Note: Descriptions are shown in the official language in which they were submitted.
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Use of Hydroxylamine Derivatives, and Method and Preparations for
Increasing the Tolerance of Field Crops against Weather Stresses
TECHNICAL FIELD
s
This invention relates to the use of hydroxylamine derivatives of
general formula (I), wherein
R 1 represents phenyl, N-heteroaryl, S-heteroaryl or a naphthyl group
which may be substituted with one ~or more halo, alkyl, alkoxy, haloal-
~o kyl or nitro, an unsubstituted or substituted phenylamino or aiky-
lamino or lower alkoxy,
X represents halo, preferably chloro or bromo, amino or an unsubsti-
tuted or substituted phenylamino group, or amino substituted with one
or two lower alkyl or a hydroxy group provided that if R 1 represents
~ 5 unsubstituted or substituted phenylamino, alkylamino or lower alkoxy,
then X may not represent halo,
Y represents hydrogen, hydroxy or acyloxy, preferably longer alkanoy-
loxy, or if Y represents hydroxy, the molecule may contain a dioxazine
ring closed at the carbon atom carrying the X group formed by formal
2o XH elimination,
R2 and R3 , independently from each other, represent hydrogen or
lower alkyl group provided that R2 and R3 may not represent hydrogen
simultaneously,
R2 and R3 along with the adjacent nitrogen atom form a 5 to 7-
2s membered saturated hetero ring,
and the method and preparation for increasing the tolerance of culti-
vated plants against weather condition stresses.
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2
BACKGROUND ART
Damages to cultivated plants by weather stresses, such as cold,
frost and drought cause significant losses for the agriculture. These
factors, within this invention briefly referred to as weather stresses,
may occur in any period of the growth or vegetation of the plant.
Although they affect the plants in various ways and the plants react to
them differently according to species and type, the effect is usually
1 o connected to the water metabolism of the plants. The protection of
plants against weather stresses is made more difficult by the widely
varied distribution of the time, strength and length of these stresses
present at most agricultural regions.
In the present invention a temperature is considered cold if it is
1s less than the minimum temperature necessary for normal physiological
functioning of the individuals belonging to a given plant species or type,
but greater than the freezing point of the water. Generally its effect may
not be determined immediately by simple observation. The damage
caused by the cold appears later, after warming up, such as the
2o decrease in plant growth, the withering or fading (chlorosis), or in the
most severe cases, death of the plant.
The frost, i.e. the temperature below zero degree centigrade does
not necessarily cause the plant to perish. After it is gone, the plant may
be regenerated but the irreversible cell damages caused by the frost will
2s strain its development, which will decrease its yield in the end.
While the cold and the frost usually appears at an early stage of
plant development and hence damages the germinating or developing
plant, the drought damages the fully developed plant and endangers
the further stage of development. Decreasing the evaporation level of
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the plant may render the reduction of the losses. For example there
exists a method, when the surface of the plant is coated with a polymer
film in order to physically limit the transpiration of the plant in the
case of drought. For this purpose polyetoxylated polyoxypropylene
copolymers described in the US Patent No. 4828602 are applied. The
disadvantage of the method is that it requires a local application of the
coating material, which may be done only by investing a great amount
of manual labour. A durable transpiration inhibition is not desirable
anyway; the system-effect transpiration inhibitors are more favourable
1o with respect to plant physiology.
Thorough research related to the effects of the weather stresses
on plants has been performed to reduce the damages of the cold, frost
and drought, and a great number of scientific publications deal with
the plant physiological relevance of cold, frost and drought tolerance.
~ 5 Since plants react to these weather stresses very differently according
to their botanical characteristics, a theoretically satisfactory explana
tion of the mechanism of the cold, frost and drought tolerance has not
yet been given, and hence the methods developed for application in
practice to improve the tolerance of plants against weather stresses are
2o very diverse.
For example, it is known in the art that growth _ regulating
materials, which are compounds of hormonal activity, affect the cold,
frost and drought tolerance of plants positively, and therefore they are
applied for the treatment of cultivated plants. A typical example is
25 abscisic acid, which is a growth regulating hormone. Abscisic acid
itself is difficult to synthesise and hence it is not applied in agriculture.
However, materials analogous to abscisic acid chemically and in their
effect are used, which have identical or stronger effect than the abscisic
acid itself , especially when combined with other compounds, which
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ensures a synergetic increase in the effect. For example, the PCT
publication WO No. 9608481 A1 describes that plants are treated with
epoxycyclohexane derivatives so as to make their development and
yield more favourable and to increase their tolerance against cold and
drought. Besides these compounds, brassidosteroids are also used as
synergetic auxiliarys. The EP No. 327309 A1 describes a compound
that contains a poly-substituted cyclohexenyl-acetylene derivative as
effective agent, and a diversely and mufti-substituted phenyl-benzyl-
urea derivative as synergetic auxiliary. With the help of this substance
of hormonal activity, the tolerance of the plant against drought may be
improved.
Compounds of hormonal activity are without any doubt signifi-
cant, because they have an intense effect even when applied in small
quantity, however their disadvantage is that they affect the metabolic
processes taking place in the plants to a large extent, modify the
hormnonal equlibrium of the plants, which may result in unpredictable
physiological changes. Therefore such compounds and products must
be applied with care in practice. Before application, it is essential to
perform preliminary experiments related to a given plant species or type
2o in order to determine the suitability and optimal application circum-
stances of the product in a given agricultural region, which limits their
use in agricultural practice.
To avoid the above mentioned disadvantages of substances of
hormonal activity, researchers turned to simpler, hormonally indiffer-
ent substances to find a suitable effective agent to improve the toler-
ance of plants against cold, frost and drought. According to the PCT
publication WO No. 92/08350 A1 tetrahydro-furfuryl-alcohol, tetrahy-
dro-furfuryl-amine, or the combination of these compounds is applied
to improve the tolerance of plants against cold. These effective agents
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lack the mentioned disadvantages of substances of hormonal activity,
their production is easier, and hence they are more economical, but in
view of the practice they are not favourable. This is because, according
to the paper cited above, it is recommended to spray the plants more
s than once with the solution of the effective agent in order to achieve a
satisfactory extent of regeneration of the cold-effected plants, and to
repeat the treatment after the cold is gone, but the most expedient way
is to spray the plants regularly. A treatment of the whole surface is
considered important to ensure the contact of the effective agent on the
to entire surface of the plant. Therefore, thorough or repeated spraying is
recommended. This requirement may be fulfilled only by investing a
great amount of manual labour.
