Strobilurins: Evolution of a new class of active substances

Angewandte Chemie - International Edition

Volumn 38, Issue 10, 1999, Pages 1328-1349

  Sauter, Hubert ^a   Steglich, Wolfgang ^b   Anke, Timm ^c  

^a BASF SE   (Germany)

^b UNIVERSITY OF MUNICH   (Germany)

^c University of Koblenz Landau   (Germany)

Author keywords

Active substance research; Fungicides; Natural products; Strobilurins; Structure activity relationships

Indexed keywords

ANTIFUNGAL AGENT; OUDEMANSIN DERIVATIVE; STROBILURIN DERIVATIVE; UNCLASSIFIED DRUG;

COMPUTER MODEL; CROP; DRUG RESEARCH; DRUG STRUCTURE; DRUG SYNTHESIS; FUNGICIDAL ACTIVITY; FUNGUS; NONHUMAN; REVIEW; STRUCTURE ACTIVITY RELATION;

EID: 0033577815     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/(sici)1521-3773(19990517)38:10<1328::aid-anie1328>3.0.co;2-1     Document Type: Review

References (162)

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24. b) "Strobilurins and Oudemansins": T. Anke, W. Steglich in Drug Discovery from Nature (Eds.: S. Grabley, R. Thiericke), Springer, Heidelberg, 1999, in press.
25. K. A. Wood, D. A. Kau, S. K. Wrigley, R. Beneyto, D. V. Renno, A. M. Ainsworth, J. Penn, D. Hill, J. Killacky, P. Depledge, J. Nat. Prod. 1996, 59, 646-649.
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31. D. Xia, C.-A. Yu, H. Kim, J.-Z. Xia, A. M. Kachurin, L. Zhang, L. Yu, J. Deisenhofer, Science 1997, 277, 60-66.
32. "β-Methoxyacrylate Antibiotics: From Biological Activity to Synthetic Analogues": T. Anke, W. Steglich in Biologically Active Molecules (Ed.: U. P. Schlunegger), Springer, Berlin, 1989, pp. 9-25.
33. G. Schramm, Dissertation, Universität Bonn, 1980.
34. W. Steglich, G. Schramm, T. Anke, F. Oberwinkler (Hoechst AG), EP-A 044448, 1980 (priority date July 4, 1980).
35. We are indebted to the Federal Ministry for Research and Technology (now the BMBF) for their support of the project Constituents of Microorganisms and Plants as New Active Substances or Models for Active Substances in Crop Protection between 1983 and 1992.
36. a) "Strobilurins - From Natural Products to a New Class of Fungicides": H. Sauter, E. Ammermann, F. Röhl in Crop Protection Agents from Nature: Natural Products and Analogues (Ed.: L. G. Copping), The Royal Society of Chemistry, Cambridge, 1996;
37. b) "Mitochondrial respiration as a target for antifungals: lessons from research on strobilurins": H. Sauter, E. Ammermann, R. Benoit, S. Brand, R. E. Gold, W. Grammenos, H. Köhle, G. Lorenz, B. Müller, F. Röhl, U. Schirmer, J. B. Speakman, B. Wenderoth, H. Wingert in Antifungal Agents, Discovery and Mode of Action (Eds.: G. K. Dixon, L. G. Copping, D. W. Hollomon), BIOS Scientific Publishers, Oxford, 1995, pp. 173-191.
38. a) B. A. M. Schwalge, Dissertation, Universität Bonn, 1986;
39. b) S. Zapf, Dissertation, Universität Kaiserslautern, 1994;
40. c) M. Engler, Dissertation, Universität Kaiserslautern, 1997.
41. We would like to thank E. Ammermann for the greenhouse test results and for helpful discussions in this context.
42. U. Schirmer, S. Karbach, E. H. Pommer, E. Ammermann, W. Steglich, B. A. M. Schwalge, T. Anke (BASF AG), EP-A 203606, 1985 (priority date May 30, 1985).
43. U. Schirmer, S. Karbach, E. H. Pommer, E. Ammermann, W. Steglich, B. A. M. Schwalge, T. Anke (BASF AG), EP-A 229974, 1985 (priority date December 20, 1985).
44. U. Schirmer, S. Karbach, E. H. Pommer, E. Ammermann, W. Steglich, B. A. M. Schwalge, T. Anke (BASF AG), EP-A 226917, 1985 (priority date December 20, 1985).
