Note: Descriptions are shown in the official language in which they were submitted.
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FUNGICIDE N-6-MEMBERED FUSED (HETERO)ARYL-METHYLENE-N-CYCLOALKYL CARBOXAMIDE
DERIVATIVES
DESCRIPTION
The present invention relates to N-(aromatic,6-membered, fused, (hetero)aryl-
methylene)-N-
cycloalkyl carboxamide derivatives, their thiocarboxamide or N-substituted
carboximidamide
analogues, their process of preparation, their use as fungicide active agents,
particularly in the
form of fungicide compositions, and methods for the control of phytopathogenic
fungi, notably of
plants, using these compounds or compositions.
International patent application WO-2001/11966 generically mentions certain
haloalkyl-2-
pyridyl-methylene-heterocyclyl-amide derivatives. However, there is no
disclosure in this
document of any such derivative substituted by any cycloalkyl group.
International patent application WO-2004/074259 discloses GABAA receptor-
bondable
compounds of the following formula:
R' NN, Y
I I I
Ar YN z
O R5 R6 4
R4
wherein Ar can represent a 5- to 10-heterocycle, R' can represent a C3-C7-
cycloalkyl while X, Y
and Z can represent N or CR1, at least one representing N.
However, there is no disclosure in this document of any compound including a 5-
membered
heterocycle or a cycloalkyl linked to the nitrogen atom.
International patent application WO-2006/120224 discloses 2-pyridyl-methylene-
carboxamide
derivatives of the following formula:
Y
/ Z3
(X) ~ I N ~A
~N Z2 Z1 O
there was no hint in this document to prepare the fungicide bicyclic
derivatives according to the
invention.
International patent application WO-2007/117778 discloses quinoline
derivatives useful as
inducible nitric oxide synthase inhibitors, including N-cyclopropyl-N-((7,8-
fluoro-2-oxo-1,2-
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dihydroquinolin-4-yl)methyl)-4-methylthiazole-5-carboxamide and N-cyclopropyl-
N-((8-fluoro-2-
oxo-l,2-dihydroquinolin-4-yl)methyl)-4-methylthiazole-5- carboxamide. These
compounds do not
form part of the present invention.
It is always of high-interest in agriculture to use novel pesticide compounds
in order to avoid or
to control the development of resistant strains to the active ingredients. It
is also of high-interest
to use novel compounds being more active than those already known, with the
aim of
decreasing the amounts of active compound to be used, whilst at the same time
maintaining
effectiveness at least equivalent to the already known compounds. We have now
found a new
family of compounds that possess the above mentioned effects or advantages.
Accordingly, the present invention provides N-(aromatic, 6-membered, fused,
(hetero)aryl-
methylene)-N-cycloalkyl-carboxamide derivatives of formula (I)
Z1
A N
~B
Z2X z 3
T
(I)
wherein
= A represents a carbo-linked, unsaturated or partially saturated, 5-membered
heterocyclyl group that can be substituted by up to four groups R a;
= B represents
4 Y1 ~3IP
W~W3
VW2
W
wherein
o W' to W5 independently represent N or CRb'
o Y' to Y3 independently represent N, 0, S, NRb2 or CRb3
o Y' to Y3 together with the atoms Wn to which they are linked, form an
aromatic 5-
or 6-membered, fused heterocyclyl ring comprising up to four heteroatoms, or
an
aromatic 6-membered fused carbocyclyl ring
o p represents 1 or 2;
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= T represents 0, S, N-R , N-ORd, N-NR Rd or N-CN ;
= Z' represents a non substituted C3-C7-cycloalkyl or a C3-C7 cycloalkyl
substituted by up
to 10 atoms or groups that can be the same or different and that can be
selected in the
list consisting of halogen atoms ; cyano ; Cl-C$-alkyl ; Cl-C$-halogenoalkyl
comprising
up to 9 halogen atoms that can be the same or different ; C, C8-alkoxy ; Cl-C$-
halogenoalkoxy comprising up to 9 halogen atoms that can be the same or
different
Cl-C$-alkoxycarbonyl ; Cl-C$-halogenoalkoxycarbonyl comprising up to 9 halogen
atoms that can be the same or different ; Cl-C$-alkylaminocarbonyl ; di-(Cl-C$-
alkyl)aminocarbonyl ;
= Z2 and Z3 independently represent a hydrogen atom ; a halogen atom ; Cl-C$-
alkyl ; Cl-
C$-halogenoalkyl comprising up to 9 halogen atoms that can be the same or
different
C2-C8-alkenyl ; CZ-C$-alkynyl ; cyano ; nitro ; Cl-C$-alkoxy ; C2-C8-
alkenyloxy ; C2-C8-
alkynyloxy ; C3-C,-cycloalkyl ; Cl-C$-alkylsulphenyl ; amino ; C, C8-
alkylamino ; di-(Cl-
C$-alkyl)amino ; Cl-C$-alkoxycarbonyl ; Cl-C$-alkylcarbonyl ; Cl-C$-
alkylcarbamoyl ; di-
(Cl-C$-alkyl)carbamoyl ; N-Cl-C$-alkyl-Cl-C$-alkoxycarbamoyl ; or
= Z2 and Z3 together with the carbon atom to which they are linked can form a
substituted
or non substituted C3-C7 cycloalkyl
= Ra independently represents a hydrogen atom ; halogen atom ; cyano ; nitro ;
amino
sulfanyl ; hydroxyl ; pentafluoro-A-6-sulfanyl ; Cl-C$-alkylamino ; di-(Cl-C$-
alkyl)amino
tri(Cl-C$-alkyl)silyl ; tri(Cl-C$-alkyl)silyl-Cl-C$-alkyl ; Cl-C$-
alkylsulfanyl ; Cl-C$-
halogenoalkylsulfanyl comprising up to 9 halogen atoms that can be the same or
different ; Cl-C$-alkyl ; Cl-C$-halogenoalkyl comprising up to 9 halogen atoms
that can
be the same or different ; C2-C8-alkenyl ; C2-C8-halogenoalkenyl comprising up
to 9
halogen atoms that can be the same or different ; C2-C8-alkynyl ; C2-C8-
halogenoalkynyl
comprising up to 9 halogen atoms that can be the same or different ; Cl-C$-
alkoxy ; Cl-
C$-alkoxy-Cl-C$-alkyl ; Cl-C$-halogenoalkoxy comprising up to 9 halogen atoms
that
can be the same or different ; C2 C8-alkenyloxy ; C2-C8-alkynyloxy ; C3-C7-
cycloalkyl
C3-C7-cycloalkyl- Cl-C$-alkyl ; Cl-C$-alkylsulphinyl ; Cl-C$-alkylsulphonyl ;
Cl-
C$alkoxyimino ; (C1-C$-alkoxyimino)-Cj-C$-alkyl ; (benzyloxyimino)-Cl-C$-alkyl
; Cl-C$-
alkylcarbonyl ; Cl-C$-halogenoalkylcarbonyl comprising up to 9 halogen atoms
that can
be the same or different ; Cl-C$-alkoxycarbonyl ; Cl-C$-halogenoalkoxycarbonyl
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comprising up to 9 halogen atoms that can be the same or different ; Cl-C$-
alkylaminocarbonyl ; di-(Cl-C$-alkyl)aminocarbonyl ;
= R and Rd, that can be the same or different, represent a hydrogen atom ; Cl-
C$-alkyl
Cl-C$-halogenoalkyl comprising up to 9 halogen atoms that can be the same or
different ; C1-C$-alkoxy-Cj-C$-alkyl ; CZ-C$-alkenyl ; C2-C8-halogenoalkenyl
comprising
up to 9 halogen atoms that can be the same or different ; C2-C8-alkynyl ; C2-
C8-
halogenoalkynyl comprising up to 9 halogen atoms that can be the same or
different
C3-C7-cycloalkyl ; C3-C,-cycloalkyl-Cl-C$-alkyl ; C3-C7-halogenocycloalkyl
comprising up
to 9 halogen atoms that can be the same or different ; formyl ; Cl-C$-
alkylcarbonyl ; Cl-
C$-halogenoalkylcarbonyl comprising up to 9 halogen atoms that can be the same
or
different ; Cl-C$-alkylsulphonyl ; Cl-C$-halogenoalkylsulphonyl comprising up
to 9
halogen atoms that can be the same or different ; phenyl that can be
substituted by up
to 5 groups Q; naphthyl that can be substituted by up to 6 groups Q;
phenylmethylene
that can be substituted by up to 5 groups Q; phenylsulphonyl that can be
substituted by
up to 5 groups Q ;
= R bl and Rb3 independently represent a hydrogen atom ; halogen atom ; nitro
; cyano
hydroxyl ; sulphanyl ; amino ; pentafluoro-,\6-sulphanyl ; Cl-C$-alkyl ; Cl-C$-
halogenoalkyl comprising up to 9 halogen atoms that can be the same or
different ; Cl-
C$-alkylamino ; di-(Cl-C$-alkyl)amino ; Cl-C$-alkoxy ; Cl-C$-halogenoalkoxy
comprising
up to 9 halogen atoms that can be the same or different ; C1-C$-alkoxy-Cj-C$-
alkyl ; Cl-
C$-alkylsulphanyl ; Cl-C$-halogenoalkylsulphanyl comprising up to 9 halogen
atoms that
can be the same or different ; Cl-C$-alkylsulphenyl, Cl-C$-
halogenoalkylsulphenyl
comprising up to 9 halogen atoms that can be the same or different, Cl-C$-
alkylsulphinyl, Cl-C$-halogenoalkylsulphinyl comprising up to 9 halogen atoms
that can
be the same or different, Cl-C$-alkylsulphonyl, C, C8-halogenoalkylsulphonyl
comprising up to 9 halogen atoms that can be the same or different ; C2-C8-
alkenyl ; C2-
C8-halogenoalkenyl comprising up to 9 halogen atoms that can be the same or
different ; C2-C8-alkynyl ; C2-C8-halogenoalkynyl comprising up to 9 halogen
atoms that
can be the same or different C2-C8-alkenyloxy ; C2-C8-halogenoalkenyloxy
comprising
up to 9 halogen atoms that can be the same or different ; C2-C8-alkinyloxy ;
C2-C8-
halogenoalkinyloxy comprising up to 9 halogen atoms that can be the same or
different ; C3-C7-cycloalkyl ; C3-C,-cycloalkyl-Cl-C$-alkyl ; C3-C7-
halogenocycloalkyl
comprising up to 9 halogen atoms that can be the same or different ; formyl ;
formyloxy ;
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formylamino ; carboxy ; carbamoyl ; N-hydroxycarbamoyl ; carbamate
;(hydroxyimino)-
Cl-C$-alkyl ; Cl-C$-alkylcarbonyl ; Cl-C$-halogenoalkylcarbonyl comprising up
to 9
halogen atoms that can be the same or different ; N-Cj-C$-alkyl-Cj-C$-
alkoxycarbamoyl ; Cl-C$-alkoxycarbonyl ; Cl-C$-halogenoalkoxycarbonyl
comprising up
5 to 9 halogen atoms that can be the same or different ; Cl-C$-
alkylaminocarbonyl ; di-
(Cl-C$-alkyl)aminocarbonyl ; Cl-C$-alkylcarbonyloxy ; Cl-C$-
halogenoalkylcarbonyloxy
comprising up to 9 halogen atoms that can be the same or different ; Cl-C$-
alkylcarbonylamino ; Cl-C$-alkylaminocarbonyloxy ; di-(Cl-C$-
alkyl)aminocarbonyloxy
Cl-C$-alkyloxycarbonyloxy ; Cl-C$-alkoxyimino ; (Cl-C$-alkoxyimino)-Cl-C$-
alkyl ; (Cl-
1o C$-alkenyloxyimino)-Cl-C$-alkyl ; (Cl-C$-alkynyloxyimino)- Cl-C$-alkyl
(benzyloxyimino)-Cl-C$-alkyl ; tri(Cl-C$-alkyl)silyl ; tri(Cl-C$-alkyl)silyl-
Cl-C$-alkyl
phenyl that can be substituted by up to 5 groups Q; benzyloxy that can be
substituted
by up to 5 groups Q; benzylsulphanyl that can be substituted by up to 5 groups
Q;
benzylamino that can be substituted by up to 5 groups Q; phenoxy that can be
substituted by up to 5 groups Q; phenylamino that can be substituted by up to
5 groups
Q; phenylsulphanyl that can be substituted by up to 5 groups Q; benzyl that
can be
substituted by up to 5 groups Q; pyridinyl that can be substituted by up to
four groups
Q and pyridinyloxy that can be substituted by up to four groups Q;
= R b2 represents a hydrogen atom ; Cl-C$-alkyl ; Cl-C$-halogenoalkyl
comprising up to 9
halogen atoms that can be the same or different ; Cl-C$-alkoxy-Cl-C$-alkyl ;
C2-C8-
alkenyl ; C2-C8-halogenoalkenyl comprising up to 9 halogen atoms that can be
the same
or different ; C2-C8-alkynyl ; C2-C8-halogenoalkynyl comprising up to 9
halogen atoms
that can be the same or different ; C3-C7-cycloalkyl ; C3-C,-cycloalkyl-Cl-C$-
alkyl ; C3-
C7-halogenocycloalkyl comprising up to 9 halogen atoms that can be the same or
different ; formyl, Cl-C$-alkylcarbonyl ; Cl-C$-halogenoalkylcarbonyl
comprising up to 9
halogen atoms that can be the same or different ; Cl-C$-alkylsulphonyl ; Cl-C$-
halogenoalkylsulphonyl comprising up to 9 halogen atoms that can be the same
or
different ; phenylsulfonyl can be substituted by up to 5 groups Q; benzyl that
can be
substituted by up to 5 groups Q;
= Q, that can be the same or different, represents a halogen atom ; cyano ;
nitro ; Cl-C$-
alkyl ; Cl-C$-alkoxy ; Cl-C$-alkylsulfanyl ; Cl-C$-halogenoalkyl comprising up
to 9
halogen atoms that can be the same or different ; Cl-C$-halogenoalkoxy
comprising up
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to 9 halogen atoms that can be the same or different ; tri(Cl-C$)alkylsilyl
and tri(Cl-
C$)alkylsilyl-Cj-C$-alkyl ; Cl-C$-alkoxyimino ; P-C$-alkoxyimino)- Cl-C$-alkyl
;
as well as salts, N-oxides, metallic complexes, metalloidic complexes and
optically active or
geometric isomers thereof provided that compound of formula (I) differs from N-
cyclopropyl-N-
((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-furane-2-carboxamide, N-
cyclopropyl-N-
((6-ethoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-furane-2-carboxamide, N-
cyclopropyl-N-((6-
methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-furane-2-carboxamide, N-
cyclopropyl-N-((7,8-
difluoro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-methylthiazole-5-carboxamide
and from N-
cyclopropyl-N-((8-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-
methylthiazole-5-carboxamide.