According to Hungarian Patent No. 181241, secondary or tertiary
(i-hydroxyethyl-amines or respective quaternary ammonium salts,
is preferably 2-hydroxy-ethyl-amines and trimethyl-(3-hydroxy-ethyl-
ammonium-chloride (choline-chloride) and, in certain cases, combina-
tions of these may be applied to improve the tolerance of plants against
cold and frost. Primarily, the effective agent is applied to the plant by
spraying. It may be concluded from the experimental section of the
2o Patent that the effective agent is aimed at changing the phospholipid
composition of the membrane of plant cells, and thus the fluidity. of the
membrane. Hence the mentioned effective agents may be applied for
the treatment of fully developed plants only. This was supported by the
experimental results as well. The treatment of seedlings and seeds,
25 which is mentioned in the Patent may not be effective with these
effective agents since the plants lack the parts with the necessary
membrane. An exception of is the choline-chloride, the application of
which for treatment of seeds is known from the publication JP No.
62161701. In this case, however, the general growth regulating effect of
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6
the substance is utilised, as described in the above mentioned paper,
and this effect causes among others the improved tolerance of the
sprouting plant against cold. However, the growth regulating sub-
stances of hormonal activity possess all of the disadvantages described
above.
To sum up the above, we may conclude that several different
attempts have been published in Patent literature aimed at improving
the tolerance of cultivated plants against weather stresses. The effective
agents and products of these Patents are, however, suitable for direct
to agricultural application only with the mentioned limiting conditions.
Our research was aimed at finding effective agents, which
increase the cold, frost and drought tolerance of plants but are hor-
monally neutral, non-toxic, the limits of their application being the
smallest possible, and which are suitable not only for the treatment of
t5 fully developed plants but also of seedlings and seeds.
DISCLOSURE OF INVENTION
2o It was found that the hydroxylamine derivatives of general
formula (I), wherein
R1 represents phenyl, N-heteroaryl, S-heteroaryl or a naphthyl group
which may be substituted with one or more halo, alkyl, alkoxy, haloal-
kyl or nitro, an unsubstituted or substituted phenylamino or alky-
25 lamino or lower alkoxy,
X represents halo, preferably chloro or bromo, amino or an unsubsti-
tuted or substituted phenylamino group, or amino substituted with one
or two lower alkyl or a hydroxy group provided that if R~ represents
unsubstituted or substituted phenylamino, alkylamino or lower alkoxy,
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then X may not represent halo,
Y represents hydrogen, hydroxy or acyloxy, preferably longer alkanoy-
loxy, or if Y represents hydroxy, the molecule may contain a dioxazine
ring closed at the carbon atom carrying the X group formed by formal
XH elimination,
R2 and R3 , independently from each other, represent hydrogen or
lower alkyl group provided that R2 and R3 may not represent hydrogen
simultaneously,
R2 and R3 along with the adjacent nitrogen atom form a 5 to 7-
to membered saturated hetero ring,
show the required effect and satisfy the mentioned requirements.
These compounds act in an inductive manner, i.e. they increase
the level of hardiness if the plant faces environmental stresses, as when
the above mentioned weather stresses affect the plant. The inducted
is metabolic processes result in an improved tolerance against cold, frost
and drought.
Based on this observation, this invention relates to the use of
hydroxylamine derivatives of general formula (I), where Rl, X, Y, R2
and R3 are as above, for the improvement of the tolerance of cultivated
2o plants against weather stresses.
In general formula (I), a lower alkyl group contains preferably 1-6
carbon atoms, most preferably 1-4 carbon atoms, and a lower alkoxy
group contains 1-6, preferably 1-4 carbon atoms. In compounds of
general formula (I), where Rl is a substituted phenyl or phenylamino
25 group, the alkyl groups attached to the phenyl ring as substituents are
preferably lower 1-6 carbon atom alkyl groups. The alkoxy substituents
of the phenyl ring preferably contain 1-6 carbon atoms. The haloalkyl
substituents of the phenyl ring contain preferably alkyl, most prefera-
bly Ci-6 alkyl. Most preferable haloalkyl substituent is the trifluoro-
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methyl group. If R1 represents alkyiamino, it preferably contains at
most 12 carbon atoms. If R1 represents N-heteroaryl, it is preferably
pyridyl or pyrazinyi group, while if R1 represents an S-heteroaryl
group, it is preferably tienyl. Finally, if Y represents a long carbon chain
alkanoyloxy, it preferably contains 12-20 carbon atoms.
Some of the hydroxylamine derivatives of general formula (I) are
known compounds. Those compounds of general formula (I) in which
R 1 represents phenyl or pyridyl or naphtyi which may be substituted
with halo or alkoxy, X represents amino and Y represents hydroxy, are
io known from Hungarian Patent No. 177.578, which also describes the
process of preparation of these compounds, as well as the different
possibilities for synthesis. These compounds, as selective beta-blocking
agents, may be applied in the therapy of angiopathy, primarily diabetic
angiopathy. Those compounds of general formula (I), in which R1
is represents phenyl or alkoxyphenyl or pyridyl or naphtyl, X represents
halo and Y is hydroxy, as well as their preparation are known from
Hungarian Patent No. 207.988. These compounds may also be applied
in the therapy of angiopathy. Those compounds of general formula (I),
in which R 1 represents naphtyl or haloalkylphenyi, X is hydroxy and Y
2o represents hydroxy, are known from published Hungarian Patent
Application No. 2385/92. These compounds have antiischemic and
antianginai effect, and hence may be applied particularly in the therapy
of heart diseases. Those compounds of general formula (I), in which R1
represents phenyl or phenyl group substituted by the above listed
25 substituents or a pyridyl group, X represents halo and Y is a hydrogen
atom, are known from the PCT publication WO No. 95/30649 A1. The
same document describes the preparation of these compounds. These
compounds have antiischemic effect and hence may be applied in the
therapy of diabetic angiopathy. Furthermore, those compounds of
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general formula (I) are also known, in which R 1 represents pheny-
lamino which is unsubstituted or substituted with alkyl, alkoxy, halo,
haloalkyl or nitro, or an alkoxy or alkylamino group, X represents
hydroxy and Y is hydrogen, hydroxy or alkanoyloxy. Their description
s may be found in the PCT publication WO No. 97/00251, which de-
scribes the preparation of these compounds as well. These compounds
have antiischemic effect and hence may be applied in the therapy of
heart and blood vessel diseases. Note that in the known compounds R2
and R3 represent the same as defined above, and therefore these two
1o substituents are not described in detail.
