Patent Grant
8367844
The present invention relates to heterocycles, e.g. as active ingredients, which have microbiocidal activity, in particular fungicidal activity. The invention also relates to preparation of these heterocycles, to heterocyclic derivatives used as intermediates in the preparation of these heterocycles, to preparation of these intermediates, to agrochemical compositions which comprise at least one of the heterocycles, to preparation of these compositions and to use of the heterocycles or compositions in agriculture or horticulture for controlling or preventing infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, preferably fungi.
Certain heterocycles for use as fungicides are described in WO 2007/014290, WO 2008/013622, WO 2008/013925, WO 2008/091580, WO 2008/091594 and WO 2009/055514.
The present invention provides compounds of formula I:
wherein
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen, cyano, hydroxy and amino;
Where substituents are indicated as being optionally substituted, this means that they may or may not carry one or more identical or different substituents. Normally not more than three such optional substituents are present at the same time.
The term “halogen” stands for fluorine, chlorine, bromine or iodine.
The term “amino” stands for —NH2.
Alkyl, alkenyl or alkynyl substituents may be straight-chained or branched. Alkyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the isomers thereof, for example, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-amyl or pivaloyl.
A haloalkyl group may contain one or more identical or different halogen atoms and, for example, may stand for CH2Cl, CHCl2, CCl3, CH2F, CHF2, CF3, CF3CH2, CH3CF2, CF3CF2 or CCl3CCl2.
The presence of one or more possible asymmetric carbon atoms in a compound of formula I means that the compounds may occur in optically isomeric froms, i.e. enantiomeric or diastereomeric forms. As a result of the presence of a possible aliphatic C═C double bond, geometric isomerism may occur, i.e. cis-trans or (E)-(Z) isomerism. Also atropisomers may occur as a result of restricted rotation about a single bond. Formula I is intended to include all those possible isomeric forms and mixtures thereof. The present invention includes all those possible isomeric forms and mixtures thereof for a compound of formula I. Likewise, formula I is intended to include all possible tautomers. The present invention includes all possible tautomeric forms for a compound of formula I.
In each case, the compounds of formula I according to the invention are in free form, in oxidized form as a N-oxide or in salt form, e.g. an agronomically usable salt form.
N-oxides are oxidized forms of teriary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book “Heterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.
Suitable salts of the compounds of formula I include those resulting after addition of acid such as those with an inorganic mineral acid e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid, or an organic carboxylic acid e.g. oxalic, tartaric, lactic, butyric, toluic, hexanoic or phthalic acid, or a sulfonic acid e.g. methane, benzene or toluene sulfonic acid.
Preferably the compound of formula I is a compound wherein:
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen, cyano, hydroxy and amino;
Preferably the compound of formula I is a compound wherein:
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen, cyano, hydroxy and amino.
Preferably the compound of formula I is a compound wherein:
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, hydroxy and halogen.
Preferably the compound of formula I is a compound wherein:
wherein the phenyl and group (b) are each optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl;
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, hydroxy and halogen.
Preferably the compound of formula I is a compound wherein:
wherein R22, R23, R24 and R25 are independently selected from hydrogen, halogen, methyl and halomethyl;
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from methyl, halomethyl, and halogen.
The invention also relates to compounds of formula I wherein
The following list provides definitions, including preferred definitions, for substituents A, T, Y1, Y2, Y3, Y4, Q, n, p, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R22, R23, R24, R25 and R30 with reference to compounds of formula I. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below. The invention includes compounds of formula having all possible combinations of substituent definitions given below or elsewhere in this document. Generally, in this document any substituent definition may be combined with any other substituent definition.
A is x-C(R10R11)—C(═O)—, x-C(R12R13)—C(═S)—, x-O—C(═O)—, x-O—C(═S)—, x-N(R14)—C(═O)—, x-N(R15)—C(═S)— or x-C(R16R17)—SO2—, in each case x indicates the bond that is connected to R1. Preferably, A is x-C(R10R11)—C(═O)—, x-C(R12R13)—C(═S)—, x-O—C(═O)—, x-O—C(═S)—, or x-C(R16R17)—SO2—, in each case x indicates the bond that is connected to R1. More preferably, A is x-CR10R11—C(═O)—, x-O—C(═O)—, or x-CR16R17—SO2—, in each case x indicates the bond that is connected to R1. Even more preferably, A is x-CH2—C(═O)—, x-CH2C(═S)—, x-OC(═O)—, x-CH2SO2—, in each case x indicates the bond that is connected to R1. Yet more preferably, A is x-CH2—C(═O)—, x-O—C(═O)— or x-CH2—SO2—, in each case x indicates the bond that is connected to R1. Most preferably, A is x-CH2—C(═O)—, wherein x indicates the bond that is connected to R1.
T is CR18 or N. Preferably, T is CH or N. Most preferably, T is CH.
n is 1 or 2. Preferably, n is 2.
p is 1 or 2, providing that when n is 2, p is 1. Preferably, p is 1.
Y1, Y2, Y3, and Y4 are independently CR19 or N, e.g. Y1, Y2, Y3, and Y4 may be independently CH or N. More preferably, Y1, Y2, Y3, and Y4 are independently CR19 or N providing that at least 2 of Y1, Y2, Y3, and Y4 are CR19. Even more preferably, Y1, Y2, Y3, and Y4 are independently CR19 or N providing that at least 2 of Y1, Y2, Y3, and Y4 are CR19 and providing that there are no N—N bonds in the ring containing Y1, Y2, Y3, and Y4. Yet more preferably, Y1, Y2, Y3, and Y4 are independently CH or N providing that at least 2 of Y1, Y2, Y3, and Y4 are CH and providing that there are no N—N bonds in the ring containing Y1, Y2, Y3, and Y4.
Q is O or S. Preferably, Q is O.
R1 is phenyl, pyridyl, imidazolyl, or pyrazolyl; wherein the phenyl, pyridyl, imidazolyl and pyrazolyl are each optionally substituted by 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen, cyano, hydroxy and amino. Preferably, R1 is phenyl or pyrazolyl; wherein the phenyl and pyrazolyl are each optionally substituted by 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen, cyano, hydroxy, and amino. More preferably, R1 is phenyl or pyrazolyl, wherein the phenyl and pyrazolyl are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen. Yet more preferably, R1 is phenyl or group (b):
wherein the phenyl and group (b) are each optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl. Even more preferably, R1 is phenyl or group (b):
wherein the phenyl and group (b) are each optionally substituted with 1 to 3 substituents independently selected from halogen, methyl and halomethyl.