Any of the compounds according to the invention can exist as one or more
stereoisomers
depending on the number of stereogenic units (as defined by the IUPAC rules)
in the compound.
The invention thus relates equally to all the stereoisomers, and to the
mixtures of all the
possible stereoisomers, in all proportions. The stereoisomers can be separated
according to the
methods that are known per se by the man ordinary skilled in the art.
According to the invention, the following generic terms are generally used
with the following
meanings:
= halogen means fluorine, chlorine, bromine or iodine ;
= heteroatom can be nitrogen, oxygen or sulphur ;
= halogenated groups, notably haloalkyl, haloalkoxy and cycloalkyl groups, can
comprise
up to nine identical or different a halogen atoms ;
= Any alkyl, alkenyl or alkynyl group can be linear or branched
= the term "aryl" means phenyl or naphthyl, optionally substituted by one to
five groups
selected in the list consisting of halogen, [Cl-C6]-alkyl, [Cl-C6]-haloalkyl,
[C2-C6]-alkenyl,
[C2-C6]-haloalkenyl, [CZ-C6]-alkynyl, [CZ-C6]-haloalkynyl, [Cl-C6]-alkoxy, [Cl-
C4]-alkoxy-
[Cl-C4]-alkyl, [C1-C4]-alkoxy-[Cj-C4]-alkoxy, [Cl-C6]-haloalkoxy and [Cl-C4]-
haloalkoxy-
[Cl-C4]-alkyl ;
= In the case of an amino group or the amino moiety of any other amino-
comprising group,
substituted by two substituents that can be the same or different, the two
substituents
together with the nitrogen atom to which they are linked can form a
heterocyclyl group,
preferably a 5- to 7-membered heterocyclyl group, that can be substituted or
that can
include other hetero atoms, for example a morpholino group or piperidinyl.
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Preferred compounds of formula (I) according to the invention are those
wherein A is selected in
the list consisting of:
Ra3 a3 Ra2 a2
/ ~V' a2 a4/ \ a2 a4 R (a4 ~ R a4R R V R V R Vi
A' A2 A3 A4
Ra2 Ra3 Ra2 Ra2 Ra2
\\ *
a4 a4 N N
~Vi R ~Vi ~Vi R ~V1.
A5 A6 A7 A8
Ra2 Ra2 Ra3 Ra3
N~ /S NS V R a4 R al /N N/ R a2
A9 A' A" A12
wherein:
= * represents the attachment point to the carbonyl moiety ;
= V' represents 0, S or NR al ;
= Ra' represents a hydrogen atom ; Cl-C$-alkyl ; Cl-C$-halogenoalkyl
comprising up to 9
halogen atoms that can be the same or different ; C1-C$-alkoxy-Cj-C$-alkyl ;
= RaZ and Ra3, that can be the same or different represent a hydrogen atom ; a
halogen
atom ; cyano ; Cl-C$-alkyl ; Cl-C$-halogenoalkyl comprising up to 9 halogen
atoms that
can be the same or different ; Cl-C$-alkoxy or Cl-C$-halogenoalkoxy comprising
up to 9
halogen atoms that can be the same or different ; C3-C7-cycloalkyl ;
= Ra4 represents a hydrogen atom, a halogen atom ; cyano ; Cl-C$-alkyl ; Cl-C$-
halogenoalkyl comprising up to 9 halogen atoms that can be the same or
different ; Cl-
C8-alkoxy or Cl-C$-halogenoalkoxy comprising up to 9 halogen atoms that can be
the
same or different ; C3-C,-cycloalkyl ; Cl-C$-alkylsulfanyl ; amino ; Cl-C$-
alkylamino ; di-
(Cl-C$-alkyl)amino ; Cl-C$-alkyloxycarbonyl.
More preferred compounds of formula (I) according to the invention are those
wherein A is
selected in the list consisting of:
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Ra3 Ra3 Ra2 Ra2
\ a2 a2
a4/ \(
a4/ ~ R a4 i * 1 R a4/ \~*
R V R V R V R Vi
A' A2 A3 A4
Ra2 Ra3 Ra2 Ra2 Ra2
\\ *
a4 a4 N N
~Vi R ~Vi ~Vi R ~V1.
A5 A6 A7 A8
Ra2 Ra2 Ra3 Ra3
N~ /S N~N/S V R
a4 R al /N N/ R a2
~
A9 A' A" A12
wherein:
= * represents the attachment point to the carbonyl group ;
= V' represents 0, S or NR al ;
= Ra' represents a hydrogen atom ; Cl-C$-alkyl ; Cl C$-alkoxy-Cl-C$-alkyl ;
= R a2 represents Cl-C$-alkyl ; Cl-C$-halogenoalkyl comprising up to 9 halogen
atoms that
can be the same or different ; Cl-C$-alkoxy ;
= Ra3 represents a hydrogen atom ; a halogen atom ; Cl-C$-alkyl ;
= Ra4 represents a hydrogen atom, a halogen atom ; Cl-C$-alkyl ; Cl-C$-
halogenoalkyl
comprising up to 9 halogen atoms that can be the same or different.
Other more preferred compounds of formula (I) according to the invention are
those wherein
= A represents A5 ;
= V' represents NR al 15 = Ra' represents Cl-C$-alkyl
= RaZ and Ra3, that can be the same or different represent a hydrogen atom ; a
halogen
atom ; Cl-C$-alkyl ; Cl-C$-halogenoalkyl comprising up to 9 halogen atoms that
can be
the same or different ; or
= A represents A4 ;
0 V' represents S
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= RaZ represents a Cl-C$-alkyl ; Cl-C$-halogenoalkyl comprising up to 9
halogen atoms
that can be the same or different ;
= Ra4 represents a hydrogen atom ; Cl-C$-alkyl ; Cl-C$-halogenoalkyl
comprising up to 9
halogen atoms that can be the same or different.
Other preferred compounds of formula (I) according to the invention are those
wherein B is
selected in the list consisting of :
w4
w4 Y1a W5~ W3
W5~ 3/ 3b
I2
I Ya w1 y1a
/
W1/ 1,2a/
yz~ y~b
B B2 3a~
W 3 ~
W5/W/Y1a WY2b W ~~W
\\ W \ W W3 W 5 W3
y3a ~W3~ 1,a
2 ~ ~2 ~ 2 ~2
Y2b W~ ~ W
w W 1 Y W 1 \y 1a W 1 / I\y2b
1 2-Y / ~Y/
B3 B4 B5 B6
wherein
= W'to W5, Y'a Yza Y3aand y3b independently represent NR b2 or CRb3
= y2b represents 0, S or NRbZ.
Other more preferred compounds of formula (I) according to the invention are
those wherein B
represent B' or B 2 ; W' to W5 Y'a Yza y3a and y3b independently represent
CRb3 ; or B
represent B5 or B6 ;W1 to W5, yla and y3a independently represent CRb' ; y2b
represents S.
Other preferred compounds of formula (I) according to the invention are those
wherein T
represents 0 or S.
Other preferred compounds of formula (I) according to the invention are those
wherein Z'
represents cyclopropyl.
Other preferred compounds of formula (I) according to the invention are those
wherein Z2 and
Z3 independently represent a hydrogen atom or Cl-C$ alkyl.
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Other preferred compounds of formula (I) according to the invention are those
wherein Q
represents a halogen atom ; Cl-C$-alkyl ; Cl-C$-alkoxy ; Cl-C$-halogenoalkyl
comprising up to 9
halogen atoms that can be the same or different ; Cl-C$-halogenoalkoxy
comprising up to 9
halogen atoms that can be the same or different.
