin-20-PEG ester transport forms: the effect of spacer groups on antitumor activityiBioorg. Med. Chem *1998), 6(5), 551-562. * cited by examiner U.S. Patent May 8, 2007 Sheet 2 0f 23 US 7,214,710 B2 ZOmEREEQQQ N 059“. of m5.102N.T, U.S. Patent May 8, 2007 Sheet 5 0f 23 US 7,214,710 B2 mu 2E0 wiry Yoko/>332668512 m 2:2“. U.S. Patent May 8, 2007 Sheet 6 0f 23 US 7,214,710 B2 o C o Ioto/\Yo\ m 959m U.S. Patent May 8, 2007 Sheet 7 0f 23 US 7,214,710 B2 an 1025-31: .¢ 2 NZNIQ .@was?“ 285%.N 5 o 6.30 .FO on Q "=20 \2mm 5.185N 959m U.S. Patent May 8, 2007 Sheet 9 0f 23 US 7,214,710 B2 was .nhnFuc d nI2 0 o of \0E :02.Nreg/23020239 NGNIQ 132908 .mm nz NGNIQ \“2S5 8o1 o c Oz o r5: /\Yo\ o moSmE U.S. Patent May 8, 2007 Sheet 10 0f 23 US 7,214,710 B2 / II II CC (642' vv O . HZNK O Flgure 10 /o{_/\O OH n O -————————--—> DIC /MAPCHZCIQ 40 U.S. Patent May 8, 2007 Sheet 11 0f 23 US 7,214,710 B2 nv : 959m av U.S. Patent May 8, 2007 Sheet 12 0f 23 US 7,214,710 B2 "255 \2.2% Op :0 @o wof 112102 .N6 NF 959m U.S. Patent May 8, 2007 Sheet 13 0f 23 US 7,214,710 B2 av 052% \2022 2 :2". U.S. Patent May 8, 2007 Sheet 14 0f 23 US 7,214,710 B2 J\\ “s5E2006z oS. 0 020132905 7 f2 2J0 :z _ 2V0 2 :2“. U.S. Patent May 8, 2007 Sheet 15 0f 23 US 7,214,710 B2 1000 um IO \ 2 05mm 0 \Q 0/o /U.S. Patent May 8, 2007 Sheet 16 0f 23 US 7,214,710 B2 N": .nmm Pu: .00m Fake/LIE O I2 0 2 .5m U.S. Patent May 8, 2007 Sheet 18 0f 23 US 7,214,710 B2 MONK/Caz: mm + IOFQCA 2 :2“. a £2 um % o O O 0 LJ LA 

Permeable, Water Soluble, Non-Irritating Prodrugs of Chemotherapeutic Agents with Oxaalkanoic Acids

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Permeable, Water Soluble, Non-Irritating Prodrugs of Chemotherapeutic Agents with Oxaalkanoic Acids

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