45. U. Schirmer, S. Karbach, E. H. Pommer, E. Ammermann, W. Steglich, B. A. M. Schwalge, T. Anke (BASF AG), EP-A 203608, 1985 (priority date May 30, 1985).
46. a) "Factors Involved in Apparent Discrepancies of Fungicide Performance": R. E. Gold, A. Akers, H. Sauter in Comparing Glasshouse and Field Pesticide Performance II (Eds.: H. G. Hewitt, J. Caseley, L. G. Copping, B. T. Grayson, D. Tyson), British Crop Protection Monograph 49, 1994, pp. 47-56.
47. b) For both phenomena the different time schedules of the tests appears to be critical. Whereas in the greenhouse test the interval between application of the active substance and evaluation of the test was generally only 8 days in the preliminary tests, in field trials it can be up to 30 days or longer depending on the indication. False positive results for individual test substances in the greenhouse tests can thus be easily explained in terms of a relatively rapid disappearance of the active substance through various breakdown pathways (e.g. photolysis, metabolism). More difficult to rationalize are false negative results. A key factor here could be the relatively slow "outflow" (i.e. the increase in the available concentration) of the active substance into discrete molecules that is necessary for any activity, particularly in cases where under greenhouse conditions compounds with higher melting points had been deposited onto the test plants in microcrystalline form. On the other hand, a slow, but continuous outflow under outdoor conditions can easily result in particularly good activity at the end of a trial. A further factor that might result in field trials yielding comparatively better results than the greenhouse tests could be a particularly slow "disappearance" as a result of high biostability of individual substances.
48. c) See Table 1 for examples of rank correlations of greenhouse results against corresponding field trial results.
49. This seemingly very serious difficulty faced by fungicide researchers increasingly became an issue during the lead structure optimization with the strobilurins, and led to an extensive reevaluation at BASF of the selection procedures adopted in going from greenhouse tests to field trials. H. Sauter is grateful to his many collaborators in this project for numerous interdisciplinary discussions on this matter, in particular the head of biological fungicide research at BASF, G. Lorenz, for her helpful support and insightful contributions.
50. Taking advantage of the different seasonal cycles of the northern and southern hemispheres makes it possible to stage two field trial campaigns each year spaced at distinct intervals.
51. We are grateful to E. H. Pommer for the field trial results.
52. s was corrected in accordance with equation 9.4 on p. 207 of the book cited above.
53. a) H. Meier, Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, Vol. 4/5a Photochemie I, 1975, pp. 189-204, pp. 254, pp. 511-519.
54. b) Experiments have shown that some enol ether stilbenes, instead of undergoing a simple photochemical cyclization of the 13,5-hexatriene system to form dihydrophenanthrenes, react preferentially by a different pathway involving the enol ether double bond of the pharmacophore (see refs. [45a, b]).
55. M. J. Bushell, K. Beautement, J. M. Clough, P. DeFraine, V. M. Anthony, C. R. A. Godfrey (ICI), EP-A 178826, 1984 (priority dates October 19, 1984, December 20, 1984, date of publication April 23, 1986).