5
The above mentioned preferences with regard to the substituents of the
compounds of formula
(I) according to the invention can be combined in various manners, either
individually, partially
or entirely. These combinations of preferred features thus provide sub-classes
of compounds
according to the invention. Examples of such sub-classes of preferred
compounds according to
10 the invention can combine:
- preferred features of A with preferred features of one or more T, Z' to Z3,
Ra, Rb, T, V' and Q;
- preferred features of T with preferred features of one or more A, Z' to Z3,
Ra, Rb, V' and Q;
- preferred features of Z' with preferred features of one or more A, T, ZZ,
Z3, Ra, Rb, V' and Q;
- preferred features of Z2 with preferred features of one or more A, T, Z',
Z3, Ra, Rb, V' and Q;
- preferred features of Z3 with preferred features of one or more A, T, Z',
ZZ, Ra, Rb, V' and Q;
- preferred features of Ra with preferred features of one or more A, T, Z' to
Z3, Rb, V' and Q;
- preferred features of Rb with preferred features of one or more A, T, Z' to
Z3, Ra, V' and Q;
- preferred features of V' with preferred features of one or more A, T, Z' to
Z3, Ra, Rb and Q;
- preferred features of Q with preferred features of one or more A, T, Z' to
Z3, Ra, Rb and V' ;
In these combinations of preferred features of the substituents of the
compounds according to
the invention, the said preferred features can also be selected among the more
preferred
features of each of A, T, Z' to Z3, Ra, Rb, V' and Q; so as to form most
preferred subclasses of
compounds according to the invention.
The present invention also relates to a process for the preparation of
compounds of formula (I).
Thus according to a further aspect of the present invention, there is provided
a process P1 for
the preparation of a compound of formula (I) wherein T represents 0, as
illustrated by the
following reaction scheme:
Z' Z'
H~N\ /B + A U' A NB
Z2nZ3 YStep 1 1Z2>KZ3
(II) (III) (I)
Process P1
wherein
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= A, Z' to Z3, W' to W5 and B are as herein-defined
= U' represents a halogen atom or a leaving group.
In process P1 according to the invention, step 1 can be performed if
appropriate in the presence
of a solvent and if appropriate in the presence of an acid binder.
N-cycloalkyl-amine derivatives of formula (II) are known or can be prepared by
known
processes such as reductive amination of aldehyde or ketone (Bioorganics and
Medicinal
Chemistry Letters, 2006, p 2014 synthesis of compounds 7 and 8), or reduction
of imines
(Tetrahedron, 2005, p 11689), or nucleophilic substitution of halogen,
mesylate or tosylate
(Journal of Medicinal Chemistry, 2002, p 3887 preparation of intermediate for
compound 28).
Carboxylic acid derivatives of formula (III) are known or can be prepared by
known processes
(WO-93/11117 ; EP-545 099 ; Nucleosides & Nucleotides, 1987, p737-759, Bioorg.
Med. Chem.,
2002, p2105-2108).
Suitable acid binders for carrying out process P1 according to the invention
are in each case all
inorganic and organic bases that are customary for such reactions. Preference
is given to using
alkaline earth metal, alkali metal hydride, alkali metal hydroxides or alkali
metal alkoxides, such
as sodium hydroxide, sodium hydride, calcium hydroxide, potassium hydroxide,
potassium tert-
butoxide or other ammonium hydroxide, alkali metal carbonates, such as cesium
carbonate,
sodium carbonate, potassium carbonate, potassium bicarbonate, sodium
bicarbonate, alkali
metal or alkaline earth metal acetates, such as sodium acetate, potassium
acetate, calcium
acetate, and also tertiary amines, such as trimethylamine, triethylamine,
diisopropylethylamine,
tributylamine, N,N-dimethylaniline, pyridine, N methylpiperidine, N,N-
dimethylaminopyridine,
diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene
(DBU).
It is also possible to work in the absence of an additional condensing agent
or to employ an
excess of the amine component, so that it simultaneously acts as acid binder
agent.
Suitable solvents for carrying out process P1 according to the invention are
in each case all
customary inert organic solvents. Preference is given to using optionally
halogenated aliphatic,
alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane,
cyclohexane,
methylcyclohexane, benzene, toluene, xylene or decalin ; chlorobenzene,
dichlorobenzene,
dichloromethane, chloroform, carbon tetrachloride, dichlorethane or
trichlorethane ; ethers, such
as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl
ether, dioxane,
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tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole ;
nitriles, such as
acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile ; amides,
such as N,N-
dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-
methylpyrrolidone or
hexamethylphosphoric triamide ; esters, such as methyl acetate or ethyl
acetate, sulphoxides,
such as dimethyl sulphoxide, or sulphones, such as sulpholane.
When carrying out process P1 according to the invention, the reaction
temperatures can
independently be varied within a relatively wide range. Generally, processes
according to the
invention are carried out at temperatures between 0 C and 160 C, preferably
between 10 C
and 120 C. A way to control the temperature for the processes according to the
invention is to
use micro-wave technology.
Process P1 according to the invention is generally independently carried out
under atmospheric
pressure. However, in each case, it is also possible to operate under elevated
or reduced
pressure.
When carrying out step 1 of process P1 according to the invention, generally 1
mol or other an
excess of the acid derivative of formula (III) and from 1 to 3 mol of acid
binder are employed per
mole of amine of formula (II). It is also possible to employ the reaction
components in other
ratios.
Work-up is carried out by customary methods. Generally, the reaction mixture
is treated with
water and the organic phase is separated off and, after drying, concentrated
under reduced
pressure. If appropriate, the remaining residue can be freed by customary
methods, such as
chromatography or recrystallization, from any impurities that can still be
present.
According to a further aspect according to the invention, there is provided a
process P2 for the
preparation of a compound of formula (I), wherein T represents S, and
illustrated according to
the following reaction scheme
z z
I I
A N B thionating A N B
YZzXZs agent ISI Zz~Zs
(I) (I)
Process P2
wherein A, Z' to Z3, W' to W5 and B are as herein-defined.
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Process P2 can be performed in the presence of a thionating agent.
Starting amide derivatives of formula (I) can be prepared according to process
P1.
Suitable thionating agents for carrying out process P2 according to the
invention can be sulphur
(S), sulfhydric acid (HZS), sodium sulfide (NaZS), sodium hydrosulfide (NaHS),
boron trisulfide
(BZS3), bis (diethylaluminium) sulfide ((AIEtZ)ZS), ammonium sulfide
((NH4)ZS), phosphorous
pentasulfide (PZS5), Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,2,3,4-
dithiadiphosphetane
2,4-disulfide) or a polymer-supported thionating reagent such as described in
J.Chem.Soc.
Perkin 1, (2001), 358.
in the presence or in the absence, of a catalytic or stoechiometric or more,
quantity of a base
such as an inorganic and organic base. Preference is given to using alkali
metal carbonates,
such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium
bicarbonate ;
heterocyclic aromatic bases, such as pyridine, picoline, lutidine, collidine ;
and also tertiary
amines, such as trimethylamine, triethylamine, tributylamine, N,N-
dimethylaniline, N,N-dimethyl-
aminopyridine or N-methylpiperidine.
Suitable solvents for carrying out process P2 according to the invention can
be customary inert
organic solvents. Preference is given to using optionally halogenated
aliphatic, alicyclic or
aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane,
methylcyclohexane, benzene, toluene, xylene or decalin ; chlorobenzene,
dichlorobenzene,
dichloromethane, chloroform, carbon tetrachloride, dichlorethane or
trichlorethane ; ethers, such
as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl
ether, dioxane,
tetrahydrofuran, 1,2-dimethoxyethane or 1,2-diethoxyethane ; nitriles, such as
acetonitrile,
propionitrile, n- or i-butyronitrile or benzonitrile ; sulphurous solvents,
such as sulpholane or
carbon disufide.
When carrying out process P2 according to the invention, the reaction
temperatures can be
varied within a relatively wide range. In general, these processes are carried
out at
temperatures from 0 C to 160 C, preferably from 10 C to 120 C. A way to
control the
temperature for the processes according to the invention is to use micro-wave
technology.
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Process P2 according to the invention is generally carried out under
atmospheric pressure. It is
also possible to operate under elevated or reduced pressure.
When carrying out process P2 according to the invention, 1 mole or an excess
of the sulphur
equivalent of the thionating agent and from 1 to 3 moles of the base can be
employed per mole
of the amide derivative (I).
It is also possible to employ the reaction components in other ratios. Work-up
is carried out by
known methods.
In general, the reaction mixture is concentrated under reduced pressure. The
residue that
remains can be freed by known methods, such as chromatography or
recrystallization, from any
impurities that can still be present.
According to a further aspect according to the invention, there is provided a
process P3 for the
preparation of a compound of formula (I), wherein T represents N-R , N-ORd, N-
NR Rd or N-CN,
and illustrated according to the following reaction scheme :
z z
~N B + A Uz A N B
H
Zz Z3 yStep 2 T Zz Z3
(II) (IV) (I)
Process P3
wherein
= A, Z' to Z3, W' to W5 and B are as herein-defined ;
= U2 represents a chlorine atom or a methylsulfanyl goup,
In process P3 according to the invention, step 2 can be performed in the
presence of an acid
binder and in the presence of a solvent.
N-cycloalkyl-amine derivatives of formula (II) are known or can be prepared by
known
processes such as reductive amination of aldehyde or ketone (Bioorganics and
Medicinal
Chemistry Letters, 2006, p 2014 synthesis of compounds 7 and 8), or reduction
of imines
(Tetrahedron, 2005, p 11689), or nucleophilic substitution of halogen,
mesylate or tosylate
(Journal of Medicinal Chemistry, 2002, p 3887 preparation of intermediate for
compound 28).
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N-substituted carboximidoyl chloride of formula (IV) are known or can be
prepared by known
processes, for example as described in Houben-Weyl, "Methoden der organischen
Chemie"
(1985), E5/1, p 628-633 and Patai, "The chemistry of amidines and imidates"
(1975), p 296-301.
5 N-substituted or N,N-disubstituted hydrazonoyl chloride of formula (IV) are
known or can be
prepared by known processes, for example as described in Tetrahedron, 1991,
47, p 447 and
Journal of Heterocyclic Chemistry, 1983, 20, p 225
N-cyano carboximidoyl chloride of formula (IV) are known or can be prepared by
known
10 processes, for example as described in Tetrahedron Letters, 1968, p 5523
and Bioorganic and
Medicinal Chemistry, 2006, p 4723.
Suitable acid binders for carrying out process P3 according to the invention
can be inorganic
and organic bases that are customary for such reactions. Preference is given
to using alkaline
15 earth metal or alkali metal hydroxides, such as sodium hydroxide, calcium
hydroxide, potassium
hydroxide or other ammonium hydroxide derivatives ; alkali metal carbonates,
such as sodium
carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate ;
alkali metal or
alkaline earth metal acetates, such as sodium acetate, potassium acetate,
calcium acetate
alkaline earth metal or alkali metal hydrides, such as sodium hydride or
potassium hydride
alkaline earth metal or alkali metal alcoolates, such as sodium methylate,
sodium ethylate,
sodium propylate or potassium t-butylate ;and also tertiary amines, such as
trimethylamine,
triethylamine, tributylamine, N,N-dimethylaniline, pyridine, N-
methylpiperidine, N,N-dimethyl-
aminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diaza-
bicycloundecene (DBU) ; or a polymer-supported acid scavenger (for example as
detailed in
http://www.iris-biotech.de/downloads/scavengers.pdf).
It is also possible to work in the absence of any additional acid binder.
Suitable solvents for carrying out process P3 according to the invention can
be customary inert
organic solvents. Preference is given to using optionally halogenated
aliphatic, alicyclic or
aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane,
methylcyclohexane, benzene, toluene, xylene or decalin ; chlorobenzene,
dichlorobenzene,
dichloromethane, chloroform, carbon tetrachloride, dichlorethane or
trichlorethane ; ethers, such
as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl
ether, dioxane,
tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole ;
nitriles, such as
acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile ; amides,
such as N,N-
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16
dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-
methylpyrrolidone or
hexamethylphosphoric triamide ; esters, such as methyl acetate or ethyl
acetate, sulphoxides,
such as dimethyl sulphoxide, or sulphones, such as sulpholane.
