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Burke, Thomas

Curran, Dennis P.

David, Bom

English

University of Kentucky

University of KentuckyUKnowledgePharmaceutical Sciences Faculty Patents Pharmaceutical Sciences6-25-2002Camptothecin Analogs and Methods ofPreparation ThereofDennis P. CurranBom DavidThomas BurkeUniversity of KentuckyRight 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 CitationCurran, Dennis P.; David, Bom; and Burke, Thomas, "Camptothecin Analogs and Methods of Preparation Thereof " (2002).Pharmaceutical Sciences Faculty Patents. 74.https://uknowledge.uky.edu/ps_patents/74(12) United States Patent Curran et al. US006410731B2 (10) Patent N0.: (45) Date of Patent: US 6,410,731 B2 Jun. 25, 2002 (54) CAMPTOTHECIN ANALOGS AND METHODS OF PREPARATION THEREOF (75) Inventors: Dennis P. Curran; Bom David, both of Pittsburgh, PA (US); Thomas G. Burke, Lexington, KY (US) (73) Assignees: University of Pittsburgh, Pittsburgh, PA (US); University of Kentucky Research Foundation, Lexington, KY (Us) ( * ) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (21) Appl. No.: 09/728,031 (22) Filed: Nov. 30, 2000 Related U.S. Application Data (63) Continuation of application No. 09/290,019, ?led on Apr. 9, 1999, now Pat. NO. 6,207,832. (51) Int. Cl.7 .................... .. C071) 491/22; C07D 491/14 (52) ......... .. 546/41; 546/14; 546/48 (58) Field of Search ............................. .. 546/48, 41, 14 (56) References Cited U.S. PATENT DOCUMENTS 11/1995 Fortunak 12/1997 Fortunak 4/1998 Curran 6/1999 Hausheer 8/1999 Hausheer * 11/1999 Bigg et al. ................ .. 514/283 5/2000 Haridas 10/2000 Curran 11/2000 Curran 4/2001 Curran et al. ............... .. 546/48 FOREIGN PATENT DOCUMENTS WO WO97/ 00876 WO WO98/ 07727 WO WO98/ 28305 WO WO98/ 35 940 WO WO99/11646 3/1999 W0 W0 00/ 50427 8/2000 OTHER PUBLICATIONS Bom, D. et al.: Novel A,B,E—ring—rnodi?ed Camptothecins displaying high lipophilicity and marked improved human blood stabilities. J. Med. Chem. vol. 42, pp. 3018—3022, 1999* Curran, D. P. and Liu, H., “New 4+1 Radical Annulations —A Formal Total Synthesis of (+/—)—Camptothecin,” J. Am. Chem. Soc., 114, 5863—5864 (1992). Published Jul. 1, 1992. Curran, D. P., “The Camptothecins —A reborn Family of Antitumor Agents”, J. Chin. Chem. Soc., 40, 1—6 (1993). Published Feb. 1993. 5,468,859 A 5,700,939 A 5,744,605 A 5,910,491 A 5,935,967 A 5,981,542 A 6,057,303 A 6,136,978 A 6,150,343 A 6,211,371 B1 * 1/1997 2/1998 7/1998 8/1998 (List continued on next page.) Primary Examiner—Charanjit S. Aulakh (74) Attorney, Agent, or Firm—Bartony & Hare (57) ABSTRACT A method of synthesizing a compound having the formula via a cascade radical 4+1 annulation includes the step Wherein the precursor or the precursor is