It should also be noted that in certain compounds of general
formula (I) tautomery may occur, i.e. they may appear in a tautomeric
structure different from but corresponding to the formula (I). In
particular, this is the case when compounds of general formula (I)
~ s contain a hydroxy group as X, where the tautomeric version containing
a -(CO)-NH- molecule part not appearing in the structural formula is
more stable.
The remaining compounds of general formula (I) form the subject
matter of our pendin patent application.
2o New compounds are those hydroxylamine derivatives of general
formula (I), in which X represents halo, Y is hydroxy, and R1represents
a group that is different from the ones described in the above men-
tinned Hungarian Patent No. 207.988 dealing with these kinds of
compounds, for example phenyl substituted with alkyl, haloalkyl or
2s nitro. These substances are prepared analogously to the cited descrip-
tion by diazotating the corresponding compound containing a NH2
group in the place of X. The necessary starting amino compounds are
produced also by known method, by the coupling reaction of the
corresponding amidoxime and a 3-amino-2-propanol derivative, for
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example according to the method described in the Hungarian Patent
No. 177.578.
N-substituted amidoximes of general formula (I), where R1
represents an aromatic group and X represents a substituted amino
s group, are also novel compounds, and may be produced by the cou
pling reaction of a suitable imidoyl-halide of general formula ( 1 ) ,
wherein Hal represents a halo and R 1 is as above, while R' is the
substituent of the amino group of X, and a 1-amino-3-aminooxy-
propane derivative of general formula (2), where R2, R3 and Y are as
to above. The reactions should be performed in a neutral solvent, for
example in chlorinated hydrocarbon, at room temperature and after
extraction separation, the product is isolated as a salt with a suitable
organic or inorganic acid.
Other novel compounds of general formula (I) are N-hydroxy
ts guanidine derivatives in which both R1 and X are substituted nitrogen
atoms. These derivatives are produced by the acylation of a suitable
aminooxy compound of general formula (2), if the acylating agent is
haloformamidine of general formula (3), where Hal represents halogen,
R 1 is as above, and R' and R" are substituents of the amino group
2o appearing as X in the product. The reaction is performed in a two phase
system, in the mixture of some organic solvent not mixable with. Water
and a aqueous base, preferably aqueous sodium-carbonate solution.
The product is isolated in this case also by extraction separation and, if
possible, by salt-formation.
25 Any of those new compounds of general formula (I), in which Y
represents acyloxy, may be produced by O-acylation of the corre-
sponding compound containing hydroxy as Y. The starting compounds
are either known from the above mentioned literature or may be
produced according to the method described.
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As acylating agent, acid halides, active esters or other usual
reagents applicable for O-acylation may be used. The reactions can be
performed in a neutral solvent, usually at room temperature and if
necessary in the presence of a suitable acid-binding agent, such as an
s organic or inorganic base, for example triethylamine or solid sodium-
carbonate. For acylating agent, the acid chlorides are preferable, where
the compound itself may behave as acid-binding agent, and hence
usually the product may be easily isolated in the form of hydrochloride
by simple ethereal crystallisation after evaporation. When using less
to reactive acylating agents, Schotten-Baumann acylation may also be
applied. The products are generally isolated in the form of their salt
with a organic or an inorganic acid.
With respect to the application of the invention, most preferable
compounds were the following ones of general formula (I):
~s N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzimidoyl-chloride hydrochlo-
ride (Compound 1 )
N-[2-hydroxy-3-( 1,1-dimethylethyl-amino)propoxy]-3-trifluoromethyl-
benzamide monohydrochioride (Compound 2)
N-[2-palmitoyloxy-3-( 1-piperininyl)propoxy]-3-pyridinecarboximidamide
2o monohydrochloride (Compound 3)
N-[3-( 1-piperidinyl)propoxy]-3-vitro-benzimidoyl-chloride monohydro-
chloride (Compound 4)
N-[2-hydroxy-3-( 1-piperidinyl)propoxy]-2-vitro-benzimidoyl-chloride
monohydrochloride (Compound 5)
2s N-[[3-(1,1-dimethylethyl)-aminoJ-2-hydroxypropoxy]-N'-phenyl-
benzamidine hydrochloride (Compound 6)
N-N'-dimethyl-N'-phenyl-N"-[3-( 1-piperidinyl)propoxyJ-guanidine
hydrochloride (Compound 7)
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N-[3-(1-piperidinyl)propoxy]-pirazine-carboximidoylchloride monohy-
drochloride (Compound 8)
3-(3-piridyl)-5-diethylaminomethyl-5,6-dihydro-1,4,2-dioxazine hydro-
chloride (Compound 9)
s N-[2-hydroxy-3-(1-piperidinyl)propoxy]-1-naphtalene-carboxamide
(Compound 10)
N-[2-hydroxy-3-(1-piperidinyl)propoxy]-ethylurethane (Compound 11)
N-hexyl-N'-[2-hydroxy-3-(1-piperidinyl)propoxy]-urea (Compound 12}
N,N-dimethyl-N'-phenyl-N"-[2-hydroxy-3-( 1-piperidinyl)propoxy]-
1o guanidine hydrochloride (Compound 13)
N-[3-(1-piperidinyl)propoxy]-tiophene-2-carboximidoylchloride hydro-
chloride (Compound 14)
N-[3-( 1-piperidinyl)propoxy]-N'-phenyl-benzamidine hydrochloride
(Compound 15)
is Compounds of general formula (I) are favourable with respect to
application in the cultivation of plants because they are suitable for
treating both the fully developed plant and the seed or the seedling.
These compounds may be applied to the plants using any of the usual
procedures widely used in plant-protection.
2o Based on the above, the invention relates to a procedure to
increase the tolerance of cultivated plants against weather stresses.
