WO2002074084A1

WO2002074084A1 - Neorustmicin d derivatives as fungicides

Info

Publication number: WO2002074084A1
Application number: PCT/EP2002/002744
Authority: WO
Inventors: Andreas Gypser; Ingo Rose; Eberhard Ammermann; Siegfried Strathmann; Gisela Lorenz; Reinhard Stierl; John-Bryan Speakman
Original assignee: Basf Aktiengesellschaft
Priority date: 2001-03-15
Filing date: 2002-03-13
Publication date: 2002-09-26

Abstract

The invention relates to novel neorustmicin D derivatives of formula (I) wherein the substituents have the following designations: R1 represents hydrogen or -C(=O)R4; R2 represents =NOR5 or =O; R3 represents hydrogen or -C(=O)R6; R4 represents hydrogen, C¿1?-C6 alkyl, phenyl or substituted phenyl; R?5¿ represents hydrogen, C¿1?-C6 alkyl, C1-C6 alkylphenyl or substituted C1-C6 alkylphenyl; and R?6¿ represents hydrogen, C¿1?-C6 alkyl, phenyl or substituted phenyl. The invention also relates to the agriculturally and/or pharmaceutically useful salts of said derivatives, with the exception of neorustmicin D. Further disclosed are fungicidally active agrochemical compositions, pharmaceutical compositions containing a compound of formula (I), and a method for controlling pathogenic fungi.

Description

NEORUSTMICIN D DERIVATIVES AS FUNGICIDES

description

The present invention relates to neorustmicin D derivatives of the formula I.

where the substituents have the following meanings:

R ^{1 is} hydrogen or -C (= 0) R ⁴ ;

R ² = NOR ⁵ or = 0;

R ^{3 is} hydrogen or -C (= 0) R ⁶ ;

R ^{4 is} hydrogen, Ci-C _ß- alkyl, phenyl or substituted phenyl;

R ^{5 is} hydrogen, Ci-Ce-alkyl, -C-C ₆ alkylphenyl or substituted Ci-Cg-alkylphenyl;

R ^{6 is} hydrogen, -CC ₆ alkyl, phenyl or substituted phenyl,

and their agriculturally and / or pharmaceutically usable salts, with the exception of Neorustmicin D,

as well as fungicidal agrochemical compositions and pharmaceutical compositions containing these neorustmicin D derivatives.

The compounds galbonolide A (rustmicin) and galbonolide B are known from the prior art from the group of polyketides (J. Antibiotics 1985, 38 1807 and J. Antibiotics 1986, 39 1760). illustration 1

Galbonolide A Galbonolide B Galbonolide C Rustmicin Neorustmicin A

The compounds show fungicidal activity against various pathogens in the human field (Candida species, Fusarium, Rhodotorula) and agricultural areas, in particular Botrytis cϊnerea and Puccinia graminis. JP 60-6197 (Meji Seika) describes the fermentation of rustmicin and galbonolide B from Micromomospora chalcea and use against rust fungi (Puccinia graminis) on wheat. DE-A-3632168 describes the fermentation of rustmicin and galbonolide B from Streptomyces galbus and its use as a fungicide against gray mold (Botrytis cinerea). It is also taught that the compounds derivatized as ester, ether or salt on the two hydroxy groups have fungicidal activity.

In the vicinity of these compounds, there are other derivatives, the so-called neorustmicins. Neorustmicin A is described in Annais of the NY Academy of Sciences 1988, 544, 128 with the structure shown in Fig. 1. In J. Antibiotics 1985, 38, 1810 the structure of galbonolide B was postulated for neorustmicin A. In the present application, the nomenclature used in Chemical Abstracts (CA) is used (see Fig. 1).

The structures of the neorustmicins B, C and D (J. Antibiotics 1986, 39, 1016) are given in Fig. 2.

Figure 2

Neorustmicin B Neorustmicin C Neorustmicin D GB-A-2324300 describes two further derivatives obtained from rustmicin or galbonolide B by biotransformation (see FIG. 3) and their preparation (see also J. Antibiotics 1998, 51, 837).

US Pat. No. 5,948,770 describes further derivatives which differ structurally in particular by the use of longer alkyl or alkoxy radicals. In addition, the macrocycle can also be closed by a lactam instead of a lactone ring (Fig. 4).

Figure 4

-Alkyl ₆ -alkyl, -CC ₆ -C ₆ -alkoxy -alkyl-alkyl

In two further publications (J. Antibiotics 1998, 51, 837; J. Biol. Chem. 1998, 273, 14942) it is described that rustmicin and the derivatives derived therefrom develop their biological action by inhibiting the enzyme inositol phosphorylceramide synthase.

