Note: Descriptions are shown in the official language in which they were submitted.
y o~
polysubstituted by halcgen and/or Cl-C3alkyli or are the
-CH~-Z-R7 group, wherein
Z is oxygen or sulfur and
R7 is hydrogen, Cl-C8alkyl or Cl-C8alkyl which is sub-
stituted by Cl-C2alkoxy; C3-C4alkenyl, prop-2-ynyl,
3-haloprop-2-ynyl~ phenyl or phenyl which is mGnO- or
polysubstituted by halogen, Cl-C3alkyl, Cl-C3alkoxy,
nitro andlor CF3i benzyl or benzyl which is mono- or
polysubstituted by halogen, Cl-C3alkyl and/or Cl-C3alkoxy,
R3, R4 and R5, each independently of the other,~re hydrogen
or Cl-C4alkyl, the total number of carbon atoms in R3,
R4 and R5 not exceeding 6, and
R6 is hydrogen or Cl C3alkyl,
together with the acid addition salts and metal complexes
thereof. The invention also relates to the production of
these compounds and as well as to agrochemical compositions
and pharmaceutical preparations which contain at least one
compound of the formula I as active ingredient, to the
production of these compositions and preparations and to the
use thereof. They may be used, on the one hand, in agriculture
or related fields for controlling phytopathogenic micro-
organisms and, on the other, as antimycotic and/or anti-
convulsive and anxiolytic agents in the pharmaceutical
field, for example for controlling parasitic fungi in warm-
blooded animals and/or for treating different forms of
epilepsy, states of anxiety, tension and excitation, andlor
manic states of mind.
'
.~
~ .
Case 5-13393/~/AP
Novel microbicidal arylphenyl ether derivatives, production
thereof and use thereof
The present invention relates to substituted arylphenyl
ether derivatives of the formula I below, and to the acid
addition salts and metal complexes thereof. The invention
also relates to the production of these compounds as
well as to agrochemical compositions and pharmaceutical
preparations which contain at least one compound of the
formula I as active ingredient, to the production of these
compositions and preparations and to the use thereof, and
further to a method of treating plants for controlling or
preventing attack by phytopathogenic microorganisms.
The arylphenyl ether derivatives of this invention
have the formula
u~
Ar--O~
Cll2-N~ !
wherein
Y is -CHa or -N=,
Ra and Rb, each independently of the other9 are hydrogen,
halogen, Cl-C3alkyl, Cl-C3alkoxy or nitro,
Ar is phenyl or naphthyl, each unsubstituted or mono-
or polysubstituted by halogen, Cl-C7alkyl, Cl-C7alkoxy,
nitro and/or CF3,
U and V, each independently of the other, are Cl-C12alkyl
which is unsubstituted or substituted by halogen or
Cl-C6alkoxy, or together form one of the following
alkylene bridges
Rl R2 3~- ~ 4 R6\X--~
/ \ ~ i t R5 or \ H
wherein
Rl and R2, each independently of the other, are hydrogen,
Cl-C12alkyl or Cl-C12alkyl which i9 mono- or poly
substituted by halogen; phenyl or phenyl which is
mono- or polysubstituted by halogen and/or Cl-C3alkyl;
or is the -CH2-Z-R7 group, wherein
Z is oxygen or sulfur and
R7 is hydrogen, Cl-C8alkyl or Cl-C8alkyl which is
substituted by Cl-C2alkoxy, C3-C~alkenyl, prop-2-ynyl,
3-haloprop-2-ynyl, phenyl or phenyl which is mono-
or polysubstituted by halogen Cl-C3alkyl, Cl-C3alkoxy
nitro and/or CF3; benzyl or benzyl which is mono-
or polysubstituted by halogen, Cl-C3alkyl and/or
Cl-C3alkoxy,
R3, R4 and R5, each independently o the other,are hydrogen
or Cl-C4alkyl, the total number o carbon atoms in
R3, ~4 and R5 not exceeding 6, and
~6 is hydrogen or Cl-C3alkyl~
together with the acid addition salts and metal complexes
thereo~
As unsubstituted or substituted phenyl or naphthyl,
the substituent Ar has e.g. ~he formula
-- 3 --
R ~C c ~ ~.
>< / d
R R ~
e e --
wherein Rc, Rd and Re, each independently of the other,
are hydrogen, halogen, Cl-C7alkyl, Cl-C7alkoxy, nitro or
CF3.
Depending on the number o~ indicated carbon atoms,
the ~erm "alkyl" by itself or as moiety of another
substituent will be understood as meaning e.g. the
following groups: methyl, ethyl, propyl, butyl, pentyl,
hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl~
and the isomers thereof, e.g. isopropyl, isobutyl, tert-
butyl, sec-butyl, isopentyl etc. Alkenyl denotes e.g.
propen-l-yl, allyl, buten~l-yl, buten-2-yl or buten-3-yl.
Throughout this specifiration, halogen denotes fluorinea
chlorine, bromine or iodine~ with chlorine or bromine
being preferred.
The invention relates both to the free compounds of
the formula I and to the acid addition salts thereof with
inorganic and organic acids, and likewise to their complexes
with metal salts.
Salts of this invention are in particular addition
salts with inorganic or organic acids which are physiologi-
cally tolerable with respect to the envisaged utility.
Examples of inorganic and organic acids which are
physiologically tolerable with respect to ~he utility as
microbicides in plant protection, are hydrohalic acids,
e.g. hydrochloric, hydrobromic or hydriodic acid, sulfuric
.
acid, phosphoric acid, phosphorous acid, nitric acid,
unsubstituted or halogenated fatty acids such as acetic
acid, trichloroacetic acid and oxalic acid, or sulfonic
acids such as benzenesulfonic acid and methanesulfonic acidO
Acids which are physiologically tolerable in respect
of the utility as medicament, i.e. pharmaceutically
acceptable acids, are eOg. pharmaceutically acceptable
mineral acids such as hydrohalic acids~ e.g. hydrochloric,
hydrobromic or hydriodic acid, nitric acid, sulfuric acid
or phosphoric acid, pharmaceutically acceptable carboxylic
and sulfonic acids such as aliphatic monocarboxylic acids
and optionally hydroxylated dicarboxylated acids, e.g.
acetic acid, fumaric acid, maleic acid, malic acid or
tartaric acid, and also aliphatic or aromatic sulfonic
acids such as lower alkanesulfonic acid or unsubsti~uted
or substituted benzenesulonic acid, e.g. methanesulfonic
acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene-
sulfonic acid and p-bromoben2enesulfonic acid, as well as
sulfamic acids, e.g. N~cyclohexylsulfamic acid.
Metal complexes of formula I consist of the basic
organic molecule and an inorganic or organic metal salt,
e.g. the halides, nitrates, sulfates, phosphates, tartrates
etc. of copper, manganese, iron, zinc and other metals.
The metal cations may exist in different valence statesO
The compounds of formula I are oils 9 resîns or solids
which are stable at room temperature and which possess
very valuable physiological properties, such as microbicidal,
e.g. phytofungicidal and pharmacological proper~ies, in
particular antimycotic as well as anticonvulsive and
anxioly~ic properties. They may therefore may be used, on
the one hand, in agriculture or related fields for con-
Z~ 3
trolling phytopathogenic microorganisms and, on the other,as antimycotic and/or anticonvulsive and anxiolytic agents
in the pharmaceutical field, for example for controlling
parasitic fungi in warm-blooded animals and/or for treating
different forms of epilepsy, states of anxiety, tension and
excitation3 and/or manic s-tates of mindO
An important group of microbicides for use in plant
protection comprises compounds of the formula I, wherein
Y is -CH= or -N=, eac:h of Ra and Rb independently of the
other is hydrogen, halogen, Cl-C3alkyl, Cl-C3alkoxy or
nitro; Ar is the group
R ~ C d
R /~-= Re~
wherein
Rc, Rd and Re, each independently of the otherg are hydrogen,
halogeng C.l-C3alkyl, Cl-C3alkoxy, nitro or CF3~
U and V, each inrlependently of the other,are Gl-C12alkyl
or together form one of the following alkylene
bridges
Rl R2 R3~ 4 R6
/ \ ~ i t R5 or
wherein
Rl and R2, each independently of the other, are hydrogen,
Cl-C3alkyl or Cl-C12alkyl which is mono or poly-
substituted by halogen, orare phenyl or phenyl which
is mono or polysubstituted by halogen and/or
Cl-C3alkyl, or are the -CH2-Z-R7 group, in which
q~
-- 6 --
~ is oxygen or sulfur and
R7 is hydrogen, Cl-C8alkyl or Cl-C8alkyl which is
subs~ituted by Cl-C2alkoxy, or is C3-C4alkenyl,
prop-2-ynyl, 3-haloprop-2-ynyl, phenyl or phenyl
which is mono- or polysubstituted by halogen,
Cl-C3alkyl, Cl-C3alkoxy~ nitro and/or CF3~ or is
benzyl or benzyl which is mono- or polysubstituted
by halogen, Cl-C3alkyl and/or Cl-C3akoxy,
R3, R4 and R5, each independently of the other, are
hydrogen or Cl-C4alkyl 7 the total number of carbon
atoms in R3, R4 and R5 not exceeding 6, and
R6 is hydrogen or Cl-C3alkyl,
and the acid addition salts and metal complexes thereof.
This subgro~lp will be designated group Ia.
A preferred group of agriculturally useful microbicides
comprises compounds of the formula I, including their salts
and metal complexes, wherein Y is -CH= or -N=, each of
Ra and Rb independently of the other is hydrogen, halogen
or Cl-C3alkyl, Ar is the group
E~
d~
~ <, _./
e
wherein each of Rc, Rd and Re independently of the other
is hydrogen, CF3 or Cl-C3alkyl, and U and V are as defined
for formula I. This group will be designated group Ib.
Preferred microbicides within subgroup Ib are those
compounds of the formula I, wherein each of U and V
~independently of the other is Cl-C3alkyl or together form
one of the following alkylene groups
~ ~a3z;~3
7 -
or 3\X ~ 4
i ~~~~ 5
wherein each of Rl, R2, R3, R4 and R5 independently of the
other is hydrogen or Cl-C4alkyl, the total number of carbon
atoms in R3, R4 and R5 not exceeding 6. This group will be
designated group Ic.
A further preferred group of agriculturally useful
microbicides comprises compounds of the formula I,
wherein Y is -CH= or -N=, Ar is as defined for formula I,
each of Ra~ Rb, Rc, Rd and Re independently of the other
is chlorine, bromine, fluorine, methyl, methoxy or nitro;
each of U and V independently of ~he other is Cl-C3alkyl
or together form one of the alkylene groups as defined
for formula I, wherein each of Rl, R2~ R3, R~, R5 and R6
independently of the other is hydrogen or Cl-C3alkyl~ or
Rl is -OEI2-0-R7, in which R7 is Cl-C3alkyl, C2~C4alkyl
which is substituted by Cl-C3alkoxy, or is C3-C4alkenyl
or phenyl. This group will be designated group Id
Particularly preferred microbicides within group Id
are those in which U and V together form an unsubstituted
or a simply substituted ethylene or propylene bridge. This
group will be designated group Ie.
Accordingly, the following individual compounds may
be cited as exemplifying particularly preferred compounds
for use in agriculture:
2-[p-(phenoxy)phenyl]-2-[1-(lH-1,2,4-triazolyl)methyl]-4-
methyl-1,3-dioxane,
f~
-- 8
2-[p-(phenoxy)phenyl] 2-[1-(lH-1,2,4-triazolyl)methyl]-4-
ethyl-1,3-dioxane,
2-[p-(phenoxy)phenyl]-2-[1-(lH-1,2,4-triazolyl)methyl~-4-
methyl-1,3-dioxolane,
2-[p-(phenoxy)phenyl]-2-[1-(lH-1,2,4-triazolyl)methyl]-4-
ethyl-1,3-dioxolane.
Interesting compounds of the formula I in respect of
their antimycotic activity are those belonging to the group
If, wherein Y is -C~= or -N-, each of Ra and Rb independently
of the other is hydrogen, halogen or Cl-C3alkyl, Ar is
the group
d~o.~
~.=./
Rc
wherein each of Rc, Rd and Re independently of the other
is hydrogen, halogen3 CF3~ Cl-C3alkyl, Cl-C3alkoxy, and U
and V are as defined for formula I.
Within subgroup If, preferred compounds of the formula
I in respect of their antimycotic activity are those in
which each of U and V independently of the other is
Cl-C6alkyl, C2-C~alkyl which is unsubstituted or substituted
by halogen or Cl~C2alkoxy, or together form one of the
following alkyl.ene groups
~ \ or I t R
wherein ea~h of ~1' R2, P'3~ R4 and R5 independentl~ o~ the
other is hydrogen or Cl-C4alkyl, the total number of carbon
atoms in R3, R4 and R5 not exceeding 6. This group will be
designated group Ig.
9r~3
g
Within subgroup Ig, preferred compounds of the
formula I in respect of their antimycotic activity are
those in which U and V together are the alkylene group
/CH20R7
wherein R7 is Cl-C4alkyl~ C2-C4alkyl which is suhstituted
by Cl-C2alkoxy, or is C3-C~alkenyl or prop-2-ynylO This
group will be designated group Ih.
A further preferr~d group of compounds of the formula I
having antimycotic activity comprises those in which Y is
-CHa, Ar is as defined for formula I, each of Ra and Rb
independently of the other is hydrogen, methyl, chlorine
or bromine, each of Rc, Rd and Re independently of the other
is hydrogen, fluorine, chlorine, bromine, methyl, methoxy,
CF3 or nitro, each of U and V independently of the other
is Cl-C3alkyl which is unsubsituted or substituted by
Cl-C2alkoxy or chlorine, or together form one of the
alkylene groups as defined for formula I, wherein each of
Rl, R2, R3, R~, R5 and R6 independently of the other is
hydrogen or Cl-C3alkyl~ or Rl is -CH20R7, wherein R7 is
Cl-C3alkyl, C2-C3alkyl which is substituted by Cl-C2alkoxy,
or is C3-C4alkenyl. This group will be designated group Ii.
The folLowing individual compounds may be cited as
exemplifying particularly preferred compounds having
antimycotic activity:
2-[p-(phenoxy)phenyl]-2~ (lH-1,2,4-triazolyl)methyl]-4-
methyl-5-~.ethyl-1,3-dioxolane;
2-[p-(phenoxy)phenyl3-2-[1-(1ll-1,2a4-triazolyl~methyl]-1~3-
dioxane;
2-[p-(phenoxy)phenyll-2-(1-imidazolylmethyl)-4-ethyl-1,3
dioxolane;
- 10 -
2-[p-(2,4-dimethylphenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p-(3-chlorophenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p-(4-chlorophenoxy)phenyl~-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p-(3-trifluoromethylphenoxy)phenyl]-2-(1-imidazolyl-
methyl)-4-ethyl-1,3-dioxolane;
2-[p-~4-chloro-3-methylphenoxy)phenyl~-2-(1-imidazolyl-
methyl)-4-ethyl-13 3-dioxolane;
2-[p-~3,4-dichlorophenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p-(2,5-dichlorophenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p~(3,4-dichlorophenoxy)phenyl~-2-(1-imidazolylme~hyl)-4-
methoxymethyl-1,3-dioxolane;
2-[p-(4-fluorophenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p-~-fluorophenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
methyl-5-methyl-1,3-dioxolane;
including their respective pharmaceutically acceptable acid
addition salts, processes for their production, phaLma-
ceutical preparations containing them, and their use as
medicaments.