According to the invention, the protected plant or its seed is treated
with a hydroxylamine derivative of general formula (I) , where R 1, X, Y,
R2 and R3 are as above. Preferably an aqueous solution of the com-
es pound of general formula (I) is used for the treatment, but alternatively
a preparation containing the usual carriers and the hydroxylarnine
derivative of general formula (I) as effective agent may be applied.
The dose and the concentration of the effective agent of general
formula (I) is dependent on the protected plant species or type and on
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the method of the application.
If the procedure according to the invention is aimed at improving
the tolerance of the plant against cold and frost, preferably the seed of
the plant should be treated with a hydroxylamine derivative of general
s formula (I), where
R1, X, Y, R2 and R3 are as above. The seed of the plant must be
covered with the proper product containing the active agent and
suitable for coating, preferably pearled, in certain cases dressed, or the
aqueous solution of the effective agent may simply be used.
1o The preferable method is to soak the seed of the plant in an
aqueous solution of a compound of general formula (I). For this purpose
a 1-200 mg/1 concentration of the compound of general formula (I) in
aqueous solution is prepared.
The procedure according to the invention may be performed by
1 s coating the seed of the plant with a solution containing a hydroxy-
lamine derivative of general formula (I). The compounds of general
formula (I) may be combined with dressing agents in certain cases.
For the coating of the seeds preferably pearling agents are
applied, which contain compounds of general formula (I) in a concen-
2o tration of 0.1-10 g/ 1 along with the usual pearling and auxiliary
materials. The pearling agents may contain other effective agents .beside
the mentioned effective agent as well, such as fungicides or additives
promoting germination, for example microelements. The pearling agent
is applied in a small volume. For example, when treating bean, soybean
2s or maize seeds, only 1 ml or less amount of pearling agent is used for
100 seeds, which is dried on the seeds uniformly while constantly
stirring.
Furthermore, this invention relates to a procedure for improving
the tolerance of cultivated plants against cold, where the plant is
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sprayed before or at the time when the cold season sets in with a spray
preparation containing a hydroxylamine derivative of general formula (I)
as effective agent.
The spraying is performed with a 1-500 mg/Iitre concentration
aqueous solution of the effective agent, which may occasionally contain
spraying auxiliary materials, such as surface active material
(detergent). In certain cases, compounds of general formula (I) may be
combined and sprayed to the plant to be protected with other effective
agents such as fungicides.
to The spraying is to be performed at the beginning of the period
hazardous in terms of cold temperature. If more than one period is to
be taken into consideration, then the plants must be sprayed at the
beginning of each such period.
According to the invention, to improve the tolerance of cultivated
t 5 plants the plant must be sprayed before or at the time when the dry
season sets in with a spray preparation containing a hydroxylamine
derivative of general formula (I) as effective agent.
The spraying is performed using a 1-500 mg/1 aqueous solution
of the active agent. The plants to be protected are sprayed before or at
2o the beginning of the period when there is a risk of drought. In every
case, the characteristics of the given plant species or type determine
the applicable quantity of the active agent. If more than one drought
period is to be taken into consideration, then the spraying must be
repeated at the beginning of each such period.
2s For the above listed treatments, a simple aqueous solution of the
hydroxylamine derivatives of general formula (I), but preferably such
preparations are used which contain proper auxiliary materials beside
the active agent, for improving the spraying, distribution and the
absorption of the active agent.
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The composition of the invention for improving the tolerance of
cultivated plants against weather stresses contains 0.001-95 m/m%
hydroxylamine derivative of general formula (I), in which R1, X, Y, R2
and R3 are as above, beside the solid or liquid carriers and possible
s auxiliary materials suitable for agricultural application.
The composition preferably contains water as liquid vehicle
agent. The aqueous solution of the active agent is a concentrate, which
should be diluted before application in order to prepare the proper
concentration mentioned above. Preferably, the aqueous solutions
to contain surfactants, those solutions for treating the seed contain
dressing and pearling auxiliary materials, such as film forming materi-
als. The sprays contain an adhesion improving agent, a substance to
improve spreading, light protecting agent, if required, a stabilising
agent and other additives beside the detergents. For spraying purposes
is ULV concentrates, emulsifiable concentrates, hydrophyl powders,
soluble granulates or microgranulates dilutable with water may be
applied. These products contain anionic or non-anionic detergents in
order to help the dilution with water. The solid products may contain
kaolin, diatomite or dolomite as vehicle, but may also contain any other
2o solid vehicle agent widely applied in such products. Preferably, perlite
is used as vehicle agent for the production of microgranulate.
The compositions of the invention may be combined or simulta-
neously applied with other pesticides, if the active agent of the latter is
compatible with the active agent of the composition of the invention. In
2s these cases, the spraying of the composition of the invention does not
require a separate process, it can be performed along with the usual
pesticide treatment of the cultivated plants.
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BEST MADE OF CARRYING OUT THE INVENTION
The invention is demonstrated by the following examples without
limiting the scope of the invention.
Example 1:
N-[2-palmitoyloxy-3-( 1-piperidinyl)propoxy]-3-
pyridinecarboximidamide monohydrochloride (Compound 3)
14.7 g (52.8 mmol) of N-[2-hydroxy-3-(1-piperidinyi) propoxy]-3-
pyridine-carboximidamide is dissolved in 160 ml of chloroform. 7.7 ml
(55 mmol) of triethylamine is added, followed by the dropwise addition
of a solution of palmitoyl chloride ( 14.7 g; 56.5 mmol) in 85 ml of
1s chloroform. The mixture is stirred overnight at room temperature. The
next day, a further 3.8 ml of triethylamine and 7.4 g of palmitoylchlo
ride are added, and the stirring is continued for one more day. Then the
solution is extracted with water, 5 V/V% acetic acid and water,
successively, dried over anhydrous sodium sulphate, and evaporated to
2o dryness.
The residue (28.2 g oil) is dissolved in ethyl acetate, and the product is
precipitated by addition of 30 ml of 1 N HCl/ethyl acetate. The thick,
white precipitate is filtered off, washed with ethyl acetate and dried.