reacted With an arylisonitrile having the formula R1 R3 NC Wherein X is a radical precursor such as Cl, Br or I. R6 is preferably —Si(R8R9R1O) or —(R7)Si(R8R9R1O), Wherein R7 is an alkylene group, an alkenylene group, or an alky nylene group; and R8, R9 and R10 are independently a CMO alkyl group, a C2_1O alkenyl group, a C2_1O alkynyl group, an aryl group or a —(CH2)NR11 group, Wherein N is an integer Within the range of 1 through 10 and R11 is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, —SRC or a nitro group. R1—R4 can be broadly substituted. R5 is preferably a CMO alkyl group, an alkenyl group, an alkynyl group, or a benZyl group. R13 is preferably H, F or —CH3. R16 is R16 is —C(O)Rf or H. The E-ring (the lactone ring) may be opened. 9 Claims, 18 Drawing Sheets US 6,410,731 B2 Page 2 OTHER PUBLICATIONS Curran, D.P. et al., “Recent Applications of Radical Reac tions in Natural Product Synthesis,” Pure Appl. Chem., 65, 1153—1159 (1993). Published Jun. 1993. Curran, D.P. et al., “Cascade Radical Reactions of Isoni triles: A Second—Generation Synthesis of (20S)—Camptoth ecin, Topotecan, Irinotecan, and GI—147211C,” AngeW. Chem. Int. Ed,. 34, 2683—2684 (1995). Published Jan. 5, 1996. Curran, D.P., Liu, H.; Josien, H; Ko, S.B., “Tandem Radical Reactions of Isonitriles With 2—pyrdonyl and other aryl radicals: Scope and Limitations, and a First Generation Sunthesis of (+/—)—Campothecin,” Tetrahedron, 52, 11385—11404 (1996). Published Aug. 1996. J osien, H. et al., “Synthesis of (S)—rnappicine and Mappicine Ketone Via Radical Cascade Reaction of Isonitirles,” Tet rahedron, 53, 8881—8886 (1997). Published Jun. 30, 1997. Josien, H. et al., “7—Silylcamptothecins (Silatecans): A NeW Family of Carnptothecin Antitumor Agents,” Bioorg. Med. Chem. Lett. 7, 3189—3295 (1997). Josien, H. et al., “A General Synthetic Approach to the (20S)—Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical CycliZation of Aryl Isoni triles,” Chem. Eur. J. 67—83 (1998). Published Jan. 1998. Zihou, M. et al., “Reduced Albumin Binding Promotes the Stability and Activity of Topotecan in Human Blood,” Biochemistry, 34, 13722—13727 (1995). Burke, T.G. and Zihou, M., “The Structural Basis of Camp tothecin Interaction With Human Serum Albumin: Impact on Drug Stability,” J. Med. Chemistry, 37, 40—46 (1994). Zihou, M. and Burke, T.G., “Marked Interspecies Variations Concerning the Interactions of Camptothecin With Serum Albumins: A Frequency—Domain ?uorescence Spectro scopic Study,” Biochemistry, 33, 12540—12545 (1994). Zihou, M. and Burke, T.G., “Differential Interactions of Camptothecin Lactone and CarboXylate Forms With Human Blood Components,” Biochemistry, 33, 10325—10336 (1994). Burke, T.G., and Zihou, M., “Ethyl Substitution at the 7 Position