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United States Patent 19 11 Patent Number: 5,726,329 Jones Et Al IIIUS005726329A United States Patent 19 11 Patent Number: 5,726,329 Jones et al. 45 Date of Patent: Mar. 10, 1998 54 MODIFIED PHOSPHOROUS 4-312541 11/1992 Japan. INTERMEDIATES FOR PROVIDING 110434 5/1964 Norway. WO 85/03704 8/1985 WIPO. FUNCTIONAL GROUPS ON THE 5' END OF WO 86/04093 7/1986 WIPO OLGONUCLEOT DES WO 87/O2777 5/1987 WIPO 75) Inventors: David S. Jones; John P. Hachmann; OTHER PUBLICATIONS Michael J. Conrad, all of San Diego; Stephen Coutts, Rancho Santa Fe; Agrawal et al. "Efficient methods for attaching non-radio Douglas Alan Livingston, San Diego, active labels to the 5' end of synthetic oligodeoxyribonucle all of Calif. otides". Nucl. Acids Res., 14(15):6227-6245 (1986). Kremsky et al., “Immobilization of DNA via oligonucle 73 Assignee: La Jolla Pharmaceutical Company, otides containing an aldehyde or carboxylic acid group at the San Diego, Calif. 5' terminus", Nucl. Acids Res., 15(7):2891-2909 (1987). Eshhar et al., “Induction of tolerance to nucleic acid deter 21 Appl. No.: 436,112 minants by administration of a complex of nucleoside D-glutamic acid and D-lysine (D-GL)".J. immunol. (1975) 22 Filed: May 8, 1995 114(2):872-876. Borel et al. "Prevention of murine lupus nephritis by car Related U.S. Application Data rier-dependent induction of immunologic tolerance to dena 62 Division of Ser. No. 335,687, Nov. 8, 1994, which is a tured DNA" Science (1973) 182:76-78. division of Ser. No. 915,589, Jul. 15, 1992, Pat. No. 5.391, Parker et al., "Modification of NZB/NZWF autoimmune 785, which is a continuation-in-part of Ser. No. 731,055, Jul. 15, 1991, abandoned, which is a continuation-in-part of Ser. disease by development of tolerance to DNA".J. immunol. No. 494,118, Mar. 13, 1990, Pat No. 5,162,515, which is a (1974) 113(1):292-297. continuation-in-part of Ser. No. 466,138, Jan. 16, 1990, Borel et al., "A possible new therapy of systemic lupus abandoned. erythematosus (SLE)” Ann. N.Y. Acad. Sci. (1986) 51 Int. Cl. ... COTF 9/655; CO7F 9/141; 475:296-306. CO7F 9/24: CO7F 9/146; CO7F 9/42 Papalian et al., "Reaction of systemic lupus erythematosus 52 U.S. Cl. ...................... 552/105; 549/221; 585/151; antinative DNA antibodies with native DNA fragments from 585/168; 585/180 20 to 1200 base pairs” J. Clin. Invest. (1980) 65:469-477. (58) Field of Search ............................ 552/105; 549/221; (List continued on next page.) 558/151,168, 180 Primary Examiner-Michael G. Ambrose 56 References Cited Attorney, Agent, or Firm-Morrison & Foerster LLP U.S. PATENT DOCUMENTS 57 ABSTRACT 2,028,403 1/1936 Mares. Phosphoramidites of the formula 2,362,326 11/1944. Thurston et al. 2,585,884 2/1952 Whetstone et al. 2,619,493 11/1952 Norris. 2,946,806 7/1960 Nentwig et al. N 3,004,894 10/1961 Johnson et al.. M. N. 3.201420 8/1965 Fuzesi et al. R1 R2 3,225,063 12/1965 D'Alelio. 3,308,064 3/1967 Schlight et al. Y M 1. 3,926,912 12/1975 Mayer-Mader et al. 4,058,550 11/1977 Shepard et al.. where R is a base-labile protecting group, R' and R are 4,191,668 3/1980 Katz. individually alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 4,220,565 9/1980 Katz. 4,465,869 8/1984 Takaishi et al. 8 carbon atoms, or aryl of 6 to 20 carbon atoms or are joined 4.575,558 3/1986 Mai et al.. together to form with the nitrogen atom a cyclic structure of 4,588,824 5/1986 Baldwin et al. 4-7 carbon atoms and 0 to 1 annular chalcogen atoms of 4,650,675 3/1987 Borel et al.. atomic number 8 to 16, G is a hydrocarbylene group of 1 to 4,751,181 6/1988 Keene. 20 carbon atoms and Z is a hydroxy-protected vicinal diol 4,845,219 7/1989 Inoue et al. group bound to G by one of the vicinal diol carbon atoms or 4,877,891 10/1989 Becker et al.. a disulfide group and bound to G by one of the sulfur atoms 4,983,759 1/1991 Inoue et al., of the disulfide group, with the proviso that G is of at least 4,997,928 3/1991 Hobbs. 4 carbon atoms when Z is said disulfide group are used in 5,252,760 10/1993 Urdea et al.. conventional automated oligonucleotide synthesis to intro 5,391,785 2/1995 Jones et al. duce a functional aldehyde or thiol group on the 5' end of the oligonucleotide to thereby provide a reactive site on. the FOREIGN PATENT DOCUMENTS oligonucleotide that may be used to conjugate the oligo 0147768 2/1989 European Pat. Off.. nucleotide to molecules that contain a free amino group or 0354323 2/1990 European Pat. Off.. an electrophilic center reactive with a thiol group. 0.399 330 A1 11/1990 European Pat. Off. 2326586 12/1973 Germany. 3937.116 5/1991 Germany. 