When carrying out process P3 according to the invention, the reaction
temperatures can be
varied within a relatively wide range. In general, these processes are carried
out at
temperatures from 0 C to 160 C, preferably from 10 C to 120 C. A way to
control the
temperature for the processes according to the invention is to use micro-wave
technology.
Process P3 according to the invention is generally carried out under
atmospheric pressure. It is
also possible to operate under elevated or reduced pressure.
When carrying out process P3 according to the invention, the amine derivative
of formula (III)
can be employed as its salt, such as chlorhydate or any other convenient salt.
When carrying out process P3 according to the invention, 1 mole or an excess
of the amine
derivative of formula (II) and from 1 to 3 moles of the acid binder can be
employed per mole of
the N-substituted carboximidoyl chloride of formula (IV).
It is also possible to employ the reaction components in other ratios. Work-up
is carried out by
known methods.
In general, the reaction mixture is concentrated under reduced pressure. The
residue that
remains can be freed by known methods, such as chromatography or
recrystallization, from any
impurities that can still be present.
Compounds according to the invention can be prepared according to the above
described
process. It will nevertheless be understood that, on the basis of his general
knowledge and of
available publications, the skilled worker will be able to adapt these
processes according to the
specifics of each of the compounds according to the invention that is desired
to be synthesized.
In a further aspect, the present invention also relates to a fungicide
composition comprising an
effective and non-phytotoxic amount of an active compound of formula (I).
The expression "effective and non-phytotoxic amount" means an amount of
composition
according to the invention that is sufficient to control or destroy the fungi
present or liable to
appear on the crops, and that does not entail any appreciable symptom of
phytotoxicity for the
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17
said crops. Such an amount can vary within a wide range depending on the
fungus to be
controlled, the type of crop, the climatic conditions and the compounds
included in the fungicide
composition according to the invention. This amount can be determined by
systematic field trials,
that are within the capabilities of a person skilled in the art.
Thus, according to the invention, there is provided a fungicide composition
comprising, as an
active ingredient, an effective amount of a compound of formula (I) as herein
defined and an
agriculturally acceptable support, carrier or filler.
According to the invention, the term "support" denotes a natural or synthetic,
organic or
inorganic compound with that the active compound of formula (I) is combined or
associated to
make it easier to apply, notably to the parts of the plant. This support is
thus generally inert and
should be agriculturally acceptable. The support can be a solid or a liquid.
Examples of suitable
supports include clays, natural or synthetic silicates, silica, resins, waxes,
solid fertilisers, water,
alcohols, in particular butanol, organic solvents, mineral and plant oils and
derivatives thereof.
Mixtures of such supports can also be used.
The composition according to the invention can also comprise additional
components. In
particular, the composition can further comprise a surfactant. The surfactant
can be an
emulsifier, a dispersing agent or a wetting agent of ionic or non-ionic type
or a mixture of such
surfactants. Mention can be made, for example, of polyacrylic acid salts,
lignosulphonic acid
salts, phenolsulphonic or naphthalenesulphonic acid salts, polycondensates of
ethylene oxide
with fatty alcohols or with fatty acids or with fatty amines, substituted
phenols (in particular
alkylphenols or arylphenols), salts of sulphosuccinic acid esters, taurine
derivatives (in particular
alkyl taurates), phosphoric esters of polyoxyethylated alcohols or phenols,
fatty acid esters of
polyols, and derivatives of the above compounds comprising sulphate,
sulphonate and
phosphate functions. The presence of at least one surfactant is generally
essential when the
active compound and/or the inert support are water-insoluble and when the
vector agent for the
application is water. Preferably, surfactant content can be comprised from 5%
to 40% by weight
of the composition.
Optionally, additional components can also be included, e.g. protective
colloids, adhesives,
thickeners, thixotropic agents, penetration agents, stabilisers, sequestering
agents. More
generally, the active compounds can be combined with any solid or liquid
additive, that complies
with the usual formulation techniques.
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In general, the composition according to the invention can contain from 0.05
to 99% by weight
of active compound, preferably 10 to 70% by weight.
Compositions according to the invention can be used in various forms such as
aerosol
dispenser, capsule suspension, cold fogging concentrate, dustable powder,
emulsifiable
concentrate, emulsion oil in water, emulsion water in oil, encapsulated
granule, fine granule,
flowable concentrate for seed treatment, gas (under pressure),gas generating
product, granule,
hot fogging concentrate, macrogranule, microgranule, oil dispersible powder,
oil miscible
flowable concentrate, oil miscible liquid, paste, plant rodlet, powder for dry
seed treatment, seed
coated with a pesticide, soluble concentrate, soluble powder, solution for
seed treatment,
suspension concentrate (flowable concentrate), ultra low volume (ULV) liquid,
ultra low volume
(ULV) suspension, water dispersible granules or tablets, water dispersible
powder for slurry
treatment, water soluble granules or tablets, water soluble powder for seed
treatment and
wettable powder. These compositions include not only compositions that are
ready to be
applied to the plant or seed to be treated by means of a suitable device, such
as a spraying or
dusting device, but also concentrated commercial compositions that must be
diluted before
application to the crop.
The compounds according to the invention can also be mixed with one or more
insecticide,
fungicide, bactericide, attractant, acaricide or pheromone active substance or
other compounds
with biological activity. The mixtures thus obtained have normally a broadened
spectrum of
activity. The mixtures with other fungicide compounds are particularly
advantageous.
Examples of suitable fungicide mixing partners can be selected in the
following lists:
(1) Inhibitors of the nucleic acid synthesis, for example benalaxyl, benalaxyl-
M, bupirimate,
clozylacon, dimethirimol, ethirimol, furalaxyl, hymexazol, metalaxyl,
metalaxyl-M, ofurace,
oxadixyl and oxolinic acid.
(2) Inhibitors of the mitosis and cell division, for example benomyl,
carbendazim, chlorfenazole,
diethofencarb, ethaboxam, fuberidazole, pencycuron, thiabendazole,
thiophanate, thiophanate-
methyl and zoxamide.
(3) Inhibitors of the respiration, for example diflumetorim as Cl-respiration
inhibitor; bixafen,
boscalid, carboxin, fenfuram, flutolanil, fluopyram, furametpyr, furmecyclox,
isopyrazam (9R-
component), isopyrazam (9S-component), mepronil, oxycarboxin, penthiopyrad,
thifluzamide as
CII-respiration inhibitor; amisulbrom, azoxystrobin, cyazofamid,
dimoxystrobin, enestroburin,
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famoxadone, fenamidone, fluoxastrobin, kresoxim-methyl, metominostrobin,
orysastrobin,
picoxystrobin, pyraclostrobin, pyribencarb, trifloxystrobin as CIII-
respiration inhibitor.
(4) Compounds capable to act as an uncoupler, like for example binapacryl,
dinocap, fluazinam
and meptyldinocap.
(5) Inhibitors of the ATP production, for example fentin acetate, fentin
chloride, fentin hydroxide,
and silthiofam.
(6) Inhibitors of the amino acid and/or protein biosynthesis, for example
andoprim, blasticidin-S,
cyprodinil, kasugamycin, kasugamycin hydrochloride hydrate, mepanipyrim and
pyrimethanil.
(7) Inhibitors of the signal transduction, for example fenpiclonil,
fludioxonil and quinoxyfen.
(8) Inhibitors of the lipid and membrane synthesis, for example biphenyl,
chlozolinate,
edifenphos, etridiazole, iodocarb, iprobenfos, iprodione, isoprothiolane,
procymidone,
propamocarb, propamocarb hydrochloride, pyrazophos, tolclofos-methyl and
vinclozolin.
(9) Inhibitors of the ergosterol biosynthesis, for example aldimorph,
azaconazole, bitertanol,
bromuconazole, cyproconazole, diclobutrazole, difenoconazole, diniconazole,
diniconazole-M,
dodemorph, dodemorph acetate, epoxiconazole, etaconazole, fenarimol,
fenbuconazole,
fenhexamid, fenpropidin, fenpropimorph, fluquinconazole, flurprimidol,
flusilazole, flutriafol,
furconazole, furconazole-cis, hexaconazole, imazalil, imazalil sulfate,
imibenconazole,
ipconazole, metconazole, myclobutanil, naftifine, nuarimol, oxpoconazole,
paclobutrazol,
pefurazoate, penconazole, piperalin, prochloraz, propiconazole,
prothioconazole, pyributicarb,
pyrifenox, quinconazole, simeconazole, spiroxamine, tebuconazole, terbinafine,
tetraconazole,
triadimefon, triadimenol, tridemorph, triflumizole, triforine, triticonazole,
uniconazole,
viniconazole and voriconazole.
(10) Inhibitors of the cell wall synthesis, for example benthiavalicarb,
dimethomorph, flumorph,
iprovalicarb, mandipropamid, polyoxins, polyoxorim, prothiocarb, validamycin
A, and valiphenal.
(11) Inhibitors of the melanine biosynthesis, for example carpropamid,
diclocymet, fenoxanil,
phthalide, pyroquilon and tricyclazole.
(12) Compounds capable to induce a host defence, like for example acibenzolar-
S-methyl,
probenazole, and tiadinil.
(13) Compounds capable to have a multisite action, like for example bordeaux
mixture, captafol,
captan, chlorothalonil, copper naphthenate, copper oxide, copper oxychloride,
copper
preparations such as copper hydroxide, copper sulphate, dichlofluanid,
dithianon, dodine,
dodine free base, ferbam, fluorofolpet, folpet, guazatine, guazatine acetate,
iminoctadine,
iminoctadine albesilate, iminoctadine triacetate, mancopper, mancozeb, maneb,
metiram,
metiram zinc, oxine-copper, propamidine, propineb, sulphur and sulphur
preparations including
calcium polysulphide, thiram, tolylfluanid, zineb and ziram.