In one group of compounds R1 is selected from group (c) or (d):
wherein R22, R23, R24 and R25 are independently selected from hydrogen, halogen, methyl and halomethyl.
In one group of compounds R1 is group (e), (f), (g), or (h):
R2, R3, R4, R5, R6, R7, R10, R11, R12, R13, R16, R17, R18 and R19 each independently are hydrogen, halogen, cyano, C1-C4alkyl, or C1-C4haloalkyl. More preferably, R2, R3, R4, R5, R6, R7, R10, R11, R12, R13, R16, R17, R18, and R19 each independently are hydrogen, halogen, C1-C4alkyl, C1-C4haloalkyl. Even more preferably, R2, R3, R4, R5, R6, R7, R10, R11, R16, R17, R18, and R19 each independently are hydrogen, fluoro, or methyl. Yet more preferably, R2, R3, R4, R5, R6, R7, R10, R11, R16, R17, R18, and R19 each are hydrogen.
R8, R14 and R15 each independently are hydrogen or C1-C4alkyl. Preferably, R8, R14 and R15 each independently are hydrogen or methyl. Preferably, R8, R14 and R15 each are hydrogen.
R9 is phenyl, benzyl or group (a):
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen, cyano, hydroxy and amino. Preferably, R9 is phenyl, benzyl or group (a):
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, hydroxy and halogen. More preferably, R9 is phenyl, benzyl or group (a):
wherein the phenyl, benzyl and group (a) are each optionally substituted with 1 to 3 substituents independently selected from methyl, halomethyl, and halogen.
In one group of compounds R9 is (i), (j), or (k):
Preferably, R22 is hydrogen or CF3. Preferably, R23, R24, and R25 are independently hydrogen or methyl.
R30 is hydrogen, halogen, cyano, C1-C4alkyl, or C1-C4haloalkyl. Preferably, R30 is hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl. Preferably, R30 is hydrogen, fluoro, or methyl. More preferably, R30 is hydrogen.
In one group of compounds at least two of Y1, Y2, Y3 and Y4 are CH and the others of Y1, Y2, Y3 and Y4 are CH or N.
In one group of compounds at least three of Y1, Y2, Y3 and Y4 are CH and the other of Y1, Y2, Y3 and Y4 is CH or N.
In one group of compounds Y1 and Y4 are CH, one of Y2 and Y3 is CH and the other of Y2 and Y3 is CH or N.
In one group of compounds Y1, Y2 and Y4 are CH, and Y3 is N.
In one group of compounds Y1, Y3 and Y4 are CH, and Y2 is N.
In one group of compounds Y1, Y2, Y3 and Y4 are CH.
In one group of compounds Y2 is N.
In one group of compounds Y3 is N.
In one group of compounds p is 1 and n is 2.
In one group of compounds R2, R3, R4, R5, R6 and R7 are H.
In one group of compounds Q is O.
In one group of compounds A is x-CH2—C(═O)—, in which x represents the bond that is connected to R1.
In one group of compounds R1 is group (f)
In one group of compounds R8 is hydrogen.
For the avoidance of doubt, when n is 1 and p is 1 compounds of formula I have the formula according to formula IA:
in which A, T, Y1, Y2, Y3, Y4, Q, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the definitions as described for formula I.
When n is 2 and p is 1, compounds of formula I have the formula according to formula IB:
in which A, T, G, Y1, Y2, Y3, Y4, Q, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the definitions as described for formula I.
When n is 1 and p is 2, compounds of formula I have the formula according to formula IC:
in which A, T, G, Y1, Y2, Y3, Y4, Q, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the definitions as described for formula I.
The invention also relates to compounds of formula IA, formula IB, and formula IC as shown above.
The invention also relates to compounds of formula ID:
wherein Y1, Y2, Y3, Y4, A, Q, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the definitions as described for formula I as defined above. Preferred definitions of Y1, Y2, Y3, Y4, A, Q, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as defined above.
The invention also relates to compounds of formula IE:
wherein Y1, Y2, Y3, Y4, A, Q, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the definitions as described for formula I as defined above. Preferred definitions of Y1, Y2, Y3, Y4, A, Q, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as defined above.
The invention also relates to a compound of formula IF:
wherein T is N or CH;
The invention also relates to a compound of formula IG:
wherein T is N or CH;
The invention also includes compounds of formula I in which R1 is a protecting group, such as an alkyl group. Accordingly the invention includes compounds of formula I.a:
wherein R1′ is C1-C8 alkyl, e.g. C1-C4 alkyl, preferably tert-butyl, and Y1, Y2, Y3, Y4, A, Q, T, n, p, R2, R3, R4, R5, R6, R7, R8, and R9 have the definitions as described for formula I as defined above. Preferred definitions of Y1, Y2, Y3, Y4, A, Q, T, n, p, R2, R3, R4, R5, R6, R7, R8, and R9 are as defined above.
The invention also relates to other intermediates useful in the preparation of compounds of formula I. Accordingly, the invention relates to a compound of formula II:
wherein Y1, Y2, Y3, Y4, A, Q, T, n, p, R1, R2, R3, R4, R5, R6 and R7 have the definitions as described for formula I as defined above. Preferred definitions of Y1, Y2, Y3, Y4, A, Q, T, n, p, R1, R2, R3, R4, R5, R6 and R7 are as defined above.
The invention relates to a compound of formula IV:
wherein Y1, Y2, Y3, Y4, A, Q, T, n, p, R1, R2, R3, R4, R5R6 and R7, have the definitions as described for formula I as defined above, and preferred definitions of Y1, Y2, Y3, Y4, A, Q, T, n, p, R1, R2, R3, R4, R5R6 and R7 are as defined above; and R26 is C1-C6 alkyl or optionally substituted aryl. Preferably, R26 is C1-C6 alkyl or phenyl optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, amino, cyano and halogen.
The invention relates to a compound of formula V:
wherein Y1, Y2, Y3, Y4, A, Q, n, p, R1, R2, R3, R4, R6 and R7, have the definitions as described for formula I as defined above, and preferred definitions of Y1, Y2, Y3, Y4, A, Q, n, p, R1, R2, R3, R4, R6 and R7 are as defined above; and R26 is C1-C6 alkyl or optionally substituted aryl. Preferably, R26 is C1-C6 alkyl or phenyl optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, amino, cyano and halogen.
The invention relates to a compound of formula X:
wherein Y1, Y2, Y3, Y4, Q, n, p, R2, R3, R4, R6 and R7 have the definitions as described for formula I as defined above, and preferred definitions of Y1, Y2, Y3, Y4, Q, n, p, R2, R3, R4, R6 and R7 are as defined above; and R26 is C1-C6 alkyl or optionally substituted aryl. Preferably, R26 is C1-C6 alkyl or phenyl optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, amino, cyano and halogen.
