Patent Grant
7205301
This application is a 371 of International Application No. PCT/IB02/05148 filed Dec. 5, 2002, which claims priority to GB 0129391.9, filed Dec. 7, 2001, the contents of which are incorporated herein by reference.
The present invention relates to novel N-phenyl-[4-(4-pyridyl)-pyrimidin-2-yl]-amine derivatives, to a method of protecting plants against attack or infestation by phytopathogenic organisms, such as nematodes or insects or especially microorganisms, preferably fungi, bacteria and viruses, or combinations of two or more of these organisms, by applying a N-phenyl-[4-(4-pyridyl)-pyrimidin-2-yl]-amine derivative as specified hereinafter to a part and/or to the site of a plant, to the use of said derivative for protecting plants against said organisms, and to compositions comprising said derivative as the active component. The invention further relates to the preparation of these novel N-phenyl-[4-(4-pyridyl)-pyrimidin-2-yl]-amine derivatives.
Certain N-phenyl-4-(4-pyridyl)-2-pyrimidineamine derivatives have been described in the art as having pharmacological properties e.g. in the PCT patent applications WO 95/09851 and WO 95/09853, as tumor-inhibiting anti-cancer substances and in WO 97/19065 and WO98/18782 for the treatment of immune diseases.
Surprisingly, it has now been found that the new N-phenyl-[4-(4-pyridyl)-pyrimidin-2-yl]-amines are effective in plant protection and related areas, showing advantageous properties in the treatment of plant diseases caused by organisms.
The novel N-phenyl-[4-(4-pyridyl)-pyrimidin-2-yl]-amine derivatives according to the invention are those of the formula I
wherein
One group of preferred compounds are of those of formula (I′) which are compounds of formula I wherein
In the context of the present specification alkyl as a group per se and as a structural element of hydroxyalkyl, thioalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl alkynyloxy or haloalkoxy—is preferably C1–C6-alkyl, more preferably lower alkyl, and is linear i.e. methyl, ethyl, propyl, butyl, pentyl or hexyl, or branched, e.g. isopropyl, isobutyl, sec.-butyl, tert.-butyl, isopentyl, neopentyl or isohexyl. Lower alkyl is preferably methyl or ethyl.
Specific examples of alkenyl and alkynyl include allyl, 2-butenyl, 3-butenyl, propargyl, 2-butinyl and 3 butynyl.
When present, the optional substituents on an alkyl, alkenyl or alkynyl moiety include one or more of halogen, nitro, cyano, oxo (and acetals and ketals formed therefrom), C3-7 cycloalkyl (itself optionally substituted with C1-6 alkyl or halogen), C5-7 cycloalkenyl (itself optionally substituted with C1-6 alkyl or halogen), hydroxy, C3-10 alkoxy, C3-10 alkoxy(C3-10)alkoxy, C1-6 alkoxy-carbonyl(C3-10)alkoxy, C3-10haloalkoxy, phenyl(C1-4)alkoxy (where the phenyl group is optionally substituted by one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, CN, nitro or halogen), C3-7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), C3-10 alkenyloxy, C3-10 alkynyloxy, SH, C3-10 alkylthio, C3-10 haloalkylthio, phenyl(C1-4)alkylthio (where the phenyl group is optionally substituted by one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, CN, nitro or halogen), C3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), tri(C1-4)alkylsilyl(C1-6)alkylthio, phenylthio (where the phenyl group is optionally substituted by one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, CN, nitro or halogen), C1-6 alkylsulfonyl, C1-6 haloalkylsulfonyl, C1-6 alkylsulfinyl, CO1-6haloalkylsulfinyl, phenylsulfonyl (where the phenyl group is optionally substituted by one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, CN, nitro or halogen), tri(C1-4)alkylsilyl, phenyldi(C1-4)alkylsilyl, (C1-4)alkyldiarylsilyl, triphenylsilyl, C3-10 alkylcarbonyl, HO2C, C3-10 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)-aminocarbonyl, N-(C1-3 alkyl)-N-(C1-3 alkoxy)aminocarbonyl, C1-6 alkylcarbonyloxy, phenylcarbonyloxy (where the phenyl group is optionally substituted by one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, CN, nitro or halogen), di(C1-6)alkylaminocarbonyloxy, phenyl (itself optionally substituted by one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, CN, nitro or halogen), naphthyl (itself optionally substituted by C1-6 alkyl or halogen), heteroaryl (itself optionally substituted by C1-6 alkyl or halogen), heterocyclyl (itself optionally substituted with C1-6 alkyl or halogen), phenyloxy (where the phenyl group is optionally substituted by substituted by one or more of C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, CN, nitro or halogen), naphthyloxy (where the naphthyl group is optionally substituted by C1-6 alkyl or halogen), heteroaryloxy, (where the heteroaryl group is optionally substituted by C1-6 alkyl or halogen), heterocyclyloxy (where the heterocyclyl group is optionally substituted with C1-6 alkyl or halogen), amino, C1-6 alkylamino, di(C1-6) alkylamino, C1-6 alkylcarbonylamino and N-(C1-6)alkylcarbonyl-N-(C1-6)alkylamino.