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(14) Further compounds like for example 2,3-dibutyl-6-chlorothieno[2,3-
d]pyrimidin-4(3H)-one,
ethyl (2Z)-3-amino-2-cyano-3-phenylprop-2-enoate, N-[2-(1,3-
dimethylbutyl)phenyl]-5-fluoro-1,3-
dimethyl-1 H-pyrazole-4-carboxamide, N-{2-[1,1'-bi(cyclopropyl)-2-yl]phenyl}-3-
(difluoromethyl)-
1-methyl-1 H-pyrazole-4-carboxam ide, (2E)-2-(2-{[6-(3-chloro-2-methylphenoxy)-
5-
5 fluoropyrimidin-4-yl]oxy}phenyl)-2-(methoxyimino)-N-methylethanamide, (2E)-2-
{2-[({[(2E,3E)-4-
(2,6-dichlorophenyl)but-3-en-2-ylidene]amino}oxy)methyl]phenyl}-2-
(methoxyimino)-N-
methylethanamide, 2-chloro-N-(1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-
yl)pyridine-3-
carboxamide, N-(3-ethyl-3,5,5-trimethylcyclohexyl)-3-(formylamino)-2-
hydroxybenzamide, 5-
m ethoxy-2-methyl-4-(2-{[({(1 E)-1-[3-
10 (trifluoromethyl)phenyl]ethylidene}amino)oxy]methyl}phenyl)-2,4-dihydro-3H-
1,2,4-triazol-3-one,
(2E)-2-(methoxyimino)-N-methyl-2-(2-{[({(1 E)-1-[3-
(trifluoromethyl)phenyl]ethylidene}amino)oxy]methyl}phenyl)ethanamide, (2E)-2-
(methoxyimino)-N-methyl-2-{2-[(E)-({1-[3-
(trifluoromethyl)phenyl]ethoxy}imino)methyl]phenyl}ethanamide, (2E)-2-{2-
[({[(1 E)-1-(3-{[(E)-1-
15 fluoro-2-phenylethenyl]oxy}phenyl)ethylidene]amino}oxy)methyl]phenyl}-2-
(methoxyimino)-N-
methylethanamide, 1-(4-chlorophenyl)-2-(1 H-1,2,4-triazol-l-yl)cycloheptanol,
methyl 1-(2,2-
dimethyl-2,3-dihydro-1 H-inden-l-yl)-1 H-imidazole-5-carboxylate, N-ethyl-N-
methyl-N'-{2-methyl-
5-(trifluoromethyl)-4-[3-(trimethylsilyl)propoxy]phenyl}imidoformamide, N'-{5-
(difluoromethyl)-2-
methyl-4-[3-(trimethylsilyl)propoxy]phenyl}-N-ethyl-N-methylimidoformamide, O-
{1-[(4-
20 methoxyphenoxy)methyl]-2,2-dimethylpropyl} 1 H-im idazole- 1 -carboth
ioate, N-[2-(4-{[3-(4-
chlorophenyl)prop-2-yn-1 -yl]oxy}-3-methoxyphenyl)ethyl]-N2-
(methylsulfonyl)valinamide, 5-
chloro-7-(4-methylpiperidin-1 -yl)-6-(2,4,6-
trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine, 5-
amino-1,3,4-thiadiazole-2-thiol, propamocarb-fosetyl, 1-[(4-
methoxyphenoxy)methyl]-2,2-
dimethylpropyl 1 H-imidazole-1-carboxylate, 1-methyl-N-[2-(1,1,2,2-
tetrafluoroethoxy)phenyl]-3-
(trifl u orom ethyl)- 1 H-pyrazo le-4-carboxam id e, 2,3,5,6-tetrachloro-4-
(methylsulfonyl)pyridine, 2-
butoxy-6-iodo-3-propyl-4H-chromen-4-one, 2-phenylphenol and salts, 3-
(difluoromethyl)-1-
methyl-N-[2-(1,1,2,2-tetrafluoroethoxy)phenyl]-1 H-pyrazole-4-carboxamide,
3,4,5-
trichloropyridine-2,6-dicarbonitrile, 3-[5-(4-chlorophenyl)-2,3-
dimethylisoxazolidin-3-yl]pyridine,
3-chloro-5-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-methylpyridazine, 4-(4-
chlorophenyl)-5-
(2,6-difluorophenyl)-3,6-dimethylpyridazine, quinolin-8-ol, quinolin-8-ol
sulfate (2:1) (salt),
benthiazole, bethoxazin, capsimycin, carvone, chinomethionat, chloroneb,
cufraneb,
cyflufenamid, cymoxanil, cyprosulfamide, dazomet, debacarb, dichlorophen,
diclomezine,
dicloran, difenzoquat, difenzoquat methylsulphate, diphenylamine, ecomate,
ferimzone,
flumetover, fluopicolide, fluoroimide, flusulfamide, fosetyl-aluminium,
fosetyl-calcium, fosetyl-
sodium, hexachlorobenzene, irumamycin, isotianil, methasulfocarb, methyl (2E)-
2-{2-
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[({cyclopropyl[(4-methoxyphenyl)imino]methyl}thio)methyl]phenyl}-3-
methoxyacrylate, methyl
isothiocyanate, metrafenone, (5-bromo-2-methoxy-4-methylpyridin-3-yl)(2,3,4-
trimethoxy-6-
methylphenyl)methanone, mildiomycin, tolnifanide, N-(4-chlorobenzyl)-3-[3-
methoxy-4-(prop-2-
yn-1-yloxy)phenyl]propanamide, N-[(4-chlorophenyl)(cyano)methyl]-3-[3-methoxy-
4-(prop-2-yn-
1-yloxy)phenyl]propanamide, N-[(5-bromo-3-chloropyridin-2-yl)methyl]-2,4-
dichloropyridine-3-
carboxamide, N-[1-(5-bromo-3-chloropyridin-2-yl)ethyl]-2,4-dichloropyridine-3-
carboxamide, N-
[1-(5-bromo-3-chloropyridin-2-yl)ethyl]-2-fluoro-4-iodopyridine-3-carboxamide,
N-{(Z)-
[(cyclopropylmethoxy)imino][6-(difluoromethoxy)-2,3-difluorophenyl]methyl}-2-
phenylacetamide,
N-{(E)-[(cyclopropylmethoxy)imino][6-(difluoromethoxy)-2,3-
difluorophenyl]methyl}-2-
phenylacetamide, natamycin, nickel dimethyldithiocarbamate, nitrothal-
isopropyl, octhilinone,
oxamocarb, oxyfenthiin, pentachlorophenol and salts, phenazine-l-carboxylic
acid, phenothrin,
phosphorous acid and its salts, propamocarb fosetylate, propanosine-sodium,
proquinazid,
pyrrolnitrine, quintozene, S-prop-2-en-1-yl 5-amino-2-(1-methylethyl)-4-(2-
methylphenyl)-3-oxo-
2,3-dihydro-1H-pyrazole-1-carbothioate, tecloftalam, tecnazene, triazoxide,
trichlamide, 5-
chloro-N'-phenyl-N'-prop-2-yn-l-ylthiophene-2-sulfonohydrazide and zarilamid.
The composition according to the invention comprising a mixture of a compound
of formula (I)
with a bactericide compound can also be particularly advantageous. Examples of
suitable
bactericide mixing partners can be selected in the following list: bronopol,
dichlorophen,
nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone,
furancarboxylic acid,
oxytetracycline, probenazole, streptomycin, tecloftalam, copper sulphate and
other copper
preparations.
The compounds of formula (I) and the fungicide composition according to the
invention can be
used to curatively or preventively control the phytopathogenic fungi of plants
or crops.
Thus, according to a further aspect of the invention, there is provided a
method for curatively or
preventively controlling the phytopathogenic fungi of plants or crops
characterised in that a
compound of formula (I) or a fungicide composition according to the invention
is applied to the
seed, the plant or to the fruit of the plant or to the soil wherein the plant
is growing or wherein it
is desired to grow.
The method of treatment according to the invention can also be useful to treat
propagation
material such as tubers or rhizomes, but also seeds, seedlings or seedlings
pricking out and
plants or plants pricking out. This method of treatment can also be useful to
treat roots. The
method of treatment according to the invention can also be useful to treat the
overground parts
of the plant such as trunks, stems or stalks, leaves, flowers and fruit of the
concerned plant.
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Among the plants that may becan be protected by the method according to the
invention,
mention may becan be made of cotton; flax; vine; fruit or vegetable crops such
as Rosaceae sp.
(for instance pip fruit such as apples and pears, but also stone fruit such as
apricots, almonds
and peaches), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae
sp.,
Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp.,
Musaceae sp.
(for instance banana trees and plantins), Rubiaceae sp., Theaceae sp.,
Sterculiceae sp.,
Rutaceae sp. (for instance lemons oranges and grapefruit); Solanaceae sp. (for
instance
tomatoes), Liliaceae sp., Asteraceae sp. (for instance lettuces), Umbelliferae
sp., Cruciferae sp.,
Chenopodiaceae sp., Cucurbitaceae sp., Papilionaceae sp. (for instance peas),
Rosaceae sp.
(for instance strawberries); major crops such as Graminae sp. (for instance
maize, lawn or
cereals such as wheat, rye, rice, barley and triticale), Asteraceae sp. (for
instance sunflower),
Cruciferae sp. (for instance colza), Fabacae sp. (for instance peanuts),
Papilionaceae sp. (for
instance soybean), Solanaceae sp. (for instance potatoes), Chenopodiaceae sp.
(for instance
beetroots), Elaeis sp. (for instance oil palm); horticultural and forest
crops; as well as genetically
modified homologues of these crops.
Among the diseases of plants or crops that can be controlled by the method
according to the
invention, mention can be made of :
Powdery Mildew Diseases such as
Blumeria diseases caused for example by Blumeria graminis;
Podosphaera diseases caused for example by Podosphaera leucotricha;
Sphaerotheca diseases caused for example by Sphaerotheca fuliginea;
Uncinula diseases caused for example by Uncinula necator;
Rust Diseases such as
Gymnosporangium diseases caused for example by Gymnosporangium sabinae;
Hemileia diseases caused for example by Hemileia vastatrix;
Phakopsora diseases caused for example by Phakopsora pachyrhizi and Phakopsora
meibomiae;
Puccinia diseases caused for example by Puccinia recondita, Puccinia graminis
or Puccinia
striiformis;
Uromyces diseases caused for example by Uromyces appendiculatus;
Oomycete Diseases such as
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Albugo diseases caused for example by Albugo candida;
Bremia diseases caused for example by Bremia lactucae;
Peronospora diseases caused for example by Peronospora pisi and Peronospora
brassicae;
Phytophthora diseases caused for example by Phytophthora infestans;
Plasmopara diseases caused for example by Plasmopara viticola;
Pseudoperonospora diseases caused for example by Pseudoperonospora humuli and
Pseudo-
peronospora cubensis;
Pythium diseases caused for example by Pythium ultimum;
Leaf spot, Leaf blotch and Leaf Blight Diseases such as
Alternaria diseases caused for example by Alternaria solani;
Cercospora diseases caused for example by Cercospora beticola;
Cladiosporium diseases caused for example by Cladiosporium cucumerinum;
Cochliobolus diseases caused for example by Cochliobolus sativus (Conidiaform:
Drechslera,
Syn: Helminthosporium) or Cochliobolus miyabeanus;
Colletotrichum diseases caused for example by Colletotrichum lindemuthianum;
Cycloconium diseases caused for example by Cycloconium oleaginum;
Diaporthe diseases caused for example by Diaporthe citri;
Elsinoe diseases caused for example by Elsinoe fawcettii;
Gloeosporium diseases caused for example by Gloeosporium laeticolor;
Glomerella diseases caused for example by Glomerella cingulata;
Guignardia diseases caused for example by Guignardia bidwellii;
Leptosphaeria diseases caused for example by Leptosphaeria maculans and
Leptosphaeria
nodorum;
Magnaporthe diseases caused for example by Magnaporthe grisea;
Mycosphaerella diseases caused for example by Mycosphaerella graminicola,
Mycosphaerella
arachidicola and Mycosphaerella fijiensis;
Phaeosphaeria diseases caused for example by Phaeosphaeria nodorum;
Pyrenophora diseases caused for example by Pyrenophora teres or Pyrenophora
tritici repentis;
Ramularia- diseases caused for example by Ramularia collo-cygni or Ramularia
areola;
Rhynchosporium diseases caused for example by Rhynchosporium secalis;
Septoria diseases caused for example by Septoria apii and Septoria
lycopersici;
Typhula diseases caused for example by Thyphula incarnata;
Venturia diseases caused for example by Venturia inaequalis;
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Root-, Sheath and Stem Diseases such as
Corticium diseases caused for example by Corticium graminearum;
Fusarium diseases caused for example by Fusarium oxysporum;
Gaeumannomyces diseases caused for example by Gaeumannomyces graminis;
Rhizoctonia diseases caused for example by Rhizoctonia solani;
Sarocladium diseases caused for example by Sarocladium oryzae;
Sclerotium diseases caused for example by Sclerotium oryzae;
Tapesia diseases caused for example by Tapesia acuformis;
Thielaviopsis diseases caused for example by Thielaviopsis basicola;
Ear and Panicle Diseases including Maize cob such as
Alternaria diseases caused for example by Alternaria spp.;
Aspergillus diseases caused for example by Aspergillus flavus;
Cladosporium diseases caused for example by Cladiosporium cladosporioides;
Claviceps diseases caused for example by Claviceps purpurea;
Fusarium diseases caused for example by Fusarium culmorum;
Gibberella diseases caused for example by Gibberella zeae;
Monographella diseases caused for example by Monographella nivalis;
Smut- and Bunt Diseases such as
Sphacelotheca diseases caused for example by Sphacelotheca reiliana;
Tilletia diseases caused for example by Tilletia caries;
Urocystis diseases caused for example by Urocystis occulta;
Ustilago diseases caused for example by Ustilago nuda;
Fruit Rot and Mould Diseases such as
Aspergillus diseases caused for example by Aspergillus flavus;
Botrytis diseases caused for example by Botrytis cinerea;
Penicillium diseases caused for example by Penicillium expansum and
Penicillium
purpurogenum;
Rhizopus diseases caused by example by Rhizopus stolonifer
Sclerotinia diseases caused for example by Sclerotinia sclerotiorum;
Verticillium diseases caused for example by Verticillium alboatrum;
Seed- and Soilborne Decay, Mould, Wilt, Rot and Damping-off diseases
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Alternaria diseases caused for example by Alternaria brassicicola;
Aphanomyces diseases caused for example by Aphanomyces euteiches;
Ascochyta diseases caused for example by Ascochyta lentis;
Aspergillus diseases caused for example by Aspergillus flavus;
5 Cladosporium diseases caused for example by Cladosporium herbarum;
Cochliobolus diseases caused for example by Cochliobolus sativus;
(Conidiaform: Drechslera, Bipolaris Syn: Helminthosporium);
Colletotrichum diseases caused for example by Colletotrichum coccodes;
Fusarium diseases caused for example by Fusarium culmorum;
10 Gibberella diseases caused for example by Gibberella zeae;
Macrophomina diseases caused for example by Macrophomina phaseolina;
Microdochium diseases caused for example by Microdochium nivale;
Monographella diseases caused for example by Monographella nivalis;
Penicillium diseases caused for example by Penicillium expansum;
15 Phoma diseases caused for example by Phoma lingam;
Phomopsis diseases caused for example by Phomopsis sojae;
Phytophthora diseases caused for example by Phytophthora cactorum;
Pyrenophora diseases caused for example by Pyrenophora graminea;
Pyricularia diseases caused for example by Pyricularia oryzae;
20 Pythium diseases caused for example by Pythium ultimum;
Rhizoctonia diseases caused for example by Rhizoctonia solani;
Rhizopus diseases caused for example by Rhizopus oryzae;
Sclerotium diseases caused for example by Sclerotium rolfsii;
Septoria diseases caused for example by Septoria nodorum;
25 Typhula diseases caused for example by Typhula incarnata;
Verticillium diseases caused for example by Verticillium dahliae;
Canker, Broom and Dieback Diseases such as
Nectria diseases caused for example by Nectria galligena;
Blight Diseases such as
Monilinia diseases caused for example by Monilinia laxa;
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Leaf Blister or Leaf Curl Diseases including deformation of blooms and fruits
such as
Exobasidium diseases caused for nexample by Exobasidium vexans.