It is also known from the literature (Annais of the NY Academy of Sciences 1988, 544, 128) that rustmicin and its derivatives are not chemically stable.

The enol ether functionality is split into the ketone under the influence of aqueous acids. Cyclization to furan takes place under anhydrous conditions. Bases such as pyridine cause epimerization of the C2 atom, conditions such as potassium carbonate / methanol cleave the macrolactone ring and lead to the formation of a δ-valerolactone within two minutes, which no longer exhibits any fungicidal activity. J. Biol. Chem. 1998, 273, 14942 states that the half-life of rustmicin in new tral solution is 80 min. The highest stability can be found at pH 5.5. In view of the low stability of these macrolides, their use as active ingredients in the agrochemical or pharmaceutical industry is not suitable for the production of agrochemical compositions or of medicaments.

The problem underlying the present invention was to provide new macrolides which have increased stability compared to the known, not sufficiently stable macrolides and at the same time show good fungicidal activity.

This problem was solved by the neorustmicin D derivatives according to the invention which no longer have a 1,3-dicarbonyl unit.

The loss of a hydroxymethyl group and the changed position of the hydroxyl group results in more favorable biophysical properties of the target molecules.

In the definitions of the symbols given in the formulas, collective terms were used which generally stand for the following substituents:

- Cχ-C6-alkyl for a straight-chain or branched alkyl radical with 1-6 C atoms, such as Methyl, ethyl, n-propyl, 1-methyl-ethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl, especially for ethyl;

- Phenyl for a phenyl radical which is unsubstituted or can be substituted one or more times, in particular one to three times. The substituents are arbitrary and can be ortho, meta or para; such as halogen atoms, nitro groups, Ci-C _ß- alkyl, halogen -CC ₆ -alkyl, -C-C ₆ -alkoxy, C3-C ₆ -haloalkoxy, -C-C ₆ -alkylthio, -C-C ₆ -Alkylsulfonyl, Ci-C _δ -Halogenalkylsulfonyl, as mentioned above;

Halogen generally represents fluorine, chlorine or bromine;

-C 1 -C ₆ haloalkyl for a C ₁ -C ₆ alkyl radical as mentioned above which is partially or completely substituted by fluorine, chlorine, bromine and / or iodine, such as trichloromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2,2,2-trichloroethyl, 2-fluoropropyl, 3-fluoropropyl, 2-chloropropyl or 3-chloropropyl, in particular for 2-fluoroethyl or 2-chloroethyl; C ₁ -C ₆ alkoxy for a straight-chain or branched C ₁ -C ₆ alkoxy radical, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or i, 1-dimethylethoxy, especially for methoxy or ethoxy;

Halogen-Ci-C _δ- alkoxy for a -CC ₆ alkoxy radical as mentioned above, which is substituted one or more times by fluorine, chlorine or bromine, for example trifluoromethoxy;

C ₁ -C ₆ -alkylthio for a straight-chain or branched Ci-Ce-alkyl hiorest, such as methylthio, ethyl hio, n-propylthio, 1-methylethylthio, n-butylthio, 1-methythio, 2-methylpropylthio or 1, 1 -Dirnethylethylthio, especially for methylthio or ethylthio;

C ₁ -C ₆ -alkylsulfonyl for a straight-chain or branched Ci-C _δ -alkylsulfonyl radical, such as, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, 1-methylethylsulfonyl, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropyl or 1-methylpropyl 1-dimethylethylsulfonyl, especially for methylsulfonyl or ethylsulfonyl;

Halogen -CC ₆ alkylsulfonyl for a C ₆ -C ₆ alkylsulfonyl radical as mentioned above, which is substituted one or more times by fluorine, chlorine or bromine.

The compounds of the formula I can also be in the form of their agriculturally and / or pharmaceutically acceptable salts, the type of salt generally not being important. In general, the salts of those cations or the acid addition salts of those acids whose cations or anions do not adversely affect the fungicidal activity of the compounds I are suitable.