The invention relates to a compound of formula XI:
wherein Y1, Y2, Y3, Y4, A, Q, n, p, R1, R2, R3, R4, R5, R6 and R7, have the definitions as described for formula I as defined above, and preferred definitions of Y1, Y2, Y3, Y4, A, Q, n, p, R1, R2, R3, R4, R5, R6 and R7 are as defined above; Hal stands for halogen.
Preferred individual compounds are:
Compounds of formula (I) can be made as shown in the following schemes.
The compounds of formula I, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, T, Y1, Y2, Y3, and Y4, n, p and Q are as defined for formula I, can be obtained by transformation of a compound of formula II, wherein R1, R2, R3, R4, R5, R6, R7, A, T, Y1, Y2, Y3, and Y4, n, p and Q are as defined for formula I, with a compound of formula III, wherein R8 and R9 are as defined for formula I, and a peptide coupling reagent, such as BOP, PyBOP, HATU. This is shown in Scheme 1.
The compounds of formula II, wherein R1, R2, R3, R4, R5, R6, R7, A, T, Y1, Y2, Y3, and Y4, n, p and Q are as defined for formula I can be obtained by saponification of a compound of formula IV, wherein R1, R2, R3, R4, R5, R6, R7, A, T, Y1, Y2, Y3, and Y4, n, p and Q are as defined for formula I and R26 is C1-C6alkyl or optionally substituted aryl, with a base, such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, etc. This is shown in Scheme 2.
The compounds of formula IV.1, wherein R1, R2, R3, R4, R5, R6, R7, A, Y1, Y2, Y3, and Y4, n, p and Q are as defined for formula I and R26 is C1-C6alkyl or optionally substituted aryl, can be obtained by reduction of a compound of formula V, wherein R1, R2, R3, R4, R6, R7, A, Y1, Y2, Y3, and Y4, n, p and Q are as defined for formula I and R26 is C1-C6alkyl or optionally substituted aryl, and hydrogen with a catalyst, such as palladium on charcoal, raney-nickel, etc, or with lithium aluminum hydride. This is shown in Scheme 3.
The compounds of formula V, wherein R1, R2, R3, R4, R6, R7, A, Y1, Y2, Y3, and Y4, n, p and Q are as defined for formula I and R26 is C1-C6alkyl or optionally substituted aryl, can be obtained by transformation of a compound of formula VI, wherein R2, R3, R5, R6, R7 n, p and A are as defined for formula I and R27 and R28 are each independently hydroxy or C1-C6alkyl or together with the interjacent boron atom form a five- or six-membered saturated heterocyclic ring, with a compound of formula VII, wherein Y1, Y2, Y3, and Y4 and Q are as defined for formula I, R26 is C1-C6alkyl or optionally substituted aryl and Hal is halogen, preferably iodo, bromo or chloro, and a catalyst. This is shown in Scheme 4.
The compounds of formula VI, wherein R1, R2, R3, R4, R6, R7 n, p and A are as defined for formula I and R27 and R28 are each independently hydroxy or C1-C6alkyl or together with the interjacent boron atom form a five- or six-membered saturated heterocyclic ring, can be obtained by transformation of a compound of formula VIII, wherein R1, R2, R3, R4, R6, R7, n and p are as defined for formula I and R27 and R28 are each independently hydroxy or C1-C6alkyl or together with the interjacent boron atom form a five- or six-membered saturated heterocyclic ring, with a compound of formula IX, wherein R1 and A are as defined for formula I and R29 is hydroxy or halogen, preferably, fluoro, chloro or bromo, and a peptide coupling reagent or a base, such as pyridine, triethylamine, ethyl diisopropylamine etc. This is shown in Scheme 5.
Alternatively, the compounds of formula V, wherein R1, R2, R3, R4, R6, R7, A, Y1, Y2, Y3, Y4, n, p and Q are as defined for formula I and R26 is C1-C6alkyl or optionally substituted aryl, can be obtained by transformation of a compound of formula X, wherein R2, R3, R4, R6, R7A, Y1, Y2, Y3, Y4, n, p and Q are as defined for formula I and R26 is C1-C6alkyl or optionally substituted aryl, with a compound of formula IX, wherein R1 and A are as defined for formula I and R29 is hydroxy or halogen, preferably, fluoro, chloro or bromo, and a peptide coupling reagent or a base, such as pyridine, triethylamine, ethyl diisopropylamine etc. This is shown in Scheme 6.
Alternatively, the compounds of formula I, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, A, T, Y1, Y2, Y3, Y4, n, p and Q are as defined for formula I can be obtained by transformation of a compound of formula XI, wherein R1, R2, R3, R4, R5, R6, R7, A, T, Y1, Y2, Y3, Y4, n, p and Q are as defined for formula I and Hal is halogen, preferably fluoro, chloro or bromo, with a compound of formula III, wherein R8 and R9 are as defined for formula I, with a base, such as pyridine, triethylamine, ethyl diisopropylamine etc. This is shown in Scheme 7.
The compounds of formula XI, wherein R1, R2, R3, R4, R5, R6, R7, A, T, Y1, Y2, Y3, Y4, n, p and Q are as defined for formula I and Hal is halogen, preferably fluoro, chloro or bromo, can be obtained by transformation of a compound of formula II, wherein R1, R2, R3, R4, R5, R6, R7, A, T, Y1, Y2, Y3, Y4, n, p and Q are as defined for formula I, with a phosphoryl halide, such as phosphoryl chloride or phosphoryl bromide, or a thionyl halide, such as thionyl chloride or thionyl bromide. This is shown in Scheme 8.
The compounds of formula IV.2, wherein R1, R2, R3, R4, R5, R6, R7, A, Y1, Y2, Y3, Y4, n, p and Q are as defined for formula I and R26 is C1-C6alkyl or optionally substituted aryl, can be obtained by transformation of a compound of formula XII, wherein R1, R2, R3, R4, R6, R7 n, p and A are as defined for formula I, with a compound of formula VII, wherein Y1, Y2, Y3, Y4 and Q are as defined for formula I, R26 is C1-C6alkyl or optionally substituted aryl and Hal is halogen, preferably iodo, bromo or chloro. This is shown in Scheme 9.
Surprisingly, it has now been found that the novel compounds of formula I have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.