Preferred substituents on an alkyl, alkenyl or alkynyl moiety include one or more of halogen, nitro, cyano, C3-7 cycloalkyl (itself optionally substituted with C1-6 alkyl or halogen), C5-7 cycloalkenyl (itself optionally substituted with C1-6 alkyl or halogen), hydroxy, C3-10 alkoxy, C3-10 alkoxy(C3-10)alkoxy, C1-6 Lkoxy-carbonyl(C3-10)alkoxy, C3-10 haloalkoxy, phenyl(C1-4)alkoxy (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), C3-7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), C3-10alkenyloxy, C3-10 alkynyloxy, SH, C3-10 alkylthio, C3-10haloalkylthio, phenyl(C1-4)alkylthio (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), C3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), tri(C1-4)alkylsilyl(C1-6)alkylthio, phenylthio (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), C1-6 alkylsulfonyl, C1-6 haloalkylsulfonyl, C1-6 alkylsulfinyl, C1-6 haloalkylsulfinyl, phenylsulfonyl (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), tri(C1-4)alkylsilyl, phenyldi(C1-4)alkylsilyl, (C1-4)alkyldiarylsilyl, triphenylsilyl, C3-10 alkylcarbonyl, HO2C, C3-10 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)-aminocarbonyl, N-(C1-3 alkyl)-N-(C1-3 alkoxy)aminocarbonyl, C1-6 alkylcarbonyloxy, phenylcarbonyloxy (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), di(C1-6)alkylaminocarbonyloxy, phenyl (itself optionally substituted by C1-6 alkyl or halogen), heteroaryl (itself optionally substituted by C1-6 alkyl or halogen), heterocyclyl (itself optionally substituted with C1-6 alkyl or halogen), phenyloxy (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), heteroaryloxy, (where the heteroaryl group is optionally substituted by C1-6 alkyl or halogen), heterocyclyloxy (where the heterocyclyl group is optionally substituted with C1-6 alkyl or halogen), amino, C1-6 alkylamino, di(C1-6) alkylamino, C1-6 alkylcarbonylamino and N-(C1-6)alkylcarbonyl-N—(C1-6)alkylamino.
More preferred substituents on an alkyl, alkenyl and alkynyl moiety include one or more of halogen, nitro, cyano, C3-7 cycloalkyl (itself optionally substituted with C1-6 alkyl or halogen), hydroxy, C3-10 alkoxy, C3-10 alkoxy(C3-10)alkoxy, C1-6 alkoxy-carbonyl(C3-10)alkoxy, C3-10haloalkoxy, SH, C3-10alkylthio, C3-10 haloalkylthio, C1-6alkylsulfonyl, C1-6 haloalkylsulfonyl, C1-6 alkylsulfinyl, C1-6 haloalkylsulfinyl, phenylsulfonyl (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), HO2C, C3-10 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, heteroaryl (itself optionally substituted by C1-6 alkyl or halogen), heterocyclyl (itself optionally substituted with C1-6 alkyl or halogen), phenyloxy (where the phenyl group is optionally substituted by C1-6 alkyl or halogen), amino, C1-6alkylamino and di(C1-6) alkylamino.
Aryl includes naphthyl, anthracyl, fluorenyl and indenyl but is preferably phenyl.
The term heteroaryl refers to an aromatic ring containing up to 10 atoms including one or more heteroatoms (preferably one or two heteroatoms) selected from O, S and N. Examples of such rings include pyridine, pyrimidine, furan, quinoline, quinazoline, pyrazole, thiophene, thiazole, oxazole and isoxazole.
The terms heterocycle and heterocyclyl refer to a non-aromatic ring containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected from O, S and N. Examples of such rings include 1,3-dioxolane, tetrahydrofuran and morpholine.
When present, the optional substituents on heterocyclyl include C1-6 alkyl as well as those optional substituents given above for an alkyl moiety.
Cycloalkyl includes cyclopropyl, cyclopentyl and cyclohexyl.
Cycloalkenyl includes cyclopentenyl and cyclohexenyl.