56. For a European patent application, there is an 18-month time lag between submission (first priority date) and publication. Following the priority date of his own application the submitter must therefore wait eighteen months before he can be certain there are no competing patents in the pipeline ahead of him.
57. [41]
58. From this point onwards reference is made in the text only to Zeneca, even though "ICI" may be technically more correct in the chronological sequence of events.
59. b) In 1992/1993 ICI was split into two separate companies. The chemicals business continue to trade under the name ICI, and the life sciences enterprises were spun off and have thereafter operated under the name Zeneca.
60. The Zeneca team has published a number of excellent reviews describing their work on the strobilurins. Reference [45 e] also gives an overall account of the historical course of strobilurin research.
61. a) "Fungicidal β-methoxyacrylates: From natural products to novel synthetic agricultural fungicides": K. Beautement, J. M. Clough, P. J. de Fraine, C. R. A. Godfrey, Pestic. Sci. 1991, 31, 499-519.
62. b) "Fungicidal β-methoxyacrylates: From natural products to novel synthetic agricultural fungicides": J. M. Clough, P. J. de Fraine, T. E. M. Fraser, C. R. A. Godfrey, ACS Symp. Ser. 1992, 504, 372-383;
63. c) "Role of Natural Products in Pesticide Discovery. The β-Methoxyacrylates": J. M. Clough, A. D. Evans, P. J. de Fraine, T. E. M. Fraser, C. R. A. Godfrey, D. Youle, ACS Symp. Ser. 1994, 551, 37-53;
64. d) "Fungicidal β-Methoxyacrylates. N-Linked Pyrroles": K. Beautement, J. M. Clough, P. J. de Fraine, C. R. A. Godfrey, ACS Symp. Ser. 1995, 584, 326-342;
65. e) "The Strobilurin Fungicides": J. M. Clough, C. R. A. Godfrey in Fungicidal Activity (Eds.: D. H. Hutson, J. Miyamoto), Wiley, Chichester, 1998, pp. 109-148.
66. One of us (T. A.) received an ICI Plant Protection Division report (Evaluation of Oudemansin for antifungal and anti-bacterial activity. January 1984) from the German subsidiary of ICI.
67. J. M. Clough, I. T. Kay (ICI), EP-A 178808, 1984, (priority dates October 18, 1984, May 23, 1985).
68. a) P. DeFraine, B. K. Snell, J. M. Clough, V. M. Anthony, K. Beautement (ICI), EP-A 206523, 1985 (priority dates August 18, 1985, April 17, 1986);
69. b) J. M. Clough, C. R. A. Godfrey (ICI), EP-A 212859, 1985 (priority date August 22, 1985).
70. a) The transport of dissolved substances in higher plants essentially takes place within two separate transport systems. In the normally fast-flowing transpiration stream of the xylem (a system of vascular bundles extending from the root to the tips of the leaves) minerals absorbed from the roots area are transported in an upwards direction (acropetally) towards the tips of the leaves. Transport in the other direction (basipetally) is possible only within the phloem system of the plant (sieve tubes). This is essential for example for the transport of assimilates from the place of their biosynthesis in the leaves in a downwards direction towards the leaf sheath and stem; see H. Mohr, P. Schopfer, Pflanzenphysiologie, Springer, Berlin, 1992, pp. 487-517.
71. ow values of about 2-4 can be regarded as optimal; see "Principles of uptake and systemic transport of fungicides within the plant": F. Jacob, S. Neumann in Modern Selective Fungicides (Ed.: H. Lyr), Longman Scientific & Technical, Essex, 1987, pp. 13-30.
72. ow values below 4). However, for individual active substances with extremely high activities, lower aqueous solubilities can sometimes be sufficient for the macroscopic observation of systemic effects, even though the amount of active substance undergoing transportation may be very low.