The compounds of formula I can be used in the agricultural sector and related fields of use e.g. as active ingredients for controlling plant pests or on non-living materials for control of spoilage microorganisms or organisms potentially harmful to man. The novel compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and may be used for protecting numerous cultivated plants. The compounds of formula I can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later e.g. from phytopathogenic microorganisms.
It is also possible to use compounds of formula I as dressing agents for the treatment of plant propagation material, e.g., seed, such as fruits, tubers or grains, or plant cuttings (for example rice), for the protection against fungal infections as well as against phytopathogenic fungi occurring in the soil. The propagation material can be treated with a composition comprising a compound of formula I before planting: seed, for example, can be dressed before being sown. The active ingredients according to the invention can also be applied to grains (coating), either by impregnating the seeds in a liquid formulation or by coating them with a solid formulation. The composition can also be applied to the planting site when the propagation material is being planted, for example, to the seed furrow during sowing. The invention relates also to such methods of treating plant propagation material and to the plant propagation material so treated.
Furthermore the compounds according to present invention can be used for controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage, in hygiene management.
In addition, the invention could be used to protect non-living materials from fungal attack, e.g. lumber, wall boards and paint.
The compounds of formula I are, for example, effective against the phytopathogenic fungi of the following classes: Fungi imperfecti (e.g. Alternaria spp.), Basidiomycetes (e.g. Corticium spp., Ceratobasidium spp., Waitea spp., Thanatephorus spp., Rhizoctonia spp., Hemileia spp., Puccinia spp., Phakopsora spp., Ustilago spp., Tilletia spp.), Ascomycetes (e.g. Venturia spp., Blumeria spp., Erysiphe spp., Podosphaera spp., Uncinula spp., Monilinia spp., Sclerotinia spp., Colletotrichum spp., Glomerella spp., Fusarium spp., Gibberella spp., Monographella spp., Phaeosphaeria spp., Mycosphaerella spp., Cercospora spp., Pyrenophora spp., Rhynchosporium spp., Magnaporthe spp., Gaeumannomyces spp., Oculimacula spp., Ramularia spp., Botryotinia spp.) and Oomycetes (e.g. Phytophthora spp., Pythium spp., Plasmopara spp., Peronospora spp., Pseudoperonospora spp. Bremia spp). Outstanding activity is observed against downy mildew (e.g. Plasmopara viticola) and late blight (e.g. Phytophthora infestans). Furthermore, the novel compounds of formula I are effective against phytopathogenic gram negative and gram positive bacteria (e.g. Xanthomonas spp, Pseudomonas spp, Erwinia amylovora, Ralstonia spp.) and viruses (e.g. tobacco mosaic virus).
Within the scope of present invention, target crops and/or useful plants to be protected typically comprise the following species of plants: cereal (wheat, barley, rye, oat, rice, maize, sorghum and related species); beet (sugar beet and fodder beet); pomes, drupes and soft fruit (apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and blackberries); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); citrus fruit (oranges, lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocado, cinnamomum, camphor) or plants such as tobacco, nuts, coffee, eggplants, sugar cane, tea, pepper, vines, hops, bananas and natural rubber plants, as well as turf and ornamentals.
The useful plants and/or target crops in accordance with the invention include conventional as well as genetically enhanced or engineered varieties such as, for example, insect resistant (e.g. Bt. and VIP varieties) as well as disease resistant, herbicide tolerant (e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®) and nematode tolerant varieties. By way of example, suitable genetically enhanced or engineered crop varieties include the Stoneville 5599BR cotton and Stoneville 4892BR cotton varieties.
The term “useful plants” and/or “target crops” is to be understood as including also useful plants that have been rendered tolerant to herbicides like bromoxynil or classes of herbicides (such as, for example, HPPD inhibitors, ALS inhibitors, for example primisulfuron, prosulfuron and trifloxysulfuron, EPSPS (5-enol-pyrovyl-shikimate-3-phosphate-synthase) inhibitors, GS (glutamine synthetase) inhibitors or PPO (protoporphyrinogen-oxidase) inhibitors) as a result of conventional methods of breeding or genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding (mutagenesis) is Clearfield® summer rape (Canola). Examples of crops that have been rendered tolerant to herbicides or classes of herbicides by genetic engineering methods include glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and LibertyLink®.
The term “useful plants” and/or “target crops” is to be understood as including also useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
The term “useful plants” and/or “target crops” is to be understood as including also useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as, for example, the so-called “pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818, and EP-A-0 353 191. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
The term “locus” of a plant as used herein is intended to embrace the place on which the plants are growing, where the plant propagation materials of the plants are sown or where the plant propagation materials of the plants will be placed into the soil. An example for such a locus is a field, on which crop plants are growing.
The term “plant propagation material” is understood to denote generative parts of the plant, such as seeds, which can be used for the multiplication of the latter, and vegetative material, such as cuttings or tubers, for example potatoes. There may be mentioned for example seeds (in the strict sense), roots, fruits, tubers, bulbs, rhizomes and parts of plants. Germinated plants and young plants which are to be transplanted after germination or after emergence from the soil, may also be mentioned. These young plants may be protected before transplantation by a total or partial treatment by immersion. Preferably “plant propagation material” is understood to denote seeds.
The compounds of formula I may be used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation. To this end they may be conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations e.g. in polymeric substances. As with the type of the compositions, the methods of application, such as spraying, atomising, dusting, scattering, coating or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.
Suitable carriers and adjuvants, e.g. for agricultural use, can be solid or liquid and are substances useful in formulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers. Such carriers are for example described in WO 97/33890.
The compounds of formula I may be used in the form of compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession with further compounds. These further compounds can be e.g. fertilizers or micronutrient donors or other preparations, which influence the growth of plants. They can also be selective herbicides or non-selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.
The compounds of formula I are normally used in the form of fungicidal compositions for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound of formula I or of at least one preferred individual compound as above-defined, in free form or in agrochemically usable salt form, and at least one of the above-mentioned adjuvants
The invention provides a fungicidal composition comprising at least one compound formula I, an agriculturally acceptable carrier and optionally an adjuvant. An agricultural acceptable carrier is for example a carrier that is suitable for agricultural use. Agricultural carriers are well known in the art. Preferably said fungicidal compositions may comprise an additional fungicidal active ingredient in addition to the compound of formula I.
