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US5276159.Pdf ||||||||||||| US005276159A United States Patent (19) 11 Patent Number: 5,276,159 Smith et al. 45 Date of Patent: Jan. 4, 1994 (54) DYNEMICIN ANALOGS: SYNTHESES, 56) References Cited METHODS OF PREPARATION AND USE PUBLICATIONS 75 Inventors: Adrian L. Smith, Bishops Stortford, Cabal et al. J.A.C.S. 112-3253 (1990). England; Chan-Kou Hwang, San Schoenen et al. Tetrahedron Lett. 30-3765-3768 Diego, Calif.; Sebastian V. (1989). Wendeborn, La Jolla, Calif.; Kyriacos Kende et al, Tetrahedron Lett. 29-4217-4220 (1988). C. Nicolaou, LaJolla, Calif.; Erwin P. Nicolaou et al. J.A.C.S. 114(23) 8908-21 (1992). Schreiner, Vienna, Austria; Wilhelm Konishi et al., J. Am. Chem. Soc. 112-3715-3716 Stahl, Frankfurt am Main, Fed. Rep. (1990). of Germany; Wei-Min Dai, San Konishi et al. J. Antibiot. 42:1449-1452 (1989). Diego; Peter E. Maligres, La Jolla, Golik et al, J.A.C.S. 109:3461-3462 (1987). both of Calif.; Toshio Suzuki, Golik et al. J.A.C.S. 109:3462-3464 (1987). Niigata, Japan Lee et al J.A.C.S. 109:3464-3466 (1987). Ellestad et al, J.A.C.S. 109:3466-3468 (1987). (73) Assignee: The Scripps Research Institute, La Primary Examiner-Cecilia Tsang Jolla, Calif. Attorney, Agent, or Firm-Dressler, Goldsmith, Shore, (21) Appl. No.: 886,984 Sutker & Milnamow, Ltd. 57) ABSTRACT (22 Filed: May 21, 1992 A fused ring system compound is disclosed that con tains an epoxide group on one side of the fused rings and Related U.S. Application Data an enediyne macrocyclic ring on the other side of the 63 Continuation-in-part of Ser. No. 788,225, Nov. 5, 1991, fused rings. The compounds have DNA-cleaving, anti which is a continuation-in-part of Ser. No. 734,613, Jul. microbial and tumor growth-inhibiting properties. Chi 23, 1991, abandoned, which is a continuation-in-part of meric compounds having the fused ring system com Ser. No. 673,199, Mar. 21, 1991, abandoned, which is a pound as an aglycone bonded to (i) a sugar moiety as the continuation-in-part of Ser. No. 562,269, Aug. 1, 1990, oligosaccharide portion or (ii) a monoclonal antibody abandoned. or antibody combining site portion thereof that im munoreacts with target tumor cells are also disclosed. 51) Int. Cl............................................. CO7D 277/60 Compositions containing a compound or a chimer are (52) U.S. C. ...................................... 548/147; 546/43; disclosed, as are methods of preparing a compound. 549/415 58) Field of Search ......................................... 548/147 1 Claim, 8 Drawing Sheets U.S. Patent Jan. 4, 1994 Sheet 1 of 8 5,276,159 FORM nao an ao an an an in FORM II sue an in . FORM ll O - O OPO P Y U.S. Patent Jan. 4, 1994 Sheet 2 of 8 5,276,159 £IR[[10IHº uo!!!q|u|u|VIIN?oz-e:OedHueuun ol?eauouedeuou?oueO1100??MouÐÁq?-Aq 00|| 08 0:2 Percentage inhibition of Growth U.S. Patent Jan. 4, 1994 Sheet 3 of 8 5,276,159 ouOquºoemuo!!(?u/sueufiouo?uu) 004 08 02 Percentage inhibition of Growth U.S. Patent Jan. 4, 1994 Sheet 4 of 8 5,276,159 EIRI[10IH9 09 019 02 Percentage inhibition of Growth U.S. Patent Jan. 4, 1994 Sheet 5 of 8 5,276,159 Form Forn Form Form Forn Forn lane: Form Form Form lane: 1 2 3 4. 5 6 7 8 U.S. Patent Jan. 4, 1994 Sheet 6 of 8 5,276,159 FIGURE 8 40.00 3 0. O O O O 20 30 40 Time (days) U.S. Patent Jan. 4, 1994 Sheet 7 of 8 5,276,159 Form Form Form U.S. Patent Jan. 4, 1994 Sheet 8 of 8 5,276,159 CHRIQ-5DIJIOT 2 Q - - TUMOR VOLUME (mm) (Thousands) 5,276,159 1. 2 Lett, 30:3765-3768 (1989); (e) Magnus et al., J. An. DYNEMICINANALOGS: SYNTHESES, METHODS Chem. Soc., 110:6921-6923 (1988); (f) Kende et al., Tet OF PREPARATION AND USE rahedron Lett, 29:4217-4220 (1988). This invention was made with government support BRIEF SUMMARY OF THE INVENTION under Contract CA 46446 awarded by the National Institutes of Health. The government has certain rights The present invention relates to novel fused ring in the invention. systems that contain an epoxide ring and an enediyne CROSS-REFERENCE TO RELATED macrocyclic ring, and thus have structural features APPLICATIONS O similar to dynemicin A. The compounds have DNA This is a continuation-in-part of application Ser. No. cleaving, antibiotic and antitumor activities. Composi 788,225, filed Nov. 5, 1991, which is a continuation-in tions and methods of making and using the compounds part of application Ser. No. 734,613, filed Jul. 23, 1991, are disclosed. now abandoned which is a continuation-in-part of appli 15 A fused ring compound of the invention has a struc cation Ser. No. 673,199, filed Mar. 21, 1991, now aban ture that corresponds to the formula doned, which is a continuation-in-part of application Ser. No. 562,269, filed on Aug. 1, 1990, now abandoned, whose disclosures are incorporated by reference. TECHNICAL FIELD 20 The present invention relates to novel DNA-cleav ing, cytotoxic and anti-tumor compounds, and particu larly to fused ring systems that contain an enediyne macrocyclic ring and also an epoxide ring, as well as chimeras that contain such a fused ring system. 