US006262257B1 (12) United States Patent (10) Patent N0.: US 6,262,257 B1 Gale et al. (45) Date of Patent: Jul. 17, 2001

(54) CALIXPYRROLES, Andreetti, G., “Crystal and Molecular Structure of CALIXPYRIDINOPYRROLES AND Cyclo{quarter[(5—t—butyl—2—hydroxy—1,3—phenylene)m CALIXPYRIDINES ethylene]} Toluene (1:1) Clathrate,” J. C.S. Chem. Comm., 1005—1007, 1979. (75) InVeIlIOrSI Philip A- Gale; JOIlathaIl L- Sessler; Asfari, et al., “Quick Synthesis of the First Double Porphy JOhIl W- Genge, all Of Austin, TX rin Double Calix[4]arene,” Tetrahedron Letters, vol. 34, No. (US); Vladimir A. Kral, Praha (CZ); 4,119 627428, 1993 Alldl‘ei Andrievsky, Rochester, NY Baeyer, A., “Ueber ein Condensationsproduct von Pyrrol mit (US); Vincent Lynch, Austin, TX (US); Aceton,” Ber Dtsch. Chem. Ges., 19:2184—2185, 1986. Petra I- 831150111, Edgewater, NJ (Us); Beer, et al, “A Neutral Upper to LoWer Rim Linked Bis— William E- Allell, Austin, TX (Us); Calix[4]arene Receptor that Recognises Anionic Guest Spe ChI‘iStOPhEI‘ T- BI‘OWII, Austin, TX cies,” Tetrahedron Letters, vol. 36, No. 5, pp. 767—770, J an., (US); Andreas Gebauer, Austin, TX 1995 _ (Us) Beer, et al., “Anion Recognition by Novel Ruthenium(II) (73) Assignee:_ ls3oard ofAReg'entrskUligiglersity_ _ of Texas SBi 052/ ridCgem l Calix cogmglunw 4 arene 126941271,Rece tor Molecules,”1994' J. Chem. ystem’ usnn’ ( ) Beer, et al., “Anion Recognition by Redox—Responsive ( * ) Notice, Subject to any disclaimer the term of this Ditopic Bis—Cobaltocenium Receptor Molecules Including a patent is extended or adgusted under 35 Novel Calix[4]arene Derivative That Binds a Dicarboxylate U_S_C_ 154(k)) by 0 days_ Dianion, Organometallzcs, 14:3288—3295, Jul., 1995.' ' Beer, et. al., “Structures of Potassium encapsulated Within (21) APPL NO; 08/833,379 the 1,3—Alternate Conformation of Calix[4]arenes,” J. _ Chem. Soc. Dalton Trans., 3479—3485, 1994. (22) Flled: Apr- 4’ 1997 Beer, et al., “Synthesis and Co—ordination Chemistry of a Related US‘ Application Data Novel BIS(B6I1ZO CroWn Ether) Substituted Calix[4]ar’ene (60) Provisional. . application. . No. 60/033,396, ?led on Dec. 17, that can Simultaneously Complex Cations and Anions, J. 1996, provisional application No. 60/033,395, ?led on Dec. c?lem' SOC‘ Daltonirans'a 3117_3123’ Oct” 1995' 17, 1996, provisional application No. 60/026,694, ?led on Bohrner, V., “Calixarenes, Macrocycles With (Almost) SeP-25, 1996, Provisiona1 application No- 60/024,203, ?led Unlimited Possibilities,” Angew. Chem. Intl. Ed. EngL, on Aug. 27, 1996, and provisional application No. 60/014, 34,713_745 Jul‘ 1995 890’ ?led on Apr' 5’ 1996' Bonar—LaW, R., “ Synthesis in Surfactant Solu 7 _ tion: Multicomponent Assembly in Micelles,” J. Org. (51) Int. Cl...... C07B 47/00, C07D 487/22 Chem.) 61:3623_3634, Jan.’ 1996. BroWn, et al., “The Condensation of Cyclohexanone With (52) US. Cl...... 540/145 Furan and ,” Canadian J‘ of Chem‘) 49: 4017_4022,