As agriculturally usable cations there are in particular ions of the alkali metals, preferably lithium, sodium and potassium, the alkaline earth metals, preferably calcium and magnesium, and the transition metals, preferably manganese, copper, zinc and iron, and ammonium, with one to four hydrogen atoms if desired Cι-C ₄ alkyl, hydroxy-Cι-C ₄ alkyl, C ₁ -C ₄ -AI- koxy-Ci-Cj-alkyl, hydroxy-C ₁ -C ₄ -alkoxy-Cι-C ₄ alkyl, phenyl or benzyl may be replaced, preferably ammonium, dimethylammonium, diisopropylammonium, tetramethylammonium, tetrabutylammonium, 2- (2-hydroxyeth-l-oxy) eth-1-ylammonium, di (2-hydroxyeth-l-yl) ammonium, trimethylbenzylammonium, furthermore, phosphonium ions, sulfonium ions, preferably tri (C ₁ -C ₄ alkyl) sulfonium and sulfoxonium ions, preferably tri (-C ₄ -al yl) sulfoxonium, into consideration.

Anions of acid addition salts which can be used in agriculture are primarily chloride, bromide, fluoride, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, nitrate, hydrogen carbonate, carbonate, hexaflourosilicate, hexafluorophosphate, benzoate and the anions of C ₁ -C ₄ -alkanoic acids, preferably Formate, acetate, propionate and butyrate.

Suitable pharmaceutically usable cations are, in particular, ions of the alkali metals, preferably sodium and potassium, and of the alkaline earth metals, preferably calcium and magnesium.

Pharmaceutically acceptable anions of useful acid addition salts are, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, lactate, citrate or hydrogen citrate, tartrate or bi-tartar, succinate, maleate, fumarate, gluconate, Saccharate, benzoate, methyl sulfonate, ethyl sulfonate, benzenesulfonate, p-toluenesulfonate and pamoates (e.g. 1, 1 '-methylene-bis- (2-hydroxy-3-nophthoate).

In the context of the present invention, the following compounds I and definitions of the radicals R ¹ -R ⁶ are preferably used alone or in combination with one another or in connection with the meanings of the various radicals or in the general description of the present invention their preferred meanings in question (Table 1):

Table 1

Also preferred are compounds with R ⁴ = hydrogen,

C ₃ -C ₆ alkyl or phenyl, where the phenyl radical can be unsubstituted or partially or completely halogenated and / or one to three substituents from the group C ₁ -C ₆ alkyl, halogen C ₁ -C ₆ alkyl, Ci-Ce-alkoxy, Cι-C ₆ -haloalkoxy, Ci-Cε-alkyl- thio, CC _δ- alkylsulfonyl and -C-C ₆ haloalkylsulfonyl can wear.

Also preferred are compounds with R ⁵ = hydrogen, Ci-Cβ-alkyl or Ci-Cβ-alkylphenyl, where the phenyl radical can be unsubstituted or partially or completely halogenated and / or one to three substituents from the group C ₁ -C ₆ alkyl, Halogen-Ci-C _δ- alkyl, Ci-C _ß -alkoxy, Ci-C _δ -haloalkoxy, Ci-C _ö alkylthio, Ci-Cβ-alkylsulfonyl and -C-C ₆ -haloalkylsulfonyl can wear.

Also preferred are compounds with R ⁶ = hydrogen, Ci-C _ß- alkyl or phenyl, where the phenyl radical can be unsubstituted or partially or completely halogenated and / or one to three substituents from the group Ci-Cβ-alkyl, halogen- can carry _Cι-C6 alkyl, Ci-Ce-alkoxy, Ci-Cβ-haloalkoxy, Cι-C ₆ -alkylthio, C _δ alkylsulfonyl and Ci-C _δ haloalkylsulfonyl.

For the purposes of the present invention, the following compounds are preferred as fungicidal active compounds:

I A

The following compounds of the formula IB are particularly preferred for the purposes of the present invention:

In addition, the following compounds of the formulas IC and ID are particularly preferred for the purposes of the present invention:

The compounds of the formula IA 1 are extraordinarily preferred (corresponds to formula IA with R ⁵ = CH ₃ )

I A 1

in particular the compounds I A 1. 1 to I A 1. 290 (Table 2)

Table 2

The compounds of the formula I A 2 are likewise preferred,

IA 2 in particular the compounds IA 2.1 to IA 2.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R5 is C ₂ H ₅ .

I A 3

in particular the compounds IA 3.1 to IA 3.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} nC ₃ H.

The compounds of the formula I A 4 are likewise preferred,

IA 4 in particular the compounds IA 4.1 to IA 4.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} iC ₃ H ₇ .

The compounds of the formula I A 5 are likewise preferred,

IA 5 in particular the compounds IA 5.1 to IA 5.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} nC ₄ H ₉ .

The compounds of the formula I A 6 are likewise preferred,

in particular the compounds IA 6.1 to IA 6.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} iC ₄ H ₉ .