Interesting compounds of the formula I in respect of
their anticonvulsive and anxiolytic activity are those
belonging to the group Ij, wherein Y is -CH= or -N=, each
of Ra and ~ independently of the other is hydrogen, halogen
or Cl-C3alkyl, Ar is phenyl or phenyl which is substi~u~ed
by Cl-C3alkyl, Cl-C3alkoxy, CF3 or halogen, and U and V are
as defined for formula I.
.,
Within subgroup Ij~ compounds of the formula I having
distinctly useful anticonvulsive and anxiolytic properties
are those in which Y is -CH= or -N=, each of ~a and Rb
independently of the other is hydrogen, methyl, chlorine
or bromine, Ar is phenyl or phenyl which is substituted by
halogen, methyl or CF3, and each of U and V independently
of the other is Cl-C3alkyl, C2-C3alkyl which is unsubstituted
or substituted by Cl-G2alkoxy~ or together form one of the
following alkylene groups
l\ _ /R2 R3~ R4
/ \ or i t-R
wherein each of Rl, R2, R3, R4 and R5 independently of the
other is hydrogen or Cl-C~alkyl, the total number of carbon
a~oms in R3, R4 and R5 not exceeding 40 This group will be
designated group Ik/
A ~urther preferred group of compounds having
pronounced anticonvulsive and anxiolytic properties
comprises those in which Y is -CH= or -N=, Ra and Rb are
hydrogen, Ar is phenyl or phenyl which is substituted by
halogen or methylg and U and V together are a group of
the formula
.
~2 j/ \j
wherein R2 is Cl-C4alkyl such as methyl or ethyl, or
Cl-C3hydroxyalkyl such as hydroxymethyl or 2-hydroxyethyl,
or Cl-C2alkoxy-Cl-C2alkyl such as methoxymethyl or ethoxy
methyl This group will be designated group Il.
- 12 -
The following individual compounds may be cited as
exemplifying particularly preerred compounds having
anticonvulsive and anxiolytic properties:
2-[p-(phenoxy)phenyl]-2-[1-(lH-1,2,4-triazolyl)methyl]-1~3-
dioxane;
2-[p-(4-chlorophenoxy)phenyl3-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p-~4-chloro-2-methylphenoxy)phenyl]-2-(1-imidazolyl
methyl)-4-methoxymethyl-1,3-dioxolane;
2-[p-(phenoxy)phenyl~-2-[l-(lH-192~4-triazolyl~methyl]-4-
hydroxymethyl-1,3-dioxolane;
2-[p-(4-fluorophenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane;
2-[p-(4-~luorophenoxy)phenyl]-2-(1 imidazolylmethyl)-~-
hydroxymethyl-1,3-dioxolane;
2-[p-(4-fluorophenoxy)phenyl~-2-[1-(lH-1,2,4-triazolyl)-
methyl]-1,3-dioxane
together with their respective pharmaceutically acceptable
acid addition salts, processes for their produc~ion, pharma-
ceutical preparations con~aining them, and their use as
medicaments.
The compounds of formula I may be obtained by
A) condensing a compou-nd of the ormula II
Me-N~S~ ~ (II),
wherein Me is hydrogen or a metal cation, with a compound
of the ormula III
Ar-O- ~ 2-X
wherein X is a leaving group, or
B) in a compound of the Eormula IV
a / = N
Ar _ O ~ -,C, 2 \ (IV)
converting the carbonyl group into a group of the formula V
O O
(V)
U------------V
or
C) condensing compounds of the formulae VI and VII
Ra -N
Ar - o_ ~ / C ~ - CH2- N ~ (VI) and X2 - R7 (VII),
O /0 Y~
Rb CH2~ CH-CH2-X
wherein one of the radicals Xl and X2 is hydroxyl or mercapto which may be in
salt orm, e.g. of the formula -Z-Me, and the other is a leaving group X, or
both Xl and X2 are hydroxyl groups, with each other to give compounds of the
formula I, wherein U and V together are a group of the formula -CH2-CH(CH2ZR7)-
and R7 is a radical which differs from hydrogen, or
D) condensing compounds of the formulae VIII and IX
Ar-x3 (VIII) and X4 ~ C _ CH ~ (IX),
Rb U-----V
~;~ wherein one of the radicals X~ and X~ is an O-Me group, in ~lich Me is hydrogen
or preferably a metal cation, and
,
~ ~ ~3
- 14 -
the other is a radical which is replaceable by aryloxy,
with each other, or
E) subjecting a compound of the formula
Ar-O-C-O-~ C~CH2-N~ (X)
R, I I
D ~ V
to intramolecular decarboxylation and, if desired, converting
a resultant compound into another compound of the formula I
and/or converting a free compound into an acid addition salt,
an acid addition salt into the free compound or lnto
another acid addition salt, or converting a free compound
or acid addition salt into a metal complex.
Examples of metal cations Me are alkali metal cations,
e.g. lithium, sodium or potassium cations, or alkaline earth
metal cations, e.g. magnesium, strontium or barium cations.
Leaving groups are e.g. reactive esterified hydroxyl
groups, such as hydroxyl groups which are esterified wi~h a
hydrohalic acid, e.g.wîthhy~o~uoricahydrochloric, hydrobromic or
hydriodic acid, or with a lower alkanesulfonic acid,an
unsubstituted or substituted benzenesulfonic or a halo-
sulfonic acid, e.g. with methanesulfonic acid, ethane-
sulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid or fluorosulfonic acid
The reaction of an azole of the formula II
,~=N
M N/ ! (II),
~9~3
- 15 -
wherein Y is -CH= or -N- and Me is preferably a metal atom,
especially an alkali metal atom9 with a compound of the
formula III
R
Ar-O- ~ H2--X ( I I I ),
U~ V
wherein Ar, Ra, Rb, U and V are as defined for formula I
and X is e.g. halogen, in particular chlorine, bromine or
iodine, or benzenesulfonyloxy, p-tosyloxy, trifluoroacetyl-
oxy or, preferably, lower a~kylsulfonyloxy, e.g. mesyloxy,
is preferably conducted in a relatively polar but inert
organic solvent, e.g. N,N dimethyl formamide, N,N-dimethyl
acetamide, dimethyl sulfoxide, acetonitrile, benzonitrile
and the like. Such solvents may be employed in combination
with other inert solvents such as aliphatic or aromatic
hydrocarbons, e.g. benzene, toluene, xylene, hexane,
petroleum ethera chlorobenzene, nitrobenæene, e~c.
If X is chlorine or bromine, an alkali iodide (such
as NaI or KI) may conveniently be added in order to speed
up the reaction, Elevated temperatures in the range rom
0 to 220C, preferably from 80 to 170C, are advantageous.
It is advantageous to heat the reaction mixture under reflux.
Where Me in formula II is hydrogen, the process is
carried out in the presence of a base. Examples of suitable
bases are inorganic bases such as the oxides, hydroxides,
hydrides, carbonates and bicarbonates of alkali metals and
alkaline earth metals, as well as organic bases e9g.
tertiary amines such as triethylamine, triethylenediamine,
piperidine, pyridine, 4-dimethylaminopyridine, ~-pyrrolidyl-
pyridine etc.
- 16 ~
In this process variant, and in the subsequent ones,
the intermediates and final products may be isolated from the
reaction medium and, if desired, purified by one of the
methods conventionally employed, e.g~ by extraction,
crystallisation, chromatography, distillation etc.
The conversion of the carbonyl group in compounds of
the formula IV into the group of the formula V is carried
out by reaction with an orthocarboxylic acid Cl-C12trialkyl
ester~ the Cl-C12alkyl groups of which may be substituted
by halogen or Cl-C6alkoxy, or in the presence of an acid,
with at least 2 moles of a monohydric alcohol of the
formula U-OH (Va), to give compounds of the formula I in
which U and V are identical unsubstituted or substituted
Cl-C12alkyl groups, or by reaction with a diol of the
formula Vb
HO - U-~-V-- OH (Vb)
to give compounds of the formula I, wherein U and V together
are one of the alkylene bridges defined at the outset. In
the foregoing, Ar, Y, Ra, Rb, U and V are as defined for
formula I.
This ketalisation reaction may be carried out in similar
manner to already known ketalisation reactions, e.g. in
similar manner to the preparation of 2-bromomethyL-2,4-
diphenyl-1,3-dioxolane [Synthesis, 1974 (I), 23].
In the preferred embodiment of the ketalisation,
both reactants are heated for several hours under reflux
together with an azeotrope former in a conventional organic
solvent. Examples of suitable azeotrope formers are benzene,
~oLuene, xylene, chloroform or carbon tetrachloride. To
hasten the reaction it may be convenient to add a strong
- 17 -
acid, e.g. p-toluenesulfonic acid. Examples of organic
solvents which may be used are in this case aromatic
hydrocarbons such as benzene, toluene, xylene etc.,
saturated hydrocarbons such as n-hexane, or saturated
halogenated hydrocarbons such as 17 1 ~ 1- trichloroethane.
The ketalisation may also be carried out by other
methods, e.g. by reacting a ketone (IV) which has been
ketalised wi~h an alcohol or phenol which differs from the
alkanol or diol of the Eormula Va or Vb respectively, and
effecting transketalisation with an excess of alkanol Va or
diol Vb to a compound (I). The starting rnaterial may be
obtained by one of process variants A), D) and E).
Compounds of the formula I, wherein U and V in
variant C) are together -CH2-CH(CH2ZR7)-, are obtained
e.g. by reaction of a compound of the formula VI with a
compound of the formula VII, wherein Xl is a -ZH group and
X2 is a group X. The reaction is preferably carried out in
an inert organic solvent. Examples o suitable solvents for
this reaction are N,N-dimethyl formamide, N,N-dimethyl
acetamide, hexamethylphosphoric triamide, dimethyl sulfoxide,
4-methyl-3-pentanone etcO Mixtures with other inert solvents,
e.g. with aromatic hydrocarbons such as benzene, toluene~
xylene etc., may also be used. In some cases it may be
convenient to carry out the reaction in the presence o
a base in order to speed up the reaction rate. Examples of
suitable bases are alkali metal hydrides or alkali metal
carbonates~ It may also be advantageous in certain cases
to convert-the compound of the formula VI first into a
suitable metal salt. This is preferably accomplished by
reaction of VI with a sodium compound, e.g. sodium
hydride, sodium hydroxide etc. This salt of the compound of
formula VI is subsequently reacted with the compound of
- 18 -
formula VII. In order to increase the reaction rate the
process may also becarried outin some cases at elevated
temperature, preferably in the range from 80 to 130C
or at the boiling point of the solvent.
Compounds of the formulae VI and VII, wherein Xl is
a group X and X2 is a -ZH group, may also be reacted in
similar manner.
In ~he condensation reaction of compounds of the
formulae VI and VIIg wherein Xl and X2 are hydroæyl, to
give compounds of the formula I in which Z is oxygen,
the reactants can be heated under reflux in a suitable
solvent, while simultaneously distilling off water from
the reaction mixturP as an a2eotrope~ Suitable solvents
are aromatic hydrocarbons such as toluene or the alcohol
HO-R7 itself. This reaction is conveniently carried out
in the presence of a ~trong acid, e.g. p toluenesulfonic
acid.
In variant D~, a start is preferably made from
compounds of the formulae VIII and IX, wherein X3 is an
OMe group and X4 is a leaving group, or conversely X3 is
the leaving group and X~ is the -OMe group, whilst Ra, Rb~
U, V~ Y and Ar are as defined for formula T and Me is
preferably hydrogen. It is advantageous to carry out ~he
reaction under the conditions described for variant A).
In variant E), the compound to be decarboxylated of
the formula X, which may be ohtained by ketalisation of
a compound of the formula XI
R
-T (XI),
~L
- 19 -
in a manner similar to that described in B)~ which compound
may in turn be obtained by reaction of a compound of the
formula Ar OH (XII) with a difunctional derivative of
carbonic acid, e.g. with phosgene, a lower alkylester of
haloformic acid or with a di-lower allyl or diphenyl
carbamate, and further reaction with a compound of the
formula XIII
a o
HO-~ -C-CH2-N~ 11 (XIII)
is heated dry or in a high boiling solvent such as a high
boiling ether, e, g. diphenyl ether or ethylene glycol
dimethyl e~her, to about 120 to 220C.
Compounds obtained by the process of the inven~ion
may be converted into other compounds of the formula I by
methods which are known per se.
Accordingly, for example, compounds obtained by th~
process of the invention may be transketalised to o~her
compounds of the formula Io For e~ample, in compounds of
the formula I, wherein U and V are identical unsubstituted
or substituted Cl-C12alkyl radicals U, a group U may be
replaced by a group V by reaction with 1 mole of another
unsubstituted or substituted Cl-C12alkanol of the formula
V-OH (Ve), or both groups U may be replaced by a divalent
radieal by reaction with a diol of the formula Vb. The
transketalisation is ~arried out in eonventional manner,
for example in the presenee of an acid eondensing agent
sueh as a mineral aeid 3 sulfonic acid or strong carboxylic
acid, e~g. hydrochloric or hydrobromic acid, sulfuric acid,
p-toluenesulfonic acid or trifluoroacetic aeid, preferably
- 20 -
while removing readily volatile reaction products by
distillation or azeotropic distillation.
Further, additional substituents may be introduced,
if desired, into the carbocyclic aryl moieties of compounds
obtained by the process of the invention. For example,
halogen can be introduced by reaction with a halogen in
~he presence of a Lewis acid, e.g. an iron, zincg boron
or antimony halide~ or by treatment with N-chlorosuccinimide.
In addition, nitro groups can be reduced to amines~
e.g. by means of suitable complex hydride3, e.g. with
l-Lthium aluminium hydride, which amines may then be
diazotised, e.g. with nitrous acid, and the diazonium
group replaced in customary manner by halogen or alkoxy.
Likewise, halogen may be replaced by alkyl by reaction with
an alkyl metal compound, e.g. with an alkyl lithium or
alkyl magnesium halide.
If the compounds of Eormula I are obtained as bases,
then they can be converted into corresponding salts o the
formula I with inorganic or organic acids, or into metal
complexes of the formula I by using preferably e~uimolar
amounts of metal salts. Conversely~ salts of the formula I
can be converted into the free bases oE the formula I by
reaction with an alkali carbonate or bicarbonate or an
alkali hydroxide.
The starting ketals of the formula III can be obtained
from the methyl aryl ketone of the formula XIV
Ar-O- .\ $ ~--CO-CH3 (XIV)
R
- 21 -
by reaction wi~h the desired diol in an inert solvent, e.g.
a halogenated hydrocarbon (such as methylene chloride,
ethylene chloride, chloroform9 carbon tetrachloride etc.),
and simultaneous or s~lbsequent halogenation. It is
advantageous to add p-toluenesulfonic acid in order to
speed up the reaction.
The ketones of the formula IV can be obtained by
halogenation of the starting ketones XIV to XV
Ar-O-o~ ~ CO-CH2-Hal (XV)
.~-
Rb
and further reaction of XV, in similar manner to variant
A), with an azole of the formula II. Hal in ormula XV is
preferably chlorine or bromine.
The ketals III, VI, IX and X are obtained in similar
manner to variant B) by reacting the starting ketone e.g,
of the formula IV with a suitable alcohol or diol.
The process vaiants described ahove likewise
constitute an object of the present invention.