The compound of formula (I) may be the sole active ingredient of a composition or it may be admixed with one or more additional active ingredients such as an insecticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may, in some cases, result in unexpected synergistic activities. Examples of suitable additional active ingredients include the following: Azoxystrobin (131860-33-8), Dimoxystrobin (149961-52-4), Enestrobin (238410-11-2), Fluoxastrobin (193740-76-0), Kresoxim-methyl (143390-89-0), Metominostrobin (133408-50-1), Orysastrobin (248593-16-0), Picoxystrobin (117428-22-5), Pyraclostrobin (175013-18-0), Azaconazole (60207-31-0), Bromuconazole (116255-48-2), Cyproconazole (94361-06-5), Difenoconazole (119446-68-3), Diniconazole (83657-24-3), Diniconazole-M (83657-18-5), Epoxiconazole (13385-98-8), Fenbuconazole (114369-43-6), Fluquinconazole (136426-54-5), Flusilazole (85509-19-9), Flutriafol (76674-21-0), Hexaconazole (79983-71-4), Imazalil (58594-72-2), Imibenconazole (86598-92-7), Ipconazole (125225-28-7), Metconazole (125116-23-6), Myclobutanil (88671-89-0), Oxpoconazole (174212-12-5), Pefurazoate (58011-68-0), Penconazole (66246-88-6), Prochloraz (67747-09-5), Propiconazole (60207-90-1), Prothioconazole (178928-70-6), Simeconazole (149508-90-7), Tebuconazole (107534-96-3), Tetraconazole (112281-77-3), Triadimefon (43121-43-3), Triadimenol (55219-65-3), Triflumizole (99387-89-0), Triticonazole (131983-72-7), Diclobutrazol (76738-62-0), Etaconazole (60207-93-4), Fluconazole (86386-73-4), Fluconazole-cis (112839-32-4), Thiabendazole (148-79-8), Quinconazole (103970-75-8), Fenpiclonil (74738-17-3), Fludioxonil (131341-86-1), Cyprodinil (121552-61-2), Mepanipyrim (110235-47-7), Pyrimethanil (53112-28-0), Aldimorph (91315-15-0), Dodemorph (1593-77-7), Fenpropimorph (67564-91-4), Tridemorph (81412-43-3), Fenpropidin (67306-00-7), Spiroxamine (118134-30-8), Isopyrazam (881685-58-1), Sedaxane (874967-67-6), Bixafen (581809-46-3), Penthiopyrad (183675-82-3), Fluxapyroxad (907204-31-3), Boscalid (188425-85-6), Penflufen (494793-67-8), Fluopyram (658066-35-4), Mandipropamid (374726-62-2), Benthiavalicarb (413615-35-7), Dimethomorph (110488-70-5), Chlorothalonil (1897-45-6), Fluazinam (79622-59-6), Dithianon (3347-22-6), Metrafenone (220899-03-6), Tricyclazole (41814-78-2), Mefenoxam (70630-17-0), Metalaxyl (57837-19-1), Acibenzolar (126448-41-7) (Acibenzolar-S-methyl (126448-41-7)), Mancozeb (8018-01-7), Ametoctradine (865318-97-4) Cyflufenamid (180409-60-3), Ipconazole (125225-28-7), Amisulbrom (348635-87-0), Ethaboxam (16650-77-3), Fluopicolide (239110-15-7), Fluthianil (304900-25-2), Isotianil (224049-04-1), Proquinazid (189278-12-4), Valiphenal (283159-90-0), 1-methyl-cyclopropene (3100-04-7), Trifloxystrobin (141517-21-7), Sulfur (7704-34-9), Copper ammoniumcarbonate (CAS 33113-08-5); Copper oleate (CAS 1120-44-1); Folpet (133-07-3), Quinoxyfen (124495-18-7), Captan (133-06-2), Fenhexamid (126833-17-8), Glufosinate and its salts (51276-47-2, 35597-44-5 (S-isomer)), Glyphosate (1071-83-6) and its salts (69254-40-6 (Diammonium), 34494-04-7 (Dimethylammonium), 38641-94-0 (Isopropylammonium), 40465-66-5 (Monoammonium), 70901-20-1 (Potassium), 70393-85-0 (Sesquisodium), 81591-81-3 (Trimesium)), 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid (2-dichloromethylene-3-ethyl-1-methyl-indan-4-yl)-amide, 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid (4′-methylsulfanyl-biphenyl-2-yl)-amide, 1,3-Dimethyl-4H-pyrazole-4-carboxylic acid [2-(2,4-dichloro-phenyl)-2-methoxy-1-methyl-ethyl]-amide, (5-Chloro-2,4-dimethyl-pyridin-3-yl)-(2,3,4-trimethoxy-6-methyl-phenyl)-methanone, (5-Bromo-4-chloro-2-methoxy-pyridin-3-yl)-(2,3,4-trimethoxy-6-methyl-phenyl)-methanone, 2-{2-[(E)-3-(2,6-Dichloro-phenyl)-1-methyl-prop-2-en-(E)-ylideneaminooxymethyl]-phenyl}-2-[(Z)-methoxyimino]-N-methyl-acetamide, 3-[5-(4-Chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine.
Another aspect of invention is related to the use of a compound of formula I or of a preferred individual compound as above-defined, of a composition comprising at least one compound of formula I or at least one preferred individual compound as above-defined, or of a fungicidal mixture comprising at least one compound of formula I or at least one preferred individual compound as above-defined, in admixture with other fungicides, as described above, for controlling or preventing infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or non-living materials by phytopathogenic microorganisms, preferably fungal organisms.
A further aspect of invention is related to a method of controlling or preventing an infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, which comprises the application of a compound of formula I or of a preferred individual compound as above-defined as active ingredient to the plants, to parts of the plants or to the locus thereof, to the propagation material thereof, or to any part of the non-living materials.
Controlling or preventing means reducing infestation by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, to such a level that an improvement is demonstrated.
A preferred method of controlling or preventing an infestation of crop plants by phytopathogenic microorganisms, especially fungal organisms, which comprises the application of a compound of formula I, or an agrochemical composition which contains at least one of said compounds, is foliar application. The frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen. However, the compounds of formula I can also penetrate the plant through the roots via the soil (systemic action) by drenching the locus of the plant with a liquid formulation, or by applying the compounds in solid form to the soil, e.g. in granular form (soil application). In crops of water rice such granulates can be applied to the flooded rice field. The compounds of formula I may also be applied to seeds (coating) by impregnating the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation.
A formulation, e.g. a composition containing the compound of formula I, and, if desired, a solid or liquid adjuvant or monomers for encapsulating the compound of formula I, may be prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
The agrochemical formulations and/or compositions will usually contain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight, of the compound of formula I, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
Advantageous rates of application are normally from 5 g to 2 kg of active ingredient (a.i.) per hectare (ha), preferably from 10 g to 1 kg a.i./ha, most preferably from 20 g to 600 g a.i./ha. When used as seed drenching agent, convenient dosages are from 10 mg to 1 g of active substance per kg of seeds.
Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use dilute formulations.
The following non-limiting examples illustrate the above-described invention in more detail.
To a solution of ethyl-3-iodobenzoate (10 g, 36.2 mmol) in dioxane (400 mL) were added successively bistriphenylphosphinpalladiumllchloride (1.26 g, 1.8 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester2 (13.44 g, 43.46 mmol), and aq. sol. sodium carbonate (11.5 g in 100 mL of water, 108.6 mmol) at RT. After stirring for 3 h at 110° C., solvent was evaporated and the resulting yellow oil was dissolved in ethylacetate (300 mL), washed with brine (300 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/heptane 0:1 to 3:7) to give 4-(3-ethoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.28 g, 94%). 1H-NMR (400 MHz, CDCl3): δ=1.39-1.43 (t, 3H), 1.53 (s, 9H), 2.55-2.59 (m, 2H), 3.64 (t, 2H), 4.17-4.22 (m, 2H), 4.35-4.42 (q, 2H), 6.12 (m, 1H), 7.39-7.43 (t, 1H), 7.55-7.58 (m, 1H), 7.91-7.94 (m, 1H), 8.05 (s, 1H). MS: m/z=332 (M+1). 1 3-Piperidin-4-yl-benzoic acid ethyl ester can also be prepared according to the following reference WO 2004092124 A2 20041028 (Merck & Co., Inc., USA).2 Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester can be prepared according to the following reference: Eastwood, P. R. Tetrahedron Letters 2000, 41, 3705 or purchased from suitable supplier (CAS 286961-14-6).
A solution of 4-(3-ethoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.28 g, 34.035 mmol) in ethanol (680 mL) was pumped through Pd/C cartridge using H-Cube apparatus (20° C., 10 bar, 2 mL/min.). The solvent was then evaporated under reduced pressure to give 4-(3-ethoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (10.55 g, 93%), which can be used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ=1.39-1.43 (t, 3H), 1.51 (s, 9H), 1.61-1.72 (dq, 1H), 1.78-1.90 (m, 1H), 2.66-2.74 (dt, 1H), 2.74-2.89 (m, 1H), 4.20-4.31 (m, 1H), 4.32-4.42 (q, 2H), 7.39-7.41 (m, 2H), 7.88-7.92 (m, 2H). MS: m/z=334 (M+1).
To a solution of 4-(3-ethoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (10.55 g, 31.64 mmol) was added a solution of 4M HCl in dioxane (79 mL, 316.41 mmol)) at RT. After stirring overnight at RT, the solvent was evaporated under reduce pressure. The resulting yellowish viscous oil was triturated with diethylether, and filtered to give 3-piperidin-4-yl-benzoic acid ethyl ester hydrochloride salt (8.53 g, quant.). 1H-NMR (400 MHz, d6-DMSO): δ=1.81-1.86 (t, 3H), 1.91-1.98 (m, 3H), 2.50-2.52 (m, 1H (overlap with DMSO), 2.95-3.05 (m, 2H), 3.32-3.39 (m, 2H), 4.31-4.39 (q, 2H), 7.49-7.52 (m, 2H), 7.81-7.83 (m, 2H), 9.5 (br, 2H). MS: m/z=234 ((M-HCl)+1).
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (5.23 g, 20.75 mmol) in DMF (50 mL) was added diisopropylethylamine (43 mL, 207.58 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (10.52 g, 22.83 mmol) at RT. After stirring 15 min. at RT, 3-piperidin-4-yl-benzoic acid ethyl ester hydrochloride salt (5.6 g, 20.75 mmol) was added to the reaction mixture. After stirring overnight at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (200 mL), washed with aq. sat. sodium bicarbonate solution (100 mL) and the aqueous phase was re-extracted with ethylacetate (200 mL). The combined organic layers were washed with 1M HCl solution (400 mL) and brine (400 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 0:1 to 1:1) to give 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid ethyl ester (4.35 g, 49.5%). 1H-NMR (400 MHz, d6-DMSO): δ=1.28-1.39 (t, 3H), 1.45-1.55 (m, 1H), 1.65-1.1.79 (m, 1H), 1.80-1.91 (m, 2H), 2.22 (s, 3H), 2.68-2.73 (m, 1H), 2.89-2.95 (m, 1H), 3.99-4.04 (m, 1H), 4.29-4.33 (q, 2H), 4.46-4.52 (m, 1H), 5.21-5.38 (dd, 2H, diastereotopic), 6.50 (s, 1H), 7.47 (t, 1H), 7.55 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H). MS: m/z=424 (M+1).
To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid ethyl ester (4.35 g, 10.27 mmol) in methanol (50 mL) was added aq. solution of sodium hydroxide (2 M, 7.7 mL, 15.41 mmol) at RT. After stirring 4 h at RT, the solvent was removed, and the residue was dissolved in THF (30 mL), and aq. solution of lithium hydroxide (121 mg in 5 mL of water) was added at RT. After stirring overnight at RT, the solvent was removed and the residue was dissolved in ethylacetate (50 mL) and the reaction mixture was acidified with 2M aq. solution of HCl until pH 1-2. After separation of phases, the aq. layer was re-extracted with ethylacetate (20 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure to give 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (2.40 g, 59%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.45-1.55 (m, 1H), 1.65-1.1.79 (m, 1H), 1.80-1.91 (m, 2H), 2.22 (s, 3H), 2.67-2.78 (m, 1H), 2.89-2.95 (m, 1H), 3.17-3.24 (m, 1H), 3.95-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.21-5.38 (dd, 2H, diastereotopic), 6.50 (s, 1H), 7.47 (t, 1H), 7.55 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H). MS: m/z=396 (M+1).
To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (100 mg, 0.25 mmol) in DMF (2 mL) was added diisopropylethylamine (0.16 mL, 0.76 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.128 g, 0.27 mmol) at RT. After stirring 15 min. at RT, (R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (0.045 g, 0.25 mmol) was added to the reaction mixture. After stirring 2 h at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (10 mL), washed with aq. sat. sodium bicarbonate solution (20 mL) and the aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with 1M HCl solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N—(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-benzamide (125 mg, 94%). 1H-NMR (400 MHz, d6-DMSO): δ=1.52-1.61 (m, 1H), 1.68-1.89 (m, 5H), 1.91-2.02 (m, 1H), 2.22 (s, 3H), 2.64-2.92 (m, 4H), 3.15-3.24 (m, 1H), 3.99-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.19-5.38 (m, 3H), 6.50 (s, 1H), 7.12-7.19 (m, 4H), 7.38 (d, 1H), 7.75 (d, 1H), 7.82 (s, 1H), 8.71 (d, 1H). MS: m/z=525 (M+1).