When present, the optional substituents on heteroaryl and aryl rings are selected, independently, from halogen, nitro, cyano, NCS—, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy-(C1-6)alkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C3-7 cycloalkyl (itself optionally substituted with C1-6 alkyl or halogen), C5-7 cycloalkenyl (itself optionally substituted with C1-6 alkyl or halogen), hydroxy, C1-10alkoxy, C1-10 alkoxy(C1-10)alkoxy, tri(C1-4)alkyl-silyl(C1-6)alkoxy, C1-6 alkoxycarbonyl(C1-10)alkoxy, C1-10 haloalkoxy, aryl(C1-4)alkoxy (where the aryl group is optionally substituted), C3-7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), C1-10alkenyloxy, C1-10 alkynyloxy, SH, C1-10alkylthio, C1-10 haloalkylthio, aryl(C1-4)alkylthio (where the aryl group may be further optionally substituted), C3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), tri(C1-4)alkylsilyl(C1-6)alkylthio, arylthio (where the aryl group is optionally substituted), C1-6 alkylsulfonyl, C1-6 haloalkylsulfonyl, C1-6 alkylsulfinyl, C1-6 haloalkylsulfinyl, arylsulfonyl (where the aryl group is optionally substituted), tri(C1-4)alkylsilyl, aryldi(C1-4)alkylsilyl, (C1-4)alkyldiarylsilyl, triarylsilyl, C1-10alkylcarbonyl, HO2C, C1-10alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, N-(C1-3 alkyl)-N-(C1-3 alkoxy)aminocarbonyl, C1-6 alkylcarbonyloxy, arylcarbonyloxy (where the aryl group is optionally substituted), di(C1-6)alkylamino-carbonyloxy, aryl (itself optionally substituted), heteroaryl (which itself may be further optionally substituted), heterocyclyl (itself optionally substituted with C1-6 alkyl or halogen), aryloxy (where the aryl group is optionally substituted), heteroaryloxy (where the heteroaryl group is optionally substituted), heterocyclyloxy (where the heterocyclyl group is optionally substituted with C1-6 alkyl or halogen), amino, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkylcarbonylamino and N-(C1-6)alkylcarbonyl-N-(C1-6)alkylamino.
For substituted phenyl and heteroaryl moieties it is preferred that one or more substituents are independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkylsulfinyl, C1-6 haloalkylsulfinyl, C1-6 alkylsulfonyl, C1-6 haloalkylsulfonyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C3-7 cycloalkyl, nitro, cyano, CO2H, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, R33R34N or R35R36NC(O); wherein R33, R34, R35 and R36 are, independently, hydrogen or C1-6 alkyl.
In the context of the specification the term halogen is fluorine, bromine, iodine or preferably chlorine; similarly haloalkyl is preferably C1–C6-alkyl, more preferably lower alkyl, that is linear or branched and is substituted by one or more, for example in the case of halo-ethyl up to five, halogen atoms, especially fluorine (an example is trifluoromethyl.
Haloalkoxy is preferably C1–C6-alkoxy, more preferably lower alkoxy, that is linear or branched and that is substituted by one or more, for example in the case of haloethyl up to five, halogen atoms, especially fluorine; trifluoromethoxy and 1,1,2,2-tetrafluoroethoxy are especially preferred.
The moiety attached to the 2-position of the pyridine ring in the compounds of the invention, namely the moiety
includes 5- and 6-membered ring systems, which are common in the art of heterocycles. Thus examples of the moieties include 2,4-dihydro-pyrazol-3-ones, 2,4-dihydro-pyrazole-3-thione, 1H-pyrazoles, 2H-pyridazin-3-ones, 4,5-dihydro-2H-pyridazin-3-ones, 1,2-dihydro-pyrazol-3-ones, 1,2-dihydro-pyrazole-3-thione, pyrazolidin-3-one, pyrazolidine-3-thione, 2H-pyridazin-3-thione and 4,5-dihydro-2H-pyridazin-3-thione.
More preferred ring systems for the moiety positioned at the 2-position of the pyridyl ring are those selected from the group comprising, 1H-pyrazoles, 2,4-dihydro-pyrazol-3-ones, 1,2-dihydro-pyrazol-3-ones, 4,5-dihydro-2H-pyridazin-3-ones.
The compounds of formula I can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, oxalic acid or amino acids, such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxy-ethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid.
The pyridine-N-oxides of formula I can form acid addition salts with strong acids, such as hydrochloric acid, nitric acid, phosphoric acid or sulfonic acids, such as benzenesulfonic acid.
Formula I according to the invention shall include all the possible isomeric forms, as well as mixtures, e.g. racemic mixtures, and any mixtures of rotamers.
In view of the close relationship between the compounds of formula I in free form and in the form of their salts, including also salts that can be used as intermediates, for example in the purification of the compounds of formula I or in order to identify those compounds, herein-before and hereinafter any reference to the (free) compounds is to be understood as including also the corresponding salts, where appropriate and expedient.
Among the compounds of formula I according to the present invention the following groups of compounds are preferred. These groups are in any combination those
In a further group of preferred compounds R2, R2A, R3, R4, R5, R6, R7, R8 and R9 independently of each other are hydrogen or methyl;
In a further group of preferred compounds R7 is hydrogen, methyl, ethyl, allyl, propargyl, methoxymethyl, thiomethoxymethyl or ethoxymethyl, more preferably hydrogen or methoxymethyl.
