Antifungal compounds

Compounds having the formula (I) below: EQU (R.sub.1 R.sub.2 N)CH.sub.2 --CH.dbd.CH--CH.sub.2 (NR.sub.3 R.sub.4)(I) wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4, which may be the same or different represent hydrogen atoms, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, a heterocyclic group, an aryl group, a heteroaryl group having from 3 to 6 atoms, an amidino group or R.sub.1, R.sub.2 and/or R.sub.3 and R.sub.4 together represent a carbocyclic or heterocyclic group comprising from 3 to 6 atoms with the proviso that R.sub.1, R.sub.2, R.sub.3 and R.sub.4 cannot simultaneously represent hydrogen and salts thereof are fungicides especially mildewicides. Preferred compounds are those wherein the groups R represent methyl or ethyl groups.

This application is a 371 of PCT/GB92/00964 filed May 28, 1992. 
1. Field of the Invention 
This invention is in the field of the control of fungal infection in 
plants. 
2. 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 [DFMA]. 
Recent work has shown that DFMO can reduce fungal growth and has led to the 
investigation of the use of DFMO as a fungicide, see for example 
N088/02986 (Weinstein 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 certain derivatives of 
2-butene-1,4-diamine exhibit considerable anti-fungal activity. 
Accordingly, the invention provides the use as a fungicide of compounds 
having the general formula (I) below: 
EQU (R.sub.1 R.sub.2 N)CH.sub.2 --CH.dbd.CH--CH.sub.2 (NR.sub.3 R.sub.4)(I) 
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4, which may be the same or 
different represent a hydrogen atom, an alkyl group having from 1 to 6 
carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, a 
heterocyclic group, an aryl group, a heteroaryl group, having from 3 to 6 
atoms or an amidino group or R.sub.1 and R.sub.2 and/or R.sub.3 and 
R.sub.4 together represent a carbocyclic or heterocyclic group comprising 
from 3 to 6 atoms, with the proviso that R.sub.1, R.sub.2, R.sub.3 and 
R.sub.4 cannot simultaneously represent hydrogen atoms. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The antifungal activity of the compounds of formula (I) is thought to be 
due mainly to their properties of polyamine metabolism interference. 
However, other mechanisms may play a role in the activity of these 
compounds as antifungal agents. 
The groups R.sub.1, R.sub.2, R.sub.3 and R.sub.4 in formula (I) may be the 
same or different. Preferably the groups R.sub.1 and R.sub.2 identical and 
the groups R.sub.3 and R.sub.4 are identical and even more preferably, the 
groups R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all identical. 
Preferred compounds are those wherein at least one of R.sub.1, R.sub.2, 
R.sub.3 and R.sub.4 are alkyl groups, preferably having 1 to 3 carbon 
atoms. More preferably at least one of R.sub.1 and R.sub.2 and at least 
one of R.sub.3 and R.sub.4 represents an alkyl group having from 1 to 3 
carbon atoms. 
A particularly preferred compound is 
E-(N',N'-dimethyl)-1,4diaminobut-2-ene. 
Another preferred group of compounds are those wherein R.sub.1, R.sub.2, 
R.sub.3 and R.sub.4 all represent alkyl groups having from 1 to 4 carbon 
atoms. A particularly preferred compound is 
E-(N,N,N',N-tetraethyl)-1,4-diaminobut-2-ene (TED). 
The compounds of formula (I) may be synthesised using the conventional 
techniques of synthetic organic chemistry. The substituted diamines may be 
synthesised by displacement of bromine from (E)-1,4-dibromo-2-butene by a 
primary or secondary amine. 
The compounds of formula (I) also exhibit antifungal activity when prepared 
in the form of their acid salts and such salts may be utilised as 
fungicides according to this invention. The compounds 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, tartaric, citric, oxalic, 
glyoxylic, alkyl or aryl-sulphonic, salicylic, malonic and ascorbic. These 
salts may be prepared by standard techniques and procedures well known in 
the art. 
The present invention also provides a method for the fungicidal treatment 
of plant material in either a preventative or curative mode. The treatment 
may be applied to growing or harvested plant materials. If the plant 
material is growing, then the plants may be treated before they are 
infected by the fungi. This can be carried out by either treating the 
whole plant (e.g. by spraying it with a solution/emulsion or suspension of 
the antifungal compounds) or by applying the compounds to specific parts 
of the plant, e.g. the leaves, stems, fruits or even seeds prior to 
planting. Treatment of the soil is another alternative since the 
antifungal compounds of the invention are systemic in their mode of 
action. Plants which have come into contact with fungi and thus already 
infected may be treated locally at site of infection or the whole plant 
may be treated. 