To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (320 mg, 0.80 mmol) in DMF (8 mL) was added diisopropylethylamine (1.01 mL, 4.85 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.41 g, 0.89 mmol) at RT. After stirring 15 min. at RT, methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amine (0.158 g, 0.80 mmol) was added to the reaction mixture. After stirring for 2 h at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (20 mL), washed with aq. sat. sodium bicarbonate solution (30 mL) and the aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with 1M HCl solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give N-methyl-3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N—(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-benzamide (200 mg, 46%). 1H-NMR (400 MHz, d6-DMSO): δ=1.45-1.59 (m, 1H), 1.63-1.91 (m, 5H), 1.91-2.02 (m, 1H), 2.22 (s, 3H), 2.61 (s, 3H), 2.64-2.92 (m, 4H), 3.15-3.24 (m, 1H), 3.99-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.19-5.38 (m, 2H), 5.74-5.81 (m, 1H), 6.50 (s, 1H), 7.12-7.23 (m, 4H), 7.28-7.47 (m, 4H). MS: m/z=539 (M+1).
To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (320 mg, 0.80 mmol) in DMF (8 mL) was added diisopropylethylamine (1.01 mL, 4.85 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.41 g, 0.89 mmol) at RT. After stirring for 15 min. at RT, Methyl-((R)-1-phenyl-ethyl)-amine (0.132 g, 0.80 mmol) was added to the reaction mixture. After stirring for 2 h at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (20 mL), washed with aq. sat. sodium bicarbonate solution (30 mL) and the aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with 1M HCl solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give N-methyl-3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N—((R)-1-phenyl-ethyl)-benzamide (170 mg, 41%). 1H-NMR (400 MHz, d6-DMSO): δ=1.55 (d, 3H), 1.62-1.71 (m, 1H), 1.82-1.89 (m, 2H), 1.99 (s, 3H), 2.22 (s, 3H), 2.54-2.73 (m, 3H), 2.81-2.90 (m, 1H), 3.12-3.21 (m, 1H), 3.99-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.19-5.38 (m, 2H), 6.50 (s, 1H), 7.12-7.41 (m, 9H). MS: m/z=513 (M+1)
To a solution of 6-bromo-pyridine-2-carboxylic acid ethyl ester (1 g, 4.35 mmol) in dioxane (40 mL) were added successively bistriphenylphosphinpalladiumllchloride (0.152 g, 0.217 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester2 (1.61 g, 5.21 mmol), and aq. sol. sodium carbonate (1.38 g in 10 mL of water, 13.04 mmol) at RT. After stirring 3 h at 110° C., solvent was evaporated and the resulting yellow oil was dissolved in ethylacetate (30 mL), washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/heptane 0:1 to 3:7) to give 3′,6′-dihydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester 6-ethyl ester (1.13 g, 78%). 1H-NMR (400 MHz, d6-DMSO): δ=1.31-1.38 (t, 3H), 1.47 (s, 9H), 2.55-2.59 (m, 2H), 3.51-3.59 (m, 2H), 4.08-4.12 (m, 2H), 4.31-4.37 (q, 2H), 6.74 (m, 1H), 7.75-7.79 (d, 1H), 7.88-7.91 (m, 1H), 7.92-7.99 (t, 1H). MS: m/z=333 (M+1).
A solution of 3′,6′-dihydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester 6-ethyl ester (1.12 g, 3.37 mmol) in ethanol (67 mL) was pumped through Pd/C cartridge using H-Cube apparatus (20° C., 10 bar, 2 mL/min.). The solvent was then evaporated under reduce pressure to give 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester 6-ethyl ester (1.001 g, 89%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.31-1.38 (t, 3H), 1.47 (s, 9H), 1.55-1.65 (m, 2H), 1.79-1.88 (m, 2H), 2.91-2.99 (m, 2H), 3.42-3.48 (m, 1H), 4.05-4.12 (m, 2H), 4.31-4.37 (q, 2H), 7.55 (d, 1H), 7.84-7.92 (m, 2H). MS: m/z=333 (M+1. MS: m/z=335 (M+1).
To a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester 6-ethyl ester (100 mg, 0.3 mmol) in methanol (5 mL) was added aq. solution of sodium hydroxide (2 M, 0.23 mL, 0.5 mmol) at RT. After stirring for 4 h at RT, the solvent was removed, and the residue was dissolved in THF (5 mL), and aq. solution of lithium hydroxide (7 mg in 1 mL of water) was added at RT. After stirring overnight at RT, the solvent was removed and the residue was dissolved in ethylacetate (10 mL) and the reaction mixture was acidified with 2M aq. solution of HCl until pH 2-3. After separation of phases, the aq. layer was re-extracted with ethylacetate (10 mL), and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure to give 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester (45 mg, 49%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.43 (s, 9H), 1.58-1.68 (m, 2H), 1.81-1.84 (m, 2H), 2.84-2.96 (m, 2H), 3.27-3.39 (m, 1H), 4.07-4.10 (m, 2H), 7.52-7.54 (d, 1H), 7.86-7.92 (m, 2H). MS: m/z=329 (M+23).
To a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester (150 mg, 0.49 mmol), methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amine (0.079 g, 0.49 mmol), and diisopropylethylamine (0.50 mL, 0.49 mmol) in DMF (10 mL) was added dropwise BOP (238 mg, 0.49 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/hexane 4:1) to give 6-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamoyl]-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (215 mg, 97%). 1H-NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 1.64-2.05 (m, 8H), 2.18-2.22 (m, 1H), 2.72-2.81 (m, 4H), 2.82 (s, 3H), 4.15-4.25 (m, 2H), 5.15-5.20 (m, 1H), 7.18-7.25 (m, 5H), 7.53-7.71 (m, 1H), 7.73-7.74 (m, 1H).
To a solution of 6-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamoyl]-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (202 mg, 0.45 mmol) was added a solution of 4M HCl in dioxane (1.13 mL, 4.5 mmol)) at RT. After stirring overnight at RT, the solvent was evaporated under reduce pressure to give 1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide hydrochloride salt (162 mg, 93%). 1H-NMR (400 MHz, d6-DMSO): δ=1.83-2.02 (m, 6H), 2.51 (s, 3H), 2.52-2.59 (m, 2H), 2.71-3.03 (m, 2H), 3.29-3.38 (m, 2H), 3.97-4.05 (m, 2H), 4.78-4.83 (m, 1H), 7.08-7.23 (m, 4H), 7.36-7.41 (m, 1H), 7.52-7.55 (m, 1H), 7.90-7.95 (m, 1H), 8.81 (br, 1H), 9.04 (br, 1H).