Preferred individual compounds of the formula I are:
The compounds according to the invention may be prepared according to methods per se known in the art (this does mean, however, that, where novel compounds are produced, the respective process of manufacture is also novel). The procedures for the preparation of compounds of formula I may be outlined as follows:
(or a salt thereof) with β-ketoester of the formula III to V under acid catalysed conditions
wherein R is H or optionally substituted alkyl and the other moieties in II to V have the meanings given for a compound of formula I thus obtaining a compound of the sub-formula Ia
Compounds of formula II may be prepared by the methods described in WO 01/93682 and illustrated in Synthesis Example 1.
with a substituted acrylate of formula VI
or with an alkyl propiolate of formula VII
thus obtaining a compound of subformula Ic wherein the moieties have the meanings given for a compound of formula I
with a substituted 1,3 dicarbonyl compound of formula VIII
with a 1,4 dicarbonyl compounds of formula IX or X wherein R is H or optionally substituted alkyl
With a nucleophile to form compounds of formula I
Compounds of forumla I.6 are prepared by the methods of W Davey and D J Tivey, J Chem Soc 1958, p1230 and illustrated in Example 7.
The R group moieties in compounds VIII, IX, X, XI and XII are as for those defined for compounds of formula I.
Compounds of formula III to XII inclusive are known compounds or may be prepared by compounds known processes.
The reaction types A to J and additional methods which can be applied per se or as analogous procedures for the synthesis of compounds of formula I are described for example in:
For 5-membred heterocylces:
Procedures for the alkylation of compounds of the subformula Ia to Id are described in the experimental section using Williamson conditions.
Conversion of C═O groups (in Ia and Ic) into C═S groups (subformulas Ib and Id) is described in the experimental section using Lawesson reagent under standard conditions or according to procedures given in
Ley, Steven V.; Leach, Andrew G.; Storer, R. Ian. J. Chem. Soc., Perkin Trans. 1 (2001), (4), 358–361.
Procedures for the palladium catalysed C—N linkage reaction (Burchwald-Hartwig amination) of compounds of formula XI with cyclic hydrazine ring systems of formula XII are given in the experimental part and are described in PCT/IB01/02821.
The subsequent examples are intended to illustrated the invention, without however limiting the scope thereof.
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (4.8 g, 0.015 mol) in hydrazine (20 ml, 0.41 mol) is refluxed for 90 minutes. The reaction is poured into ethanol (300 ml) with efficient stirring. The resulting precipitate is filtered with suction to yield the title compound, m.p. 201–203° C.
A mixture of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (3.14 g, 0.010 mol) and Methyl acetoacetate (1.28 g, 0.010 mol) in EtOH (30 ml) and Acetic acid (30 ml) is stirred at reflux for one hour. At room temperature the resulting precipitate is filtered with suction to yield the title compound,(3.50 g, 92%) m.p. 149–150° C.
A mixture of 2-{4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-5-methyl-2,4-dihydro-pyrazol-3-one (3.42 g, 0.009 mol), iodomethane (2.52 g, 0.018 mol) and potassium carbonate anhydrous (3.78 g, 0.027 mol) in DMF (30 ml) is stirred at room temperature for three hours. After stirring the resulting is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified twice by silicagel chromatography to give all possible Isomers of the title compounds IIIa to IIIf. IIIa (0.10 g, 2.8%) m.p. 185–188° C.,
A mixture of 2-{4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-4,4,5-trimethyl-2,4-dihydro-pyrazol-3-one (0.21 g, 0.0005 mol) and Lawesson reagent (0.22 g 0.0005 mol) in toluene (3 ml) is stirred at 100° C. for one hour. After cooling the resulting solution is directly purified by silicagel column chromatography to the title compounds (IVb) (0.19 g, 88.1%) m.p. 167–168° C.,
To a mixture of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (7.82 g, 0.025 mol) and Methyl acrylate (2.58 g, 0.030 mol) in tert BuOH (80 ml) is added Potassium tert-butoxyde (5.6 g, 0.05 mol) in portions at 25° C. After stirring for two hours the resulting brown solution is poured in water (500 ml), acidified with acetic acid and partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by crystallizing from acetone. The resulting precipitate is filtered with suction to yield the title compound. (1.55 g, 16.9%) m.p. 222–226° C.
A mixture of 1-{4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-4,5-dihydro-1H-pyrazol-3-ol (0.734 g, 0.0020 mol), iodomethane (175 μl, 0.0028 mol) and potassium carbonate anhydrous (0.497 g, 0.0036 mol) in acetonitrile (4 ml) and DMF (2 ml) is stirred at 45° C. for seven hours. After stirring the resulting is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by silicagel chromatography to give both possible Isomers of the title compounds.
VIa (0.192 g, 25.2%) mp. 143–144° C.
VIb (0.036 g, 4.7%) mp. 202–205° C.