~ 11 the above described ketalisation reactions of a
ketone with a substituted ~ or ~,y-diol result in the
formation primarily of mixtures of diastereoisomers of the
resultant ketal. Likewise, mixtures of diastereoisomers of
the final products of the formula I are generally obtained
from the starting ketones. The compounds of formula I may
be obtained eOg. in the two following diastereoisomeric
forms:
- 22 -
Ar-~a ~02N Ar-O,~ /N/ N
~c~ type A
7 ~ ~
(XVI) C112ZR7 (XVII) R3
The configuration of type A will be designated here and
referred to subsequently as ~Itrans~-isomer.
Ar-,~Ra =N type B Ar-O~R c~ y
~ '? 1 ~
(XVIII) C112~R; (XIX) R ~
The symbols in the three-dimensional s~ructures reproduced
above have the following meanings:
..~. = behind
_ = in
~æ~ - in front of the drawing planeO
The configuration of type B will be correspondingly
designated as "cis"-isomer. The separation of the two
diastereoisomers may be effected e.g. by fractional
crystallisation or by chromatography ~thin-layer
chromatography, column chromatography, liquid high-pressure
chromatography etc.~. The two isomers have different
biological properties~ For practical purposes the
mixtures of diastereoisomers will normally be used.
. ;
- 23 -
The invention relates to all isomeric compounds of
the formula I, and the salts and metal complexes thereof.
The process for obtaining compounds of the formula I
as described in variants A, B, C, and E likewise constitutes
an object of the invention.
Some of the starting materials and intermediates
employed in process variants A, B, C, D and E are known,
and others can be prepared by methods which are known per
se~ Some are novel and théir preparation is described
herein.
~ Aryl)~thimidazolyl ketals, wherein aryl denotes
substituted phenyl or naphthyl, are described as fungicides
and bactericides in the following references: US patent
specifieations 3 575 999, 3 936 470, 4 lOl 664, 4 lOl 666
and 4 156 008.
Surprisingly, it has been found that compounds of the
formula I have for practical purposes a very advantageous
microbicidal spectrum against phytopathogenic fungi and
baeteria, as well as antimycotie and/or anticonvulsive
properties whieh indicate their use as medicaments, For
example, the compounds of formula I have very advantageous
eurative, preventive and systemic phytotherapeutic properties
and can be used for protecting cultivated plants, With the
compounds of formula I it is possible to inhibit or destroy
the microorganisms which oceur in plants or parts of plants
(fruit, blossoms, leaves, stems, tubers, roots) in
different crops of useful plants, while at the sam~ time
the parts of plants whieh grow later are also protected
from attack by such mieroorganisms.
- 24 -
The compounds of ~ormula I are effective in
particular against the phytopathogenic fungi belonging
to the following groups: Ascomycetes (e~g. Venturia,
Podosphaera, Erysiphe, Monilinia, Uncinula); Basidomycetes
(e.g. the genera Hemileia, Rhizoctonia, Puccinia); Fungi
imperfecti (e.g Botrytis, Helminthosporium, Fusarium,
Septoria, Cercospora and Alternaria). In addition, the
compounds of formula I have a systemic action. They can
also be used as seed dressing agents for protecting seeds
(fruit, tubers, grains~ and plant cuttings aga;nst fungus
infections as well as against phytopathogenic micro-
organisms which occur in the soil. The compounds of the
invention are also es;pecially well tolerated by plants.
Accordingly, the invention also relates to micro-
bicidal compositions and to the use of compounds of the
formula I for controlling phytopathogenic microorganisms,
especially harmful fungi,and for the preventive treatment
of plants to protect them from attack by such micro-
organisms.
In addition, the invention rela~es to the preparation
of agrochemical compositions, comprising intimately mixing
a compound of the formula I with one or more substances or
groups oi substances described herein. The invention further
relates to a method of treating plants, which comprises
applying thereto compounds of the formula I or novel
compositions containing theml
Target crops to be protected within the scope of the
present invention comprise e.g. the following species of
plants: cereals (wheat, barley, rye,oats, rice9 sorghum and
related crops), beet (sugar beet and fodder beet)) drupes,
';~;
- 25 -
pomes and soft fruit (apples, pears, plums~ peaches,
almonds, cherries, strawberries, rasberries and black-
berries), leguminous plants (beans, lentils, peas, soybeans),
oil plants (rape, mustard, poppy~ olives, sunflowers,
coconuts, castor oil plants, cocoa beans, groundnuts),
cucumber plants (cucumber, marrows~ melons) fibre plants
(cotton, flax, hemp, jute), citrus fruit (oranges, lemonsg
grapefruit, mandarins), vegetable (spinach, lettuce,
asparagus, cabbages, carrots, onions, tomatoes, potatoes,
paprika), lauraceae (avocados, cinnamon, camphor)~ or
plants such as maize~, tobacco, nuts, coffee, sugar cane,
tea, vines, hops, bananas and natural rubber plants, as
well as ornamentals (composites).
The compounds of formula I are normally applied
in agriculture in the form of compositions and may be
applied to the crop area or plant to be treated,
simultanPously or in succession, with further compounds.
These compounds can be both fertilisers or micronutrient
donors or other preparations that influence plant growth.
They can also be selective herbicides, insecticides,
fungicides, bactericides~ nematicides, mollusicides or
mixtures of several of these preparations, if desired
together with further carriers, surfactants or
application-promoting adjuvants customarily employed in
the art o~ formulation~ Suitable carriers and adjuvants
for all formulations can be solid or liquid and correspond
to the useful non~toxic substances ordinarily employed
in formulation technology, e.g natural or regenerated
mineral substances, solvents, dispersants, wetting agents,
tackifiers, thickeners or binders~
A preferred method in agriculture of applying a
compound of the formula I or an agrochemical composition
- 26 -
to an infested plant, is foliar (leaf) application. The
number of applications and the rate of application depend
on the intensity of infestation by the corresponding
pathogen (type of fungus). However, the compounds of
formula I can also penetrate the plant through the roots
via the soil (systemic action) by impregnating the locus
of the plant with a liquid composition, or by applying the
compounds in solid form to the soil, e.g. in granular form
(soil application). The compounds of formula I may also
be applied to seeds (coating), by impregnating the seeds
either with a liquid formulation containing a compo~nd of
the formula I, or coating them with a solid formulation.
In special cases, further types of application are also
possible3 e.g. selective treatment of the plank stems
or buds.
The compounds of the formula I are used in unmodified
form or, preferably, together with the adjuvants
conventionally employed in the art of formulation, and are
therefore formulated in known manner to emulsifiable
concentrates, coatable pastes, directly sprayable or
dilutable solutions, dilute emulsions, wettable powders,
soluble powders, dusts, granulates, and also encapsulations
in e.g. polymer substancesO Like the nature of the
compositions, the methods of application, such as spraying,
atomising, dusting, scattering or pouring, are chosen in
accordance with the intended objectives and the prevailing
circumstances. Advantageous rates of application are
normally from 50 g to 5 kg of active ingredient (a.i.) per
hectare, preferably from 100 g to 2 kg a i /ha, most
preferably from 200 g to 600 g a.i./ha.
The agrochemical formulations, i.e. the compositions or
preparations containing the compound (active ingredient) of
- 27 -
the formula I and, where appropriate, a solid or liquid
adjuvant, are prepared in known manner, e.g. by
homogeneously mixing and/or grinding the active ingredients
with e~tenders, e g. solvent, solid carriers and, where
appropriate, surface-active compounds (sur~actants).
Suitable solvents are: aromatic hydrocarbons,
preferably ~he fractions containing 8 to 12 carbon atoms,
e.g. xylene ~lixtures or substituted naphthalenes,
phthalates such as dibutyl phthalates or dioctyl phthalate,
aliphatic hydrocarbons such as c~clohexane or paraffins,
alcohols and glycols and their ethers and esters, such as
ethanol, ethylene glycol monomethyl or monoethyl ether,
ketones such as cyclohexanone, strongly polar solvents such
as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethyl
formamide, as well as epoxidised vegetable oils such as
epoxidised coconut oi] or soybean oil; or water.
The solid carriers used e.gO for dusts and dispersible
powders, are normally natural mineral fillers such as
calcite, talcum,kaolin, montmorillonite or attapulgite.
In order to improve the physical properties it is also
possible to add highly dispersed silicic acid or highly
dispersed absorbent polymers ! Suitable granulated adsorptive
carriers are porous types, far example pumice, broken brick,
sepolite or bentonite; and suitable nonsorbent carriers are
materials such as calcite or sand. In addition, a great
number of pregranulated materials of inorganic or organic
nature can be used, e.g. especially dolomite or pulverised
plant residues.
Depending on the nature of the compound of the formula I
to be formulated, suitable surface-active compounds are
nonionic, cationic and/or anionic surfactants having good
28 -
emulsifying, dispersing and wetting properties. The term
"surfactants" will also be understood as comprising
mixtures of surfactants.
Suitable anionic surfactants can be both water~
soluble soaps and water-soluble synthetic surface-active
compounds D
Sui-table soaps are the alkali metal salts, alkaline
earth metal salts or unsubstituted or substituted ammonium
salts of higher fatty acids (C10-C22~, e.g. the sodium or
potassium salts of oleic or stearic acid, or of natural
fatty acid mixtures which can be obtained e.g. from
coconut oil or tallow oil. Mention may also be made of
fatty acid methyl taurin salts.
More frequently, however, so-called synthetic
surfactan~s are used, especially fatty sulfonates, fatty
sulfates, sulfonated benzimidazole derivatives or alkyl-
arylsulfonates~
The fatty sulfonates or sulfates are usually in the
form of alkali metal salts, alkaline earth metal salts or
unsubstituted or substituted ammonium salts and con~ain
a C8-C22alkyl radical which also includes the alkyl
moiety of acyl radicals, e.g. the sodium or calcium salt
of lignosulfonic acid, of dodecylsulfate or of a mixture
of fatty alcohol sulfates obtained from natural fatty
acids. These compounds also comprise the salts o~ sulfuric
acid esters and sulfonic acids of fatty alcohol/ethylene
oxide adducts. The sulfonated benzimidazole derivatives
preferably contain 2 sulfonic acid groups and one fatty
acid radical containing 8 to 22 carbon atoms. Examples
of alkylarylsulfonates are the sodium, calcium or
~2~
- 29 -
triethanola~ine salts of dodecylbenzenesulfonic acid,
dibutylnaph~halenesulfonic acid, or of a naphthalene-
sulfonic acid/formaldehyde condensation product. Also
suitable are corresponding phosphatesg e.g. salts of the
phosphoric acid ester of an adduct of p-nonylphenol with
4 to 14 moles of ethylene oxide.
Non-ionic sur~actants are preferably polyglycol ether
derivatives of aliphatic or cycloaliphatic alcohols, or
saturated or unsaturated fatty acids and alkylphenols,
said derivatives containing 3 to 30 glycol ether groups
and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon
moiety and 6 to 18 carbon atoms in the alkyl moiety of the
alkylphenols.
Further suitable non-ionic surfactants are the water-
soluble adducts of polyethylene oxide with polypropylene
glycol, ethylenediamine propylene glycol and alkylpoly-
propylene glycol containing 1 to 10 carbon atoms in the
alkyl chain, which adducts contain 20 to 250 ethylene
glycol ether groups and 10 to 100 prpylene glycol ether
groups, These compounds us~ally contain 1 to 5 ethylene
glycol units per propylene glycol unit.
Representative examples of non-ionic surfactants are
nonylphenolpolyethoxyethanols, castor oil polyglycol
ethers, polypropylenelpolyethylene oxide adducts, tributyl-
phenoxypolyethoxyethanol, polyethylene glycol and octyl
phenoxyethoxyethanol. Fatty acid esters o:E polyoxyethylene
sorbitan and polyoxyethylene sorbitan trioleate are also
suitable non ionic surfactants.
Cationic surfactants are preferably quaternary
ammonium salts which contain, as N-substituent, at least
- 30 -
one C8-C22alkyl radical and, as further substituents, lower
unsubstituted or halogenated alkyl 7 benzyl or lower hydroxy-
alkyl radicals. The salts are preferably in the form of
halides, methylsulfates or ethylsulfates, e.g. s~earyl-
trimethylammonium chloride or benzyldi(2-chloroethyl)-
ethylammonium bromide~
The surfactants customarily employed in the art of
formulation are described e.g. in "McCutcheon's Detergents
and Emulsifiers Annual''g MC Publishing Corp. Ringwood,
New Jersey, 1979, and Sisely and Wood, "Encyclopedia of
Surface Active Agents", Chemical Publishing Co., Inc.
New York, 1980.
The agrochemical compositions usually con~ain 0.1 to
99%, preferably 0.1 to 95%, of a compound of the formula I,
99.9 to 1%, preferably 99.8 to 5%, of a solid or liquid
adjuvant, and among the adjuvants 0 ~o 25%, preferably 0.1
to 25% of a surfactant.
Whereas commercial products are preferably formulated
as concentrates, the end user will normally employ dilute
formulations.
The compositions may also contain further ingredients,
such as stabilisers, antifoams, viscosity regulators, binders,
tackifiers as well as fertilisers or other active ingredients
in order to obtain special effects.
Such agrochemical compositions also constitute an
object of the presen~ invention.
~ ~h~W ~9
- 31 -
The antimycotic properties which indicate the utility
of the compo~lnds of the formula I and their pharmaceutically
acceptable acid addition salts for controlling parasitic
fungi in warm-blooded animals, may be demonstrated e.g.
in vitro by means of conventional microbiological test
methods, e g by determining their toxic action against
fungus strains which are parasites of warm-blooded animals,
for example against Trychophyton mentagryphites, Microsporum
canis, Sporotrichum schenkii, Aspergillus fumigatus and
Candida albicans; and also in vivo in guinea pigs by
de~ermining the curative effect on experimental infestations
on the dorsal skin with Trichophyton, e.g. T. rubrum, after
peroral or local application.
The anticonvulsive properties of the compounds of
formula I and their pharmaceutically acceptable acid
addition salts may be demonstrated in vivo e.gO in mice
by means of the pentatetrazole spasm test in the dose
range from about 10 to 100 mg/kg p.o., and also by means
of the electroshock test in the dose range from about 10
to 100 mg/kg p.o~ The anxiolytic properties can be
demonstrated e.g. in mice and other small rodents by
means of the Gellert test and the Quatre-Plaque test in the
dose range from about 10 to 100 mg/kg p.o. It may also be
inferred that the novel compounds have significant
antimanic properties.
Accordingly, the present invention also relates to
the use of compounds of the formula I and their pharma
ceutically acceptable acid addition salts for the topical,
local and systemic control of fungi which are parasites of
warm-blooded animals, and for the systemic treatment of
different forms of epilepsy, of states of anxiety and
tension and of manic states o mind, in particular as
- 32 -
active ingredients of pharmaceutical preparations, or for
the production of pharmaceutical preparations, for enteral
or parenteral or topical or local application, and relates
also to such pharmaceutical preparations.
The pharmaceutical preparations of this invention
which contain compounds of the formula I or pharmaceutically
acceptable sal~s thereof, are accordingly ~hose for
enteral, such as oral or rectal, and parenteral,
administration, as well as for topical application to
warm~blooded animals, which preparations contain the
pharmacological active ingredient alone or together with
a pharmaceutically acceptable carrier therefor. The dosage
of the active ingredient depends on the species of warm-
blooded animalg on the age and individual condition of the
patient, and on ~he mode of administration or application.
For oral administration to a warm-blooded animal
having a body weight of about 75 kg the approximate daily
dose will normally be from 50 to 500 mg, conveniently
distributed over several equal partial doses.