Yield: 10.9 g (37%)
2s Mp.: 110-113 °C
Example 2:
N-[2-hydroxy-3-( 1-piperidinyl)propoxy]-2'-nitro-
benzenecarboximidoyl chloride monohydrochloride (Compound 5)
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6.0 g ( 16.7 mmol) of N-[2-hydroxy-3-( 1-piperidinyl) propoxy]-2'-
nitro-benzene-carboximidamide monohydrochloride is dissolved in 21
ml of water, then 48 ml of concentrated hydrochloric acid is added. The
solution is cooled to -5 °C, then a cold solution of 2.1 g (33.3 mmol)
of
sodium nitrite in 9 ml of water is added dropwise. Throughout the
reaction the internal temperature is maintained at 0°C. When the
addition is completed, the mixture is stirred for a further four hours
and cooled overnight. The product is filtered off, washed with cold water
and dried.
Yield: 3.9 g (63%). Mp.: 159-162 °C
IR (KBr): 3298, 2983, 2932, 2746, 1593, 1574, 1535, 1445, 1391,
1354, 1317, 1288, 1242, 1198, 1117, 1092, 1069, 1020, 968, 947,
914, 852, 793, 756, 708, 577 cm-1
1s
Example 3
N-[[3-( 1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-N'-phenyl-
benzamidine hydrochloride (Compound 6)
20 4 g (24.7 mmol) of benzanilide-imide-chloride is dissolved in 45
ml of chloroform. Then 5.32 g (24.7 mmol) of 1-aminooxy-3.-..[(1,I-
dimethyl-ethyl)-amino]-2-hydroxy-propane dissolved in 45 ml of
chloroform is added dropwise to the resulting solution. The reaction
mixture is stirred at room temperature for 3 hours, and then washed
2s with 25 ml of 1 M aqueous sodium-carbonate solution. The chloroform
phase is dried over sodium-sulphate, filtered and evaporated. The
evaporation residue is cristallysed with hexane. The resulting base is
dissolved in (5.33 g) 50 ml of ethyl-acetate and then 3.35 ml of 3.67 N
hydrochloric acid / ethyl-acetate is added. The isolated crystals are
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filtered off, washed with ethyl-acetate and dried.
Yield: 2.97 g (72%). M.p.: 140-143 °C
1H-NMR (solvent: CDCIs; reference: CDC13 [ppm]): 9.7 (m,1H) and 8.1
(m, l H,NHa+); 7.8 (s, l H,NH-O); 6.7-7.4 (m, lOH,2xPh); 5.7 (d, I H,OH); 4.5
s (m,1H,CH); 4.25 (d,2H,OCHa); 3.1 (m,2H,NCHa); 1.25 (s,9H,tBu).
Example 4
N-N'-dimethyl-N'-phenyl-N"-(3-( 1-piperidinyl)propoxy]-guanidine
hydrochloride (Compound 7)
20 ml of 1 M aqueous sodium-carbonate solution is added to
1,040 g (6.5 mmol) of 1-aminooxy-3-(1-piperidinyl)propane dissolved in
10 ml of ether. While intensely stirring, 1200 ml (6.5 mmol) of N,N-
dimethyl-N'-phenyl-chloroformamidine dissolved in 10 ml of ether is
is added. After 2 hours of stirring, further 20 mg (0.1 mmol) of N,N-
dimethyi-N'-phenyl-chloroformamidine is added. After further 3 hours
of stirring, the phases are separated and the ethereal phase is dried
over sodium-sulphate, filtered and evaporated. The residue ( 1700 mg of
yellow oil) is dissolved in 10 ml of ethyl acetate. 10.5 ml of 0.54 M
2o hydrochloric acid/ethyi-acetate is added, and then the product is
cooled and the isolated crystals are filtered off. The raw _ product is
crystallised from methanol-ether mixture to give 847 mg of white
crystalline material.
Yield: 847 mg (38%). M.p.: 138-139 °C (methanol-ether)
2s 1H-NMR (solvent: CDCls; reference: CDCIs (ppm]): 7.2 (t,2H,Ph-m); 7.1
(d,2H,Ph-o); 6.9 (t,lH,Ph-p); 6.6 (m,lH,NH+); 4.0 (t,2H,OCHa); 3.5
(m,2H); 3.0 (t,2H,CH2); 2.6 (s,6H,2xNCHa); 2.2-2.5 (m,6H,3xNCHa); 1.8
(m,4H) and 1.3 (m,2H,piperidine).
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The product crystallised from isopropanol melts at 213-216°C.
Example 5
N-[3-(1-piperidinyl)propoxy]-N'-phenyl-benzamidine hydrochlo-
s ride (Compound I5)
0.8 g (5 mmol) of 1-aminooxy-3-(1-piperidinyl)propane is dis-
solved in 7.5 ml of chloroform. 1.08 g (5 mmol) of benzanilide-imide-
chloride dissolved in 7.5 ml of chloroform is added dropwise and then
to the reaction mixture is stirred for 3 hours. Then it is washed with two
times 10 ml of water, and the chloroform phase is dried over sodium-
sulphate, filtered and evaporated. The evaporation residue is dissolved
in 20 ml of 2 N aqueous sodium-hydroxide solution and the solution is
extracted with 20 ml of ethyl-acetate. The ethyl-acetate phase is dried
15 over sodium-sulphate and filtered, and then 0.8 ml of 3.45 M hydro-
chloric acid/ethyl acetate is added. The isolated precipitate is filtered
and dried.
Yield: 0.8 g (46%). M.p.: 164-166 °C (crystallised from ethyl-
acetate)
C13-NMR (solvent: CDC13; reference: CDCls (ppm]): 157.55 (C-amidine);
20 135.75 (N-Ph-ipso); 132.84 (C-Ph-ipso); 128.95 (N-Ph-m); 128.84 (C-Ph-
m); 126.66 (N-Ph-p); 125.34 (N-Ph-p); 124.0 (C-Ph-p); 74.02 (4.CH2);
54.20 (NCH2); 53.30 (2.6 piperidine); 23.19 (CHa); 22.63 (3.5
piperidine); 21.76 (4 piperidine) .