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (81 mg, 0.39 mmol), 1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide hydrochloride salt (150 mg, 0.39 mmol), and diisopropylethylamine (0.41 mL, 0.39 mmol) in DMF (10 mL) was added dropwise BOP (191 mg, 0.39 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate) to give 1′-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (150 mg, 71%). M.p 62-65° C. 1H-NMR (400 MHz, CDCl3): δ=1.67-2.02 (m, 6H), 2.18-2.22 (m, 1H), 2.30 (s, 3H), 2.71 (s, 3H), 2.72-2.75 (m, 2H), 3.17-3.27 (m, 2H), 3.97-4.05 (m, 2H), 4.58-4.78 (m, 2H), 4.96 (s, 2H), 5.05-5.15 (m, 1H), 6.33 (s, 1H), 7.10-7.24 (m, 4H), 7.28-7.32 (m, 1H), 7.57-7.58 (m, 1H), 7.76-7.78 (m, 1H).
Table 1 below illustrates examples of individual compounds of formula I according to the invention.
where
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
wherein A, Q, R1 and R9 are as defined in Table 1.
Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus and the method is: (HP 1100 HPLC from Agilent, Phenomenex Gemini C18, 3 μm particle size, 110 Angström, 30×3 mm column, 1.7 mL/min., 60° C., H2O+0.05% HCOOH (95%)/CH3CN/MeOH 4:1+0.04% HCOOH (5%)—2 min.—CH3CN/MeOH 4:1+0.04% HCOOH (5%)—0.8 min., ZQ Mass Spectrometer from Waters, ionization method: electrospray (ESI), Polarity: positive ions, Capillary (kV) 3.00, Cone (V) 30.00, Extractor (V) 2.00, Source Temperature (° C.) 100, Desolvation Temperature (° C.) 250, Cone Gas Flow (L/Hr) 50, Desolvation Gas Flow (L/Hr) 400)).
The compounds according to the present invention can be prepared according to the above-mentioned reaction schemes, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I).
Phytophthora infestans/Tomato/Leaf Disc Preventative (Tomato Late Blight)
Tomato leaf disks are placed on water agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf disks are incubated at 16° C. and 75% rh under a light regime of 24 h darkness followed by 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (5-7 days after application).
Compound I.n.001, I.n.003, I.n.005, I.n.009, I.n.011, I.n.049, I.n.097, I.t.001, I.v.001, I.z.001 and I.z.005 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Phytophthora infestans/Potato/Preventative (Potato Late Blight)
2-week old potato plants cv. Bintje are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants are inoculated by spraying them with a sporangia suspension 2 days after application. The inoculated test plants are incubated at 18° C. with 14 h light/day and 100% rh in a growth chamber and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (5-7 days after application).
Compound I.n.001, I.n.003, I.n.005, I.n.009, I.n.049, I.v.001, I.z.001 and I.z.005 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Phytophthora infestans/Potato/Long Lasting (Potato Late Blight)
2-week old potato plants cv. Bintje are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants are inoculated by spraying them with a sporangia suspension 6 days after application. The inoculated test plants are incubated at 18° C. with 14 h light/day and 100% rh in a growth chamber and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (9-11 days after application).
Compounds I.n.001, I.n.003, I.n.005, I.n.097, I.t.001, I.v.001, I.z.001 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Phytophthora infestans/Potato/Curative (Potato Late Blight)
2-week old potato plants cv. Bintje are inoculated by spraying them with a sporangia suspension one day before application. The inoculated plants are sprayed in a spray chamber with the formulated test compound diluted in water. The inoculated test plants are incubated at 18° C. with 14 h light/day and 100% rh in a growth chamber and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (3-4 days after application).
Compounds I.n.001, I.n.003, I.n.005, I.n.009, I.v.001, I.z.001 and I.z.005 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Plasmopara viticola/Grape/Leaf Disc Preventative (Grape Downy Mildew)
Grape vine leaf disks are placed on water agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf disks are incubated at 19° C. and 80% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf disks (6-8 days after application).
Compounds I.n.001, I.n.003, I.n.005, I.n.009, I.n.011, I.n.049, I.n.097, I.t.001, I.v.001, I.z.001 and I.z.005 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Plasmopara viticola/Grape/Preventative (Grape Downy Mildew)
5-week old grape seedlings cv. Gutedel are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants are inoculated by spraying a sporangia suspension on their lower leaf surface one day after application. The inoculated test plants are incubated at 22° C. and 100% rh in a greenhouse and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (6-8 days after application).
Compounds I.n.001, I.n.003, I.n.005, I.n.009, I.n.011, I.v.001, I.z.001 and I.z.005 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Plasmopara viticola/Grape/Long Lasting (Grape Downy Mildew)
5-week old grape seedlings cv. Gutedel are sprayed in a spray chamber with the formulated test compound diluted in water. The test plants are inoculated by spraying a sporangia suspension on their lower leaf surface 6 days after application. The inoculated test plants are incubated at 22° C. and 100% rh in a greenhouse and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (11-13 days after application).
Compounds I.n.001, I.n.003, I.n.005, I.n.009, I.t.001, I.v.001, I.z.001 and I.z.005 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Plasmopara viticola/Grape/Curative (Grape Downy Mildew)
5-week-old grape seedlings cv. Gutedel are inoculated by spraying a sporangia suspension on their lower leaf surface one day before application. The inoculated grape plants are sprayed in a spray chamber with the formulated test compound diluted in water. The inoculated test plants are incubated at 22° C. and 100% rh in a greenhouse and the percentage leaf area covered by disease is assessed when an appropriate level of disease appears on untreated check plants (4-6 days after application).
Compound I.n.001, I.n.003, I.n.005, I.n.009, I.n.049, I.v.001 and I.z.001 at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
| Number | Date | Country | Kind |
|---|---|---|---|
| 09167741 | Aug 2009 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2010/061464 | 8/6/2010 | WO | 00 | 2/10/2012 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2011/018415 | 2/17/2011 | WO | A |
| Number | Date | Country |
|---|---|---|
| 2005115369 | Dec 2005 | WO |
| 2007014290 | Feb 2007 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20120142698 A1 | Jun 2012 | US |