The compounds of the formula I A 7 are likewise preferred,

I A 7

in particular the compounds IA 7.1 to IA 7.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} sC ₄ H ₉ . The compounds of the formula IA 8 are likewise preferred,

I A 8

in particular the compounds IA 8.1 to IA 8.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} tC ₄ Hg.

The compounds of the formula I A 9 are likewise preferred,

I A 9

in particular the compounds IA 9.1 to IA 9.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} nCsHi.

The compounds of the formula I A 10 are likewise preferred,

IA 10 in particular the compounds IA 10.1 to IA 10.290, which differ from the compounds IA 1.1 to IA 1.290 (Table 2) in that R ^{5 is} nC ₆ Hι ₃ .

The compounds of the formula IB are extraordinarily preferred

I B

in particular the compounds I B 1 to I B 290 (Table 3)

Table 3

0

_c The compounds of the formula IC are extremely preferred

in particular the compounds I C 1 to I C 17 (Table 4)

0 Table 4

5

0

5 The compounds of the formula ID are extraordinarily preferred

I D

in particular the compounds I D 1 to I D 17 (Table 5)

Table 5

The inventions according to the invention are synthesized analogously to the synthesis described from neorustmicin D, which is accessible via the fermentation process described in J. Antibiotics 1986, 1016.

The compounds of type IB are accessible via the sequential (if R ^{4 is} not equal to R ⁶ ) or simultaneous protection of the hydroxyl groups (in all cases R ^{4 is} equal to R ⁶ ).

The easy-derivatized Neorustmicin D analogues are doing by reacting Neorustmicin D with acid chlorides (under Schotten-Baumann or Einhorn conditions Protective Groups in Organic Synthesis, 2 ed ^nä, Wiley & Sons Inc, NY., 1991.) In the stati - synthetic mixture synthesized. The resulting three products can be separated from each other by chromatography.

Neorustmicin D I C I D

The differently substituted derivatives I B can then be prepared from I C or I D by reaction with a further acid chloride (see below).

I D

The structural variants of type I A are produced from the derivatives of type IB.

IB is first converted into the oxime ether by reaction with hydroxylamine hydrochloride. Polar solvents such as alcohols (e.g. methanol, ethanol) are suitable as solvents. The hydroxylamine salt is usually used in excess. The subsequent etherification of the hydroxyl group with alkyl halide and a base gives the oxime ether I A. Polar aprotic solvents such as, for. B. Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) in question. Suitable bases are alkali metal carbonates, e.g. B. potassium carbonate, sodium carbonate. As a rule, the alkyl halide is used in excess.

I B I A

The compounds according to the invention are distinguished by better stability compared to the neorustmicin derivatives known from the prior art. The half-life at pH 7 is the appropriate criterion for characterizing the stability. While the half-life of neorustmicin A at pH 7 is 80 min, the compounds according to the invention have a half-life increased by at least 20%.

The compounds I are distinguished by an excellent action against a broad spectrum of phytopathogenic fungi, in particular from the class of the Ascomycetes, Deuteromycetes, Phycomycetes and Basidiomycetes. They are partly systemically effective and can therefore also be used as leaf and soil fungicides.

Usually the plants are sprayed or dusted with the active ingredients or the seeds of the plants are treated with the active ingredients.

The formulations (fungicidal agents) are prepared in a known manner, e.g. by stretching the active ingredient with solvents and / or carriers, if desired using emulsifiers and dispersants, and in the case of water as diluent other organic solvents can also be used as auxiliary solvents. The following are essentially considered as auxiliaries: solvents such as aromatics (e.g. xylene), chlorinated aromatics (e.g. chlorobenzenes), paraffins (e.g. petroleum reactions), alcohols (e.g. methanol, butanol), ketones (e.g. cyclohexanone), amines (e.g. Ethanolamine, dimethylformamide) and water; Carriers like natural

Rock meal (e.g. kaolins, clays, talc, chalk) and synthetic rock meal (e.g. highly disperse silica, silicon Kate); Emulsifiers such as nonionic and anionic emulsifiers (eg polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates) and dispersants such as lignin sulfite waste liquors and methyl cellulose.