The pharmaceutical preparations of this invention
contain e~g. from about 10% to 80%, preferably from about
20% to 60%, of active ingredient. Pharmaceutical preparations
for enteral or parenteral administration are e.g. those in
dosage unit form such as dragées, tablets, capsules or
suppositories and also ampoules. These are prepared in a
manner known per se, e.g. by conventional mixing, granulating,
sugar-coating, dissolving or lyophilising methods. Thus
pharmaceutical preparations for oral administration may be
obtained by combining the active ingredient with solid
carriers, optionally granulating the resultant mixture and,
if desired or necessary, after addition of suitable adjuncts,
processing the mi~ture or granulate to tablets or dragée
cores.
- 33
Suitable carriers for tablets and/or dragées are in
particular fillers such as sugar, for example, lactose,
saccharose, mannitol or sorbitol, cellulose preparations
and/or calcium phosphates, e.g. tricalcium phosphate or
calcium hydrogen phosphate, also binders such as starch
pastes, for example maiæe, corn, rice or potato starch
paste, gelatin, tragacanth, methyl celluloseg hydroxy~
propylmethylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidone, and/or, if desired, disintegrators,
such as the above starches, also carbogymethyl starch,
crosslinked polyvinylpyrrolidone, agar, alginic acid or
a salt ~hereof, such as sodium alginate. Adjuncts are
chiefly glidants and lubricants, for example, silicic acid,
talc, stearic acid or salts thereof, such as magnesium
stearate or calcium stearate, and/or polyethylene glycol.
Sugar-coated tablet cores are provided with suitable coatings
that can be resistant to gastric juices, using, inter alia,
concentrated sugar solutions which may contain gum arabic,
talc, polyvinylpyrrolidone, polyethylene glycol and/or
titanium dioxide, shellac solutions in suitable organic
solvents or solvent mixtures or, for the preparation of
coatings resistant to gastric juices, solutions of suitable
cellulose preparations, such as acetylcellulose phthalate
or hydroxypropylmethylcellulose phthalate. Dyes or pigments
can be added to the tablets or dragees cores, for example
to identify or indicate different doses of active ingredient.
Further pharmaceutical preparations for oral
administration are dry-filled capsules, and also soft
sealed capsules made from gelatin and a plasticiser, such
as glycerol or sorbitol. The dry-filled capsules may
contain the active ingredient in the form of granules, for
example in admixture with fillers such as lactose, binders
such as starch and/or lubricants such as talcum or
34 -
magnesium stearate, and optionally stabilisers. In soft
capsules, the active ingredient is pre~erably dissolved or
suspended in suitable liquids, for e~ample in fatty oils,
paraffin oil or liquid polyethylene glycols, to which
stabilisers can also be added.
Suitable dosage forms for rectal administration
are for example suppositories, which consist of a combination
of the active ingredient with a suppository base. Examples
of suitable suppository bases are natural or synthetic
triglycerides, paraffin hydrocarbons, polyethylene glycols
or higher alcohols. Gelatin rectal capsules, which consist
of a combination of the active components with a base
material, can also be employed. Suitable base materials are
for example liquid triglycerides, polyethylene glycols or
paraffin hydrocarbons.
Particularly suitable ~or parenteral administration
are aqueous solutions of an ac~ive ingredient in water-
soluble form, e.g. a water-soluble salt, and also suspensions
of the active ingredient such as suitable oily injection
suspensions for which suitable lipophilic solvent~ or
vehicles such as fatty oils, e.g. sesame oil, or synthetic
fatty acid esters, e.g. ethyl oleate or triglycerides, are
used, or aqueous injection suspensions which contain
substances which increase the viscosity, e.g. sodium
carboxymethylcellulose, sorbitol and/or dextrane~ and, if
desired, also stabilisers.
Pharmaceutical preparations for topical application
are e.g~ creams, ointments, pas~es, foams~ tinctures and
solutions, which contain the acti-ve ingredient in an
amount from about 0.5% to about 20%.
3~ ~
- 35 -
Creams are oil-in-water emulsions which contain more
than 50% of water. Fatty alcohols are chiefly used as
oleaginous base, for example lauryl~ cetyl or stearyl
alcohol, fatty acids, for example palmitic or stearic acid,
liquid to solid waxes, for example isopropyl myristate, wool
wax or bees-wax, and/or hydrocarbons, for example petroleum
jelly (petrolatum) or paraffin oil. Suitable emulsifiers
are surface-active substances with primarily hydrophilic
properties, such as corresponding non-ionic emulsifiers,
for example fatty acid esters of polyalcohols or ethylene
oxide adducts thereof, such as polyglycerol fatty acid
esters or polyoxyethylene sorbitan fatty acid esters
(Tweens~; polyoxyethylene fatty alcohol ethers or esters,
or corresponding ionic emulsifiers, such as alkali metal
salts of fatty alcohol sulfates, for example sodium lauryl
sulfate, sodium cetyl sulfate or sodium stearyl sulfate,
which are customarily used in the presence o fatty
alcohol, for example cetyl alcohol or stearyl alcohol.
Additives to the water phase include agents which reduce
water loss through evaporation, for example polyalcohols,
such as glycerol, sorbitol, propylene glycol and/or poly-
ethylene glycols, as well as preservatives, perfumes etc.
Ointments are water-in-oil emulsions which contain
up to 70%, but preferably from about 20% to 50%9
of water or aqueous phase. The oleaginous phase comprises
chiefly hydrocarbons, for example petroleum jelly~
paraffin oil and/or hard paraffins, which contain preferably
hydroxy compounds suitable for improving the water-
absorption, such as fa~ty alcohols or esters thereof, for
example cetyl alcohol or wool wax alcohols, or wool wax.
Emulsifiers are corresponding lipophilic substances~ such
as sorbitan fatty acid esters (Spans)g for example sorbitan
oleate and/or sorbitan isostearate. Additives to the water
- 36 -
phase include humectants, such as polyalcohols, for
example glycerol, propylene glycol, sorbitol and/or
polyethylene glycol, and preservatives, perfumes etc.
Greasy ointments are anhydrous and contain as base
in particular 'nydrocarbons, for example paraffin,
petroleum jelly and/or liquid paraffins, furthermore natural
or partially synthetic fat, for example coconut fatty acid
triglycerides, or preferably hardened oils, for example
hydrated ground nut or castor oil, and also fatty acid
partial esters of glycerol, for example glycerol mono- and
distearate, and~ for example, the fatty alcohols,
emulsifiers and/or additives for increasing the water-
absorption mentioned in connection wîth the ointments.
Pastes are creams and ointments containing powdered
ingredients which absorb secretions, such as metal oxides9
for example titanium oxide or zinc oxide, and talc and/or
aluminium silicates whose purpose it is to bind moisture or
secretion present.
Foams are administered from pressurised dispensers
and are liquid oil-in-water emulsions in aerosol form,
with halogenated hydrocarbons such as chlorofluoro-lower
alkanes, for example dichlorodifluoromethane and dichloro-
tetrafluoroethane, being used as propellants. For the
oleaginous phas~ there are used, inter alia, hydrocarbons,
for example paraffin oil, fatty alcohols, for example cetyl
alcohol, fatty acid esters, for example isopropyl myristate~
and/or other waxesO As emulsifiers there are used, inter
alia, mixtures of these emulsifiers with primarily
hydrophilic properties, such as polyoxyethylene sorbitan
fatty acid esters (Tweens), and those with primarily
lipophilic properties, such as sorbitan fatty acid esters
(Spans~. In addition, the conventional additives are used,
such as preservatives etc.
- 37 -
Tinctures and solutions generally have an aqueous
ethanolic base to which are added, inter alia, polyalcohols,
for example glycerol, glycols, and/or polyethylene glycol,
as humectants for reducing water loss, and fat-restoring
substances, such as ~atty acid esters with lower poly-
ethylene glycols, i.e lipophilic subs~ances which are
soluble in the aqueous mixture as substitute for fatty
substances which are taken from the skin with the ethanol,
and, if necessary, other assistants and additives.
The pharmaceutical compositions for topical
application are obtained in known manner, for example by
dissolving or suspending the active ingredient in the
base or in a part thereof, if necessary. When processing the
active ingredient in the form of a solution, it is usually
dissolved in one of the two phases be~ore the emulsi~ication,
and when processing the active ingredient in the form of a
suspension, it is mixed wi~h a part of the base before the
emulsification and then added to the remainder of the
formulation
The following Examples will serve to illustrate the
invention in more detail, but without implying any restriction
to what is described therein. Parts and percentages are by
weight and pressures are in millibars (mbar).
- 38 -
Preparatory Examples
Example 1: Preparation of
/ \ / 3
.
o~ c ~12 ~ I
=. = =--
2-[p-(Phenoxy)phenyl]-2-[l-(lH-1,2~4-triazolYl)methyll-4
methyl-1,3-dioxane
a) Preparation of the intermediate
/ \ /C~l3
t I (.
/ \ /- C---CH2Br
.=, .= .
2-[p-(Phenoxy)phenyl]-2-bromomethyl-4-methyl-1,3-dioxane
10 parts of 2-[p-(phenoxy)phenyl]-2-oxy-l-bromoethane and
4 parts of 1,3-butanediol are heated under reflux for 3
hours in 40 ml of absolute toluene in the presence of 0.2
part of p-toluenesulfonic acid as catalyst~ while removing
the water of reaction with a water separator. The reaction
mixture is cooled to room temperature, then washed with two
20 ml portions of water, dried over sodium sulfate and
filtered. The solvent is removed by evaporation and the
crude product is recrystallised from isopropanol to give
colourless crystals with a melting point of 96-106C.
b) Preparation of the final product
3.3 parts of the sodium salt of 1,2,4-triazole and a
catalytic amount of potassium iodide are stirred in 40 ml
of dimethyl sulfoxide together with 10.2 parts of the 2-[p-
(phenoxy)phenyl]-2-bromomethyl-4-methyl-1,3-dioxane
~3
- 39 -
obtained in a) for 3~ hours at a temperatur~ of 120C. The
reaction mixture is cooled to room temperature, then
diluted with 300 ml of water and extracted with three 30 ml
portions of ethyl acetate. The combined extracts are
w~shed with two 20 ml portions of water, dried over sodium
sulfate, filtered, and the solvent is removed by evaporationO
The oiiy residue is purified by column chromatography over
silica gel with ethyl acetate. The eluant is removed by
evaporation and the oily residue crystallises from~
petrolèum ether to give brownish crystals with a melting
point of 99,5-lOl~C.
Example 2: Preparation of
/ 2 3
' Cl~ -0--~ ^~-~C/--CII~N/ I (3.226)
--. ~ = . =--
CH3
2-[p-(4-Chloro-2-methylphenoxy)phenyl]-2-(1-imidazolyl-
methyl)-4 methoxymethyl-1,3-dioxolane
16 parts of 2-~p-(4-chloro-2-methylphenoxy)phenyl~-2-(1-
imidazolylmethyl)~4-hydroxymethyl-1,3-dioxolane are
dissolved in 150 ml of N,N-dimethyl formamide and then 1.9
parts of 55% sodium hydride dispersion are stirred in while
introducing nitrogen. The mixture is heated for 2 hours
to 80C, then cooled to room temperature, treated dropwise,
with stirring, with 6.3 parts o~ methyl iodide over 1 hour,
then heated for 2 hours to 60C, diluted with 800 ml of
ice-water and extracted with three 300 ml portions o~ ethyl
acetate. The combined extracts are washed with two 50 ml
portions of water, dried over sodium sulfate, filtered, and
the solvent is removed by evaporation. The residue is
purified by column chromatography over silica gel with
- 40 -
acetone/ethyl acetate (1:1). The eluant is then removed by
evapora~ion and the mixture of diastereoisomers is
crystallised by treatment with hexane~ giving beige-
coloured crystals with a melting point of 92-106C
ExamplQ 3: Preparation of
N0 _ / 2 5
CF3~ 0- ~ C/0 CH2-N~ 3 0 263)
2-[p-(2-Nitro-4-trifluoromethylphenoxy)phenyl]-2-(1-
imidazolylmethyl)-4-ethyl-1~3-dioxolane
8,3 parts of 2-~p-(2-nitro-4-trifluoromethylphenoxy)phenyl]-
2-~1-imidazolylmethyl)-4-ethyl-1,3-dioxolane are dissolved
in 300 ml of dimethyl sulfoxide and to the solution are
added 1.84 parts of ground potassium hydroxide,
whereupon the temperature rises from 23 to 36C. Ater
heating for 2 hours to 70C, 7.4 parts of 4-chloro-3-
nitrobenzotrifluoride in 100 ml of dimethyl sulfoxide
are added dropwise and stirring is continued for 3 hours
at 70C. The reaction mixture is cooled to room temperature,
poured into 2 litres of water and extracted with two 200 ml
portions of diethyl ether. The combined extracts are washed
with two 70 ml portions of water, dried over sodium sulfate,
and the solvent is removed by evaporation. The oily residue
is purified by column chromatography over silica gel with
ethyl acetate. The eluant is removed by evaporation,
leaving as residue a mixture of diastereoisomers in the form
of a viscous mass.
- 41 ~
Example 4: Synthesis of
&H2CE13
CH 2-N~ i ( 3 .1 2 )
2-[p-(3-Ghlorophenoxy)phenyl3-2-(l~imidazolylmethyl)-4-
ethyl-1,3-dioxolane
1.2 parts of imidazole sodium salt, 4 parts of 2-[p-(3-
chlorophenoxy~phenyl]-2-bromomethyl-4-ethyl-l 3 3-dioxolane
and a catalytic amount of potassium iodide are stirred in
50 ml o dimethyl formamide for 17 hours at a temperature
of 125C, The brown reaction mixture is cooled to room
tempera~ure, diluted with 150 ml of water and extrac~ed
with three 50 ml portions of ethyl acetate. The comblned
extracts are washed with two 50 ml portions of water, and
dried over sodium sulfate. The solvent is removed by
evaporation and the crude product is chromatographed over
a 35 cm column of silica gel with acetone/ethyl acetate
(1:1). The eluant is remcved by evaporation and the oily
residue is crystallised from petroleum ether in the form
of slightly yellowish crystals with a melting point of
69-71Co
Example 5: Preparation of
/CH2CH3
/ ~ C/ CEI ~ (3 7)
=- .=~ .=.
2~U~
- 42 -
2-[p-(4-Chlorophenoxy)phenyl]-2-(1-imidazolylmethyl)-4-
ethyl-1,3-dioxolane
a) Synthesis of the intermediates
K) Preparation of
/ 2 3
Cl--\ /--o-~ C~3
=. .=.
2-[p-(4-Chlorophenoxy)phenyl]-2-methyl-4 ethyl-1,3-
dioxolane
37 parts of 4-(p-chlorophenoxy)acetophenone, 18 parts of
1,2-butanediol and 2 parts of p-toluenesulfonic acid as
catalyst are heated under reflux in 400 ml of absolute
toluene for 14 hours on a water separator. The reaction
mixture is cooled to room temperature, washed with two
400 ml portions of water, dried over sodium sulfate and
filtered. The solvent is removed by evaporation and the
crude product is purified over a 1 m column of silica gel
with ligroin/hexane/ethyl acetate/toluene (5:3~ The
product is obtained in the form of a slightly yellowish
oil; nD : 1.5527.
~) Preparation of
/ 2 3
Cl ~ o- ~ C~2-
.=. .=.