Taphrina diseases caused for example by Taphrina deformans;
Decline Diseases of Wooden Plants such as
Esca disease caused for example by Phaeomoniella clamydospora, Phaeoacremonium
aleophilum and Fomitiporia mediterranea;
Ganoderma diseases caused by example by Ganoderma boninense;
Diseases of Flowers and Seeds such as
Botrytis diseases caused for example by Botrytis cinerea;
Diseases of Tubers such as
Rhizoctonia diseases caused for example by Rhizoctonia solani;
Helminthosporium diseases caused for example by Helminthosporium solani;
Club root diseases such as
Plasmodiophora diseases, cause for example by Plamodiophora brassicae.
Diseases caused by Bacterial Organisms such as
Xanthomanas species for example Xanthomonas campestris pv. oryzae;
Pseudomonas species for example Pseudomonas syringae pv. lachrymans;
Erwinia species for example Erwinia amylovora.
The fungicide composition according to the invention can also be used against
fungal diseases
liable to grow on or inside timber. The term "timber" means all types of
species of wood, and all
types of working of this wood intended for construction, for example solid
wood, high-density
wood, laminated wood, and plywood. The method for treating timber according to
the invention
mainly consists in contacting one or more compounds according to the
invention, or a
composition according to the invention ; this includes for example direct
application, spraying,
dipping, injection or any other suitable means.
The dose of active compound usually applied in the method of treatment
according to the
invention is generally and advantageously from 10 to 800 g/ha, preferably from
50 to 300 g/ha
for applications in foliar treatment. The dose of active substance applied is
generally and
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27
advantageously from 2 to 200 g per 100 kg of seed, preferably from 3 to 150 g
per 100 kg of
seed in the case of seed treatment.
It is clearly understood that the doses indicated herein are given as
illustrative examples of the
method according to the invention. A person skilled in the art will know how
to adapt the
application doses, notably according to the nature of the plant or crop to be
treated.
The fungicide composition according to the invention can also be used in the
treatment of
genetically modified organisms with the compounds according to the invention
or the
agrochemical compositions according to the invention. Genetically modified
plants are plants
into genome of that a heterologous gene encoding a protein of interest has
been stably
integrated. The expression "heterologous gene encoding a protein of interest"
essentially means
genes that give the transformed plant new agronomic properties, or genes for
improving the
agronomic quality of the modified plant.
The compounds or mixtures according to the invention can also be used for the
preparation of
composition useful to curatively or preventively treat human or animal fungal
diseases such as,
for example, mycoses, dermatoses, trichophyton diseases and candidiases or
diseases caused
by Aspergillus spp., for example Aspergillus fumigatus.
The various aspects of the invention will now be illustrated with reference to
the following table of
compound examples and the following preparation examples.
The following table illustrates in a non-limiting manner examples of compounds
according to the
invention.
In the following table, M+H (or M-H) means the molecular ion peak, plus or
minus 1 a.m.u. (atomic
mass unit) respectively, as observed in mass spectroscopy and M (Apcl+) means
the molecular ion
peak as it was found via positive atmospheric pressure chemical ionisation in
mass spectroscopy.
In the following table, the logP values were determined in accordance with EEC
Directive
79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on a
reversed-phase
column (C 18), using the method described below :
Temperature: 40 C - Mobile phases : 0.1 % aqueous formic acid and acetonitrile
- linear gradient
from 10% acetonitrile to 90% acetonitrile.
Calibration was carried out using unbranched alkan-2-ones (comprising 3 to 16
carbon atoms)
with known logP values (determination of the logP values by the retention
times using linear
interpolation between two successive alkanones).
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The lambda max values were determined in the maxima of the chromatographic
signals using
the UV spectra from 190nm to 400nm.
The following examples illustrate in a non-limiting manner the preparation of
the compounds of
formula (I) according to the invention.
y
A N B
T ~Z2/ \Z3
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
1 A5 N-Me Me - F 0 H H 338
2 A5 N-Me Me - F 0 Me H 352
3 A5 N-Me Me - F S H H 354
4 A5 N-Me Me - F S Me H 368
A5 N-Me CHF2 - H 0 H H 356
6 A5 N-Me CHF2 - H 0 Me H 370
7 A5 N-Me OMe - H 0 H H 336
8 A5 N-Me OMe - H 0 Me H 350
9 A5 N-Me Me - F 0 H H 352
A5 N-Me Me - F S H H 368
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
11 A5 N-Me CHF2 - H 0 H H 370
12 A5 N-Me CHF2 - H 0 Me H 384
13 A2 N-Me H H H 0 Me H 333
14 Al 0 Me H Me 0 Me H 348
15 A2 S Me H H 0 Me H 350
16 A5 N-Me Me - F 0 Me H 366
17 A5 N-Me OMe - H 0 H H 350
18 A5 N-Me CF3 - F 0 Me H 420
19 Al 0 Me H H 0 Me H 334
20 A5 N-Me OMe - H 0 Me H 364
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
21 Al N-Me H CF3 H 0 Me H 401
22 A5 N-Me Me F 0 H H N 339
23 A5 N-Me CHF2 - H 0 H H ,IN 357
24 A5 N-Me Me - F 0 H H 416
Br
25 A5 N-Me Me - F S H H 4,39
Br
26 A5 N-Me CHF2 - H 0 H H 3,68
Br
27 A5 N-Me OMe - H 0 H H 3,24
B~~r
28 A5 N-Me OMe - H S H H 4,25
Br
F F
29 A5 N-Me Me F 0 H H F 407
F
N
30 A5 N-Me Et - F 0 H H F 421
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Ex. N A Vi RaZ Ra3 Ra4 T Z2 Z3 B LogP M+H
F F
31 A5 N-Me CHF2 - H 0 H H F 425
32 A5 N-Me CHF2 - H 0 H H 406
33 A5 N-Me Me - F 0 H H O~N 383
0
34 A5 N-Me CHF2 - H 0 H H O~N 401
11
O
35 A5 N-Me OMe - H 0 H H O~NJ 381
p
36 A5 N-Me Me - F 0 H H 352
37 A5 N-Me Me - F 0 Me H
38 A5 N-Me Me - F S Me H
39 A5 N-Me Me - F S Me H I
40 A5 N-Me CHF2 - H 0 H H 3,25
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
41 A5 N-Me OMe - H 0 H H 350
42 A5 N-Me OMe - H S H H 366
43 A5 N-Me OMe - H 0 Me H
44 A2 N-Me H H H 0 H H 319
45 Al 0 Me H Me 0 H H 334
46 A2 S Me H H 0 H H 336
47 A5 N-Me CF3 - F 0 H H 406
48 Al 0 Me H H 0 H H 320
49 Al N-Me H CF3 H 0 H H 387
50 A5 N-Me Me - F 0 H H I 339
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
51 A5 N-Me CHF2 - H 0 H H 357
N
52 A5 N-Me CHF2 - H S H H I 373
53 A5 N-Me OMe - H 0 H H 337
54 A5 N-Me Me - F 0 H H 3,62
55 A5 N-Me CHF2 - H 0 H H 3,69
56 A5 N-Me OMe - H 0 H H 414
57 A5 N-Me Me - F 0 Me H 430
58 A5 N-Me Et - F 0 Me H 444
59 A5 N-Me CHF2 - H 0 Me H 448
60 Al 0 Me H Me 0 Me H 5,2
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
61 A5 N-Me CF3 - H 0 COOMe H 432
62 Al N-Me H CF3 H 0 COOMe H 431
63 A5 N-Me Me - F 0 COOMe H 2,92
64 A5 N-Me Me - F 0 H H 338
65 A5 N-Me Me - F 0 Me H 352
66 A5 N-Me Me - F S Me H 368
67 A5 N-Me Et - F 0 Me H 366
68 A5 N-Me Et - F S Me H 382
69 A5 N-Me CHF2 - H 0 COOMe H 3,02
70 A5 N-Me CHF2 - H 0 H H 356
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
71 A5 N-Me CHF2 - H 0 Me H 370
72 A5 N-Me CHF2 - H S H H 372
73 A5 N-Me OMe - H 0 COOMe H 394
74 A5 N-Me OMe - H 0 H H 336
75 A5 N-Me OMe - H 0 Me H 2,86
76 A2 N-Me H H H 0 Me H 319
77 Al 0 Me H Me 0 Me H 334
78 A2 S Me H H 0 Me H 336
/
79 A5 N-Me CF3 - F 0 Me H 406
80 A5 N-Me Me - F 0 Me H
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
81 A5 N-Me Me - F 0 Me H C,~~ ~
82 Al N-Me H CHF2 H 0 Me H 369
83 A5 N-Me Me - F 0 Et H I 366
84 Al 0 Me H H 0 Me H 320