The alkali, alkaline earth, ammonium salts of aromatic sulfonic acids, e.g. Lignin, phenol, naphthalene and dibutylnaphthalenesulfonic acid, as well as of fatty acids, alkyl and alkylarylsulfonates, alkyl, lauryl ether and fatty alcohol sulfates, and salts of sulfated hexa-, hepta- and octadecanols, as well as fatty alcohol glycol ethers, condensation products of sulfonated naphthalene and its derivatives with formaldehyde, condensation products of naphthalene or naphthalenesulfonic acids with phenol and formaldehyde, polyoxyethylene octylphenol ether, ethoxylated iso-octyl, octyl or nonylphenol, alkylphenol, tributylphenyl polyglycol ether, alkyl aryl polyether alcohols, iso-tridecyl alcohol, ethoxylated fatty alcohol alcohol Castor oil, polyoxyethylene alkyl ether or polyoxypropylene, lauryl alcohol polyglycol ether acetate, sorbitol ester, lignin sulfite waste liquor or methyl cellulose.

Powders, materials for broadcasting and dusts can be prepared by mixing or grinding the active substances together with a solid carrier.

Granules, e.g. Coated, impregnated and homogeneous granules can be produced by binding the active ingredients to solid carriers. Solid carriers are mineral earths such as silica gel, silicas, silica gels, silicates, talc, kaolin, limestone, lime, chalk, bolus, loess, clay, dolomite, diatomaceous earth, calcium and magnesium sulfate, magnesium oxide, ground plastics, fertilizers such as Ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas and vegetable products, such as corn flour, tree bark, wood and nutshells, cellulose powder or other solid carriers.

Examples of such preparations are:

I. a solution of 90 parts by weight of a compound I according to the invention and 10 parts by weight of N-methyl-2-pyrrolidone, which is suitable for use in the form of tiny drops;

II. A mixture of 10 parts by weight of a compound I according to the invention, 70 parts by weight of xylene, 10 parts by weight of the adduct of 8 to 10 moles of ethylene oxide

1 mol of oleic acid-N-monoethanolamide, 5 parts by weight of calcium salt of dodecylbenzenesulfonic acid, 5 parts by weight of Storage product of 40 moles of ethylene oxide with 1 mole of castor oil; A dispersion is obtained by finely distributing the solution in water.

III. an aqueous dispersion of 10 parts by weight of a compound I according to the invention, 40 parts by weight of cyclo-hexanone, 30 parts by weight of isobutanol and 20 parts by weight of the adduct of 40 mol of ethylene oxide and 1 mol of castor oil;

IV. An aqueous dispersion of 10 parts by weight of a compound I according to the invention, 25 parts by weight of cyclohexanol, 55 parts by weight of a mineral oil fraction with a boiling point of 210 to 280 ° C. and 10 parts by weight of the addition product of 40 moles of ethylene oxide with 1 mole of castor oil;

V. a mixture of 80 parts by weight of a preferably solid compound I according to the invention, 3 parts by weight of the sodium salt of di-isobutylnaphthalene-2-sulfonic acid, 10 parts by weight of a

Sodium salt of a lignin sulfonic acid from a sulfite waste liquor and 7 parts by weight of powdered silica gel; a spray mixture is obtained by finely distributing the mixture in water;

VI. an intimate mixture of 3 parts by weight of a compound I according to the invention and 97 parts by weight of finely divided kaolin; this dust contains 3% by weight of active ingredient,

VII. An intimate mixture of 30 parts by weight of a compound I according to the invention, 62 parts by weight of powdered silica gel and 8 parts by weight of paraffin oil which was sprayed onto the surface of this silica gel; this preparation gives the active ingredient good adhesion;

VIII. A stable aqueous dispersion of 40 parts by weight of a compound I according to the invention, 10 parts by weight of the sodium salt of a phenolsulfonic acid-urea-formaldehyde condensate, 2 parts by weight of silica gel and 48 parts by weight of water can be further diluted;

IX. a stable oily dispersion of 20 parts by weight of a compound I according to the invention, 2 parts by weight of the calcium salt of dodecylbenzenesulfonic acid, 8 parts by weight of fatty alcohol polyglycol ether, 20 parts by weight of the sodium salt a phenolsulfonic acid-urea-formaldehyde condensate and 50 parts by weight of a paraffinic mineral oil.

The compounds I are of particular importance for combating a large number of fungi on various crops such as wheat, rye, barley, oats, rice, corn, lawn, cotton, soybeans, coffee, sugar cane, wine, fruit and ornamental plants and vegetable plants such as cucumbers Beans and pumpkin plants, as well as on the seeds of these plants.

The compounds are used by treating the fungi or the seeds, plants, materials or the soil to be protected against fungal attack with a fungicidally active amount of the active compounds. It is used before or after the infection of the materials, plants or seeds by the fungi.