2-[p-(4-Chlorophenoxy)phenyl]-2-bromomethyl-4-ethyl-1,3-
dioxolane
36.8 parts of 2~[p-(4-chlorophenoxy)phenyl]-2-methyl-4-
ethyl-1,3-dioxolane obtained in K) are heated to the boil
.:
- ~3 -
in 350 ml of chloroformO Under irradiation with a 150 watt
spot lamp~ a solution of 19.4 parts of bromine in 50 ml
of chloroform is added dropwise and the reaction mixture is
subsequently heated under reflux for 2 hours. The reaction
mixture is cooled to room temperature, then washed with
two 200 ml portions of water, clried over sodium sulfate
and filtered. The solvent is then stripped off under a water
jet vacuum~ The crude product is purified by chromatography
over a 1 m column of silica gel with toluene. The product
is obtained in the form of an oil with a refractive index
of n23: 1.5803,
b) Synthesis of the inal product
4.4 parts of imidazole sodium salt, a catalytic amount of
potassium iodide and 14.7 parts of 2-[p-(4-chlorophenoxy)-
phenyl]-2-bromomethyl-4-ethyl-1,3-dioxolane obtained in ~)
are s~irred in 80 ml of dimethyl formamide for 17 hours
at a bath ~emperature of 125C. The reaction mixture is
cooled to room temperature, then poured into 600 ml of
water and extracted with three 200 ml portions of ethyl
acetate. The combined extrac~s are washed with two 200 ml
portions o water, dried over sodium sulfate and filtered.
The solvent is then removed by evaporation and the oily
residue is chromatographed over a 50 cm column of silica
gel with acetone/ethyl acetate (1:1). The eluant is
removed by evaporation and the product is obtained in the
orm of a brown oil with a refractive index of 1.5750
Example 6: Synthesis of
&H2CH3
.. ._. ~ o
o_ ~ ~-~/ CH -N/ T (1 9,
. = . . . = .
- 44 -
2-[p-(Phenoxy)phenyl]-2-(1ll-1,2,4-triazolylmethyl)-4-ethyl-
1,3-dioxolane
17 parts of 2-[p-(phenoxy)phenyl]-3-bromomethyl-4-ethyl-
1,3-dioxolane, 8.4 parts of potassium carbonate, 4.2 parts
of 1,2,4-triazole and a catalytic amount of sodium iodide
are stirred in 100 ml of dimethyl formamide for 24 hours
at a temperature of 125~C. The reaction mixture is cooled
to room temperature, then poured into 600 ml of water and
extracted with three 200 ml portions of ethyl acetate. The
combined extracts are washed with 200 ml portions of water,
dried over sodium sulfate and filtered~ The solvent is removed by
evaporation and the oily residue is chroma~ographed over a
50 cm column of silica gel with chloroform/ether (1:1). The
eluant is removed by evaporation and the oily residue is
crystallised from petroleum ether in the form of wllite
crystals with a melting point of 81.5-83.5C.
Example 7: Synthesis of
.
/ \
~--0-~ C~CH2 N~
r = ~
2-~p-(Phenoxy)phenyl~-2-(lH-1,2,4-~riazolylmethyl)-1,3-
dioxane
14 parts of 2~[p-(phenoxyphenyl~-2-bromomethyl-1,3-dioxane,
7.2 parts of potassium carbonate, 3.6 parts o 1~2,4-
triazole and a catalytic amount of potassium iodide are
stirred in 100 ml of dimethyl formamide for 20 hours at
a temperature of 140C. The reaction mixture is cooled
to room temperature, diluted with 600 ml of water and
extracted with three 200 ml portions of ether~ The combined
extracts are washed with two 200 ml portions of wa~er, dried
over sodium sulfate and filtered. The solvent is evaporated
and the oily residue is chromatographed over a 50 cm column
of silica gel with chloroform/ether (1:1). The eluant is
evaporated and the residue is crystallised from petroleum
~ther in the form o-f white crystals with a melting point
o~ 129-130C
Example 8: Synthesis of
~CH20H
~ ~ CH2-N~N ~ (1. 23)
_ . . = = .
2-[p-(Phenoxy)phenyl]~2-tlH 1,2,4-triazolylmethyl)-4-
hydroxymethyl-1,3-dioxolane
4.5 parts of 2-[p~(phenoxy)phenyl]-2-bromomethyl-4-
hydroxymethyl-1,3~dioxolane, 2.2 part 9 0f po tassium
carbonate, 1.1 parts of 1,2,4-triazoLe and a catalytic
amoun~ of potassium iodide are stirred in 50 ml of
dimethyl sulfoxide for 4 hours at a temperature of 140C.
The reaction mixture is cooled to room ~empera~ure, then
poured into 600 ml of wa er and extracted with two 200 ml
portions of ethyl acetate~ The combined ex-~racts are
washed with two 200 ml portions of water, dried over
sodium sulfate and filtered. The solvent is evaporated and
the oily residue is chromatographed over a 50 cm column of
silica gel with acetone. The solvent is evaporated and the
oily residue is crystallised from petroleum ether in the
form of beige-coloured crystals with a melting point of
111-112C.
~ 2
46 -
~xample 9: Synthesis of
2 2 3
,-o ~ c~H2 N~ T (1 17)
, = . . = . .
2-~p-(Phenoxy)phenyl~2-(lH-1,2,4-triazolylmethyl)-4-n-
propyl-1,3-dioxolane
lU.3 parts of the nitrate of 1-(p-phenoxyphenyl)-2w(1,2,4
triazolyl)-ethanone, 6.1 parts of 1,2-pentanediol~ 6.9 parts
of p-toluenesulfonic acid, ~0 parts of l-pentanol and 200
parts of xylene, are heated under reflux for 6 days on a
water separator. The reaction mixture is then cooled to
room temperature and then washed with two 200 ml portions
of dîlute sodium hydroxide solution and with two 200 ml portions
of waterO The organic phase is dried over sodium sulfate
and filtered. The solvent is evaporated and the oily
residue is chromatographed over a 1 m column of silica gel
with ethyl acetate. The eluant is evaporated and the oily
residue crystallises slowly in the form of beige-coloured
crystals with a melting point of 68.5-71C,
The following compounds of the formula I can also be
prepared in analogous manner (unless otherwise specified,
mixtures of diastereoisomers having different mixture
ratios):
In the ollowing Tables 3 the symbol A stands for a
diastereoisomer of type A, and B stands for a diastereo-
isomer of type B.
Table 1: Compounds of the formula.
~ --\ /-7~ CH2 N\y T (XXI)
\Rlo
including isomeric forms:
Com- R Y Salt Physical data
po~md 10
1.1 H N - m.p.100~102
1.2 H N HN03
1.3 H CH
1.4 CH3 N - m.p. 76.5-8l
1.5 CH3 N HCl
1.6 CH3 N CuC12
1.7 CH3 CH
1.8 CH3 N Mn(N03)2
1.9 C2H5 N - m.p. 81.5-83-5
1.10 C2HS N HN03
1.11 C2H5 N ZnC12
1.12 C2H5 N Mn(N03)2
1.13 C2H5 N FeCl3
1.14 C2H5 CH - light brown oil
1.15 C2H5 CH ~uC12
1.16 3 7 C}l
1.17 3 7 N - m.p. 68.5-71
- 1.18 C3ll7~n N ZnC12
1 .1 9 3 7 N HCl
.~,.,
,
'~ ~D ~f,~ q
- 48 -
Table 1 (cont . )
Com- Rlo Y Sal t Physical data
po~md
1.20 C4H9-n N --
1.21 C~Hg-n CH
1.22 CH2Cl N
1.23 CH20H N - m.p, 111-122
1.24 ~-~' 011 ; nD =1.5865
. = .
1.25 ~ m-p- 83-85 B
.= .
_ .
1.26 2 \ / 3 m.p. ]07-109 A
.= .
1.27 2 \ / 3 m-p- 90-94 B
.= .
1.28 CH20H CH
1.29 CH20CH3 CH
1.30 C2H5 N 1/2CuS04
1.31 CH20C2H5 N
1.32 CH20CH3 N
1.33 CH20CH2CH20CH3 N
. .~."~.
3~ 3
- 49 -
Table 2: Compounds of the formula
~0~~ C - CH N/ T (XXII)
11 12
including ~he isomeric forms:
Com- R R Y Salt Physical data
pound 11 12 (C)
2.1 CH3C2H5 CH
2.2 CH3C2H5 N
2.3 CH3C2H5 CH HN03
2.4 CH3C21~5 N HN03
2.5 CH3 3 7 CH
2.6 CH3 3 7 N
2.7 CH3 3 7 N HN03
2.8 CH3 3 7 N Mn(No3)2
2.9 CH3 CH3 CH
2.10 CH3 CH3 CH C~ICl2
2.11 CH3C2H5 CH Mn(N03)2
2.12 CH3C2H5 CH CuCl2
2.13 CH3C2H5 N CuC12
2.14 CH3 2 S N ZnC12
2.15 CH3C2H5 N Mn(N03)2
2.16 CH3C2H5 N FeC13 23
2.17 CH3 CH3 N - oil ; nD = 1.5643
2.18 CH3 CH3 N HN03
2.19 C2H5CH3 CH MnC12
2.20 C2H5CH3 N MnC12
2.21 C2H5CH3 CH H2S04
2.22 C2H5CH3 CH ZnC12
L13
Table 2 (cont.)
Com- R R Y Salt
pound 11 12
2.23 C2H5 C2H5 CH
2.24 C2H5 C2H5 CH H2SO4
2.25 C2H5 C2H5 N
2.26 C2H5 C2H5 N HNO3
2.27 C2H5 C2H5 N HCl
2.28 C2H5 3 7 N
2.29 C2H5 3 7 N .
2.30 C2H5 3 7 CH
2.31 C2H5 C3H7-n N HCl
2.32 C2H5 C2H5 N Mn(N03)2
2.33 CH3C2H5 N (COOH) 2
2.34 CH3C2H5 CH (COOH)2
2.35 CH33 7 N
2.36 CH3C3H7-i 2 4
2.37 -(CH2)4- CH
2.38-(CH2)4- CH HNO3
2.39-(CH2)4- N
2.40-(CH2)4- N Mn (NO3)2
2.41-(CH2)4- N (COOH)2
2.42-(CH2)4- N ZnC12
2.43( 2)4 N HCl
2.44-(CH2)4- CH ZnC12
~,
- 51 -
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Com- 12 R13 14 15 16 Salt Physical data
3.157 H CH20GH3 H CF3 H H N
3.158 H CH20CH3 H H CF3 H CH
3.159 H CH20CH3 H H CF3 H N
3.160 H C2H5 H H CF3 H CH -
3.161 H CH2OCH3 Cl H Cl H CH - ,
3.162 H C2H5 Cl H H 5-Cl CH -nD = 1.5837
3.163 H CH20CH3 Cl H H 5-Cl N - 22
3.164 H C2H5 Cl H Cl H CH -nD = 1.5779
3.165 H H Cl H Cl H N
3.166 H CH20CH3 Cl H Cl H N
3.167 ~- CH20CH3 Cl H H 5-ClCH
3.168 H C2H5 Cl H H 5-Cl N - nD = 1.5788
3.169 H CH20CH3 Cl H H 6-ClCH
3.170 H CH20CH3 Cl H H 6-Cl N - 23
3.171 H C2'~5 H Cl Cl H CH - nD = 1.5835
3.172 H C2H5 H Cl Cl H N - m.p. 90-97
3.173 H C2H5 H C] H 5-Cl CH
3.174 H C2H5 Cl H H 6-Cl CH
- 61 -
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o o C ~ U') O U~ I~ o o O O C O O ~ O C~
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- 65 -
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u~ o o o ou~ o o o o o Ln ~
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a) ~ r r~ O r~ ~ ~ ~ u ) ~ O
- 66 -
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P~ æ ~ ~ ~ æ ~ z z ~ z ~ z z z ~ z z;
r~ $~) ~S7 r~ r"' r~ r~ r~ X~ ~ r~ r~
P~ $ r
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r, ~ r r x $ r ~ :~
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- 67
J
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æ c~ z ~ z z c~ z c~ ~ z z ~ ; z c~ z z
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s~
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- 68 -
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x ~ $ m m ~ $ ~ ~ ~ $ ~ m ~ ~: $
Ul
X X ~ m $ $ m ~ ~ $ ~q
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$ x m ~ x ~ s
P:l m m~ m~ ~ $~ $~ m~
~ cm, ~ ~ m ~ m
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t~ _ r~ ) ~ ~ ~ ~ r-~ ~ ~ ~ ~ ~ ~ r~
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$ ~ ~ _, ~ ~ ~ ~ ~
$ $ $
r`~ $~ ~ s~ ~ $~ s~ s~ ~ s~" s~ $~ $~ s~`
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p ;~ X :~ $ ~ :~ ~ $
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- 70 -
U~
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~) Z~; C~ ~> U C~ Z ~ % ~ Z C~ Z
~D
~ ~ ~c 3~ 3 ~ ~ ~, 3 3 ~ 3 ~ 3 3 3 X 3
U~
3 3:~ ~ 14 ~ ~ ~ ~ ~ 1:~ ~ ~ ~ 3 ~ ~ 3
P~ ~ ~, ~ ~ ~ 3 3 ~ 3 3 3 3 ~:: 3 ~ 3 ~ 3
D~ 3 3:~ 3 3 ~ 3 3 ~ ~ ~ 3 ~
--~ o 1-- o o ~ O O o
3 ~ 3 ~ 3 3 3 ~ 3
`
3 3
3 X~C 3 ~ ~ 3 ~ ~ ~ ~ 3
~' ' J~ O ~ (~ ~ ~
- 71 -
V~ IIIIIIIIIIIIIIIII
Z Z Z Z ~C Z ~ X æ z; z Z Z
~D
$ 5: ~ ~ S ~ ~ ~ ~ X
U~
p~ ~ X $ X ~ X
h 1~ h h , ~ SJ ~
~n n
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~ m ~ 3 X
o
CJ
d $ ~C X ~ ~ X
n ~ o ~ ~ n ~ ~ c) .
,~ ~3 . 'n u~ 'n ~ 'n ~ ~D ~ ~D ~D
td O~ ................
,,
- 72 -
~1 0
(J~ ~ r--l r--l
O O
~n
~; Z Z Z ~ Z Z
5~ 5~ ~ 5~ 5~ 5' ~ ~ 5
u~
~r
5~ ~ 5 m
F~ ~ 5l 5
n ~n
5~ ~7
n ~ C l~ o o u~ o c O
~ ~ ~ ~ 5~ 5~ ~ ~ ~
o
,_~ ~
~; 5~ ~ 5~ 5 5~ 5~ ~ ~ 5
o ~
Table 4: Compounds of the fo-rmula
Rl4~ /Rl3 ~18
R ~ ~~-\ ~i 7 C\O 2 ~ _~ (XXI~)
16 R
includlng the isomeric forms:
pound 11 R12 R13 R14 Rl5 R16 YR17 R Salt , ;~
4.1 2 5 Cl H Cl H N 3-N2 H -
4.2 2 5 3 H H N 2-CH3 H
4.3 H C2H5 3 3 N 3-CH3 H HN03
4.4 H C2H5 Cl H Cl 3 3
4.5 H C2H5 Cl H Cl H N 2-Cl H CuC12
4.6 2 5 H 1i Cl H N 2
4.7 H C2H5 ~I H Cl H CH 3-NO H
4.8 2 5 H Cl H 5-Cl N 2-Cl H
4.9 C2H5 H H Cl H 6-Cl CH 2-N02 H
4.10 CH3 CH3 ~ Cl H 6-Cl N 2-N02 H ~In(N03)2
4.11 H C2H5 Cl H H H N 2-Cl H
~ ~i2~P3
- 74
~a
J- ~
(1)
r-l L
O u~
a
~O
U~ IIIIIIII~IIIIIIIII
r-~ ~ r-l
CO C~ O ~
c~ z æ c~ z z z ~ z z z z æ z t~ æ z æ
r ~ ~W S S ~ 5
r r
S ~ ~ S
r~lE3 ~r~ ~ ~r r-l ~ l ~ ~ r~J ~ ~ ~r r~l ~ ~ ~ ~
r~ r ~ r ~t ~t `;t `J ~t ~r ~-r ~t ~t ~t ~t ~t t ~t ~t ~-r ~t
'.~
. .