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (5 g) in acetic acid (80 mL) was added 2.8 g of Mucochloric acid. The mixture was heated at 125° C. for 4 h. The solvent was concentrated and the crude was poured into water (500 mL). The suspension was neutralised by addition of solid potassium carbonate until pH 7. The aqueous phase was extracted with ethyl acetate (3×200 mL). The organic phases were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-tetrahydrofuran (1-0 to 1-1), afforded the title compound as a solid (3.11 g, 44%). Mp 238–240° C., 1H NMR (DMSO-d6) 10.3 (1H, s, NH), 8.84 (1H, d, 5 Hz), 8.76 (1H, d, 5 Hz), 8.42 (1H, s), 8.38 (1H, s), 8.28 (1H, 2 Hz, 5 Hz), 8.04 (1H, t, 2 Hz), 7.74 (1H, dd), 7.62 (1H, d, 5 Hz), 7.32 (1H, t, 8 Hz), 7.02 (1H, dd, 2 Hz, 8 Hz). 13CNMR DMSO-d6) 160.3, 160.2, 159.9, 155.5, 153.5, 150.2, 146.6, 141.7, 136.7, 136.6, 134.0, 132.9, 130.1, 121.9, 121.1, 118.7, 118.2, 117.3, 109.3.
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (2 g) in acetic acid (40 mL) was acetate (3×200 mL).). The organic phase were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-tetrahydrofuran (1-0 to 1-1), afforded the title compound as a solid (1.39 g, 55%). Mp 187–189° C., 1H NMR (DMSO-d6) 9.8 (1H, s, NH), 8.86 (1H, d, 5 Hz), 8.80 (1H, d, 5 Hz), 8.35 (1H, s), 8.28 (1H, dd, 2 Hz, 5 Hz), 8.14 (1H, t, 2Hz), 7.73 (1H, m), 7.7.48 (1H, d, 10 Hz), 7.36 (1H, t, 8 Hz), 7.14 (1H, d, 10 Hz), 7.08 (1H, dd, 1 Hz, 7 Hz), 2.39 (3H,s), 13CNMR (DMSO-d6) 160.8, 160.5, 160.3, 159.0, 154.8, 150.5, 146.7, 145.4, 142.2, 135.4, 133.3, 130.8, 130.5, 121.5, 119.2, 118.6, 117.7, 109.6, 20.58.
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (2 g) in n-Butanol (40 mL) was added of 0.744 g of levulinic acid. The mixture was heated at reflux. After 3 h, the mixture was cooled at 0° C. and the 4-({4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-methyl-butyric acid (1.92 g, 73%) was recovered by filtration. Mp 218–220° C., 1H NMR DMSO-d6) 12.1 (1H, OHacid), 9.93 (1H, s, NH), 9.48 (1H, s, NH), 8.64 (1H, d, 5 Hz), 8.24 (1H, d, 5 Hz), 8.0 (1H, s), 7.76 (2H, m), 7.46 (1H, d, 5 Hz), 7.38 (1H, dd, 2 Hz, 5 Hz), 7.30 (1H, t, 8 Hz), 6.98 (1H, dd, 1 Hz, 8 Hz), 2.51 (4H, s), 1.92 (3H, s), 13C NMR (DMSO-d6 176.2, 164.6, 161.6, 161.2, 150.5, 150.1, 147.5, 144.0, 134.9, 132.1, 122.97, 120.13, 119.2, 113.7, 111.1, 105.9, 35.33 (CH2), 32.56(CH2), 18.09 (CH3), MS (ES−) 409 (M−1, 100), 819 (2M−1, 30). The 4-({4-[2-(3-Chloro-phenylamino)-pyrimnidin-4-yl]-pyridin-2-yl}-hydrazono)-4-methyl-butyric acid (1.5 g) was dissolved in acetic acid (40 mL). The solution was stirred at 110° C. for 3 h then the solution was poured in a mixture of water and ice (250 mL) and neutralised with a solution saturated of sodium hydrogenocarbonate until pH 7. The mixture was extracted with ethyl acetate (3×100 mL). The organic phase were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-tetrahydrofuran (3-1), afforded the title compound as a solid (0.7263 g, 51%). Mp 189–192° C., 1H NMR (DMSO-d6) 10.07(1H, NH), 8.73 (1H, d, 5 Hz), 8.69 (1H, d, 5 Hz), 8.16 (1H, s), 8.06 (2H, m), 7.73 (1H, dd, 3 Hz, 10 Hz), 7.60(1H, d, 5 Hz), 7.31 (1H, t, 8 Hz), 7.03(1H, dd, 3 Hz, 8 Hz), 2.63 (4H, m), 2.07 (3H, s). 13C NMR (DMSO-d6) 165.3, 160.3, 159.6, 159.3, 154.9, 153.9, 149.0, 141.1, 132.5, 129.7, 120.7, 119.2, 117.8, 117.6, 116.7, 108.66, 26.4, 25.3, 22.0. MS (ES+) 393 (MH+, 100), 785 (2 MH+, 60).