The new compounds are particularly suitable for combating the following plant diseases: Erysiphe graminis (powdery mildew) in cereals, Erysiphe cichoracearum and Sphaerotheca fuliginea on pumpkin plants, Podosphaera leucotricha on apples, Uncinula necator on vines, Puccinia species on cotton crops and lawn, Ustilago species on cereals and sugar cane, Venturia inaequalis (scab) on apples, Helminthosporium species on cereals, Septoria nodorum on wheat, Botrytis cinerea (gray mold) on strawberries, vines, ornamental plants and vegetables, Cercospora arachidicola on peanuts, Pseudocercosella herpotrichoides on wheat, barley, Pyricularia oryzae on rice, Phytoph thora infestans on potatoes and tomatoes, Fusarium and Verticillium species on various plants, Plasmopara vi ticola on vines, AIfcernaria species on vegetables and fruit.

The fungicidal compositions generally contain between 0.1 and 95, preferably between 0.5 and 90% by weight of active ingredient.

Depending on the type of effect desired, the application rates are between 0.025 and 2, preferably 0.1 to 1 kg of active ingredient per ha.

In the case of seed treatment, amounts of active compound of 0.001 to 50, preferably 0.01 to 10 g per kg of seed are generally required.

In the use form as fungicides, the compositions according to the invention can also be present together with other active compounds, for example with herbicides, insecticides, growth regulators, fungicides or else with fertilizers. When mixed with fungicides, the fungicidal activity spectrum is enlarged in many cases.

The following list of fungicides with which the compounds according to the invention can be used together is intended to explain the possible combinations, but not to limit it:

Sulfur, dithiocarbamates and their derivatives, such as ferridimethyldithiocarbamate, zinc dimethyldithiocarbamate, zinc ethylene bisdithiocarbamate, manganese ethylene bisdithiocarbamate, manganese-zinc ethylenediamin-bis-dithiocarbamate, tetramethylthiurium -diamid-dibi-ethamidulfide ), Ammonia complex of zinc (N, N '-propylene-bis-dithiocarbamate), zinc (N, N'-propylene-bis-dithiocarbamate), N,' -polypropylene-bis- (thio-carbamoyl) - disulfide;

Nitroderivate, such as dinitro- (1-methylheptyl) phenyl crotonate, 2-sec-butyl-4, 6-dinitrophenyl-3, 3-dimethylacrylate, 2-sec-butyl-4, 6-dinitrophenyl-iso-propyl carbonate, 5- Nitro-iso-phthalic acid di-iso-propyl ester;

heterocyclic substances, such as 2-heptadecyl-2-imidazoline acetate, 2, 4-dichloro-6- (o-chloroanilino) -s-triazine, 0.0-diethyl-phthalimidophosphonothioate, 5-amino-l- [bis - (dimethylamino) phosphinyl] -3-phenyl-l, 2, 4-triazole, 2, 3-dicyano-l, 4-di-thioanthraquinone, 2-thio-l, 3-dithiolo [4, 5- b] quinoxaline, 1- (butyl-carbamoyl) -2-benzimidazole-carbamic acid methyl ester, 2-methoxycarbonylamino-benzimidazole, 2- (furyl- (2)) -benzimidazole, 2- (thiazolyl- (4)) -benzimidazole, N- (1, 1,2, 2-tetrachloroethylthio) tetrahydrophthalimide, N-trichloromethylthio-tetrahydrophthalimide, N-trichloromethylthio-phthalimide, N-dichlorofluoroethylt-hio-N ', N' -dimethyl-N-phenyl -sulfuric acid diamide, 5-ethoxy-3-tri-chloromethyl-1, 2, 3-thiadiazole, 2-rhodanmethylthiobenzothiazole, 1, 4-dichloro-2, 5-dimethoxybenzene, 4- (2-chlorophenyl-hydrazono) -3-methyl -5-isoxazolone, pyridine-2-thione-l-oxide,

8-hydroxyquinoline or its copper salt, 2, 3-dihydro-5-carbox-anilido-6-methyl-l, -oxathiin, 2, 3-dihydro-5-carbox-anilido-6-methyl-l, 4-oxathiine -4, 4-dioxide, 2-methyl-5, 6-di-hydro-4H-pyran-3-carboxylic acid anilide, 2-methyl-furan-3-carboxylic acid anilide, 2, 5-dimethyl-furan-3 -carboxylic acid anilide, 2,4,5-trimethyl-furan-3-carboxylic acid anilide, 2,5-dimethyl-furan-3-carboxylic acid-cyclohexylamide, N-cyclohexyl-N-methoxy-2,5-dimethyl-furan -3-carboxamide, 2-methyl-benzoic acid anilide, 2-iodo-benzoic acid aniide, N-formyl-N-morpholine-2, 2,2-trichloroethyl acetal, piperazine-l, 4-diylbis- (1- (2,2,2-trichloroethyl) for amide,