85 A5 N-Me Et - F 0 Et H I 380
86 A5 N-Me CHF2 - H 0 Et H I 384
87 A5 N-Me Et - F 0 Me H
88 A5 N-Me Et - F 0 Me H
/
89 A5 N-Me CHF2 - F 0 Me H 388
90 Al N-Me H CF3 H 0 Me H 387
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
91 A5 N-Me CF2Me - H 0 Me H 384
N, / CI
92 A5 N-Me OMe - H 0 H H 405
CI
N CI
93 A2 N-Me H H H 0 H H 374
CI
N, ~CI
94 Al 0 Me H Me 0 H H 389
1 CI
N / CI
95 A2 S Me H H 0 H H 391
CI
N CI
96 A5 N-Me CF3 - F 0 H H T 461
CI
N, ~CI
97 A5 N-Me Me - F 0 H H r 407
' CI
N CI
98 A5 N-Me CHF2 - H 0 H H YI 425
CI
CI
99 Al 0 Me H H 0 H H 375
CI
WCI
100 Al N-Me H CF3 H 0 H H 442
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
N
101 A5 N-Me OMe - H 0 H H ~ 337
~\ N
102 A2 N-Me H H H 0 H H 306
N
103 Al 0 Me H Me 0 H H I 321
N
104 A2 S Me H H 0 H H 323
105 A5 N-Me CF3 - F 0 H H I 393
N
106 A5 N-Me Me - F 0 H H 339
N
107 A5 N-Me CHF2 - H 0 H H I 357
108 Al 0 Me H H 0 H H I 307
N
109 Al N-Me H CF3 H 0 H H ~ 374
110 A5 N-Me OMe - H 0 H H / 366
~ ~ ~
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
111 A2 N-Me H H H 0 H H / 335
112 Al 0 Me H Me 0 H H / 350
113 A2 S Me H H 0 H H / 352
114 A5 N-Me CF3 - F 0 H H / 422
115 A5 N-Me Me - F 0 H H 368
116 A5 N-Me CHF2 - H 0 H H 386
117 Al 0 Me H H 0 H H / 336
118 Al N-Me H CF3 H 0 H H / 403
119 A5 N-Me Me - F 0 Me H 382
120 A5 N-Me Et - F 0 Me H 396
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
121 A5 N-Me CHF2 - H 0 Me H 400
122 Al 0 Me H Me 0 Me H 364
123 A5 N-Me OMe - H 0 H H 366
124 A2 N-Me H H H 0 H H 335
125 Al 0 Me H Me 0 H H 350
126 A2 S Me H H 0 H H 352
127 A5 N-Me CF3 - F 0 H H 422
128 A5 N-Me Me F 0 H H 368
129 A5 N-Me CHF2 H 0 H H 386
130 Al 0 Me H H 0 H H 336
O
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
131 Al N-Me H CF3 H 0 H H l' 403
O
132 A5 N-Me OMe - H 0 H H (396
O
133 A2 N-Me H H H 0 H H 365
O
134 Al 0 Me H Me 0 H H 380
O
135 A2 S Me H H 0 H H 382
136 A5 N-Me CF3 - F 0 H H ~ i 452
o
O
137 A5 N-Me Me - F 0 H H 398
\ \ 0/
O
138 A5 N-Me CHF2 - H 0 H H 416
\ \ 0/
,O
139 Al 0 Me H H 0 H H 366
O
140 Al N-Me H CF3 H 0 H H c433
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
/
-N
141 A5 N-Me OMe - H 0 H H 379
N
142 A2 N-Me H H H 0 H H - 348
N
143 Al 0 Me H Me 0 H H 363
/
N
144 A2 S Me H H 0 H H - 365
N
145 A5 N-Me CF3 - F 0 H H 435
/
N
146 A5 N-Me Me - F 0 H H 381
N
147 A5 N-Me CHF2 - H 0 H H ~- 399
N
148 A1 O Me H H O H H 349
N
149 Al N-Me H CF3 H 0 H H 416
N /
150 A5 N-Me Me - F 0 Me H 395
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
/
N
151 A5 N-Me Et - F 0 Me H 409
N
152 A5 N-Me CHF2 - H 0 Me H 413
N
153 A5 N-Me OMe - H 0 H H 351
~ \\\\\\~~\
\
154 A2 N-Me H H H 0 H H 320
155 Al 0 Me H Me 0 H H 335
N
156 A2 S Me H H 0 H H 337
N
157 A5 N-Me CF3 - F 0 H H 407
N
158 A5 N-Me Me - F 0 H H 353
N
159 A5 N-Me CHF2 - H 0 H H 371
160 Al 0 Me H H 0 H H 321
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
N
161 Al N-Me H CF3 H 0 H H I 388
a
Br
162 A5 N-Me OMe - H 0 H H 415 &
163 A2 N-Me H H H 0 H H 384 B-
164 Al 0 Me H Me 0 H H 399 B-
165 A2 S Me H H 0 H H 401
B-
166 A5 N-Me CF3 - F 0 H H 471 B-
167 A5 N-Me Me - F 0 H H 2,9 B-
168 A5 N-Me CHF2 - H 0 H H 435 B-
169 Al 0 Me H H 0 H H 385
B-
170 Al N-Me H CF3 H 0 H H 452
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
171 A5 N-Me Me - F 0 H H 405
F
172 A5 N-Me OMe - H 0 H H 404
F F
173 A2 N-Me H H H 0 H H 373
F F
388
174 Al 0 Me H Me 0 H H FF
F
F 1I
175 A2 S Me H H 0 H H 390
F-'~F ~
F ~
176 A5 N-Me CF3 - F 0 H H 460
F F
F
177 A5 N-Me Me - F 0 H H 406
F F
F
178 A5 N-Me CHF2 - H 0 H H 424
F F
F
179 Al 0 Me H H 0 H H 374
F F
F ~
180 Al N-Me H CF3 H 0 H H 441
F F :/
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
N
181 A5 N-Me OMe - H 0 H H 337
N
182 A2 N-Me H H H 0 H H 306
N
183 Al 0 Me H Me 0 H H 321
N
184 A2 S Me H H 0 H H 323
N
185 A5 N-Me CF3 - F 0 H H 393
N
186 A5 N-Me Me - F 0 H H 339
-~N
187 A5 N-Me CHF2 - H 0 H H J 357
N
188 Al 0 Me H H 0 H H 307
N
189 Al N-Me H CF3 H 0 H H 374
190 A5 N-Me OMe - H 0 H H I I 337
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
191 A2 N-Me H H H 0 H H 306
(Nf
192 Al 0 Me H Me 0 H H 321
193 A2 S Me H H 0 H H 323
194 A5 N-Me CF3 - F 0 H H 393
N
195 A5 N-Me Me - F 0 H H 339
196 A5 N-Me CHF2 - H 0 H H 357
N
197 Al 0 Me H H 0 H H 307
198 Al N-Me H CF3 H 0 H H 374
O /
199 A5 N-Me OMe - H 0 H H ~ 366
200 A2 N-Me H H H 0 H H ~ 335
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
O
201 Al 0 Me H Me 0 H H ~ 350
O /
202 A2 S Me H H 0 H H ~ 352
O
203 A5 N-Me CF3 - F 0 H H ~ 422
204 A5 N-Me Me - F 0 H H -c 368
205 A5 N-Me CHF2 - H 0 H H 386
O /
206 Al 0 Me H H 0 H H ~ 336
207 Al N-Me H CF3 H 0 H H ~ 403
208 A5 N-Me OMe - H 0 H H 414
Br
209 A2 N-Me H H H 0 H H 383
Br
210 Al 0 Me H Me 0 H H 398
Br
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
211 A2 S Me H H 0 H H 400
Br
212 A5 N-Me CF3 - F 0 H H 470
Br
Br
213 A5 N-Me Me - F 0 H H 416
Br
214 A5 N-Me CHF2 - H 0 H H 434
Br
215 Al 0 Me H H 0 H H ~ -, 384
216 Al N-Me H CF3 H 0 H H 451
Br
217 A5 N-Me OMe - H 0 H H 396
I O/
O
218 A2 N-Me H H H 0 H H 365
I O
219 Al 0 Me H Me 0 H H 380
220 A2 S Me H H 0 H H O I O/ 382
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
221 A5 N-Me CF3 - F 0 H H 452
I O/
O
222 A5 N-Me Me - F 0 H H 2,96
O O
223 A5 N-Me CHF2 - H 0 H H 416
224 Al 0 Me H H 0 H H 366
O' O
225 Al N-Me H CF3 H 0 H H OJ: j-O/ 433
226 A5 N-Me Me - F 0 H H 341
~
227 A5 N-Me CHF2 - H 0 H H N- 359
228 A5 N-Me Me - F 0 H H I 341
\N
229 A5 N-Me CHF2 - H 0 H H 359
N 230 A5 N-Me Me - F 0 H H 373
CI
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
231 A5 N-Me Et - F 0 H H 387
CI
N
232 Al 0 Me H Me 0 H H C 355
'CI
233 A5 N-Me Me - F 0 H H S 344
234 A5 N-Me Et - F 0 H H CS 358
\
235 A5 N-Me CHF2 - H 0 H H I S 362
236 A5 N-Me Me - F 0 H H 382
237 A5 N-Me Et - F 0 H H 396
238 A5 N-Me CHF2 - H 0 H H O 400
239 Al 0 Me H Me 0 H H \ I O 364
240 A5 N-Me Me - F 0 Me H 370
F
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Ex. N A Vl Raz Ra3 Raa T ZZ Z3 B LogP M+H
i i
241 A5 N-Me CHF2 - H 0 Me H 388
F
242 A5 N-Me Et - F 0 Me H 384
WB, 243 A5 N-Me Me F O H H 416
244 A5 N-Me Et - F 0 H H 430
Br
245 A5 N-Me CHF2 - H 0 H H 434
Br
246 Al 0 Me H Me 0 H H 398
Br
General preparation example 1 preparation of an amide derivative of formula
(I) on
OptimizerTM micro-waves apparatus
In a 8 ml OptimizerTM vial is weighted 1.7 mmole of amine (II). 2 ml of a 1
molar solution of the
acyl chloride (III) (2 mmoles) in acetonitrile are added followed by 1 ml of
triethylamine. The vial
is sealed, pre-stirred 10 s at ambient temperature then heated at 180 C for
60 s under micro-
waves. After cooling, the vial is opened and poured onto 10 ml of a saturated
solution of
potassium carbonate. The watery layer is extracted twice by 5 ml of
dichloromethane. The
organic phases are dried over magnesium sulfate. The solvents are removed and
the crude
amide is analyzed by LCMS and NMR. Insufficiently pure compounds are further
purified by
preparative LCMS.
General preparation example 2 : thionation of an amide derivative of formula
(I) on
ChemspeedTM apparatus
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In a 13 ml ChemspeedT"' vial is weighted 0.27 mmole of phosphorous
pentasulfide (P2S5). 3 ml
of a 0.18 molar solution of the amide (I) (0.54 mmole) in dioxane is added and
the mixture is
heated at reflux for two hours. The temperature is then cooled to 80 C and 2.5
ml of water are
added. The mixture is heated at 80 C for one more hour. 2 ml of water are then
added and the
reaction mixture is extracted twice by 4 ml of dichloromethane. The organic
phase is deposited
on a basic alumina cardridge (2g) and eluted twice by 8 ml of dichloromethane.