73. a below 5) and is therefore present mainly as the anion in the slightly alkaline environment of the phloem (pH 7.4-8.7); see ref. [49b] and D. A. Kleier, Pestic. Sci. 1994, 42, 1-11.
74. ow < 0) are no longer easily able to penetrate the cuticle, and will require other routes of entry into the interior of the plant and/or special additives to the formulation; see P. J. G. Stevens, E. A. Baker, N. H. Anderson, Pestic. Sci. 1988, 24, 31-53;
75. E. A. Baker, A. L. Hayes, R. C. Butler, Pestic. Sci. 1992, 34, 167-182.
76. f) Systemic transport does, of course, mean that the active substance must have adequately high metabolic stability in the plant system to ensure its lifetime under these conditions is sufficiently long.
77. V. M. Anthony, J. M. Clough, P. DeFraine, C. R. A. Godfrey (ICI), EP-A 242070, 1986 (priority dates April 17, 1986, January 22, 1987).
78. V. M. Anthony, J. M. Clough, P. DeFraine, C. R. A. Godfrey, P. J. Crowley, K. Anderton (ICI), EP-A 243012, 1986 (priority dates April 17, 1986, Januray 26, 1987).
79. C. R. A. Godfrey, I. Streeting, R. Cheetham (ICI), EP-A 382375, 1989 (priority date February 10, 1989).
80. V. M. Anthony, J. M. Clough, P. DeFraine, C. R. A. Godfrey, I. Ferguson, P. Crowley, M. G. Hutchings (Zeneca), EP-A 242081, 1986 (priority dates April 17, 1986, December 23, 1986).
81. [45e]
82. However, as one knows, there where an emergency emerges, a source of rescue emerges as well (adapted from Friedrich Hölderlin, Patmos).
83. "Now it is no longer done with grumbling and cursing. (...) A despairing illness wants a daring medicine." (translated from Friedrich Schiller in Die Verschwörung des Fiesco zu Genua, act 4, scene 6).
84. B. Wenderoth, C. Rentzea, E. Ammermann, E. H. Pommer, W. Steglich, T. Anke (BASF AG), EP-A 253213, 1986 (priority date July 16, 1986).
85. V. M. Anthony, J. M. Clough, C. R. A. Godfrey, T. E. Wiggins (ICI), EP-A 254426, 1986 (priority date July 18, 1986).
86. H. Sauter is indebted to F. Röhl both for the establishment and automation of this test, the reliable and expert testing of thousands of strobilurin variants, and the swift dispatch of the test results and their assessments.
87. For details of the test system, see a) F. Röhl, H. Sauter, Biochem. Soc. Trans. 1994, 22, 63S;
88. b) ref. [28].
89. For the fundamental importance of biochemical test models in the discovery and optimization of lead structures, see for example J. Dancer, A. Schulz, T. Peine, K. Wright, Pestic. Outlook 1998, 9(3), 36-41, and references therein
90. For the synthesis see Section 6.
91. a) "Phenoxyphenyl alkoxyiminoacetamides. New broad spectrum fungicides": Y. Hayase, T. Kataoka, M. Masuko, M. Niikawa, M. Ichinari, H. Takenaka, T. Takahashi, Y. Hayashi, R. Takeda, ACS Symp. Ser. 1995, 584, 343-353;
92. b) M. Masuko, Annu. Rep. Shionogi Res. Lab. 1997, 47, 33-57.
93. Y. Hayase, T. Kataoka, H. Takenaka, M. Ichinari, M. Masuko, T. Takahashi, N. Tanimoto (Shionogi), EP-A 398692, 1989 (priority dates May 17, 1989, December 29, 1989).
94. S. Brand, E. Ammermann, G. Lorenz, H. Sauter, K. Oberdorf, U. Kardorff, C. Künast (BASF AG), EP-A 477631, 1990 (priority date September 22, 1990).
95. a) A. Fredenhagen, A. Kühn, H. H. Peter, V. Cuomo, U. Giuliano, J. Antibiot. 1990, 43, 655-660;
96. b) A. Fredenhagen, P. Hug, H. H. Peter, J. Antibiot. 1990, 43, 661-667.
97. a) P. J. de Fraine, A. Martin (Zeneca), EP-A 370629, 1988 (priority dates November 21, 1988, March 9, 1989);
98. b) H. P. Isenring, S. Trah, B. Weiss (Hoffmann-La Roche), WO-A 90/07493, 1988 (priority date December 29, 1988);