Extends the Half—Life of 10—HydroXycamptothecin in the Presence of Human Serum Albumin,” J. Med. Chem istry, 37:17, 2580—2582 (1993). Burke, T.G. et al., “Lipid Bilayer Partitioning and Stability of Carnptothecin Drugs,” Biochemistry, 32:20, 5352—5364 (1993). Zihou, M. and Burke, T.G., Preferential Binding of the CarboXylate Form of Camptothecin by Human Serum Albu min, Anal. Biochem., 212, 285—287 (1993). Burke, T.G. and Tritton, T.R., “Structural Basis of Anthra cycline Selectivity for Unilamellar Phosphatidylcholine Vesicles: An Equilibrium Binding Study,” Biochemistry, 24, 1768—1776. Burke, T.G. and Tritton, T.R., “Location and Dynamics of Anthracycline Bound to Unilamellar Phosphatidylcholine Vesicles,” Biochemistry, 24, 5972—5980 (1985). Burke, T.G. et al., “The Important Role of Albumin in Determining the Relative Human Blood Stabilities of the Camptothecin Anticancer Drugs,” J. Parm. Sciences, 84:4 (1995). * cited by examiner U.S. Patent Jun. 25,2002 Sheet 2 0f 18 US 6,410,731 B2 Synthesis of New AB-Ring Modi?ed Homosilatecan Derivitives NaH. LiBr DMFIDME 10a, R6; SiMe3, 63% b, R6 = SiMeZtBu, 58% R6 R2 Yield 0a SiMeZtBu NHBoc 15% 11b SiMeZ'BU NH2 89%3 1|c SiMe3 NHBoc 53% 3 11a SiMe3 NH; 45% 0e SiMeZ'Bu OAc 20% 3 0f silvlez‘su OH 79% 1g SiMeztBu H 27% 11h SiMe3 H 37% FIG. 2A U.S. Patent Jun. 25,2002 Sheet 3 0f 18 US 6,410,731 B2 General Route to A-, B-, and A/B Substituted Homocamptothecins I ' I )l I N\ (K N O\ substituted _______,__ oxidative allyl alcohol / -——~ I *' MC(R“’)(R‘“)CO2R‘5 o cleavage R5 R5 OC(O)H R“ N o\ 1)halogenative~ O s - 1) Refo'matsky I / desilylation 1) R ‘2 —.---.--~ - HN __ 33mm‘! Rs 2) demethylation \ o 2) cascade radical reaction Y \ R1: Ho R5 R13 R‘[ R13 R1: R2 R3 NC 4 FIG. 2B U.S. Patent Jun. 25,2002 Sheet 4 0f 18 US 6,410,731 B2 Fuorescence Emission Spectra of 1 pM DB-38 lipid concentration 5 mM, xex = 410 nm, EX resolution 4nm, EM resolution 4nm, without lEM polarizer, HV=82D V in 538 C Kmax = 531 nm - _ - in P Xmax= 515 nm 8 in Ethanol kex - 421 nm _ - in DMPG Kmax: 517 nm “ \ ‘ ‘_ in Ethanol kmax= 510 nm S - - in Ethanol 5P, — in PBS >- 6 ~ -- in DMPC t: _ - in DMPG m 2 LL! ‘ 2 t5‘ 2 4 — LU 0 co m n: O D ._l u. 2 i 0 l *r \ t i 400 450 500 550 600 EMISSION WAVELENGTH (nm) FIG. 3 U.S. Patent Jun. 25,2002 Sheet 5 0f 18 US 6,410,731 B2 Equilibrium binding of DB-38, [DB-81, DB-91, CPT and TPT to DMPC at 37°C m ,m\ N w W N E C N O C C D. M D _ w5 0O.U. 0  0250 .2 015 1 10 DMPC CONCENTRATION (mM) FIG. 4 U.S. Patent Jun. 25,2002 Sheet 9 0f 18 US 6,410,731 B2 pH Dependence of the Stability of the B-OH Lactone Moiety of DB-38 200 r 150 160 TIME (Min) 0.2 -< 00 UZOPOS ZOFOémFIG. 8 U.S. Patent Jun. 25,2002 Sheet 10 0f 18 US 6,410,731 B2 MZQPUS "-0ZOFO<~E w. .w 0 M e T n O 4.m 5789a .3% L H oovv 0. B1  e h t ..T...1| On_C t 1.WB WD f m oS e In I t f 0 & C l n e d n e ID. e D H _ 2_ p o as4. 