Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1993-11-19
1995-10-24
Robinson, Allen J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
A01N 3302
Patent
active
054610796
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 92/00963 filed May 28, 1992.
FIELD OF THE INVENTION
This invention is in the field of the control of fungal infection in plants.
DESCRIPTION OF THE PRIOR ART
Polyamines are essential for the growth and development of all organisms, including plants and fungi. However, whereas plants possess two pathways for polyamine biosynthesis, i.e. via the enzymes ornithine decarboxylase [ODC] and arginine decarboxylase [ADC], fungal polyamine biosynthesis appears to be a result of ODC activity only.
Plants are attacked by a wide range of fungi which are the cause of considerable losses of yield and quality. Since fungi possess only the ODC pathway of polyamine biosynthesis, the inhibition of this enzyme should control their growth.
Such inhibitors have been extensively researched but the major breakthrough was directly attributable to the synthesis of enzyme-activated irreversible inhibitors of ODC and ADC notably difluoromethylornithine [DFMO], which has been tested as an anti-cancer agent and also as an anti-parasitic agent, and difluoromethylarginine [DFHA].
Recent work has shown that DFHO can reduce fungal growth and has led to the investigation of the use of DFMO as a fungicide, see for example WO88/02986 (Heinstein and Galston) and U.S. Pat. No. 4,760,091 (Carson et al.).
The effect of compounds (including DFMO) which interfere with polyamine metabolism on the growth of the fungus Botrytis cinerea has been investigated (Smith et al., J. Gen. Microbiol. 1990, 136, 985). This work demonstrated that the DFMO inhibition of fungal growth could be reversed with the addition of putrescine, cadaverine, spermidine and spermine. "Butenediamine", caused some inhibition of fungal growth but significantly reversed the inhibitory effect of DFMO.
SUMMARY OF THE INVENTION
It has surprisingly been found that the diamine (E)-2-butene-1,4-diamine (the trans isomer) exhibits considerable anti-fungal activity. Accordingly, the invention provides the use as a fungicide of (E)-2-butene-1,4-diamine.
The diamine may also be used as a salt with organic or inorganic acids.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The antifungal activity of (E)-2-butene-1,4-diamine is thought to be due mainly to its properties of polyamine metabolism interference. However, other mechanisms may play a role in the activity of this compound as an antifungal agent which cannot be ruled out at this stage.
(E)-2-butene-1,4-diamine may be synthesised and isolated as a salt using the conventional techniques of synthetic organic chemistry. The preferred syntheses are those which use (E) starting materials and yield exclusively the trans-diamine, i.e. in which substantially all of the diamine produced is the trans-diamine.
The diamine may comprise a minor proportion of the (Z) (cis) isomer say up to 10% or even 25% but the use of such mixtures is less preferred as the cis isomer is less effective than the corresponding trans isomer.
(E)-2-butene-1,4-diamine may be synthesised as its dihydrochloride salt from (E)-1,4-dibromobut-2-ene by conversion into the bisphthalimide with potassium phthalimide followed by acid hydrolysis. It may also be prepared by heating (E)-1,4-dibromobut-2-ene at reflux in benzene with sodium azide in the presence of tetrabutylammonium bromide, subsequent addition of triethyl phosphate and treatment with dry hydrogen chloride, according to the method of Koziara et al., Synthesis 1985, 202. Another synthesis which may be employed is that reported by L. H. Amundsen et al., J. Am. Chem. Soc. 1951, 73, 2118 which utilises the trans form of butene-1,4-diol rather than the cis form used by Amundsen. (E)-2-butene-1,4-diamine also exhibits antifungal activity when prepared in the form of its acid salts and such salts may be utilised as fungicides according to this invention. The compound can form salts with mineral acids such as HCl, HBr, HI, H.sub.2 SO.sub.4, HNO.sub.3, H.sub.3 PO.sub.4 or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartari
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M. V. Rajam et al., "Effect of polyamine biosynthesis inhibitors on polyamine levels in bean seedlings", Current Science 60 (3), 178-180 (Feb. 1991).
Robins David J.
Walters Dale R.
British Technology Group Limited
Robinson Allen J.
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