99. c) K. Tsubata, N. Nijno, E. Endo, Y. Yamamoto, H. Kanno (Nihon Nohyaku), EP-A 414153, 1989 (priority date August 22, 1989);
100. d) M. Watanabe, T. Tanaka, H. Kobayashi, S. Yokoyama (Ube), EP-A 426460, 1989 (priority dates November 2, 1989, February 27, 1990);
101. e) H. P. Isenring, B. Weiss (Ciba-Geigy), EP-A 460575, 1990 (priority dates June 5, 1990, April 23, 1991);
102. f) S. Brand, U. Kardorff, R. Kirstgen, B. Müller, K. Oberdorf, H. Sauter, G. Lorenz, E. Ammermann, C. Künast, A. Harreus (BASF AG), EP-A 463488, 1990 (priority date June 27, 1990);
103. g) J. M. Clough, C. R. A. Godfrey, P. J. de Fraine (Zeneca), EP-A 472300, 1990 (priority date August 22, 1990);
104. h) J. M. Clough, C. R. A. Godfrey, P. J. de Fraine, I. R. Matthews (Zeneca), WO-A 92/13830, 1991 (priority dates January 30, 1991, August 14, 1991).
105. BASF had also pursued a discreet interest in the acquisition of Maag, to no avail. At the forefront, however, of the interest shown by BASF was not the strobilurins, but the already exisiting fungicide business of Maag (e.g. Corbel).
106. This term is unfortunately still used too often in a pejorative sense. This is usually unjustified since the art of finding a usable gap in a tightly formulated patent claim demands rare creativity, and secondly because such "me too" variants could always lead to unusual and unexpected increases in activity, as was the case here (see text).
107. Compare with ref. [20e] and P. J. de Fraine, J. M. Clough, Pestic. Sci. 1995, 44, 77-79.
108. a) "CGA279202. A new Plant Health Product for Protection Against Diseases of Agronomic Crops, Vegetables, Tree Crops and Turf": Novartis Technical Bulletin 1998;
109. b) "CGA279202: A new broad-spectrum strobilurin fungicide": P. Margot, F. Huggenberger, J. Amrein, B. Weiss, Abstr. Pap. Brighton Crop Prot. Conf. Pests and Diseases (Farnham, UK) 1998, pp. 275-382.
110. For an excellent introduction to this subject, see L. G. Copping, H. G. Hewitt, Chemistry and Mode of Action of Crop Protection Agents, The Royal Society of Chemistry, Cambridge, 1998.
111. See for example "Optimization of Physicochemical and Biophysical Properties of Pesticides": I. J. Graham-Bryce, ACS Symp. Ser. 1994, 225, 185-207.
112. H. Sauter is grateful to H. Köhle for numerous discussions and ideas in this context.
113. Over 15000 strobilurin variants have been synthesized at BASF to date.
114. a) H. Köhle, R. E. Gold, E. Ammermann, H. Sauter, Biochem. Soc. Trans. 1994, 22, 65S.
115. A more detailed discussion is given in ref. [28a].
116. B. Wenderoth, H. Sauter, E. Ammermann, E. H. Pommer (BASF), EP-A 280185, 1987 (priority date February 20, 1987).
117. R. Benoit, H. Sauter, R. Kirstgen, G. Lorenz, E. Ammermann (BASF), EP-A 498188, 1991 (priority date February 7, 1991).
118. a) B. Müller, H. Sauter, F. Röhl, R. Dötzer, G. Lorenz, E. Ammermann (BASF), WO-A 93/15046, 1992 (priority dates January 29, 1992, June 26, 1992, October 5, 1992).
119. b) Here there was further competition between rival patents. Ishihara's more weakly active N-alkylcarbamates were submitted first: T. Komyoji, I. Shigehava, N. Matsuo, H. Shimoharada, T. Ohshima, T. Akagi, S. Mitani (Ishihara), EP-A 498 396, 1991 (priority dates February 7, 1991, October 23, 1991).
120. [80a] Finally, Nihon Nohyaku also submitted an application for the N-methoxycarbamates: c) H. Ohnishi, S. Tajma, Y. Yamamoto, H. Kanno (Nihon Nohyaku), EP-A 619 301, 1993 (priority date April 4, 1993).
121. a) R. J. Brown, K.-M. Sun, D. A. Frasier (DuPont), WO-A 95/14009, 1993 (priority date November 19, 1993).