25 Example 6
N,N-dimethyl-N'-phenyl-N"-[2-hydroxy-3-( 1-piperidinyl)propoxy]-
guanidine hydrochloride (Compound 13)
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1,1 SO mg (6.58 mmol) 1-aminooxy-2-hydroxy-3-( 1-piperidinyl)-
propane) is dissolved in 20 ml of ether and to this solution 20 ml of I M
sodium carbonate solution is added, then 1,206 mg (6.58 mmol) of N,N-
dimethyl-N'-phenyl-chloroformamidine dissolved in 10 ml of ether is
s added. After two hours, 22 mg (0.11 mmol) of N,N-dimethyl-N'-phenyl-
chloroformamidine is also added to the reaction mixture. After stirring
for further 3 hours, the layers are separated, the ether layer is dried
over sodium-sulphate, filtered and evaporated. The residual 1,800 mg
of yellow oil is taken in 10 ml of ~~ethyl acetate, and to this solution
10.46 ml of 0.54 M HCl/ethyl acetate is added, cooled and the yellow
crystals are filtered off. Impurities are removed by recrystallization first
in acetone, then in ethyl acetate.
Yield: 674 mg (28%) pale yellow powder. Mp.: 127-129 °C (ethyl
acetate)
15 IH-NMR (solvent: CDC13; reference: CDC13 [ppm]): 7.1-7.4 (m,SH,Ph);
5,9 (m,1H,OH); 4.6 (m,1H,CH); 4,1 (m,2H,OCH2); 3.6 (m,4H,2-6
piperidine); 3.4 (m,2H); 3.2 (m,1H,NH); 1.8 {m,4H,3-5 piperidine); 1.4
(m,2H,4 piperidine)
2o Example 7
Increasing chilling tolerance by treating seeds
In this experiment the tolerance of maize, soybean and pepper
seeds treated with the active agent against cold was tested. This test
25 imposed temperature and oxygen deficiency stresses on the seeds and
was carried out according to Barla-Szabo and Dolinka CSVT (Complex
Stressing Vigour Test). For a single test, two hundred seeds were
soaked for 48 hours at 25°C and another 48 hours at S°C in 150
ml
distilled water containing the active agent in 10 mg/ 1 concentration.
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Following the 96 hours of soaking, the seeds were further germinated
between rolled wet paper for 96 hours at 25°C. There were 25 seeds in
each roll, the rolls were placed vertically into containers and covered
with a plastic bag in order to reduce evaporation. During the whole
procedure the seeds were kept in darkness.
At the end of the experiment the number of normally developing
and ungerminated seeds were recorded. The length of the normal
seedlings was measured and the average length of the five longest
seedlings was calculated. Seedlings longer than 0.33 times the average
to length of the five longest seedlings were considered to be of high vigour,
and low vigour seedlings were shorter than this length.
In experiments with maize, it was found that the tested active
agents did not influence the germination and development of the Mo 17
inbred maize line germinated in optimal circumstances, at 25°C. Under
is the circumstances of the CSVT test, however, they proved to be effec-
tive, as it is shown in Table 1.
Table 1. Active agent Ratio of high vigour plants (%)
Compound 1 38*
Compound 2 29*
Compound 9 33*
Compound 11 24
Compound 3 47*
Compound 12 23*
Compound 4 28*
Compound 5 32*
Compound 6 35*
Compound 7 36*
Control 19
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Results marked with * are significant compared to the control, if
P<0.05.
s Using the same experimental method for the HMv09 inbred maize
line compounds, shown in Table 2., proved to be effective, the ratio of
plants of high vigour increased significantly.
Table 2.
Active agent Ratio of high vigour plants (%)
Compound 2 49*
Compound 10 52*
Compound 4 40*
Compound 6 57*
Compound 13 56*
Compound 14 45*
Compound 15 53*
Control 33
to Results marked with * are significant compared to the control, if
P<0.05.
In the case of a further experiment with maize of low chilling
tolerance (LT) and high chilling tolerance (HT) populations (Ref: P.
1s Landi, E. Frascaroli, A. Lovato; EUPHYTICA 64 21-29 (1992)], the
following positive effects were found (Table 3.).
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Table 3.
Active agent Ratio of high vigour plants
(%)
HT LT
Compound 2 98* 94*
Compound 3 92* 86*
Compound 4 94* 88*
Compound 5 96* 92*
Control $4 74
Results marked with * are significant compared to the control, if
P<0.05.
Experiments with McCall soybeans also showed that the active
agents have no effect on the germination and development of the plants
under normal conditions. When applying the CSVT test, the following
results were obtained (Table 4.).
to
Table 4.
Active agent Ratio of high vigour plants
(%)
Compound 2 43*
Compound 4 46*
Compound 8 47*
Control 38
Results marked with * are significant compared to the control, if.
t s It was further observed that Compound 8 decreased the number
of ungerminating seeds by 50% (control: 33%, treated: 17%, significant
at P<0.05).
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Experiments with green peppers showed similarly that the active
agents have no effect under normal circumstances, do not influence the
germination of the seeds and the development of the plants kept at
25°C. Under the circumstances of the CSVT test, they increased the
length of the sprouts and the roots along with the proportion of the
high vigour seedlings. The ratio of the ungerminating seeds decreased
by 30% on average due to the treatment with the active agents. The
results are demonstrated in Table 5.
to Table 5.
Active agent Ratio of high vigour plants (%)
Compound 2 47*
Compound 4 45*
Control 36
Results marked with * are significant compared to the control, if
P<0.05.
In order to make the results more comprehensible, it should be
noted that the CSVT procedure is developed to predict the expected
minimal ratio of sprouting seeds under environmental stresses. In a
given set of seeds, the ratio of those seeds that safely sprout and
properly germinate in cold spring weather is 90% for seeds which
proved to be of high vigour in the CSVT test, while the ratio of those
2o seeds which safely sprout and properly germinate in cold spring
weather is only 60% for seeds that proved to be of low vigour in the
test. Hence, if an active agent improves the vigour of the seedlings, it in
the end improves the sprouting ratio under open field conditions in the
case of ground temperature colder than optimal.
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The above experiments prove that the compounds of general
formula (I) are able to improve the vigour of the seedlings and hence
improve the chance of sprouting, if unexpectable weather stresses
occur after the sowing.
s
Example 8
Pearling of soybean seeds
Soybean seeds are treated with a pearling agent, which contains 1
to mg/ml of N-13-(1-piperidinyl)propoxy]-3-nitro-benzimidoyl-chloride
monohydrochloride (Compound 4) in a 5% aqueous polyvinylalcohol
solution. 100 seeds and 1 ml of pearling agent are filled into a glass
vessel and while the vessel is rotated, the seeds are coated with the
agent and then it is left to dry. For seeds treated this way, we obtained
15 the following results when placed under the conditions of the CSVT test
described in Example 7.