To a suspension of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (2 g) in n-Butanol (40 mL) was added of 1.14 g of 3-benzoylpropionic acid. The mixture was heated at reflux. After 3 h, the mixture was cooled at 0° C. and the 4-({4[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-phenyl-butyric acid (2.19 g, 72%) was recovered by filtration. Mp 144–146° C., 1H NMR (DMSO-d6).12.0 (1H, OH), 10.4 (1H, s, NH), 10.1 (1H, s, NH), 8.77 (1H, d, 5 Hz), 8.42 (1H, d, 5 Hz) 8.12 (1H, s), 8.06 (1H, s), 7.80 (3H, m), 7.6 (1H, d, 5 Hz) 7.53 (1H, d, 5 Hz), 7.45 (3H, m), 7.34 (1H, t, 8 Hz), 7.08 (1H, m) 3.4 (2H, m), 2.95 (2H, m), MS (ES+) 473 (MH+, 100),. MS (ES−) 471 (M−1, 100). To a solution of 4-({4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-hydrazono)-4-phenyl-butyric acid (0.48 g) in tetrahydrofuranne (40 mL) was additionned N,N′-dicyclohexylcarbodiimide (0.23 g) and 1-Hydroxybenzotriazole (0.1401 g). The solution was stirred at reflux for 2 h then the solvent was evaporated. The crude was chromatographied, eluting with ethyl acetate to gave the title compound as a solid (0.3366 g, 78%). Mp 165–167° C., 1H NMR (CDCl3) 9.6 (1H,s, NH), 8.76 (1H, d, 5 Hz), 8.59 (1H, d, 5 Hz), 8.21 (1H, s), 7.86 (4H, m), 7.44 (4H, m), 7.26 (2H, m), 7.01 (1H, m), 3.18 (2H, t, 8 Hz), 2.87 (2H, t, 8 Hz). 13C NMR (CDCl3) 166.3, 162.4, 160.4, 159.8, 154.8, 152.9, 150.1, 146.7, 140.9, 135.7, 134.9, 130.5, 130.3, 129.0, 126.7, 122.9, 120.1, 119.6, 118.8, 117.55, 109.6, 28.4, 23.6. MS (ES+) 455 (MH+, 100), 909 (2 MH+, 10).
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in ethanol (10 mL) was added of 0.220 mg of potassium carbonate. The mixture was heated to reflux for 4 h. The suspension was poured into water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-hexane (9:1), afforded the title compound as a solid (0.130 g, 35%). Mp 196–198° C., 1H NMR (CDCl3) 8.80 (1H, d, 3 Hz), 8.60 (1H, d, 6 (1H, s), 8.02 (2H, d, m), 7.93 (1H, s), 7.46 (1H, dd, 6 Hz, 3 Hz), 7.31 (1H,m), 7.29 (1H, d 3 Hz), 7.28 (1H, s), 4.43 (2H, q, 6 Hz), 1.56 (3H, t, 6 Hz).
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in acetonitrile (10 mL) was added of 0.15 mL of ethylmercaptan and 0.280 mg of potassium carbonate. The mixture was heated to reflux for 2 h. The suspension was filtered and the solid was washed with ethyl acetate to gave the title compound (0.220 g, 46%). Mp 80–100° C., 1H NMR (DMSO-d6) 8.8 (1H, d, 3 Hz), 859 (1H, d, 6 Hz), 8.37 (1H, s, NH), 7.98 (1H, d, 6 Hz, 3 Hz), 7.92 (1H, t, 3 Hz), 7.86 (1H, s), 7.46 (1H, d, 9 Hz, 3 Hz), 7.40 (1H,s), 7.27(2H, m), 7.04(1H, d, 9 Hz), 3.12 (2H, q, 6 Hz), 1.47 (3H, t, 6 Hz).
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in acetonitrile (10 mL) was added of 0.09 g of sodium azide. The mixture was heated to reflux for 4 h. The suspension was filtered to give the title compound as a solid (0.280 g, 95%). Mp 184–186° C., 1H NMR (DMSO-d6) 10.1 (1H, s, NH), 8.75 (1H, d, 6 Hz), 8.67 (1H, d, 3 Hz), 8.28 (1H, s), 8.27 (1H, s), 8.18(1H, dd, 1 Hz, 3 Hz), 7.97 (1H, m), 7.65 (1H, dd), 7.57(1H, d, 6 Hz), 7.25 (1H, t, 9 Hz), 6.94 (1H, dd).
A suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in cyclopropylamine (10 mL) was heated at reflux for 2 h. The solvent was evaporated under vacuum. Flash silica chromatography, eluting with ethyl acetate-hexane (1:1), afforded the 5-Chloro-4-cyclopropylamin-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one as a solid (Mp 117–121° C., 0.082 g, 26%) and the 5-cyclopropylamin-4-chloro-2-{4-[2-(3-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (Mp 90–100° C., 0.180 g, 58%) as a solid.
To a solution of butanol (0.18 mL) in tetrahydrofuran (40 mL) was added a solution of Lithium diisopropylamide (1.5 M, 1.3 mL) at room temperature. The solution was stirred for 15 minutes followed by the addition of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.7 g). The mixture was heated at 85° C. for 1 h. The suspension was poured into brine (200 mL) and extracted with ethyl acetate (3×100 mL). The organic phase were combined, dried over MgSO4, and concentrated under vacuum. Flash silica chromatography, eluting with ethyl acetate-cyclohexane (1:1), afforded the title compound as a solid (0.4128 g, 55%). Mp 118-127° C.