122. b) Shortly after the publication of this application in May 1995 Novartis had submitted patent applications for strobilurins with similar cyclic pharmacophores and specific side chains: H. Ziegler, R. Zurflüh, A. C. O'Sullivan (Novartis), WO-A 97/02255, 1995 (priority dates July 4, 1995, May 24, 1996).
123. B. W. Krüger, L. Assmann, H. Gayer, P. Gerdes, U. Heinemann, D. Kuhnt, U. Philipp, T. Seitz, J. Stetter, R. Tiemann, H. W. Dehne, S. Dutzmann, G. Häussler (Bayer AG), WO-A 95/04728, 1993 (priority dates August 11, 1993, March 10, 1994).
124. a) T. Ohtsuka, T. Murashi, S. Suzuki, M. Masuko, H. Takenaka (Shionogi), WO-A 95/27693, 1994 (priority dates April 6, 1994, July 7, 1994, November 4, 1994, January 27, 1995);
125. b) K. Oberdorf, H. Sauter, H. König, A. Harreus, B. Müller, R. Kirstgen, W. Grammenos, H. Bayer, F. Röhl, G. Lorenz, E. Ammermann, V. Harries (BASF AG), WO-A 96/07633, 1994 (priority date September 10, 1994).
126. a) "The synthetic strobilurin BAS490F: profile of a modern fungicide": R. E. Gold, E. Ammermann, H. Köhle, G. M. E. Leinhos, G. Lorenz, J. B. Speakman, M. Stark-Urnau, H. Sauter in Modern Fungicides and Antifungal Compounds (Eds.: H Lyr, P. E. Russell, H. D. Sisler), Intercept, Andover, 1996, pp. 79-92;
127. b) R. E. Gold, G. M. E. Leinhos, Pestic. Sci. 1995, 43, 250-253.
128. c) Kresoxim-methyl, active substance brochure of BASF, Ludwigshafen, 1993.
129. d) The terms "protective" and "curative" refer to the timing of the fungicide treatment, that is, whether it is before or after a fungal infection.
130. H. Sauter is indebted to H. Kubinyi for these and other QSAR calculations and for numerous other informative discussions.
131. W. Grammenos, H. Kubinyi, H. Sauter, unpublished results.
132. ow only by about 0.3.
133. Here too there was - at least in hindsight - a fascinating patent competition: a) H. Ziegler, S. Trah, S. Farooq, R. Zurflüh (Ciba-Geigy), WO-A 95/18789, 1994 (priority dates January 5, 1994, July 1, 1994);
134. b) H. Bayer, H. Sauter, R. Müller, W. Grammenos, A. Harreus, R. Kirstgen, F. Röhl, E. Ammermann, G. Lorenz (BASF AG), WO-A 95/21153, 1994 (priority dates February 4, 1994, June 17, 1994);
135. c) H. Bayer, H. Sauter, R. Müller, W. Grammenos, A. Harreus, R. Kirstgen, F. Röhl, E. Ammerrnann, G. Lorenz (BASF AG), WO-A 95/21154, 1994 (Prioriotät: 4.2.1994, 17.6.1994);
136. d) H. Bayer, H. Sauter, R. Müller, W. Grammenos, A. Harreus, R. Kirstgen, F. Röhl, E. Ammerrnann, G. Lorenz (BASF AG), WO-A 95/21156, 1994 (priority dates February 4, 1994, June 17, 1994).
137. e) See also ref. [81b], in which Novartis claims the special "double oxime ether" side chain with a "new" cyclic pharmacophore.
138. Despite ceding priority, BASF submitted its own patent applications for active substance mixtures with some of these strobilurins with a "double oxime ether" side chain, for example B. Schwalge, R. Müller, H. Bayer, H. Sauter, R. Saur, K. Schelberger, E. Ammermann, G. Lorenz, S. Strathmann (BASF AG), WO-A 97/06678, 1995 (priority date August 17, 1995).
139. R. Kirstgen, W. Grammenos, H. Bayer, R. Doetzer, H. Koenig, K. Oberdorf, H. Sauter, H. Wingert, G. Lorenz, E. Ammermann, V. Harries (BASF AG), WO-A 94/19331, 1993 (priority date February 23, 1993).
140. G. Kleefeld, A. Klausener, W. Krämer, W. Brandes, S. Dutzmann, G. Häussler (Bayer AG), EP-A 331966, 1988 (priority date March 5, 1988).
141. S. Trah, F. Gantz (Maag AG), EP-A 433233, 1989 (priority date December 14, 1989).
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