US005981691A Ulllted States Patent [19] [11] Patent Number: 5,981,691 Sikes [45] Date of Patent: Nov. 9, 1999 [54] IMIDE-FREE AND MIXED AMIDE/IMIDE 5,424,391 6/1995 Paik et al. ............................. .. 528/328 THERMAL SYNTHESIS OF 5,442,038 8/1995 Wood et a1. 528/363 POLYASPARTATE 5,443,651 8/1995 Kalota et al. 134/2 5,449,748 9/1995 Ramsey ................................. .. 530/300 Inventor:_ CI Steven_ _ Sikes, Mobile, Ala' _ (List continuedAdler eton a1. next ........................... page.) .. [73] Ass1gnee: University of South Alabama, Mobile, Ala, OTHER PUBLICATIONS Herrera, Science , vol. 96, p. 14 (1942). [21] Appl' N05 08/842,016 Katchalski, Advances in Protein Chemistry, vol. 6, pp. [22] Filed: Apr. 23, 1997 123485 (1951) FoX et al, Science, vol. 128, p. 1214 (1958). [51] Int. Cl.6 ................................................... .. C08G 69/10 Fox et al, A Laboratory Manual ofAnalytical Methods of [52] US. Cl. ........................ .. 528/328; 528/363; 562/553; Protein Chemistry, P. Alexander and H. P. Lundgren, eds., 562/571; 525/432 vol. 4, Pergamon Press, Oxford, pp. 127—151 (1966). [58] Field of Search ................................... .. 528/328, 363; Harada, Journal of Organic Chemistry, vol. 24, pp. 562/553; 525/66, 432 16624666 (1959) Pivcova et al, Biopolymers, vol. 20, pp. 1605—1614 (1981). [56] References Cited Pivcova et al, Polymer Reports, vol. 23, pp. 1237—1241 (1982). Us PATENT DOCUMENTS Saudek et al, Biopolymers, vol. 20, pp. 1615—1623 (1981). 3,052,655 9/1962 Fox et a1. ................................ .. 260/78 Won‘ 9 a1’ Macromoleculess) VOL 27’ PP' 7613_7620 3,076,790 2/1963 Fox et a1. .. 260/78 (1994) _ 3,846,380 11/1974 Fujimoto et a1. ................... .. 360/78 A Freeman et al, In Hydrogels and Biodegradable Polymers 4,363,797 12/1982 Jacquet et a1. .......................... .. 424/70 for Bioapplications, R. M. Ottenbrite et al, Eds, ACS 4,534,881 8/1985 Sikes et a1. 252/180 Symposium Series 627, American Chemical Society, Wash 4,585,560 4/1986 Sikes et a1. ..... .. 210/698 ington, DC, PP- 119—136(1996) 4582021 5/1986 Wheeler etaL ~~ 210/698 Matsubara et al, Polymer Preprints, Spring 1996, pp. 4,590,2604,603,006 5/19867/1986 HaradaSikes et etal. a1. ........................... ........................ .. 528/328252/180 - - - - 476967981 9/1987 Harada et a1‘ 525/328'2 IgI9e3r1_8e9t7a2,1.9I7o;t)rnal 0f Medicinal Chemistry, Vol. 16, PP. 4,839,461 6/1989 Boehmke .... .. 528/363 _ ' _ _ _ _ _ 478667161 9/1989 Sikes et aL 530/324 Termine et al,Archives ofBiochemistry and Biophysics, vol. 4,868,161 9/1989 Roberts . .. 514/49 140,119 307—317 (1970) 4,868,287 9/1989 sikes et a1, 530/324 Termine et a1, Calcif Tis. Res., vol. 22, pp. 149—157 (1976). 5,051,401 9/1991 Sikes - - - - - - - - - - - - - - - -- 514/7 Sarig et al, Desalination, vol. 17, pp. 215—299 (1975). 