- 75 -
r~l r~J C~
U~ I I $ I ~ I ~ I I c, I I ~ I I I I
C~
~ C
~r~ ~ X$ X $ ~: $ ~ ~ C $ ~ ~ p: ~D $ $ $
r~ ~ ~ Z ~F C~ c~ c~ r I r
~ X 1~ $ ~r1 ~1 tr! ~ C~ ~ ~ N
$ r
P~ ZZZiZZ~C~ZC~Z~;ZZZZZZZ
~ $ ~ $
~ $ C~l ~ $ ~ ~ ~ $ p $ $ $ ;~ ~ ~ $
~4 $ x $ c, $ $ P~ $ P~ îq ~ $ $ î~
C~ I y ~ C~ 1, C~ ~ '' C~ ''
r-l ~ ~C~ ~(~ ~ ~ ~ ~ ~ $ C$ C$~ c~ m $ ~ $ $ $ $
Y; $ $ ~ $ $ $ ~ ~
r-l ~ r l 51 ,~ r-l ~ $
$ ~C$ C~ C~ C~ ~ C~
r ~ p: $ C~ 5 P:l $ $ W ~ $ W ~1 ~ $ $ tl $
~ C~ C~ C~ C~ C~ ~ C~ C~ C~ C~ Cl C~ C~ C~
o
~ ~r~ c~ c~ p~ $ ~ $ ~ $
aJ I
rn ~ ~ O r~ O r~ ~ ~ ~ ~ ~ ~
- 76 -
~: ,
.. , .. ,
a~
o ~ .,, .~
o U~ o
C) C~ ,~
~r~ O ~ .~
O
C~
rj ~ ~ D
I
cn
r~
r~ r~ r~ rr~ r~ r~ ~ 7
r- c~ c~ c~ cl ~3 c~ c~ c~ c~ y Cl C~ y y y y y C~
p~ r,~l r.~ ~ r.~l r,~ r.~ J r.~l r~ C~ C~l r.~l r,~) r.~l r,~l r~l r,~l
Z Z Z Z Z Z C~ Z C~ Z Z C~ C~ C~ Z C~ C~
~D
rY~ rr~ rr~ r~
o 5 C~ O ~ ~ ~ L~
r,Y~ r,~7 r.~ r,r~ r,Y~
~l o u o u u u u o o ~ u
~ C~ ~ C~ C~ C~ C~ C~ C~ C~
o ~ ~
--' I` t" u~
~I rY) ~rr~ ,3 r_ ~C
C~ C~ C~ C~ C~ X ~C ,,,~ _
a), ~
r.~o r ~ O ~ r,~l r.") ~t L~ r~ C~ O ~ r.~ ~'1 ~ U~
O ~ u~ u~ u~ u~ u~ u~ U~ u~
Table~ 4 (cont . )
Com- R RL2 R13 R14 R15 R16 Y Rl7 Rl8 Salt ( ~C)
4. 6 6 H CH3 H H F H CH 2-CH3 H
4.67 H CH20CH3 H H Cl H N 2-C1 H
4. 6 8 H C2H5 H Br H H CH 2-CH3 H
4. 6 9 H C2H5 F H H H CH 2-CII3 H -
4.70 H CH3 H H F H CH 2-CII3 H _ light broT.~Tn resin
4.71 H CH20CH3 Er H H H N 2-Cl H -
4.72- H CH20CH3 H Br H ~ CH 2-Cl H -
4.73 H 2 3 H Br H CH 2-C1 H
4.74 H C2H5 H H Br H N 2-C1 H -
4.75 H CH20CH3 H H J H CH 2-C1 H
4.76 H CH20CH3 H H J H N 2-C1 H
4-77 H 3 7 3 H ~I N 2-CH3 H H~3 m.p, 105-110
4.78 H CH3 3 H ~T ~T 2-CH3 H HNO3 m . p . 92-95 B
4-79 H C2H7_n ~- CH3 H H CH 2-C1 H
4-80 H CH20CH3 CH3 H H ~ CH 2-C1 H
4.81 H CH3 3 H 11 N 2-CH3 H HNO3 m.p. 129-134~ A
4.82 H CH20CH3 H H CH3 H ~T 2-C1 H
4.83 H CH20CH3 H H CH3 H CHT 2-CH3 H
Table 4 (cont.)
Com- R R R R R R Y R R Salt Physical data
pound 11 12 13 14 15 16 17 18
( C)
4.84 H C2H5 H H C2H5 H N 2-C1 H
4.85 H 2 -3 C3H7i H H CH H ~ _
4.86 H CH20CH3 C3H/i H H El CEI 2-NO2 H
4.87 H 2 3 2 5 1I CH 3-CH3 H -
4.88 H 2 3 2 5 H N 2-Cl H _
4.89 CH3 CH3 H H OCH3 E~ N 2-CH3 H - resin B
4,90 H 3 7 H H OCH3 H N 2-C113 H - oil ;~
4.91 H C3H7-n H H OCH3 H N 2-CH3 H - oil B
4.92 CH3 C~13 H H 3 N 2-C113 H - resin A
4.93 H C2El5 1~ El 3 N 2-CE~3 H - resin
4.94 El 3 7 H H OCH3 H N 2-CH3 El - oil
4.95 H CH OC H NO H H 11 CH 2-Br H
4.96 H CH20CE13 H El No2 1I Cll 2-Cl H
4.97 H CH2ll 3 ll Cll 3-Cll3 H
4.98 H CH2CH3 H H CF3 H Cll 2-C1 ll
4.99 H CH20CH3 H C1 H H CH 2-C1 H
4.100 H CH20CH3 B~ H B~ H Cll 2-C1 H
4.101 1I CH20CH3 C1 H Cl H CH 2-C1 ll
Table 4 (cont . ~
Con~- R R12 R13 R14 R15 R16 Y R17 R18 Salt
!.102 CH20H H (CH=CH)2 H H CH 2-Cl H
4.103 C2H5 H CH3 ¦ H Cl H CH 2-OCH3 6-ocH3
4.104 C2H5 H (CH=CH) H H CH 2-Cl H
4.105 CH~QCH3 H (CH=CH)2 H H CH 2-Cl H _
4.106 CH20CH3 H (CH=CH)2 H H N H H -
4.107 C2H5 H H (CH=CH)2 H CH 2-Cl H _
4.108 C2H5 H H (CH=CH)2 H N 2-Cl H _
4.109 C2H5 E~. (CH=CH)2 Cl H CH 2-Cl H _
4.110 C2H5 H (CH=CH)2 Cl H N 2-Cl H
4.111 (CH2)4 H H Cl H CH H H
4.~12 CH20CH3 H Cl Cl H H CH 2-Cl H
'.113 C113 H H H Cl H N 3
4.114 C H H H H Cl H N 2-OCH3 6-ocH3
4.115 C2H5 H H H Cl H CH 2-OCH3 6-oCH3
'.116 C2H5 H H H Cl H N 2-CH3 H
4.117 CH3 CH3 H H F H N 2-CH3 H
'.118 CH3 CH3 H H F H CH 2-CH3 H
4.119 CH3 C2H5 H H ~ H N 2-CH3 H
~P ~U ~.D
- ~0
u
r~ _
I ) (3
~ ~C
r~
r~
C) o h
rl r
S~ h
I
oo
$ $ ~ ~: $ ~ ~ $ P: ~ ~ S
~a ~ ~ ~ $ $ ~ ~ ~ ~ x $ ~ $ $ $
$ ~d $ ~ ~ ~ ~;
Z ~ Z C~ Z ~) Z ~ Z Z Z
~o
:~$$$X$$~ $$$$$:C$
U~
~
P~ ~ $ $ m $ ~ tc $ $ $ ~
r-l
P~ ~ ~ $ $ ~ ~ ~ ~ ~ ~ ~ $ $ $ ~ X
U~ $ $ C~ C u~ C
$ ~ ~ ~I ~ ~ $ ~ ~
C~ $ ~ Y y ~ ~ $ ~ ~ ~
~ X $ $ $ $ ~ $ $ $ ~ $
'
'r~fJ!Ai~ ~
~ 81 -
Table 5: Compounds of the formula
R18
2-N\y
;
including the isomeric forms:
Com- ~11 R12 Rl7 18 SaltPhysical data
pounc ( C)
5.1 CH3 C2H5 2-Cl H CH
5.2 CH3 C2H5 2-Cl H N
5.3 CH3 C2H5 2-C1 6-Cl CH HN03
5.4 CH3 C2H5 2-CH3 H N HN03
5.5 CH3 C3H7~n 2-Cl H CH
5.6 CH C H -n 2-Cl H N
5-7 CH3 c3H7-n 3-Cl H N ~N03
5.8 CH3 C3H7-n 3-C1 6-Cl N Mn(N03)2
5.9 CH3 CH3 2-Cl H CH
5.10CH3 CH3 2-C1 6-Cl CH CuC12
5.11CH3 C2H5 2-Cl H CH Mn(N03)2
5.12C~13 C2H5 2-CH3 6~CH3 CH CuC12
5.13CH3 CH3 2-CH3 H N HN03 m.p. l58-160
5~14CH3 CH3 2-CH3 H N HBr m.p. 192-204
5.15CH3 C2H5 2-CH3 H N Mn(N03)2
5.16CH3 C2H5 2-N02 H N FeC13
5.17 CH3 CH3 2-Cl H N
5.18CH3 CH3 2-C1 5-Cl N HN03
5.192 5 3 3-Cl H CH MnC12
2 5 3 2-CH3 H N MnC12
5.21C2H5 CH3 2-CH3 H N CuC12
2 5 3 2-C1 5-Cl N ZnC12
2 5 2 5 2-Br H Cll
5.24 HC2H5 2-OCH3 6-OCH3 CH
3~
- ~32 -
Table 5 (cont . )
''om- ~ R R R Y Salt Physical data
pound 11 12 1/ l8 (C)
5.25 H H 2-C1 11 N
5.2G H H 2-C1 ~I Cll
5.27 H H 2-C1 G-C1 Cll
5.28 H H 2-C1 H N Mn(;NO )
5.29 11 H 2-C1 6-C1 N
5.30 H CH3 2-C1 H N
5.31 H CH3 2-C1 1I N IL~03
5.32 H CH3 2-C1 6-C1 N
5.33 H CH3 2-C1 H CH
5.34 H CH3 2-OCH 6-OCII CH
5.35 H CH3 3-C1 H N
5.36 ~ CH3 2-CH3 H N HN03 m.p.132-134"
5.37 H CH3 3-CH3 H N
5.38 H C2H53-CH3 H CH CuC12
5.39 H C2H52-CH3 6-CH3 N
5.40 H C2H52-CH3 H N HN03 m.p.108-110
5.41 H C2H5 2-Br 5-Br N
5.42 H C2H5 2-C1 H N
5 43 H C H -n2-C1 H N
5.44 H 3 7 2-C1 6-C1 N
5.45 H C3H7-i2-CH3 H N
5.46 H C3H7-i?--CH3 H CH
5.47 H C3H7-i2-OC113 '~-OCH3 N MnC12
2 5 2 5 2-C1 H N
5.49C2H5 C2H5 2-C1 H N HN03
2 5 2 5 2-C1 6-C1 N HC1
5.51 H H 2-OCII ;-OCII CH
5.52C2H5 C3H7 i 2 C113 N
~.~
._~
- 83 -
Table 5 (cont.)
Com- 1~ R R17 ~18 Salt Physical data
5.53 H C2115 2-oCH G-OCll N
5.54 H C2H5 2-OC~13 G-OC113 ~ -
5.55 H 1-1 2-OCli G-OCH N
5.56 C~13 C2H5 3-Cl H N (COOH)2
5.57 CH3 C2H5 2-CU3 6-C113 CH (COOH)2
5.58 CH3 C3H7-i 2-Cl H N
5.59 CH C 11 -i 2-C1 6-Cl N H2S4
5.60 -(CH2)4- 2-Cl H CEI
5.61 -(CH2)4- 2-Cl H CH HN03
5.62 -(CH2)4- 2-Cl H N
5.63 -(CH2)4- 3-Cl H N ~In(N03)2
5.64 -(CH2)4- 3-C1 6-Cl N (COOH)2
5.65 -(CH2~4- 3-C1 5-Cl N ZnC12
5.66 -(CH2)4- 3-C1 6-Cl N IICl
5.67 -(CH2)4- 2-Cl H CH ZnC12
5.68 H H 2-CH3 H CH
5.69 CH3 CH3 2-CH3 H CH
5.70 H C3~17-n 2-CH3 H CH ~ yellow resin
5.71 H CH2CH3 2-CH3 H CH - resin
5.72 11 CH3 2-CH3 H CH
5.73 H C2H5 2-CH3 H CH
5.74 H CH2H 2-CH3 11 CH
5.75 H 2 3 3 N - oil
5.76 11 C2H5 2-C113 ~ N - resin
5.77 H H 2-C~13 ~I N - m .p . 103-loi
5.78 H C3117-n 2-C1~3 11 N - resin
5.79 ~I C1120~1 2-Cl 11 Cll
5.80 H C2~15 2-Br 11 Cll
5.81 11 C21-15 2-Cl 11 Cll
O O O O O 'D 0~ n ~ W ~ ~ O ~D Co ~J O~ ~A ~ W ~ _ ~ y
w ~ 1-- 0 _. (D
~: ~ ~ ~ ~ ~ ~ w
~QQ~QQQQQ~QQ~QQQQQQQQQ
~n O ~n O ~ o o ~ o o ~ n ~I O O O O O O
Q QQ Q~ !~Q Q~QQ
W ~ ~ ~ ~ W W
~ ~ ~ ~ W ~ ~ ~ ~ ~ ~ W ~ ~ ~ W ~ ~ ~ ~ ~ ~ ~ ~ ,
zzoQQ~~zzQQzzzzwzz~wwwQ
~-- ~ ~ ~ ~ O O O O ~ O O ~ ~ rt ~ Co C
Co ~
~ ~ X~ ~Z_Qzz=zz-QzQ ~
r ~
O
o ~
O O
~I r~
C~
.,1 N O~
rn ~ a~
5:
~N
r,Y~
~ " ~ N
0~ 0 `~ C~
$
z z c~ z æ z z z z z
Cl~ r,~ rY~ ~ r.~
~;~ m m $ m m C~ ~Cc ~ ~ cm,
\z~
N
~ r~m ~ r,~ ~ ~ ~ ~'7
r,~ ~ ~ N ~q $ r m m x ~
:q c~ r~,~ c~ C~ ro C~ m c~
o~
C / \.~
~1 O-- r~ rn r~ ~ ~ ~ ~ ~ ~ ~
a~ ~ sO ~~ $ x tCC cm, cm, ~ X cm
J~ // \
~ i~ m m m m m m m m m m
r- I
r.~ o
m m c~ x m m m ~ o c3~
./ ~ ~ P~ m $ ~ ~ m m m
r,,~ ~ I
m ~ m m ~ c~ c$~
r~ O
P ~ ~ r.~ r.~ o r~ r~ ~ ,~
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- 86 -
~d
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.,, _,
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P~
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s î~ ~ ~ 0
o ~ ~ ~ æ
o o C~ ~ o --
Z C~ Z Z Z Z Z Z C~ Z Z Z C~ Z Z
~ X
~L~P~cg ~3
- 87 -
t~, t~,
t~, t~,
N I I 1 1:4 1 1 1 1 ~ I $ I æ$
P~ z z z z z ~ z ~ z z ~ z z æ æ ~ z
~ t~
t~t~ $ ,t~) ~ '1 ~ ') P:~ $~
p; t.. ~ , $ e~: $ ~ $
~ ~ t,~ t"
t,O $ t~ 1 t/~ C $ t~ $
p; ~ ~ ~ t~ ~ ~ X $ ~ X
$ $ ~ $ $ $ tf) $t~ t~ t~) t~) t')
~,_, t,) t~ t`l ~ ~J ~ $ Pd ` ~ ' $ ~ ~ 5 ~ $ ~ ~ C
~I .-1 t" ~ S~
$ $ $ ~D ~ $ $ $ ~: ~ ~ $
U~ t'~ t~'l
~ ' ~ $ 3~ $ $ ~
g~ ~1: $ ~ $ tl:l $ $ $ ~ ~ $ ~ C~ $
m ~
a~ o ~ ~ ~ ~ Ir) ~o ~ 00 a~ o ~ ~ ~ ~ 1
po ~ .. . . ~ . . . . " . .