2.225 200 175 TIME (Min) FIG. 9 U.S. Patent Jun. 25,2002 Sheet 12 0f 18 US 6,410,731 B2 pH Dependence of the Stability of the B-OH Lactone Moiety of DB-91 0.0 0 25 50 75 100 125 150 175 200 TIME (Min) FIG. 11 U.S. Patent FRACTION OFLACTONE Jun. 25, 2002 Sheet 13 0f 18 US 6,410,731 B2 Comparison of the Stabilities of ci-Lactone Silateoans with their corresponding Hornosilatecans in PBS Buffer at 37°C 0.8 ~ 0.5 — O CHJ792 O DB-SB 0.4 - 0.2 - 0.0 120 . 08-202 O DB-81 0.4 - 0.2 . \H 0.0 I 1 i J 0 SD 120 180 1.0 C 0.8 - KO 0.6 - . DB-204 O DB-90 0.4 -i 0.2 - 0.0 I , I 0.0 i I i J 0 60 120 180 0 60 120 180 TIME (Min) FIG. 12 U.S. Patent Jun. 25,2002 Sheet 14 0f 18 US 6,410,731 B2 Comparison of the Stabilities of ot-Lactone Silatecans with their corresponding Homosilatecans in PBS/HSA at 37°C 0.8 . Q DB-202 O DB-81 O CHJ792 °-4 - 0 08-38 U1 2' P 0.2 - C.) ‘5 \\. '- O o I | I 0.0 i I I u. 0 so 120 180 o 60 120 180 1.0 C 0.8 ~ 0 08-204 05 _ 0 05-90 0‘4 q \ 0.2 - 0-0 l r r 0-0 . I I 0 so 120 180 0 60 120 180 TtME (Min) FIG. 13 U.S. Patent Jun. 25,2002 Sheet 15 0f 18 US 6,410,731 B2 m2OHU<J OZQ xEm m 2 a v. lmm S B P ‘mn 1a m H .m m a 1m C 1 m B .m {w 0 im H “0mm f mmwm ‘0 .W. oovv N Is 2 m S 4.. _d_ 0 0 a64. 21. O  0TIME (Min) FIG. 14 U.S. Patent Jun. 25,2002 Sheet 16 0f 18 US 6,410,731 B2 Stability of Homosilatecans in Red Blood Cells 1.0 V C A Lu . -~_. 3 —9 2 \QO 0.8 _ |__ 0% <0 _.1i LL 0.6 ~ Q» 21 Q 0.4 - |.-_- 0 DB-38 (if 0 DB-81 if v DB-QO LL: 0.2 - v DB-91 0-0 I I I I l t | 0 25 50 75 100 1 25 1 50 1 75 200 TIME (Min) FIG. 15 U.S. Patent Jun. 25,2002 Sheet 17 0f 18 US 6,410,731 B2 Comparison of the Stabilities of or-Laotone Silatecans with their corresponding Homosilatecans in Whole Blood at 37°C 1 o A 1.0 . O CHJ792 o DB-38 0.8 0 Q8 _ I DB-202 o DB-81 ‘)5 - 0.6 . 0.4 - _ LLI % 0.2 _ 0.2 _ |_ O < ..J 0.0 . . , 0,0 I I I LI- 0 60 120 100 0 so 120 100 O z 1.0 C Q R .- \Q\€ % 0.8 _ Ll. 0.6 - 0.4 _. \\ 0 DB-67 0 05-204 0.2 - O DB-91 0.2 < 0 [38-90 I a I I r l 0 60 120 180 0 60 120 180 TIME (Min) FIG. 16 U.S. Patent Jun. 25,2002 Sheet 18 0f 18 US 6,410,731 B2 Comparison of the Stability of Homosilatecans with Clinically Relevant Campothecins in Whole Blood at 37°C 1.0 .1“ V>_‘\ l\"_~‘ _ \ - ‘r .p\\ \‘ = 0.3 _ l v \\ . LIJ I!C) - E3 0.6 \E 0 <5 \ Lll. . SAC O \ 0 cm’ I: \ V TPT C) v SN-38 F: ‘o I [DB-67 (J 0 4 " U DB-38 E ‘ * 0 05-90 ' <> DB~91 Ll- A [DB-81 . \\ 0.2 ~ . ‘ Q 0.0 1 I 0 60 120 180 TIME (Min) FIG. 17 

Camptothecin Analogs and Methods of Preparation Thereof

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Camptothecin Analogs and Methods of Preparation Thereof

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