25 BACKGROUND ART Dynemicin A (Compound 1 shown below), 30 wherein A is a double or single bond; R is selected from the group consisting of H, C1-C6 alkyl, phenoxycarbonyl, benzyloxycarbonyl, C1-C6 alkoxycarbonyl, substituted C1-C6 alkoxycarbonyl (particularly substituted ethoxycarbonyl where the sub 35 stituent is phenylsulfonyl or naphthylsulfonyl, with phenylsulfonyl most particularly preferred), o-nitroben zyloxycarbonyl and 9-fluorenylmethyloxycarbonyl; R2 is selected from the group consisting of H, car boxyl, hydroxylmethyl and carbonyloxy C1-C6 alkyl; OH OH R3 is selected from the group consisting of H and where Me is methyl, is a potent antibacterial and anti C1-C6 alkoxy; cancer agent recently isolated from Micromonospora R is selected from the group consisting of H, hy chersina (a) Konishi et. al., J. Am. Chem. Soc., droxyl, C1-C6 alkoxy, oxyacetic acid, oxyacetic C1-C6 112:3715-3716 (1990); (b) Konishi et al., J. Antibiot, 45 hydrocarbyl or benzyl ester, oxyacetic amide, ox 42:1449-1452 (1989)). Its striking molecular structure combines characteristics of both the enediyne Golik et yimidazilthiocarbonyl and C1-C6 acyloxy; al., J. Am. Chem. Soc., 109:3461-3462 (1987); Golik et R6 and R7 are each H or together with the unsatu al., J. Am. Chem. Soc., 109:3462-2464 (1987); Lee et al., rated carbon atoms of the intervening vinylene group J. Am. Chem. Soc., 109:3464-3466 (1987); Ellestad et al., 50 form a one, two or three fused aromatic six-membered J. Am. Chem. Soc., 109:3466-3468 (1987) and the an ring system; thracycline "Anthracycline Antibiotics', H. S. El Kha W together with the carbon atoms of the depicted, dem, ed., Academic Press, New York (1982) and "Re intervening vinylene group forms an aromatic hydro cent Aspects in Anthracyclinone Chemistry', Tetrahe carbyl ring system containing 1, 2 or 3 six-membered dron Symposia-in-Print No. 17, T. R. Kelly, ed., Tetra 55 hedron; 40:4537-4794 (1984) classes of antibiotics, and rings such that the fused ring compound contains 3,4 or presents a considerable challenge to organic synthesis as 5 fused rings, all but two of which are aromatic, and in well as a unique opportunity for the development of which that aromatic hydrocarbyl ring system, W, is new synthetic technology and therapeutic agents. joined a, b) to the structure shown (i.e., W is joined The calicheamicin and esperamicin derivatives are 60 a,b) to the nitrogen-containing rings of the structure perhaps the best known of the enediyne compounds. shown); and For a key paper describing the first synthesis of cali R8 is hydrogen or methyl, with the proviso that R8 is cheamicinone, see: (a) Cabal et al., J. Am. Chem. Soc., 112:3253 (1990). For other selected studies of model hydrogen when W, together with the carbon atoms of systems in the area of calicheanicins-esperamicins, see: 65 the intervening vinylene group is 9,10-dioxoanthra. (b) Nicolaou et al, J. Am. Chem., Soc., 110:4866-4868 In preferred practice, W together with the interven (1988); (c) Nicolaou et al., J. Am. Chem. Soc., ing vinylidene group forms a benzo ring so that a com 110:7247-7248 (1988); (d) Schoenen et al., Tetrahedron pound has the structural formula shown below. 5,276, 159 4. More preferably, R is C1-C5 alkoxy, hydroxyl, C1-C6 acyloxy, carboxyl, C1-C6 hydrocarbyl or benzyl carboxylate, oxyethanol, oxyacetic acid, oxyacetic acid amide, oxyethanol tertiary amino- or quaternary am monium-substituted C2-C3 alkyl carboxylate or 3 hydroxyprop-1-ynyl and R is hydrogen (H) or hy droxyl so that a fused ring compound has the structural formula shown below. O wherein R is selected from the group consisting of 15 hydrogen, C1-C6 alkoxy, hydroxyl, C1-C6 acyloxy, oxyethanol, oxyacetic acid, oxyacetic acid amide, oxya cetic C1-C6 hydrocarbyl ester, oxyethanol tertiary amino- or quaternary ammonium-substituted C2-C3 alkyl carboxylate, 3-hydroxyprop-1-ynyl, o-nitroben zyloxy and halo, and A and the remaining R groups are as before described. Also contemplated is a chimeric compound (also More particularly, in one embodiment, R2, R3, R5, referred to as a chimer or chimera) that is comprised of R7 and R8 are hydrogen so that a compound of the a before-described fused ring compound as an aglycone invention corresponds to the structural formula shown 25 portion bonded to (i) an oligosaccharide portion or (ii) below, where R1 and Rare as previously defined.
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