1- (3,4-dichloroanilino) -1-formylamino-2,2,2-trichloroethane, 2,6-dimethyl-N-tridecyl-morpholine or its salts, 2,6-dimethyl-N-cy- clododecyl-morpholine or its salts, N- [3- (p-tert-butylphenyl) -2-methylpropyl] -cis-2, 6-dimethylmorpholine, N- [3- (p-tert. -Bu- tylphenyl) -2-methylpropyl] piperidine, 1- [2- (2, -Dichlorophenyl) -4-ethyl-l, 3-dioxolan-2-yl-ethyl] -1H-1,2, 4-triazole 1- [2- (2,4-dichlorophenyl) -4-n-propyl-l, 3-dioxolan-2-yl-ethyl] -lH-l, 2,4-triazole, N- (n-propyl) - N- (2, 4, 6-trichlorophenoxyethyl) -N'-imidazol-yl urea, 1- (4-chlorophenoxy) -3, 3-dimethyl-l- (1H-1, 2, 4- triazol-l-yl) -2-butanone, (2-chlorophenyl) - (4-chlorophenyl) -5-pyrimidine-methanol, 5-butyl-2-dimethylamino-4-hydroxy-6-methylpyrimidine , Bis- (p-chlorophenyl) -3-pyridinomethanol, 1,2-bis- (3-ethoxycarbonyl-2-thioureido) -benzene, 1,2-bis- (3-methoxycarbonyl-2-thioureido) -benzene , [2- (4-chlorophenyl) ethyl] - (1, 1-dimethylethyl) -1H-1,2,4-triazole-1-ethanol, 1- [3- (2-chlorophenyl) -1- ( 4-fluorophenyl) oxiran-2-yl-methyl] -lH-l, 2,4-triazole, and

various fungicides, such as dodecylguanidine acetate,

3- [3- (3, 5-dimethyl-2-oxycyclohexyl) -2-hydroxyethyl] glutarimide,

Hexachlorobenzene, DL-methyl-N- (2,6-dimethyl-phenyl) -N-furoyl (2) -alaninate, DL-N- (2,6-dimethyl-phenyl) -N- (2'-methoxyace - tyl) -alanine methyl ester, N- (2, 6-dimethylphenyl) -N-chloroacetyl-D, L-2-aminobutyrolactone, DL-N- (2, 6-dimethylphenyl) -N- (phenylacetyl) - alanine methyl ester, 5-methyl-5-vinyl-3- (3, 5-dichlorophenyl) -2, 4-dioxo-l, 3-oxazolidine, 3- [(3, 5-dichlorophenyl) -5-methyl -5-methoxymethyl-l, 3-oxazolidin-2,4-dione, 3- (3,5-dichlorophenyl) -1-iso-propylcarbamoylhydantoin, N- (3,5-dichlorophenyl) -1,2-dimethylcyclopropane-l , 2-dicarboxylic acid imide, 2-cyano- [N- (ethylaminocarbonyl) -2-methoximino] acetamide, 1- [2- (2,4-dichlorophenyl) pentyl] -1H-1,2,4- triazole, 2,4-difluoro or a (1H-1,2,4-triazolyl-l-methyl) -benzhydryl alcohol,

N- (3-chloro-2, 6-dinitro-4-trifluoromethylphenyl) -5-trifluoromethyl-3-chloro-2-aminopyridine, 1- ((bis- (4-fluorophenyl) methylsilyl) -methyl) -1H-1,2,4-triazole,

Strobilurins such as methyl-E-methoximino- [α- (o-tolyloxy) -o-tolyl] acetate, methyl-E-2- {2- [6- (2-cyanophenoxy) pyridimin-4-yloxy] phenyl} -3-methoxyacrylate, methyl-E-methoximino- [a- (2,5-dimethyl-loxy) -o-tolyl] acetamide,

Anilino-pyrimidines such as N- (4, 6-dimethylpyrimidin-2-yl) aniline, N- [4-methyl-6- (l-propynyl) pyrimidin-2-yl] aniline, N- (4-methyl-6- cyclopropyl-pyrimidin-2-yl) aniline,

Phenylpyrroles such as 4- (2,2-difluoro-1,3-benzodioxol-4-yl) pyrrole-3-carbonitrile, Cinnamic acid amides such as 3- (4-chlorophenyl) -3- (3, 4-dimethoxyphenyl) acrylic morpholide.