To a solution of succinic anhydride (2.16 g) in chloroform (60 mL) 1.16 mL of methyl hydrazine were added at room temperature. The solution was stirred 2 h at room temperature then heated at reflux for 1 h. The solvent was evaporated. 1 g of the obtained solid was dissolved in tetrahydrofuran (10 mL) followed by the addition of 1.55 g of N,N′-dicyclohexylcarbodiimide and 1.01 g of 1-hydroxybenzotriazole. The mixture was heated at reflux for 1 h. The mixture was cooled to 0° C. and a solution of oxalic acid (0.617 g) in methanol was added. The suspension was filtered and the solvent was evaporated. Flash silica chromatography, eluting with ethyl acetate-methanol (5%), afforded the 1-Methyl-tetrahydro-pyridazine-3,6-dione as a solid (0.4128 g, 24%). 0.014 g of Pd(dba)3 and xantphos (0.018 g) were dissolved in toluene (2 mL). The mixture was stirred at room temperature for 20 minutes. Then the 1-Methyl-tetrahydro-pyridazine-3,6-dione, the (3-Chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (0.2 g) and sodium terbutanolate (0.085 g) were added. The mixture was heated at reflux for 2 h. The suspension was poured into water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated. Flash silica chromatography, eluting with ethyl acetate, afforded the title compound as a solid (0.169 g, 65%). Mp 201–204° C.
The compounds in the following Tables further illustrate the invention
Compounds of general structure I are any combination of the definitions given in Table A and the appropriate Table B, wherein n, R10, m and R1 correspond with a line of Table A and wherein R2–R9 and p correspond with a line of the appropriate Table B.
For the following example compounds physico-chemical data have been obtained and are displayed in order to illustrate the working of the present invention, including the outlined methods of synthesis. The number of given data may not be interpreted as a limitation of the invention. Analysis of compounds 6.610 to 6.684: Reversed-phase was performed on a Waters Alliance 2790 LC equiped with a Waters996 UV detector using a YMC CombiScreen ODS-AQ cartridge (30×4.6 mm, S-5 □m, 12 um) Mobile phase: A: H2O/CH3CN 10/TFA, B: CH3CN/TFA 0., C: MeOH.Gradient: 89% A 11% B, 0–3.5 min; 90% B 10% C 0.5 min.
In the following, examples of test systems in plant protection are provided which can demonstrate the efficiency of the compounds of the formula I (designated as “active ingredient” or “test compounds”):
a) Residual Protective Activity
1 week old wheat plants cv. Arina are treated with the formulated test-compound (0.02% active substance) in a spray chamber. Two days after application wheat plants are inoculated by spraying a spore suspension (1×105 ureidospores/ml) on the test plants. After an incubation period of 1 day at +20° C. and 95% relative atmospheric humidity (r. h.) plants are kept for 9 days at +20° C. and 60% r.h. in a greenhouse. The disease incidence is assessed 10 days after inoculation.
At the indicated concentration compounds 1.01/028; 2.02/028; 1.03/028; 1.07/028; 2.03/028; 2.05/028; 2.06/028 exhibited over 70% control of the fungal infection in this test.
a) Residual Protective Activity
3 week old tomato plants cv. Roter Gnom are treated with the formulated test compound (0.02% active substance) in a spray chamber. Two day after application the plants are inoculated by spraying a sporangia suspension (2×104 sporangia/ml) on the test plants. After an incubation period of 4 days at +18° C. and 95% r. h. in a growth chamber the disease incidence is assessed.
At the indicated concentration compounds 1.01/028; 1.03/028; 1.04/028; 1.07/028 exhibited over 70% control of the fungal infection in this test.
5 week old potato plants cv. Bintje are treated with the formulated test compound (0.02% active substance) in a spray chamber. Two days after application the plants are inoculated by spraying a sporangia suspension (1.4×105 sporangia/ml) on the test plants. After an incubation period of 4 days at +18° C. and 95% r. h. in a growth chamber the disease incidence is assessed.
5 week old grape seedlings cv. Gutedel are treated with the formulated test compound (0.02% active substance) in a spray chamber. One day after application grape plants are inoculated by spraying a sporangia suspension (4×104 sporangia/ml) on the lower leaf side of the test plants. After an incubation period of 6 days at +22° C. and 95% r. h. in a greenhouse the disease incidence is assessed.
At the indicated concentration compounds 1.01/028;3.01/028; 1.04/028 exhibited over 70% control of the fungal infection in this test.