.. j
c`J
~ o o ~
7 ~ I I 1 57 1 11 I C~ I I
Z Z Z Z C~ Z Z Z Z C~ Z ~ ; Z Z
P~; ~ g P~ l 57 57 7 ~C7C~ C~ 57 57 C~ C~ 57
5~ ~ ~ 5~ 5151 ~) $ ~q ~ 5 P:~
$ C~ ) $ 57 C) ,~7
.
$ ~`I 51 5' ~ ) 5' 5' 5~
57 X P 7 ~ 7 C~ ) 51 C~ C~ 57 ~Cl 51 ~)
~D y y C~
~7 $ 51 $ 5~ D ~ D ~D~I7 57 57 P: C7
51 C.)51 P: 51 51 C~51 ~ 51 51 ~ 51 ~ 5 P:~
~ $ 5î m ::r 5î m 5î 5î 5l $ 5î m ~ " '~
m $ m m m m m 51 5 m
$ $ C~ ~ Y ~ ~ $ $ $ $
;
E3 -- ~ ~ u~ Lr) u~ D ~D ~D ~D
D ~D ~ ~D ~D ~ ~D ~D ~D ~D ~D ~D ~D ~D ~D ~D ~D ~D
:
:
Table 6 ~cont.)
Com- R R R R R R R Y Salt Physical data
poun~ 13 14 15. 16 17 18 19 (C)
6.65 H (CH=CH)2 H CH3 CH3 CH3 N
6.66 H (CH=CH)2 H H H H CH
6.67 Cl (CH=CH)2 H H H H N - ,
6.68 Cl (CH=CH)2 H CH3 CH3 CH3 N - ~ 3b
6.69 Cl (CH=CH)2 H C2H5 H H N - ' .
6.70 Cl (CH=CH)2 6-Cl CH3 CH3 CH3 N -
6.71 H (CH=CH)2 6-Cl CH3 CH3 CH3 N HN0
6.72 Br (CH=CH)2 H CH3 C2H5 CH3 N -
6.73 CH3 (CH=CH)2 ~ CH3 C113 CH3 N
6.74 Cl Cl H 5-Cl H H H N
6.75 Cl H Cl 5-Cl H H H N
6.76 CH3 CH3 H H H H H CH
6.77 F H H H CH3 H H N
6.78 H F H H H H H N
6.79 H H F H H H H CH - oil
6.80 H H F H Cll3 il ~ CH - viscous mass
6.8i H H F H Cl13 H 11 N
6.82 Cl H H H C113 H 11 N
~9~
- 90 -
z ~ ~ æ ~ X æ $ æ
a~
~ X ~ P: s ~ X ~:
00
m x ~
C~ ~ $
~O
~'~ ~ $ ~ $ ~ $ ~C
h
O ~ ~ ~ ~ ~ ~ ~ $ P: ~d
~~ .
~ O ~D
2~ ?
Table 7: Compounds o~ the formula
14\ / 13
C\ - CU2-N/ ~ (XXVII)
16 R2/ \ /
22 23
[R13 = R14 = H]
including the isomeric forms:
Com- R 2 R R24 R15 R16 Y Salt Physical data
7.1 H CH3 H H H N
7.2 H CH3 H H H CH -
7.3 CH3 CH3 H H H N - m.p. 122-124
7.4 CH3 CH3 H H H N HN03
7.5 CH3 CH3 CH3 H H N Mn(N03)2
7.6 CH3 CH3 CH3 H H CH -
7.7 CH3 CH3 H Cl 6-Cl - oil; nD = 1.5782
C 3 C2H5 H H H N
3 C2HS H H H N CuC12
7.10 CH3 C2H5 CH3 CH3 6-CH3 CH (COOH)2
7.11 C2H5 C2H5 H H H N HN03
7.12 C2H5 C2H5 H H H N
7.13 C2H5 C2H5 H H H CH HCl
7.14 C2H5 C2H5 H H H CH FeC13
7-15 C2H5 C2H5 H H H CH -
7.16 H C2H5 H 3 N
7.17 H C2H5 H H H N HN03
7.18 HC2H5 H H H ` CH -
7.19 H3 7 H H N CuC12
7.20 HC3H7 n H H H CH -
7.21 CH3 C113 C31]7 n H H N - m.p. 119-121
7.22 HH H H H CH -
7.23 CH3 CH3 H H H CH -
~ ~3
Tablc 7 (cont . )
Com- 1~22 23 R24 r~l5 ~ Salt Physical data
pound
7 . 24 H H C113 ll H CH -
7 . 25 ll H C113 ll 11 N 1/2 C~ISO
7 . 2G H H 1-1 H 6-F N
7.27 H H H F H N -
7 . 28 H H H H 6-Cl N
7 . 29 H H CH3 H 6-Cl Cll -
7 . 30 H H H H 5-Cl Cll -
7 . 31 H H H il 5-Cl N
7 . 32 H H CE13 Cl H Cll -
7.33 H H H Cl H Cll - viscous mass
7.34 H H H Cl ~ N - oil
7 . 35 H H CH3 Cl H N
7 . 36 H H H CH3 H N
7 . 3 7 H H H 3 7 N
7 . 38 H H H N02 H N
7 . 39 H H H H 6-CF3 N
7 . 40 H H CH3 H 5-CF3 N
7 . 41 H H H CF3 H N
7 . 42 H H H Cl 5-Cl N
7 . 43 11 H H Cl 5-C113 CH -
3 2 5 No2 5-C113 N -
7 . 45 CH3 C113 H C~3 6-Cl Cll -
7.46 C113 CH3 C 117-1~ C~ N 2
2~
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- 95 -
tq P~ ' tr~ :
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a.~ r 1
Table 8 ~cont.)
pound 11 Rl2 R13 R14 R15 R16 17 18 19 Physical data
8.66 2-CH3 H H E' H H H H H CH - brown resin
8.67 2-CH3 H F H H H H H H N
8.68 2-CH3 E~ H H Cl H H H H N -
8 69 2-CH H H H Cl l~ H H H CH - brown resin
8.70 2-CH3 H H H Cl H CH3 H H N -
8.71 2-CH H H H Cl H CH3 EL H CH - -~
8.72 2-CH H H H F H H H H N - resin . ~U
8.73 2-CH3 H H H F H H H H CH -
8.74 2-CH3 H H H F H CH3 El H N
8.75 2-CH3 H H H F H Cl13 H H CH
- 98 -
Table 9: Compounds of the formula
14\ ~13 ~11
R -o~ ~a-O~ 9 - C - C~l -N/ T (XXIX)
16 12 ~\
2 ~ \
R `R
including the isomeric forms:
~ound 11 12 13 R14 R15 R16 R22R23 R24 Y Salt
9.1 2-Cl H H H H H H CH3 H N
9.2 2-Cl H 11 Cl H 6-Cl H CH3 H CH -
9.3 2-Br H Br H H H 3 3 H N
9.4 2-CH3 6-CH3 H H H H 3 3 H N HN03
9.5 2-C1 6-Cl Cl H H 6-Cl CH3CH3 CH3 N Mn(N03)2
9.6 2-Cl o-Cl H Cl H H 33 CH3 CH -
9.7 2-C1 5-Cl H H Cl H 3CH3 H
9.8 2-Cl H H Cl Cl H 2 2 5 N
9.9 2-Cl H Cl H H H CH3 C2H5 H N CuC12
9.10 3-C1 5-Cl Cl H H 6-Cl CH3 C2H5 CH3 CH (COOH)2
9.11 2-C1 6-Cl H H Cl H C2H5 C2H5 H N HN03
3 3 C2H5 C2H5 H N
9.13 2-CH3 ll CH3 CH3 H H C2H5 C2H5 H CH HCl
9.14 2-Cl H 3 H H C2H5 C2H5 H CH FeC13
9.15 2-C1 5-Cl Cl H H H C2H5 C2H5 H CH -
9.16 2-Cl H Cl Cl Cl 5-Cl H C2H5 H N
9.17 2-Cl H H Cl Cl H H C2H5 H N HN03
9.1S 2-CH3 5-CH3 CH3 ~I H 6 3 C2H5 H CH -
9.19 2-CH3 6-CH3 H H CH3 H 3 7 N CuC12
9.20 2-C1 6-Cl H H CH3 H H C3H7 n H CH -
9.21 3-N02 H H H Cl H H H CH3 N
9.22 H H Cl H Cl 6-CH3 CH3 CH3 H N
9.23 H H CH H Br 6-Cl CH CH C H -n CH -
9.24 ~I H CH3 H Br 6-Cl CH3 C2H5 H N
Tabl.e 10 :. Compounds of the formula
~C~ 2 ~:T ~xxx~
including the isomeric forms:
pound 11 R12 R13 R14 R15 16 U V Salt
10.1 H H C1 H C1 H N CH3 CH3
10.2 H . H C1 H C1 H N C1~3 CH31 ( 3)2
10. 3 H H CH3 3 Cll Cl-l 2 5
10. 4 H H CH3 H Ci~3 S-CH3 N C2~15 ~ C2Hs -
10.5 H H H C1 H 5-Cl N C 1-1 -n 4 9
10. 6 H H H Cl ~1 6-Cl ~ C3i~7-i 3 7 CuC12
10. 7 H H H H H H i~l C~13 3
10. ~ H H T,~ H :~ 11 CH C1~3 C~13
10. 9 H H H H 11 ~E ~ C3H7~n C3H7-n (COOH) 2
10.10 2-C1 H H H C1 H iY C~13 C~3
10. 11 2-C1 6-Cl 1~ Cil3 C~13
10.12 3-C1 H H H 1-1 1i ~' C21~5 C,H5
10.13 2-C1 6-C1 H H C1 H . 8 17 8 17
Table 1() (cont . ~
Com- Rll R12 R13 R14 R15 16 U V Salt
pound
10.14 2-CH3 H H CH3 H H 2 5 C2H5 HCl
10.15 2-CH 6-CH CH H H H N C3H7-i 3 7
10.16 2-CH3 H CH3 CH3 H H N C5Hll-n 5 11
10.17 2-C1 5-Cl Cl H H 6-Cl N CH3 3
10.18 2-C1 5-Cl H H Cl H N C4Hg-s C4Hg-s ~
10.19 2-C1 6-Cl Cl Cl Cl 6-Cl CH CH3 3 , _
10.20 2-Cl H (CH=CH)2 H H N CH3 3
10.21 2-CH3 H (CH=CH)2 H H N CH3 3 7
10.22 H H 77. H H H CH CH3 3
10.23 H H H H H H 2 5 C2H5
10.24 H H H H H H 4 9 4 9
10.25 H 7i H H 7d 2 2 3 2 2 3
10.26 H H H H H H ~ 2 2 2 5 2 2 2 5
10.27 7d H H H H 8 17 8 17
10.28 H H H H H H N (CH2)20CH3 (CH2)20 3
10.29 2-CH3 H H H H H CH CH3 CH3
10.3G 2-CH3 H H H H H N ~CH2)2~CH3 (CH2)20 3
10.31 2-Cl H H H H H CH (CH2)20CH3(CH2)20CH3
- lOL -
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- 102 -
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- 105 -
Formulation Examples for a~rochemical compositions
containin~ liquid active in~redients of the formula I
(throughout, percentages are by weight)
10. Emulsifiable concentrates a) b) c)
compound of Tables 1 to 10 25% 40% 50%
calcium dodecylbenzenesulfonate 5% 8% 6%
castor oil polyethylene glycol
ether (36 moles of ethylene
oxide) 5% - -
tributylphenol polyethylene
glycol ether (30 moles of
ethylene oxide) - 12% 4%
cyclonexane - 15% 20%
xylene mixture 65% 25% 20%
Emulsions of any required concentration can be produced
from such concentrates by dilution with water.
11. Solutions a) b) c) d)
compound of Tables 1 to 10 80% 10% 5% 95%
ethylene glycol monomethyl
ether 20% - - -
polyethylene glycol 400- - 70%
N-methyl-2-pyrrolidone - 20%
epoxidised coconut oil - - 1% 5%
ligroin (boiling range
160-190C) - - 94%
These solutions are suitable for application in the form
of microdrops.
.
2~
- 106 -
12. Granulates a) b)
compound of Tables 1 to 10 5% 10%
kaolin 94%
highly dispersed silicic acid 1%
attapulgite - 90%
The active ingredient is dissolved in methylene chloride,
the solution is sprayed onto the carrier, and the solvent
is subsequently evaporated off in vacuo.
13. Dusts a) b)
compound of Tables 1 to 10 2% 5%
highly dispersed silicic acid .1% 5%
talcum 97%
kaolin - 90%
Ready for use dusts are obtained by intimately mixing ~he
carriers with the active ingredient.
Formulation examples for agrochemical compositions
containing solid active ingredients of the formula I
(throughout, percentages are by weight)
14. Wettable powders a) b) c)
compound of Tables 1 to 10 25% 50% 75%
sodium lignosulfonate 5% 5%
sodium laurylsulfate 3% - 5%
sodium diisobutylnaphthalene-
sulfonate - 5% 10%
octylphenol polyethylene
glycol ether (7-8 moles o
ethylene oxide) - 2%
highly dispersed silicic acid 5% 10% 10%
kaolin 62% 27%
- 107 -
The active ingredient is thoroughly mixed with the adjuvants
and the mixture is thoroughly ground in a suitable mill,
affording wettable powders which can be diluted with water
to give suspensions of the desired concentration.
15. Emulsifiable concentrates
compound of Tables 1 to 10 10%
octylphenol polyethylene glycol ether
(4-5 moles of ethylene oxide) 3%
calcium dodecylbenzenesulfonate 3~/0
castor oil polyglycol ether
(36 moles of ethylene oxide) 4%
cyclohexanone 20%
xylene mixture 50%
coconut oil 10%.