The compounds of the present invention offer new therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migr Asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty and by-pass surgery, benign prostate hyperplasia, cirrhosis of the liver, erectile dysfunction, ischemic and intoxication-induced kidney failure or hypertension, Metastasis and growth of mesenchymal tumors, contrast-mediated kidney failure, pancreatitis, especially acute pancreatitis, gastrointestinal ulcers.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intavenously, intramuscularly, intraperotonally) in the customary manner. It can also be applied with vapors or sprays through the nasopharynx.

The dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active substance is between approximately 0.5 and 50 mg / kg body weight when administered orally and between approximately 0.1 and 10 mg / kg body weight when administered parenterally.

The new compounds can be used in the customary pharmaceutical application forms solid or liquid, for. B. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al. : Pharmaceutical Technology, Thieme Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain the active ingredient in an amount of 0.1 to 90% by weight.

The invention is explained in more detail using the following exemplary embodiment:

One equivalent of Neorustmicin D is dissolved in methanol and three equivalents of hydroxylamine hydrochloride are added. The mixture is left to stir overnight.

For working up, it is first diluted with water and then extracted with ethyl acetate. The combined organic phases are washed with sodium hydrogen carbonate and then with water. After evaporation of the solvent, the ketone is obtained as a crude product, which is used in the next step without further purification.

The oxime is dissolved in DMF (dimethylformamide) and potassium carbonate is added as the base. The mixture is heated to 60 ° C. and then a solution of three equivalents of n-propyl chloride in DMF is added dropwise. The mixture is stirred at this temperature for 24 h.

For working up, it is first diluted with water and then extracted with ethyl acetate. The combined organic phases are washed with dilute hydrochloric acid, then with sodium bicarbonate and then with water.

After evaporation of the solvent, the crude product is obtained, which is purified chromatographically.

Claims

claims

1. Neorustmicin D derivatives of the formula I

where the substituents have the following meanings:

R ^{1 is} hydrogen or -C (= 0) R ⁴ ; R ² = N0R ⁵ or = 0; R ^{3 is} hydrogen or -C (= 0) R ⁶ ;

R ^{4 is} hydrogen, Ci-Cβ-alkyl, phenyl or substituted

phenyl; R ^{5 is} hydrogen, Ci-Cβ-alkyl, -CC ₆ alkylphenyl or substituted Ci-C ₆ alkylphenyl; R ^{6 is} hydrogen, Ci-Cβ-alkyl, phenyl or substituted phenyl;

and their agriculturally useful salts, with the exception of Neorustmicin D.

2. Neorustmicin D derivatives according to claim 1, wherein the radicals have the following meanings:

R ¹ -C (= 0) R ⁴ ; R ² = N0R ⁵ ;

R ³ -C (= 0) R ⁶ ;

3rd Neorustmicin D derivatives according to claim 1, wherein the radicals have the following meanings:

R ¹ -C (= 0) R ⁴ ;

R ² = 0;

R ³ -C (= 0) R ⁶ ;

4. Neorustmicin D derivatives according to claim 1, wherein the radicals have the following meanings:

R ⁱ -C (= 0) R ⁴ ; R ² = 0;

R ³ -H;

5. Neorustmicin D derivatives according to claim 1, wherein the radicals have the following meanings:

R ¹ -H;

R ² = 0;

R ³ -C (= 0) R ⁶ ;

6. Agrochemical composition containing as active ingredients at least one compound according to claims 1 to 5.

7. Use of compounds of formula I according to claims 1 to 5 as a fungicide or a composition according to claim 6 as an agrochemical composition with a fungicidal action.

8. Use of compounds of formula I according to claims 1 to 5 or a composition according to claim 6 for controlling harmful fungi in plants.

9. A method of combating harmful fungi in plants, characterized in that the harmful fungi, their habitat or the plants, areas, materials or spaces to be kept free by them with a fungicidally effective amount of a compound of the formula I according to Claims 1 to 5 or a composition according to claim 6.

10. Pharmaceutical compositions containing as active ingredients at least one compound of formula I according to the claims

1 to 5.

11. Pharmaceutical compositions containing a compound of formula I according to claims 1 to 5 for the manufacture of medicaments with antifungal activity.

12. A process for the preparation of pharmaceutical compositions having an antifungal activity, characterized by the use of compounds of the formula I according to claims 1 to 5.