11 Claims, 5 Drawing Sheets 5,726,329 Page 2 OTHER PUBLICATIONS Fréchet et al., "Use of polymers as protecting groups in organic synthesis. III. Selective functionalization of poly Stollar et al., "Secondary structure in denatured DNA is hydroxy alcohols" Can. J. Chem. (1976) 54:926-934. responsible for its reaction with antinative DNA antibodies of systemic lupus erythematosus sera” J. Clin. Invest. (1980 Ichikawa et al., “An asymmetric synthesis of glycerol 66:210-219. derivatives by the enantioselective acylation of prochiral Borel et al., "Oligonucleotide linked to humangammaglobu glycerol" Chen Lett. (1984) pp. 949-952. lin specifically diminishes anti-DNA antibody formation in Sedarevich, "Glyceride isomerizations in lipid chemistry"J. cultured lymphoid cells from patients with systemic lupus Amer: Oil Soc. (1967) 44(7):381-393. The corresponding erythematosus" J. Clin. Invest. (1988) 82:1901-1907. Chemical Abstract, specifically Chem. Abstract (1967) Mitsuo et al., "Preparation of lecithin-type of phospholipid 67:10965 (abstract No. 116524m), was previously submit analogues and mesomorphic states" Chem. Pharm. Bull. ted, (1978) 26(5):1493-1500. Shvets et al., "Lipids. LIX. Determination of the configu Gupta et al., "A general method for the synthesis of 3'-sulf ration of a B-diglycerides prepared from D-mannitol" Zh. hydryl and phosphate group containing oligonucleotides" Org. Kihim. (1968) 4(4):597-603. The corresponding Chem. Abstracts (1991) 115:976 (abstract No. 183758p). Chemical Abstract, specifically Chem Abstract (1968) U.S. Defensive Publication No. T909012 to McCollum (3 69:231 (abstract No. 2454z), was previously submitted. Apr. 1973). Williams et al., "Stereocontrolled transformations of orthoe Hedgley et al., "Glycerol esters of thiobenzoic O-acids and ster intermediates into substituted tetrahydrofurans' J. Am. thioglycerol esters of benzoic acid" J. Chem. Soc. (1970)pp. Chem. Soc. (1984) 106(9):2641-2644. 467-471. Verkade et al., "Synthesen von glyceriden mit hilfe von Schneider, K.C. et al.; "Oligonucleotides Containing Flex tritylverbindungen IV" Recl. Tray. Pays-Bas (1940) ible Nucleoside Analogues"; J. Am. Chem. Soc. (1990) 112: 59:1123-1140. 453-455. Baggett et al., "Aspects of stereochemistry. PartxXI. Abso lute configuration of benzylidene derivatives of some acy Database CA on STN, accession No. 110:231967, Colum clic polyhydric alcohols" J. Chem. Soc. (1965) pp. bus: Chemical Abstracts Service (Veeneman et al.). 1988. 3394-3400. Veeneman et al.; "Synthesis of a Cell Wall Component of Jackson et al., "Synthetic glycerides. IV. Esters of aromatic Haemophilus (Actinobacillus) Pleuropneumoniae Type 2"; and aliphatic acids”. Am. Chem. Soc. (1933) 55:678-680. Recl. Trav. Chim. Pays-Bas (1988) 107(10):610-12. U.S. Patent Mar. 10, 1998 Sheet 1 of 5 5,726,329 °OSO/OWNWN HO sºdalo:son IOSWNGI8JL Z8O swadio:::OZ{{ U.S. Patent Mar 10, 1998 Sheet 2 of 5 5,726.329 Z8O sºdalo:spºorwa | JÁd/IOLWCI U.S. Patent Mar. 10, 1998 Sheet 3 of 5 5,726.329 JLVNCIO„LVdIIGIIwao):º(Id-!)N~~~' U.S. Patent Mar. 10, 1998 Sheet 4 of 5 5,726,329 - M.V. w - Mir-e- FG, 4. U.S. Patent Mar. 10, 1998 Sheet 5 of 5 5,726.329 Rif F.G. s. 5,726.329 1. 2 MOOFED PHOSPHOROUS A principal object of the present invention is to provide INTERMEDIATES FOR PROVIDENG novel modified phosphorous intermediates that may be FUNCTIONAL GROUPS ON THE 5' END OF employed in the various types of oligonucleotide synthesis OLGONUCLEOT DES methods and which have activatable groups that may be converted to a free aldehyde or sulfhydryl group once they CROSS REFERENCE TO RELATED have been added onto the 5' end of an oligonucleotide. The APPLICATIONS free aldehyde/sulfhydryl group is useful for coupling or conjugating the oligonucleotide to labels, ligands, polymers This application is a divisional of application Ser. No. or solid surfaces. These new intermediates meet the follow 08/335/687 filed Nov. 8, 1994, which is a divisional of Ser. 0 ing criteria: 1) the activatable group is compatible with all No. 07/915,589, filed Jul 15, 1992, now U.S. Pat. No. steps of conventional oligonucleotide synthesis procedures; 5.391,785, which is a continuation-in-part of Ser. No. 07/731055, filed Jul. 15, 1991, now abandoned, which is a 2) the activation is effected under conditions that do not continuation-in-part of Ser. No. 07/494,118, filed Mar. 13, damage the oligonucleotide; 3) the coupling is effected 1990, now U.S. Pat. No. 5,160,515, which is a continuation under conditions that do not damage the oligonucleotide or in-part of Ser.
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