The solvents
are removed and the crude thioamide is analyzed by LCMS and NMR.
Insufficiently pure
compounds are further purified by preparative LCMS.
Efficacy example A: in vivo preventive test on Pyrenophora teres (Barley net
blotch)
The active ingredients tested are prepared by homogenisation in a mixture of
acetone/tween/DMSO, then diluted with water to obtain the desired active
material
concentration.
Barley plants (Express variety) in starter cups, sown on a 50/50 peat soil-
pozzolana substrate
and grown at 12 C, are treated at the 1-leaf stage (10 cm tall) by spraying
with the active
ingredient prepared as described above. Plants, used as controls, are treated
with the mixture
of acetone/tween/DMSO/water not containing the active material.
After 24 hours, the plants are contaminated by spraying them with an aqueous
suspension of
Pyrenophora teres spores (12,000 spores per ml). The spores are collected from
a 15-day-old
culture. The contaminated barley plants are incubated for 24 hours at about 20
C and at 100%
relative humidity, and then for 12 days at 80% relative humidity.
Grading is carried out 12 days after the contamination, in comparison with the
control plants.
Under these conditions, good (at least 70%) or total protection is observed at
a dose of 500
ppm with the following compounds:. 1, 2, 3, 6, 8, 9, 11, 12, 16, 18, 24, 25,
26, 27, 33, 36, 40, 42,
47, 50, 54, 55, 57, 58, 59, 64, 65, 66, 67, 69, 71, 72, 75, 79, 80, 81, 82,
83, 85, 86, 87, 88, 89,
100, 109, 116, 119, 120, 145, 149, 166, 167, 168, 176, 177, 178, 204, 213,
214, 222, 226, 227,
228, 240, 241 and 242.
Efficacy example B: in vivo preventive test on Sphaerotheca fulipinea
(cucurbit powdery mildew)
The active ingredients tested are prepared by homogenisation in a mixture of
acetone/tween/DMSO,
then diluted with water to obtain the desired active material concentration.
Gherkin plants (Vert petit de Paris variety) in starter cups, sown on a 50/50
peat soil-pozzolana
substrate and grown at 20 C/23 C, are treated at the 2 first leaves stage by
spraying with the
aqueous suspension described above Plants, used as controls, are treated with
the mixture of
acetone/tween/DMSO/water not containing the active material.
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After 24 hours, the plants are contaminated by spraying them with an aqueous
suspension of
Sphaerotheca fuliginea spores (100,000 spores per ml). The spores are
collected from a
contaminated plants The contaminated gherkin plants are incubated at about 20
C/25 C and at
60/70% relative humidity.
5 Grading (% of efficacy) is carried out 11-12 days after the contamination,
in comparison with the
control plants.
Under these conditions, good (at least 70%) or total protection is observed at
a dose of 500 ppm
with the following compounds:. 2, 6, 8, 11, 12, 17, 18, 22, 23, 25, 26, 36,
40, 41, 42, 47, 49, 50,
51, 53, 55, 56, 57, 58, 59, 63, 64, 65, 66, 67, 69, 70, 71, 72, 74, 75, 79,
80, 81, 82, 83, 85, 86,
10 87, 88, 89, 100, 105, 109, 120, 128, 129, 136, 137, 138, 149, 157, 158,
159, 166, 167, 168, 176,
177, 178, 180, 185, 194, 195, 196, 198, 204, 205, 221, 222, 240, 241 and 242.
Efficacy example C: in vivo preventive test on Mycosphaerella praminicola
(wheat leaf spot)
The active ingredients tested are prepared by homogenisation in a mixture of
acetone/tween/DMSO,
15 and then diluted with water to obtain the desired active material
concentration.
Wheat plants (Scipion variety), sown on a 50/50 peat soil-pozzolana substrate
in starter cups and
grown at 12 C, are treated at the 1-leaf stage (10 cm tall) by spraying with
the active ingredient
prepared as described above.
Plants, used as controls, are treated with the mixture of
acetone/tween/DMSO/water not containing
20 the active material.
After 24 hours, the plants are contaminated by spraying them with an aqueous
suspension of
Mycosphaerella graminicola spores (500,000 spores per ml). The spores are
collected from a
7-day-old culture The contaminated wheat plants are incubated for 72 hours at
18 C and at 100%
relative humidity, and then for 21 to 28 days at 90% relative humidity.
25 Grading (% of efficacy) is carried out 21 to 28 days after the
contamination, in comparison with the
control plants.
Under these conditions, good (at least 70%) or total protection is observed at
a dose of 500 ppm
with the following compounds: 1, 2, 5, 6, 7, 8, 9, 11, 17, 18, 22, 23, 24, 26,
27, 32, 33, 34, 36, 40, 41,
47, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 63, 64, 65, 67, 69, 70, 71,
74, 75, 79, 80, 81, 83, 84, 85,
30 86, 87, 88, 89, 94, 96, 97, 100, 105, 109, 115, 116, 119, 120, 128, 129,
134, 136, 137, 138, 140, 145,
146, 147, 149, 155, 157, 158, 161, 164, 166, 167, 168, 170, 172, 174, 176,
177, 178, 180, 183, 185,
186, 187, 190, 192, 194, 195, 221, 225, 226, 227, 228, 229, 240, 241 and 242.
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Efficacy example D : in vivo test on Puccinia recondita f. Sp. tritici (wheat
brown rust).
The active ingredients tested are prepared by homogenisation in a mixture of
acetone/tween/DMSO,
then diluted with water to obtain the desired active material concentration.
Wheat plants (Scipion variety) in starter cups, sown on 50/50 peat soil-
pozzolana substrate and
grown at 12 C, are treated at the 1-leaf stage (10 cm tall) by spraying with
the active ingredient
prepared as described above. Plants, used as controls, are treated with the
mixture of
acetone/tween/DMSO/water not containing the active material.
After 24 hours, the plants are contaminated by spraying the leaves with an
aqueous suspension of
Puccinia recondita spores (100,000 spores per ml). The spores are collected
from a 10-day-old
contaminated wheat and are suspended in water containing 2.5 ml/I of tween 80
10%. The
contaminated wheat plants are incubated for 24 hours at 20 C and at 100%
relative humidity, and
then for 10 days at 20 C and at 70% relative humidity. Grading is carried out
10 days after the
contamination, in comparison with the control plants.
Under these conditions, good (at least 70%) or total protection is observed at
a dose of 500
ppm with the following compounds: 1, 2, 9, 16, 24, 25, 26, 36, 47, 49, 54, 57,
58, 63, 64, 65,
66, 67, 80, 83, 85, 87, 88, 89, 94, 100, 109, 119, 120, 134, 136, 137, 138,
140, 149, 158,
167, 176, 177, 178, 240 and 242.
Example E: in vivo test on Alternaria brassicae (Leaf spot of crucifers)
The active ingredients tested are prepared by homogenization in a mixture of
acetone/tween/DMSO,
and then diluted with water to obtain the desired active material.
Radish plants (Pernot variety), sown on a 50/50 peat soil-pozzolana substrate
in starter cups and
grown at 18-20 C, are treated at the cotyledon stage by spraying with the
active ingredient prepared
as described above.
Plants, used as controls, are treated with the mixture of acetone/tween/water
not containing the
active material.
After 24 hours, the plants are contaminated by spraying them with an aqueous
suspension of
Alternaria brassicae spores (40,000 spores per cm3). The spores are collected
from a 12 to 13
days-old culture.
The contaminated radish plants are incubated for 6-7 days at about 18 C, under
a humid
atmosphere.
Grading is carried out 6 to 7 days after the contamination, in comparison with
the control plants.
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Under these conditions, good protection (at least 70%) is observed at a dose
of 500ppm with
the following compounds: 2, 6, 12, 16, 18, 26, 47, 49, 57, 65, 66, 67, 69, 79,
80, 83, 166, 167,
176, 204, 213, 214 and 240.
Example F: in vivo test on Botrytis cinerea (Grey mould)
The active ingredients tested are prepared by homogenization in a mixture of
acetone/tween/DMSO,
then diluted with water to obtain the desired active material.
Gherkin plants (Vert petit de Paris variety), sown on a 50/50 peat soil-
pozzolana substrate in starter
cups and grown at 18- 20 C, are treated at the cotyledon Z11 stage by spraying
with the active
ingredient prepared as described above.
Plants, used as controls, are treated with an aqueous solution not containing
the active material.
After 24 hours, the plants are contaminated by depositing drops of an aqueous
suspension of
Botrytis cinerea spores (150,000 spores per ml) on upper surface of the
leaves. The spores are
collected from a 15-day-old culture and are suspended in a nutrient solution
composed of :
- 20 g/L of gelatin;
- 50 g/L of D-fructose;
- 2 g/L of NH4NO3;
- 1 g/L of KH2PO4.
The contaminated cucumber plants are settled for 5-7 days in a climatic room
at 15-11 C (day/night)
and at 80% relative humidity.
Grading is carried out 5/7 days after the contamination, in comparison with
the control plants.
Under these conditions, good (at least 70%) protection is observed at a dose
of 500ppm with the
following compounds: 36, 64, 65, 67,80 and 89.
Example G: In vivo test on Peronospora parasitica (Crucifer downy mildew)
The active ingredients tested are prepared by homogenization in a mixture of
acetone/tween/DMSO,
and then diluted with water to obtain the desired active material.
Cabbage plants (Eminence variety) in starter cups, sown on a 50/50 peat soil-
pozzolana substrate
and grown at 18-20 C, are treated at the cotyledon stage by spraying with the
aqueous suspension
described above. Plants, used as controls, are treated with an aqueous
solution not containing the
active material. After 24 hours, the plants are contaminated by spraying them
with an aqueous
suspension of Peronospora parasitica spores (50 000 spores per ml). The spores
are collected from
infected plant. The contaminated cabbage plants are incubated for 5 days at 20
C, under a humid
atmosphere. Grading is carried out 5 days after the contamination, in
comparison with the control
plants.
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Under these conditions, good (at least 70% of disease control) to total
protection (100% of disease
control) is observed at a dose of 500 ppm with the following compounds : 2, 6,
8, 19, 27, 48, 49, 57,
73, 75, 83, 84, 87, 88, 94, 99, 108, 109, 129, 134, 135, 136, 149, 155, 164,
169, 174, 176, 179, 183,
198, 219 and 240 according to the invention whereas weak protection (less than
30% of disease
control) to no protection at all is observed at a dose of 500 ppm with the
compounds of examples 5,
45 and 50 disclosed in patent application WO-2006/120224
Examples 5, 45 and 50 disclosed in patent application WO-2006/120224
correspond, respectively,
to following compounds :
N-cyclopropyl-N-[(3-Chloro-5-trifluoromethyl-pyrid in-2-yl)-methylene]-2,5-
dimethyl-furane-3-
carboxamide;
N-cyclopropyl-N-[(3-Chloro-5-trifluoromethyl-pyrid in-2-yl)-methylene]-5-
fluoro-1,3-dimethyl-1 H-
pyrazole-4-carboxam ide;
N-cyclopropyl-N-[(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-methylene]-5-fluoro-
3-(trifluoromethyl)-1-
methyl -1 H-pyrazole-4-carboxamide;
These results show that the compounds according to the invention have a much
better biological
activity than the structurally closest compounds disclosed in WO-2006/120224