The present invention also includes treatment of harvested plant parts for 
the control of fungal diseases. For this, various ways of carrying out the 
treatment can be employed. These will be well known to those skilled in 
the art, for example, treatment can be to the harvested plant itself by 
for example dipping the plant part into a solution of the antifungal 
agent, or by impregnating fungicide into the wrapper, carton, crate, etc. 
in which the plant will be transported. Alternatively, the harvested plant 
material may be fumigated with the fungicide in a special room, car or 
tank. 
This invention also provides fungicidal compositions comprising at least 
one compound having the formula (I) together with a suitable diluent or 
carrier. Such diluents or carriers must not be phytotoxic to the plant 
materials. Suitable diluents and carriers include water and organic 
solvents. Preferably the concentration of the compounds is between 
0.001-0.1 molar. 
Seeds may be treated prior to planting and again this may be carried out 
among other methods by fumigation. 
Thus, the compounds can be dispersed on a finely-divided solid to form a 
dust. Also, the compounds can be dispersed in water, typically with the 
aid of a wetting agent, and the resulting aqueous dispersion employed as a 
spray. In other procedures the compounds can be employed as a constituent 
of organic liquid compositions, oil-in-water and water-in-oil emulsions or 
dispersions, with or without the addition of wetting, dispersing or 
emulsifying agents. 
Suitable adjuvants of the foregoing type are well known to those skilled in 
the art. The methods of applying the solid or liquid fungicidal 
formulations are similarly well known. 
The concentration of the active compounds in solid or liquid compositions 
generally is from about 1 to about 20 percent by weight or more. 
Concentrations from about 5 to about 10 percent by weight are often 
employed. In compositions to be employed as concentrates, the active 
compound can be present in a concentration from about 15 to about 50 
weight percent, preferably 20 weight percent. The compositions containing 
the active compounds can also contain other compatible additives, for 
example, phytotoxicants, plant growth regulants, pesticides, other 
fungicides and the like which are suitable for application to 
agricultural, horticultural, forestry and amenity crops. The present 
compositions can be applied by the use of power dusters, boom and hand 
sprayers, spray dusters and by other conventional means. The compositions 
can also be applied from airplanes as a dust spray since the ingredients 
are effective at very low application rates. 
The exact rate to be applied is dependent not only on the specific diamine 
being applied, but also on the particular treatment desired (e.g. seed, 
soil, or foliage) the particular crop being treated, climatic conditions, 
severity of any infection and the like. Thus, it is also to be understood 
that all of the active compounds of the present invention and compositions 
containing the same may not be equally effective at similar concentrations 
or against the same fungal species. 
In foliar treatments, the active compounds of the present invention are 
usually applied at an approximate rate of from about 50 to 500 g/ha, a 
rate of from about 80 to 400 g/ha being preferred and a rate of from about 
100 to about 350 g/ha being particularly preferred. 
In seed treatments, the active compounds of the present invention are 
usually applied at an approximate rate of from about 60 to about 250 g per 
100 kg seed, a rate of from about 100 to about 200 g per 100 kg seed being 
preferred and a rate of from about 140 to about 180 g per 100 kg seed 
being particularly preferred. 
In soil treatments, the active compounds of the present invention are 
usually applied at an approximate rate of from about 50 to about 350 g/ha, 
a rate of from about 100 to about 300 g/ha being preferred and a rate of 
from about 200 to about 280 g/ha being particularly preferred. 
A typical solid composition is formulated by dry milling the active 
compound with BARDEN clay. This solid formulation or dust can contain the 
active compounds in amounts of from about 1 to about 25 percent by weight 
or more if desired. The dust is suitable for application to cereal seeds 
prior to planting. 
A typical liquid composition is formulated by dissolving the active 
compound in a mixture of water and isopropanol (80:20 water/isopropanol 
ratio) containing a surfactant. This liquid formulation can contain the 
active compound in amounts of from about 15 to about 40 percent by weight 
or more if desired. The aqueous formulation is suitable for application to 
cereal foliage or application as a seed drench, after suitable dilution 
with water.