Table 6.
Treatment Ratio of high vigour plants (%)
sprout root
untreated control 47 40
pearled with PVA 52 49
pearled with PVA and 63* 58*
Compound 4
Results marked with * are significant compared to the control, if
P<0.05.
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PVA slightly increased the ratio of high vigour plants. The PVA
solution containing Compound 4 proved to be such a pearling agent
which was able to increase the ratio of high vigour plants significantly
under the experimental conditions, increasing the length of both the
sprouts and the roots.
In a further CSVT experiment also using McCall soybeans,
polyvinylalcohol (PVA) was applied for pearling the seeds. The 2.5 mg
doses of the active agents were dissolved in 1 ml of 2.5% PVA solution,
and this quantity was applied to 100 pieces of seeds. The improvement
to of the chilling tolerance is observed by the significant elongation of the
germ and the roots. The results are demonstrated in Table 7.
Table 7.
Active agent Relative length (control=100)
germ root
Compound 2 106 128
Compound 9 110 131
Compound 3 133 150
Compound 5 116 135
Compound 6 127 152
The experiments show clearly that, according to the results of the
vigour test, the chances of sprouting of the plants increased after
pearling with the active agent.
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Example 9
Increasing the drought tolerance of beans
s Based on the experiences of our preliminary experiments, the
plants were hardened before the application of the active agent; by
withholding the water for a few days, until the first signs of withering
appeared. Then the plants were watered and the active agent was either
dissolved in the water, or sprayed to the plants directly. Afterwards, the
1o plants were subjected to different periods of drought according to the
given experiment, watered again, and after a week-long regeneration
period, the survival ratio was determined.
a) Seaway bean cultivar was hardened for 5 days by withholding
the water. Afterwards the plantlets were watered for two days nor-
ts mally. During this time, a 10 mg/litre and 100 mg/litre concentration
solution of the active agent was applied two times a day dissolved in
water or by direct spraying. Then the water was withheld for 7 days,
and after a week-long regeneration period, the survival ratio was
determined. The results are summarised in Table 8.
Table 8
Active agent Watering ( l Omg/ 1) Watering ( 100mg/ 1) Spraying ( 1 OOmg/ 1)
survival (%)
Control 17 17 0
Compound 2 30* 41 * 71
Compound 6 25* 36* -
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Results marked with * are significant compared to the control, if
P<0.05.
b) In this experiment, bean plants (cv. Seaway) were hardened for
s 7 days instead of the 5 days described in Part a. Then a 10 mg/litre
and 100 mg/ litre concentration solution of the active agent was applied
two times a day for two days. Then 7 days without water followed, and
after a week-long regeneration period, the results of the experiment
were evaluated. The results are summarised in Table 9.
Table 9.
Active agent Survival (%)
Compound 2 14*
Compound 4 39*
Control 0
Results marked with * are significant compared to the control, if
P<0.05.
1s
Example 10
Increasing the drought tolerance of soybeans
Soybeans of soybean cv. Bolyi 44 were hardened for 6 days by
2o withholding the water. This was followed by two days of watering, and
the active agent was applied in the water. The concentration of the
solution of the active agent was 50 mg/litre. After a 4-day-long cease of
watering and a one week regeneration period, the number of surviving
plants was recorded. The results are listed in Table 10.
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Table 10.
Active agent Survival (%)
Compound 2 25*
Compound 4 33*
Control 18
Results marked with * are significant compared to the control, if
s P<0.05.
Watering was ceased for 10 days for a certain group of plants in
the experiment. It was observed that almost every plant perished. Each
of the 4 surviving plants had previously been treated with the active
~ o agent.
Example 11
Increasing the frost tolerance of beans
t s Seedlings of bean cv. Seaway were cultivated under normal
conditions for the first two weeks, then they were treated with 10
mg/litre and 100 mg/litre concentration solutions of the examined
active agents 2 and 1 days before the initiation of the frost tolerance
experiments. In the experiment, the plants were kept at -2°C for 8
2o hours, then grew under normal conditions for 1 week, and the survival
ratio was determined. 4 trays were used for each experiment and 6
seeds were planted in each tray. The compounds in Table 11. signifi-
cantly increased the survival ratio.
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Table 11.
Active agent Treatment Survival (%)
Compound 2 spraying, 100 mg/1 40*
Control spraying 25
Compound 2 watering, 10 mg/1 25*
Compound 4 watering, 10 mg/1 40*
Control watering 18
Results marked with ' are significant compared to the control, if
P<0.05.
s
Example 12
Increasing the chilling tolerance of maize in a gradient chamber
The experiment was performed using the Mo 17 maize inbred
o line. The seeds were coated with a 2% solution of the examined com-
pound dissolved in 2 ml polyvinylalcohol before germination, where the
above quantity of solution is applied for 100 seeds. The seeds were
germinated for 3 days wrapped in wet filter paper, they were sown and
then cultivated in gradient chamber for 5 weeks. In the gradient
t s chamber, the temperature was maintained on a scale between 1$ and
12°C, with differences of 1 °C. This was followed by a one week
regen-
eration at 23/20°C temperature.
In the experiment, the length of the plants was measured 16, 31
and 43 days after the sowing, and at the end of the experiment the
2o fresh weight of the plants was measured. The experiment was per
formed on 4 plants at each temperature and by each treatment. The
results demonstrate the increased germination potential of the exam-
ined maize inbred line, and the imrovement of the early development of
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the seedlings compared to the untreated control. The experimental
results are summarized in Table 12.
Table 12.