Emulsions of any required concentration can be obkained from
this concentrate by dilution with water.
16. Dusts a) b)
: compound of Tables 1 to 10 5% 8%
talcum 95%
kaolin - 92%
Ready for use dusts are obtained by mixing the active
ingredient with the carriers, and grinding ~he mixture in
a suitable mill.
17. Extruder ~ranulate
compound of Tables 1 to 10 10%
sodium lignosulfonate 2%
carboxymethylcellulose 1%
kaolin 87%.
;
?3
- 108 -
The active ingredient is mixed and ground with the adjuvants,
and the mixture is subsequently moistened with water. The
mixture is extruded and then dried in a stream of air.
18. Coated ~ranulate
compound of Tables 1 to 10 3%
polyethylene glycol 200 3%
kaolin 9~%
The finely ground active ingredient is uniformly applied,
in a mixer, to the kaolin moistened with polyethylene glycol.
Non-dusty coated granulates are obtained in this manner.
19. Suspension concentrate
compound of Tables 1 to 10 ~0 %
ethylene glycol 10 %
nonylphenol polyethylene glycol
ether (15 moles of ethylene oxide) 6 %
sodium lignosulfonate 10 %
carboxymethylcellulose 1 %
37% aqueous formaldehyde solution 0.2%
silicone oil in the form of a 75%
aqueous emulsion 0.8%
water 32 %.
The finely ground active ingredient is intimately mixed
with the adjuvants, giving a suspension concentrate from
which suspensions of any desired concentration can be
obtained by dilution with water.
Formulation Examples for Pharmaceutical Preparations
20. Ointments
An ointment containing 5% of 2-[p~(4-chlorophenoxy)phenyl]-
2-(1-imidazolylmethyl)-~-ethyl-dioxolane may be prepared as
follows:
- log -
Composition
Active ingredient 5.0%
white petroleum jelly45-0%
liquid paraffin 19.6%
cetyl alcohol 5.0%
beeswax 5-0%
sorbitan sesquloleate5.0%
p-hydroxybenzoate 0.2%
demineralised water to make up 100.0%
The fatty substance and emulsifiers are melted together.
The preservative is dissolved in water and the solution
is emulsified into the fatty melt at elevated temperature.
After cooling, a suspension of the active ingredient in
part of the fatty melt is incorporated into the emulsion.
21. Cream
A cream con~aining 10% of 2-[p-(chlorophenoxy)phenyl~-2~
imidazolylmethyl)-4-ethyl-1,3-dioxolane may be prepared as
follows:
Composition
active ingredient 10.0%
isopropyl palmitate 8.0%
cetyl palmitate 1.5%
silicone oil 100 0.5%
sorbitan monostearate 3.0%
polysorbate 60 3-5%
1,2-propylene glycol PH 20.0%
acrylic acid polymer 0.5%
triethanolamine 0.7%
demineralised water to make up 100.0%
The acrylic acid polymer is suspended in a mixture of
demineralised water and 1,2~propylene glycol. Triethanolamine
- 110 -
is then stirred in to give a mucilage. A mixture of iso-
propyl palmitate, cetyl palmitate, silicone oil, sorbitan
monostearate and polysorbate is heated to about 75C and
then stirred into the mucilage, which is also heated to
about 75C. After it has cooled to room temperature, the
cream base is used to prepare a concentrate with the active
ingredient. This concentrate is homogenised using a
continuous homogenisex, and then added in portions to ~he
base.
A cream containing 5% of 2-[p-(chlorophenoxy)phenyl~-2-(1-
imidazolylmethyl)-4-ethyl-1,3-dioxolane may be prepared as
follows:
Composition
active ingredient 5.0%
cetyl palmitate PH 2.0V/~
cetyl alcohol PH 2.0%
triglyceride mixture of saturated medium fatty
acids 5.0%
stearic acid 3.0%
glycerol stearate PH ~.0%
Cetomacrogol 1000 1.0%
microcrystalline cellulose 0.5%
1,2-propylene glycol (dist.) 20.0%
dem-Lneralised water to make up 100.0%
The cetyl alcohol, cetal palmitate, triglyceride mixture,
stearic acid and glycerol stearate are melted together. The
microcrystalline cellulose is dispersed in a portion of the
water. The Cetomacrogol is dissolved in the remainder o~ the
water and both the propylene glycol and the mucilage are
blended therewith. The fatty phase is ~hen stirred into the
aqueous phase and the mix is st-Lrred cold. Finally, the
active ingredient is milled with a portion of the base and
~2~U3
then incorporated in the rest of the cream.
22. Hydro~e~s
A transparent hydrogel containing 5% of 2-[p-(chlorophenoxy)-
phenyl]-2-(1-imidazolylmethyl)-4-ethyldioxolane is prepared
as follows:
Composition
active ingredient 5%
propylene glycol 10-20%
isopropanol 20%
hydroxypropyl methyl cellulose2%
water to make up 100%
The hydroxypropyl methyl cellulose is expanded in water. The
active ingredient is dissolved in a mixture of isopropanol
and propylene glycol. The active ingredient solution is then
blended with an expanded cellulose derivative and~ if desired,
perfume (0.1%) is added.
23. Foam sprays
A foam spray containing 1% of 2-[p-(chlorophenoxy)phenyl]-2-
(l-imidaæolylmethyl)-4-ethyldioxolane may be prepared as
follows:
Composition
active ingredient 1.00%
cetyl alcohol PH 1.70%
liquid paraffin (viscous) 1.00%
isopropyl myristate 2.00%
Cetamacrogol 2.40%
sorbitan monostearate 1.50%
1,2-propylene glycol PH 5.00%
me~hyl parabene 0.18%
- 112 ~
propyl parabene 0.02%
Chemoderm 314 0.10%
demineralised water to make up 100.00%
The cetyl alcohol, liquid paraffin, isopropyl myristate,
Cetomacrogol and sorbitan stearate are fused together. The
methyl and propyl parabene are dissolved in hot water. The
melt and the solution are then blended. A swspension of the
active ingredient in propylene glycol is incorporated in the
base. Chemoderm is then added and the composition is bulked
with water to the final weigh~.
Fillin~
20 ml of the composition are filled into an aluminium
dispenser. The dispenser is fitted with a pressure cap and
filled with propellant gas under pressure.
24. Capsules
Gelatin capsules containing 200 mg o~ [p-(pheno~y)phenyl]-2-
[l-tlH-1,23~ riazolyl)methyl]-1,3-dioxane as active in-
gredient may be prepared as follows:
Composition (for 1000 capsules)
active ingredient 100 g
lactose (gound) 100 g
The active ingredient and the lactose ~micronised) are well
mixed. The resultant powder is sieved and packed into gelatin
capsules of 0.2 g.
25. Tablets
Tablets containing 25 mg o~ active ingredient, e.g. 2-[p-
(phenoxy)phenyl[-2-~1-(lH-1,2,~-triazolyl)methyl]-1,3-dioxane,
may be prepared as follows:
....
~ 2~ 3
- 113 -
Composition (for 1000 tablets)
active ingredient 25.0 g
lactose 100.7 g
corn starch 7.5 g
polyethylene glycol 60005.0 g
talcum 5.0 g
magnesium stearate 1.8 g
demineralised water q.s.
Preparation
All the solid ingredients are first passed through a sieve
having a mesh size of 0.6 mm. Then the active ingredient,
the lactose, talcum, magnesium stearate and half of the
starch are blended together. The other half of the starch
is suspended in 40 ml of water and this suspension is added
to a boiling solution of the polyethylene glycol in 1000 ml
of water and the mixture is granulated, if necessary with
the addition of water. The granulate is dried overnight at
35C, passed through a 1.2 mm sieve and compressed to
biconcave tablets of about 6 mm diameter.
Tablets containing 75 mg of active ingredient, e.g. 2-~p-
(phenoxy)phenyl]-2-[1-(lH-1,2,~-tria~olyl)methyl] 1,3-dioxane,
may be prepared as follows:
Composition ( for 1000 tablets)
active ingredient 75.0 g
lactose 100.7 g
corn starch 7.5 g
polyethylene glycol 60005.0 g
talcum 5.0 g
magnesium stearate 1.8 g
demineralised water q.s~
114 -
Preparation
All the solid ingredients are first passed through a sîeve
having a mesh size of 0.6 mm. Then the active ingredient, the
lactose, talcum, magnesium stearate and half of the starch
are blended together. The other half of the starch is sus-
pended in 40 ml of water and this suspension is added to a
boiling solution of the polyethylene glycol in 100 ml of
water and the mixture is granulated, if necessary with the
addition of water. The granulate is dried overnight at 35C,
passed through a 1. 2 mm sieve and compressed to biconcave
tablets of about 6 mm diameter.
Pharmaceutical preparations containing another compound of
Tables 1 to 10 may laso be prepared in analogous manner.
Biolo~ical Examples
Example 26 Ac~ion a~ainst Puccinia ~ramini~ on wheat
a) Residual-protec~ive action
Wheat plants are treated 6 days after sowing with a spray
mixture prepared from a wettable powder formulakion of the
active ingredient (0~06%)o After 24 hours the treated plants
are infected with a uredospore suspension of the fungus.
The infected plants are incubated for 48 hours at 95-lOOa/o
relative humidity and about 20~C and then stood in a green-
house at about 22C. Evaluation of rust pustule development
is made 12 days after infection.
b) Systemic action
Wheat plants are treated 5 days after sowing with a spray
mixture prepared from a wettable powder formulation of the
active ingredient (0~06% based on the volume of the soil).
After 48 hours the treated plants are infected with a uredos-
pore suspension of the fungus. The plants are then incubated
for 48 hours at 95-100% relative humidity and about 20C
and then stood in a greenhouse at about 22C. Evaluation
~ P~u
- I15 -
of rust pustule development is made 12 days after infection.
Compounds of Tables 1 to 10 are very effective against
Puccinia fungi. Puccinia infestation is 100 ~ on untreated,
infected control plants. Residual-protective treatment with
compounds 1.17, 1.24, 2.17, 3.1, 3.6, 3.7, 3.133, 3.164,
3.168, 3.220, 3.267, 3.311, 3.314, 4.50, 4.77, 4.81, 4.90,
4.91, 493, 4.94, 5.13, 5.14, 5.36, 5.70, 6.8 and 7.7 among
others, inhibits fungus attack to 0-5%. In addition, compound
6.8 has a full systemic action (0% attack3 even when diluted
to a concentration of 0.006%.
xample 27: Action a~ainst Cercospora arachidicola in
~roundnut plants
Groundnut plants 10-lS cm in height are sprayed with a spray
mix~ure prepared from a wettable powder formulation of the
active ingredient (concentration 0.02%) and infected 48 hours
la~er with a conidia suspension of the fungus. The infected
plants are incubated for 72 hours at about 21C and high
humidity and then stood in a greenhouse until the typical lea~
specks occur. Evaluation of the fungicidal action is made 12
days af~er infection, and is based on the number and size
of the specks.
Compared with untreated and infected controls (number and
size of the specks = 100%), the plants treated with compounds
of Tables 1 to 10 exhibit greatly reduced attack by
Cercospora. For example, compounds 1.9, 1.14, 1.17, 1.24,
1~26, 1.27, 2.17, 3.6, 3.7, 3.11, 3.133, 3.162, 3.171, 3.172,
3.176, 3.177, 3.221, 3.231, 3.232, 3.234, 3.314,4050, 4.89,
4.90, 4.91, 4.92, 4.93. 4.94, 5.13, 5.14, 5.36, 5.40, 5.70,
5.71, 5.73, 5.75, 5.76, 5.78, 6.1 and 6.8 inhibit the
formation of specks in tis test almost completely (0 to 5 %
attack).
~A~U ~
- 116 -
Example 28: Ac~ion a~ainst Erysiphe ~raminis on barley
a) Residual protective ac~ion
Barley plants about 8 cm in height are sprayed with a spray
mixture (0.02%) prepared from the ac~ive ingredient
formulated as a wettable powder. The treated plants are
dus~ed with conidia of the fungus af~er 3-~ hours. The
infected barley plants are then stood in a greenhouse at
about 22~C. The f~mgus a~tack is evaluated after 10 days.
b) Systemic action
Barley plants about 8 cm in height are ~rea~ed with a spray
mixture (o.006%, based on the volume of the soil) prepared
from the ~c~ive ingredient formulated as we~able powder.
Care is taken that the spray mixture does not come in
contac~ with the parts of the plants above the soil. The
treated plants are infected 48 hours later with a conidia
suspension of the fungus. The infected barley plants are
then stood in a greenhouse a~ about 22~C and evaluation
of fungus infestation is ~ade after 10 days.
Compounds of the formula I have a good residual-protective
action against Erysiphe fungi. Erysiphe infestation of
untreated, infected control plants is 100%. Among others,
compounds 1.1, 1.9, 1.17~ 1.23~ 1.24~ 1.25~ 1.26~ 1.27~ 2.17
3.1 t 3.2 ~ 3.6 ~ 3.7 ~ 3.8, 3.11, 3.12 ~ 3.26 3.127 r 3.133 ~
3.164, 3.168~ 3.172~ 3.176, 3.177, 3.193~ 3.226~ 3.231,
3.233, 3.267, 3.274, 3.311, 3.314, 4.50, 4.78, 4.~9, 4.90,
~.91~ 4.92~ 4.93~ 4.94~ 5.13~ 5.14~ 5.36~ 5.~0~ 5.70~ 5.7
5.73, 5.75, 5.76~ 5.78~ 6.1/ 6.8, 7.3~ 7.7 and 7.21 inhibit
fungus attack to less than 5 % . Compound 4.50 iS also
effective in soil treatment (systemic action~ and when
diluted to a concentration of 0.006%.
117 -
Example 29: Residual-protective action a~ainst Venturia
inaequalis on apple shoots
Apple cuttings with 10-20 cm long fresh shoots are sprayed
with a spray mixture prepared from a wettable powder
formulation of the active ingredient (0.06%. After 2~ hours
the treated plants are infected with a conidia suspension
of the fungus. The plants are then incubated for 5 days at
90-100% relative humidity and stood in a greenhouse for a
further 10 days at 20-24C. Scab infestation ls evaluated
15 days after infection. Compounds 1.9, 1.17, 1.24, 2.17,
3.6, 3.7, 3.11, 4.50, 4.81, 4.89, 4.90, 4.91, 4.92, 5.13,
5.14, 5.36, 5.40, 5.70, 6.1 and 6.8 and others inhibit
infestation to less than 10%. Venturia infestation is 100%
on untreated, infected shoots.
Example 30: Action a~ainst Botrytis cinerea on beans
a) Residual protective action
Bean plants abcut 10 cm in height are sprayed with a spray
mixture (0.02%) prepared from the ac-tive ingredient
~ormulated as wettable powder. After 48 hours, ~he treated
plants are infected with a conidia suspension of the fungus.
The infec~ed plants are incubated for 3 days at 95-100%
relative humidity and 21C, and evaluation of the fungus
attack is then made. Compounds of Tables 1 to 10 very strongly
inhibit fungus infestation in many cases. At a concentration
of 0.02 %, compounds l.l, l.9, 3.6, 3.7, 3.231, 4.50, 4.78,
5.13, 5.36, 5.40, 5.70, 5.71, 5.73, 5.75, 5.77, 6.1 and 6.8
are fully effective (0 to 5 % attack). sotrytis infestation
of untreated, inf~cted bean plants is loO gd.