5,057,597 10/1991 Koskan ....... .. 528/328 Kokufuta et a1, Biosystems) VOL 9, pp 211_214 (1977)_ 571167513 5/1992 KOSka“ 6‘ a1~ 210/698 English Abstract of JP 8277329 (Oct. 22, 1996). 5,152,902 10/1992 Koskan et a1. 210/698 . 571757285 12/1992 Lehmann et a1‘ _ 544/141 Noti?cation of Transmittal of the International Search 572197952 6/1993 Koskan et a1_ 525/419 Report or the Declaration issued in corresponding PCT 5,221,733 6/1993 Koskan et a1. 530/333 Application NO- PCT/US98/07630 On Jul- 8, 1998 5,247,068 9/1993 Donachy et a1. 530/350 Saudek, Biopolymers, vol. 20, 1625—1633 (1981). 5,260,272 11/1993 Donachy et al- - 524/12 Eisenreich et al, Environmental Letters, vol. 9, pp. 43—53 5,284,512 2/1994 Koskan et a1. 106/416 (1975)' 5,284,936 2/1994 Donach et a1. 530/350 - 5,286,810 2/1994 Wood ....... .. 525/421 gig/11666552566’ lothEd"MarthaWmdh°1Z’Ed"N°'853’ 5,288,783 2/1994 Wood .................................... .. 525/418 ' ' _ _ 5,292,858 3/1994 Wood .................................... .. 528/345 CRCHandbOOk of Chemistry and Physics) 68th Ed» Robert 5,292,864 3/1994 Wood et a1. .. 528/490 0 Weast, Ph-D, Ede P- C—699 (1998) 5,296,578 3/1994 Koskan et a1. 528/363 Termine et al,Archives ofBiochemistry and Biophysics, vol. 5,315,010 5/1994 Koskan et a1. 548/520 140, 318—325 (1970). 5,319,145 6/1994 Paik et a1. ............................. .. 528/328 5,328,690 7/1994 Sikes ..................................... .. 424/401 Primary Examiner—Cecilia J. Tsang 5,329,020 7/1994 Kalota et al. 548/520 Assistant Examiner—David Lukton 5,350,735 9/1994 Kinnefsley et a1~ 504/147 Attorney, Agent, or Firm—Oblon, Spivak, McClelland, 5,357,004 10/1994 Calton et a1. 525/435 Maier & Neustadt, RC 5,367,047 11/1994 Wood ...... .. 528/363 5,371,177 12/1994 Paik et al. .. 528/361 [57] ABSTRACT 5,371,179 12/1994 Paik et al. 528/363 5,371,180 12/1994 Groth et a1. .. 528/363 Thermal polymerization of a salt of aspartic acid affords 5,373,088 12/1994 Koskan et a1 528/363 polyaspartate directly Without hydrolyZing polysuccinimide. 5,380,817 1/1995 Paik et a1~ 528/328 CopolymeriZation of a salt of aspartic acid With aspartic acid ‘gold itself affords a copolymer of succinimide and aspartate 5,393,868, , 2/1995 Freemanos an e eta. a1. .. 528/480 w?nchhmayt- :16 mild?’- dingimzgd- - t? produce a Sulfonated’ 5,401,428 3/1995 Kalota et a1. .. 252/493 p 05p on“ or y mp O 1Z6 p0 ymer' 5,408,028 4/1995 Wood et a1. .... .. 538/328 5,410,017 4/1995 Bortnick et a1. ...................... .. 528/363 47 Claims, 10 Drawing Sheets 5,981,691 Page 2 US. PATENT DOCUMENTS 5,510,427 4/1996 Wood .................................... .. 525/435 5 463 017 “V1995 Paik et al 5286“ 5,522,863 6/1996 Spano et a1. ............................ .. 607/45 ’ ’ ' """"""""""""""" " 5,523,023 6/1996 Klernstuck et a1. .................. .. 