Increasing maizein gradient
the chamber
chilling with
tolerance
of
Compounds
2,
5
and
6
Control Compound Compound Compound
2 5 6
Temp. Time Length FW Length FW Length FW Length FW
(days) (cm) (g) (cm) (g) (cm) (g) (cm) (g)
18 C 16 12.9 - 13.2 - 15.0 - 14.6 -
31 22.0 - 28.4 - 28.4 - 25.0 -
43 35.0 5.3 37.0 6.0 38.0 6.2 39.0 7.6
17 C 16 13.1 - 17.0 - 19.7 - 17.8 -
31 22.9 - 27.7 - 31.2 - 29.9 -
43 36.0 4.8 36.5 5.5 37.3 6.6 44.3 9.7
16 C 16 10.2 - 15.2 - 15.4 - 12.4 -
31 20.6 - 24.8 - 26.8 - 26.4 -
43 33.1 4.2 32.3 4.5 34.5 5.0 42.3 7.7
C 16 9.2 - 10.0 - 10.2 - 9.5 -
31 15.0 - 17.7 - 2I.3 - 22.2 -
43 21.2 2.0 28.5 3.6 32.3 4.4 34.0 5.4
14 C 16 5.2 - 7.6 - 9.7 - 5.8
31 10.8 - 15.4 - 17.2 - 11.6 -
43 20.3 1.6 25.9 2.7 25.1 2.9 20.3 1.3
13 C 16 5.0 - 6.0 - 7.4 - 4.7 -
31 10.8 - 10.1 - 13.1 - 10.0 -
43 17.2 1.0 16.0 1.0 23.8 2.1 18.5 1.1
12 C 16 5.4 - 5.0 - 5.8 - 4.5 -
31 8.7 - 7.9 - 11.3 - 10.9 -
43 17.8 0.9 18.9 1.2 20.1 1.5 25.5 2.0
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In the following examples, results of field experiments are shown,
which were arranged with early sowing in order to determine the effect
of the hydroxylamine derivatives of the invention on the development
and yield of the plants in this case under natural conditions.
s
Example 13
Increasing the yield of field soybean cultivation
The experiment was performed using soybean cv. Bolyi 44. Before
to sowing, the seeds were treated with Rhyzobium Japonicum nitrogen-
binding bacterium, which forms a root nodule providing 50-70% of the
nitrogen demand of the plant.
The examined compounds were applied by pearling the seeds; 1
ml of pearling agent containing 1 mg of active agent in a 5% aqueous
is PVA solution was used for 100 seeds.
The plants were sown after soil preparation in the autumn, using
a crop rotation system, 3-5 cm deep in the ground, with a 45-50 cm
row distance, a S cm plant distance and 450,000-500,000 plant/ha
density. The date of sowing was April 15, 1997. During the develop-
2o ment of the plant, the usual cultivation procedures were followed and
the usual pesticides were used. The harvest took place in September -
October, with the water content of the grains being between 16-18%.
The results are listed in Table 13.
2s
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Table 13.
Active agent Weight of the crop (kg/m2) Improvement compared to
the control (%)
Control 0.45
Compound 6 0.52 15.5
Compound 5 0.50 11.1
Compound 2 0.55 22.2
Example 14
Increasing the yield of maize in field cultivation
The experiments were perfomed on the Mo 17 and AMO 406
lines. Before sowing, the seeds were dressed with fungicides, insecti-
cides and rodent-control agents, and, at the same time, the tested
compounds were applied in the form of a 2.5 mg/ml concentration
to solution in a 2% PVA solution; 2 ml of solution was used for 100 seeds.
The plants were sown after soil preparation in the autumn, using
a crop rotation system, 4-8 cm deep in the ground, with a 45 cm row
distance, a 30 cm plant distance and 60,000-80,000 plant/ha density.
The date of the sowing was April 15, 1997. During the development of
~s the plant, the usual cultivation procedures were followed, and the
usual pesticides were applied. Harvest took place when the water
content of the grains decreased below 28%. At harvest, the weight of
the plants and of the crop were determined. The results are listed in
Table 14. and 15.
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Table 14.
Field cultivation of the Mo 17 maize line
Active agent Weig ht of the crop (kg/m2)Ratio
to the
control
(Compound No.)
Control 1 St 1.55 100% 0.09 100%
2nd 1.42 100% 0.088 100%
6 1 St 2.03 130.9% 0.101 112.2%
2nd 2.0 140.8% 0.11 125%
1St 1.97 127% 0.109 121.1%
2nd 0.093 105.6%
2 1 St 1.85 119.3% 0.108 120%
2nd 2.0 140.8% 0.111 126.1%
5 Table 15.
Field cultivation of the AMO 406 maize line
Active agent Weight Ratio
of the to the
crop (kg/m2) control
(Compound No.)
Control 1 st 1.65 100% 0.097 100%
2nd 1.13 100% 0.075 i 00%.
6 1 st 2.2 133.3% 0.115 118.5%
2nd 1.75 154.8% 0.097 129.3%
5 1 st 1.8 109% 0.1 103.0%
2nd 1.8 159.2% 0.1 133.3.6%
2 1 St 2.35 140.6% 0.16 164.9%
2nd 1.25 110.6% 0.089 118.6%
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Example I5
Foliar spray
The foliar spray is prepared with the following composition
(proportions by weight):
Compound 2 20
sodium-lauryl-sulphate 3
sodium-lignine-sulphonate 6
t o water 63
kaolin 8
Example 16
Foliar spray
~5
Foliar spray is prepared with the following composition
(proportions by weight):
Compound 4 20
alkyl-aryl-sulphonate 5
2o water 75
Example 17
Pearling agent
Pearling agent is prepared with the following composition
2s (proportions by weight):
Compound 3 0.25
2 % aqueous solution of
polyvinylalcohol 9.75
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The pearling agent must be applied as active agent in a quantity
of 0.01-0.02 m/m% with respect to the weight of the seed.
Example 18
Granulate
Granulate is prepared with the following composition
(proportions by weight):
Compound 13 10
limestone-powder 64
ethylene-glykol 3
high dispersity silicic acid 4
sodium-ligninesulphonate 4
water 15
The mixture of the components must be ground in a hammer mill
until it reaches the particle size of 5 micron.
2o Example 19
Powder preparation
Powder preparation is prepared with the following composition
(proportions by weight):
2s Compound 6 50
poly-vinyl-pyrrolidon 10
silicon-dioxide 25
china-clay (kaolin) 15
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Example 20
Powder preparation
Powder preparation is prepared with the following composition
(proportions by weight):
Compound 1 50
calcium-ligninesulphonate 5
isopropyl-naphtalene-sulphonate 1
1 o silicon-dioxide 4
filler (kaolin) 40