4 week old apple seedlings cv. McIntosh are treated with the formulated test compound (0.02% active substance) in a spray chamber. One day after application apple plants are inoculated by spraying a spore suspension (4×105 conidia/ml) on the test plants. After an incubation period of 4 days at +20° C. and 95% r. h. the plants are transferred to standard greenhouse conditions at 20 and 60% r.h. where they stayed for 2 days. After another 4 day incubation period at +20° C. and 95% r. h. the disease incidence is assessed. At the indicated concentration compounds 2.03/028; 1.001/028 exhibited over 70% control of the fungal infection in this test.
a) Residual Protective Activity
Barley plants, cv. Regina of approximately 8 cm height were treated with the formulated test compound (0.02% active substance) in a spray chamber and duste 2 days after inoculation with conidia of the fungus. The infected plants are placed in a greenhouse at +20° C. 6 days after infection, the fungal attack was evaluated.
At the indicated concentration compounds 1.01/028; 1.03/028; 1.04/028, 2.05/028; 2.09/028; 3.014/028; 3.030/028 exhibited over 70% control of the fungal infection in this test.
5 week old grape seedlings cv. Gutedel are treated with the formulated test compound (0.02% active substance) in a spray chamber. Two days after application grape plants are inoculated by spraying a spore suspension (1.5×105 conidia/ml) on the test plants. After an incubation period of 3 days at +21° C. and 95% r. h. in a greenhouse the disease incidence is assessed.
At the indicated concentration compounds 1.01/028; 1.03/028; 1.04/028, 1.05/028; 1.06/028, 1.07/028;2.03/028; 2.05/028; 2.08/048; 2.09/028; 3.012/028; 3.013/028;3.014/028; 2.012/028 exhibited over 70% control of the fungal infection in this test.
4 week old tomato plants cv. Roter Gnom are treated with the formulated test compound 0.02% active substance) in a spray chamber. Two days after application tomato plants are inoculated by spraying a spore suspension (1×105 conidia/ml) on the test plants. After an incubation period of 4 days at +20° C. and 95% r. h. in a greenhouse the disease incidence is assessed.
At the indicated concentration compounds 1.01/028; 2.02/028; 3.01/028; 1.04/028; 1.06/028; 2.06/028; 2.05/028; 2.08/048; 4.02/028; 7.270/028 exhibited over 70% control of the fungal infection in this test.
3 week old rice plants cv. Sasanishiki are treated with the formulated test compound (0.02% active substance) in a spray chamber. Two days after application rice plants are inoculated by spraying a spore suspension (1×105 conidia/ml) on the test plants. After an incubation period of 6 days at +25° C. and 95% r. h. the disease incidence is assessed. At the indicated concentration compounds 1.02/028; 1.04/028; 2.03/028; 2.06/028; 2.07/028 exhibited over 70% control of the fungal infection in this test.
1 week old barley plants cv. Regina are treated with a formulated test compound (0.02% active substance) in a spray chamber. Two days. after application barley plants are inoculated by spraying a spore suspension (3×104 conidia/ml) on the test plants. After an incubation period of 2 days at +20° C. and 95% r.h. the disease incidence is assessed.
At the indicated concentration compounds 1.01/028; 2.02/028; 3.01/028; 5.01/028; 1.03/028; 1.04/028, 1.01/048; 1.06/028, 1.07/028; 1.08/028; 2.03/028; 2.05/028; 2.07/028; 2.08/048; 2.09/028; 3.012/028; 3.013/028; 3.014/028; 2.012/028; 2.011/028; 3.016/028; 3.017/0283.027/028; 3.028/028; 7.270/028 exhibited over 70% control of the fungal infection in this test.
A conidia suspension of F. culmorum (7×105 conidia/ml) is mixed with the formulated test compound (0.002% active substance). The mixture is applied into a pouch which has been equipped before with a filter paper. After the application wheat seeds (cv. Orestis) are sown into the upper fault of the filter paper. The prepared pouches are then incubated for 11 days at approx. +10° C. to +18° C. and a relative humidity of 100% with a light period of 14 hours. The evaluation is made by assessing the degree of disease occurrence in the form of brown lesions on the roots.
1 week old wheat plants cv. Arina are treated with a formulated test compound (0.02% active substance) in a spray chamber. One day after application wheat plants are inoculated by spraying a spore suspension (6×105 conidia/ml) on the test plants. After an incubation period of 1 day at +22° C. and 95% r.h. plants are kept for 7 days at +22° C. and 60% r.h. in a greenhouse. The disease incidence is assessed 8 days after inoculation.
At the indicated concentration compounds 1.01/028; 2.02/028; 3.01/028; 5.01/028; 1.03/028; 1.06/028, 1.07/028; 2.03/028; 2.04/028; 2.05/028; 2.06/028; 2.09/028; 3.012/028; 2.012/028; 3.028/028 exhibited over 70% control of the fungal infection in this test.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0129391.9 | Dec 2001 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB02/05148 | 12/5/2002 | WO | 00 | 6/3/2004 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO03/047347 | 6/12/2003 | WO | A |
| Number | Date | Country |
|---|---|---|
| 0431421 | Jun 1991 | EP |
| 9509847 | Apr 1995 | WO |
| 0193682 | Dec 2001 | WO |
| 02053560 | Jul 2002 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050085496 A1 | Apr 2005 | US |