252/542 272227359) £32 gj’s‘ld ~~~~ ~~ ~~ 5,525,257 6/1996 Kleinstuck et a1. 252/181 574687838 11/1995 Boehmke et a1‘ 528/363 5,530,091 6/1996 Wagner et a1. ....................... .. 528/328 574707843 11/1995 Stahl et a1‘ ~~~~~~ n 514/61 5,531,934 7/1996 Freeman et a1. ...................... .. 252/390 5,470,942 11/1995 Alexander et a1‘ ' 528/328 5,536,813 7/1996 Charpenel et a1. ................... .. 530/324 574787919 12/1995 Koskan et a1‘ ' 528/363 5,543,490 8/1996 Groth et a1. .......................... .. 528/328 5,484,860 1/1996 Wood et al. .. 525/432 5543491 8/1996 W°°d 6‘ a1~ 528/328 5,484,878 1/1996 Paik et a1. ....... .. 528/328 5,548,036 8/1996 Kroner et 91- ~~ 525/419 574847945 1/1996 Nagamoto et aL " 548/520 5,552,514 9/1996 Adler et al. 528/328 5,488,088 1/1996 Wood et a1_ ____ __ __ 525/432 5,552,516 9/1996 Ross et a1. ............................ .. 528/363 5,491,212 2/1996 Paik et a1_ __ 528/363 5,552,517 9/1996 Martin ................................... .. 528/363 5,491,213 2/1996 BatZel ...... .. .. 528/480 5,554,721 9/1996 Adler et a1. 528/328 5,493,004 2/1996 Groth et al. .. 528/363 5,556,938 9/1996 Freeman et a1. .. 528/328 5,494,995 2/1996 Wood et a1. .. 528/328 5,587,146 12/1996 Wood et a1. ..... .. 424/49 5,496,914 3/1996 Wood et al. .. 528/328 5,593,947 1/1997 Kinnersley et a1. 504/283 5,502,117 3/1996 Wood .. 525/435 5,594,077 1/1997 Groth et a1. 525/451 5,506,335 4/1996 Uhr et a1. .. 528/322 5,648,082 7/1997 Sikes ......... .. 424/401 5,508,434 4/1996 BatZel et a1. 548/520 5,681,920 10/1997 Vallino et a1. 528/328 5,510,426 4/1996 Wood .................................... .. 525/435 5,773,564 6/1998 Sikes ..................................... .. 528/363 U.S. Patent Nov. 9, 1999 Sheet 2 0f 10 5,981,691 U.S. Patent Nov. 9, 1999 Sheet 3 0f 10 5,981,691 656.9 1152.7 l1 15001000 1421.41690.2 | 2000 FIG’.2 4000 00 %T 000 U.S. Patent Nov. 9, 1999 Sheet 4 0f 10 5,981,691 1000 I500 1715.7 2000 FIG.3 34423 400035003000 100.00' U.S. Patent Nov. 9, 1999 Sheet 5 0f 10 5,981,691 I 1000 14003;56.45% 1697.9;43.74781 1 1500 1647.0;43.65%1 2000 —3439.8;28.10%1 FIG’.4 0.00 U.S. Patent Nov. 9, 1999 Sheet 6 0f 10 5,981,691 554.3 | 500 1060.0\ 12265 852.515913 1l 1516.11580.914118 1501.8 200015001000_ 1CM 3055.2 3349.5 40003500 1 FIG’.5 110.56— Z1 1056 U.S. Patent Nov. 9, 1999 Sheet 7 0f 10 5,981,691 560.5670-‘ cm‘15001000 I206.1 1705.71396.9 1584.1 FIG.6 250020001500 2369.8 3000 3386.2 3500 4000 100.73 m —3462 U.S. Patent Nov. 9, 1999 Sheet 8 0f 10 5,981,691 130.05 %T 356 U.S. Patent Nov. 9, 1999 Sheet 9 0f 10 5,981,691 1 1000 l 1500 FIG.8 l 4000 42 %T —1458 U.S. Patent Nov. 9, 1999 Sheet 10 0f 10 5,981,691 a w vnNw g2252285%6 m. 2.62:5 5,981,691 1 2 IMIDE-FREE AND MIXED AMIDE/IMIDE residues Was already knoWn from measurements of refrac THERMAL SYNTHESIS OF tive index (Kovacs, J ., et al., Naturwissenschaften, vol.