(58) Field of Search ...... 540/145 1971' (56) References Cited (List continued on next page.) U.S. PATENT DOCUMENTS Primary Examiner—Robert Gerstl (74) Attorney, Agent, or Firm—Thorpe, North & Western 5,808,059 * 9/1998 Sessler ...... 450/474 LLP FOREIGN PATENT DOCUMENTS (57) ABSTRACT 0 233 701 8/1987 (EP). The present invention provides calixpyrrole, WO 89/08092 9/1989 (WO) . WO 93/13150 calixpyridinopyrrole, and calixpyridine macrocycles, having 7/1993 (WO) . 4, 5, 6, 7, or 8 heterocyclic rings, as Well as syntheses, OTHER PUBLICATIONS derivatives, conjugates, multimers, and solid supports Aoyama, et al., “Multi—Point Interaction of Phosphates With thereof. Such macrocycles have proved to be effective and Protonated Pyridylporphyrin Discrimination of Monoalkyl selective ion- and neutral molecule-binding agents forming and Dialkyl Phosphates,” Chemistry Letters, pp. 1241—1244, supramolecular ensembles, and ion- and neutral molecule 1991. separation agents. The macrocycles are fully meso-non Vogel, et al., “2,7,12,17—Tetraproplyporphycene—Counter hydrogen-substituted porphyrinogens, a feW molecules of part of Octaethylporphyrin in the Porphycene Series,” Which Were previously knoWn but not recognized as pos Angew. Chem. Int. Ed. Engl., 26, No. 9, pp. 928—931, 1987. sessing anion- or molecule-binding properties. The binding Vogel, et al., “NeW Porphycene Ligands: Octaethyl— and mode is noncovalent, primarily that of hydrogen-bonding, Etioporphycene (OEPc and EtioPc)—Tetra — and Pentaco thereby providing a neW mode for liquid chromatography, ordinated Zinc Complexes of OEPc,” Angew. Chem. Intl. that of Hydrogen Bonding Liquid Chromatography. Further Ed. EngL, 32, No. 11, pp. 1600—1604, 1993. useful applications of the macrocycles provided herein Pending Application in India; No. 708/MAS/97 to Gale et al. include environmental remediation by removal of undesired ?led Apr. 3, 1997. ions or neutral molecules, and removal of phosphate for Allen, et al., “Binding of Neutral Substrates by Calix[4] kidney dialysis. ,” J. Am. Chem. Soc., vol. 118, No. 49, pp. 12471—12472, Sep., 1996. 1 Claim, 30 Drawing Sheets US 6,262,257 B1 Page 2

OTHER PUBLICATIONS Fujimoto, et al., “Synthesis and Crystallographic Studies of a Calix[4]arene With a 1,3—Alternate Conformation,” J. ChelintZev, B., and Tronov, V., “Simple condensation of Chem. Soc., Perkin Trans. 2, pp. 643—648, 1992. pyrrole With methyethyl and methylhexyl ketone, Gale, et al., “Calix[4]pyrroles: C—rim substitution and tun mixed condensation With acetone and methyethyl ketone, ability of anion binding strength,” Chem. Commun., pp. and relation of these reactions to the determination of the 665—666, 1997. formulas of and hemin,” J. Russian Physical Gale, et al., “Calix[4]pyrroles: Old Yet NeW Anion—binding Chem. Soc., 48:1197—1209, 1916, Chemical Abstracts only, Agents,” J. Am. Chem. Soc., vol. 118, No. 21, pp. p. 1418. 5140—5141, Jan., 1996. ChelintZev, V.V., and Tronov, B.V., “Process of condensation Gale, et al., “Calixprroles: old yet neW anion binding of pyrrole and acetone. 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Fig.1A U.S. Patent Jul. 17, 2001 Sheet 2 0f30 US 6,262,257 B1 U.S. Patent Jul. 17, 2001 Sheet 3 0f30 US 6,262,257 B1 U.S. Patent Jul. 17, 2001 Sheet 4 0f30 US 6,262,257 B1

Fig.2B U.S. Patent Jul. 17, 2001 Sheet 5 0f30 US 6,262,257 B1 U.S. Patent Jul. 17, 2001 Sheet 6 6f30 US 6,262,257 B1 U.S. Patent Jul. 17, 2001 Sheet 7 0f30 US 6,262,257 B1 U.S. Patent Jul. 17, 2001 Sheet 8 0f30 US 6,262,257 B1

U.S. Patent Jul. 17, 2001 Sheet 10 0f 30 US 6,262,257 B1

mat U.S. Patent Jul. 17, 2001 Sheet 11 0f30 US 6,262,257 B1

.mtN U.S. Patent Jul. 17, 2001 Sheet 12 0f 30 US 6,262,257 B1

Fig. 8

U.S. Patent Jul. 17, 2001 Sheet 14 0f 30 US 6,262,257 B1

Fig. 10 U.S. Patent Jul. 17, 2001 Sheet 15 0f 30 US 6,262,257 B1

16001400120010008006004002000 mV Fig. 118 U.S. Patent Jul. 17, 2001 Sheet 16 0f 30 US 6,262,257 B1

1600 1200 800 400 0 -400 -800 mV Fig. 12A

(1) (2) \ (3)

1600140012001000800600400 200 0 mV Fig . 123 U.S. Patent Jul. 17, 2001 Sheet 17 0f 30 US 6,262,257 B1

Fig. 13