WO2002074086A1

WO2002074086A1 - Neorustmicin b derivatives as fungicides

Info

Publication number: WO2002074086A1
Application number: PCT/EP2002/002749
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 B 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 B. Further disclosed are fungicidally active agrochemical compositions, pharmaceutical compositions containing a compound of formula (I), and a method for controlling pathogenic fungi.

Description

NEORUSTMICIN B DERIVATIVES AS A FUNGICIDE

description

The present invention relates to neorustmicin B 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 ⁵ ;

R ^{4 is} hydrogen, Ci-Cg-alkyl, phenyl or substituted phenyl; R ^{5 is} hydrogen, Ci-Cg-alkyl, Ci-Cg-alkylphenyl or substituted Ci-C _ß- alkylphenyl;

R ^{6 is} hydrogen, Ci-Cε-alkyl, phenyl or substituted phenyl;

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

as well as agrochemical compositions with fungicidal activity and pharmaceutical compositions containing these neorustmicin B 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). Fig. 1

Galbonolide A Galbonolide B Galbonolide C Rustmicin Neurustmicin A

The compounds show fungicidal activity against various pathogens in the human field (Candida species, Fusarium, Rhodotorula) and agricultural areas, in particular Bofcryfcis cinerea and Puccinia grami is. 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.

Fig. 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).

Fig. 3

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 via a lactam instead of a lactone ring (Fig. 4) ...

Fig. 4

Cβ-alkyl Cβ-alkyl C _δ -alkyl, Ci-C _δ -alkoxy C ₆ -alkyl C ₆ -alkyl

Two other publications (J. Antibiotics 1998, 51, 837; J. Biol. Chem. 1998, 273, 14942) describe that rustmicin and the derivatives derived from it have their biological effects Develop inhibition of 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.

Under the influence of aqueous acids, the enol ether functionality is split into the ketone. 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 6-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 neutral 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 B derivatives according to the invention.

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

Ci-Cg-alkyl for a straight-chain or branched alkyl radical with 1-6 C-atoms, e.g. 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, eta or para; such as halogen atoms, nitro groups, C ₁ -C ₆ -alkyl, halogen Cx-Cg-alkyl, C ₁ -C ₆ alkoxy, Ci-Cg-haloalkoxy, -C-C ₆ alkylthio, Ci-Cg-alkylsulfonyl, Ci-C _ß -haloalkylsulfonyl, as mentioned above;

- Halogen generally stands for fluorine, chlorine or bromine;

Ci-Cg-haloalkyl for a CC _ß -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;

Ci-Cg-alkoxy for a straight-chain or branched Ci-C _ß alkoxy radical, such as methoxy, ethoxy, n-propoxy,

1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy, in particular for methoxy or ethoxy;

- Halogen-Ci-Cρ-alkoxy for a Ci-Cg-alkoxy radical as mentioned above, which is substituted one or more times by fluorine, chlorine or bromine, e.g. trifluoromethoxy;

Ci-Cg-alkylthio for a straight-chain or branched Ci-Cg-alkylthio radical, e.g. Methylthio, ethylthio, n-propylthio, 1-methylethylthio, n-butylthio, 1-methythio, 2-methylpropylthio or 1, 1-dimethylethylthio, especially for methylthio or ethylthio;

Ci-Cg-alkylsulfonyl for a straight-chain or branched Ci-Cg-alkylsulfonyl radical, e.g. Methylsulfonyl, ethylsulfonyl, .n-propylsulfonyl, 1-methylethylsulfonyl, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl or 1, 1-dimethylethylsulfonyl, especially for methylsulfonyl or ethylsulfonyl;

- Halogen-Ci-Cε-alkylsulfonyl for a Ci-Cg-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 are or anions do not adversely affect the fungicidal activity of the compounds I.

In particular, ions of the alkali metals, preferably lithium, sodium and, come as agriculturally usable cations

Potassium, the alkaline earth metals, preferably calcium and magnesium, and the transition metals, preferably manganese, copper, zinc and iron, and ammonium, where if desired one to four hydrogen atoms by C 1 -C ₄ -alkyl, hydroxy-C 1 -C ₄ -alkyl, C ₁ -C ₄ -Al- koxy -CC ₄ -alkyl, hydroxy -CC ₄ -alkoxy -CC ₄ -alkyl, phenyl or ^" benzyl can 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, sufonium ions, preferably tri ( C 1 -C ₄ alkyl) sulfonium and sulfoxonium ions, preferably tri (C ₄ -C ₄ alkyl) sulfoxonium, into consideration.

Anions of useful 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.

Possible 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 usable anions of usable acid addition salts are, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, .phosphate or hydrogenphosphate,.

Acetate, lactate, citrate or hydrogen citrate, tatrat or bi-tadate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methyl sulfonate, ethyl sulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (e.g. 1, 1 '-methylene-bis- (2-hydroxy-3-naphthoate).

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

Also preferred are compounds with R ⁴ = 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-Cg-alkyl, halogen -Ci-Cg-alkyl, Ci-Cg-alkoxy, Ci-Cg-haloalkoxy, Ci-Cg-alkylthio, Ci-Cg-alkylsulfonyl and Ci-Cg-haloalkylsulfonyl can wear.

Also preferred are compounds with R ⁵ = hydrogen, Ci-Cg-alkyl or Ci-Cg-alkylphenyl, where the phenyl radical can be unsubstituted or partially or completely halogenated and / or one to three substituents from the group Ci-Cg-alkyl, halo - Can carry Ci-Cg-alkyl, Ci-Cg-alkoxy, Ci-Cg-haloalkoxy, Ci-Cg-alkylthio, Ci-Cg-alkylsulfonyl and Ci-Cg-haloalkylsulfonyl.

Also preferred are compounds with R ⁶ = hydrogen, Ci-Cg-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-Cg-alkyl, halogen-Ci -Cg-alkyl, Ci-Cg-alkoxy, Ci-Cg-haloalkoxy, Ci-Cg-alkylthio, Ci-Cg-alkylsulfonyl and Ci-Cg-haloalkylsulfonyl can wear.

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:

I B

In addition, the following compounds of the formulas I C and I D are particularly preferred for the purposes of the present invention:

I C I D

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 R ^{5 is} CHs.

The compounds of the formula I A 3 are likewise preferred,

IA 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 ₇ .

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

I A 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 IA 5 are likewise preferred,

I A 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 Hg.

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

I A 6

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 Hg.

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} nCsHn.

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} nCHι 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

10

_j _g Extraordinary preferred are the compounds of formula IC

I C

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

Table 4

30

35

40

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 B, which is accessible via the fermentation methods described in J. Antibiotics 1986, 1016.

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

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

^• Neorustmicin BICID ^"

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 IA 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. diethylformamide (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 .Ascomycetes, JDeuteromycetes,

Phycomycetes and Basidiomycetes, from. They are partly systemically effective and can therefore also be used as foliar 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, for example by extending the active ingredient with solvents and / or carriers, if desired using emulsifiers and dispersants, and if water is used as the diluent, other organic solvents can also be used as auxiliary solvents. The following are essentially considered as auxiliaries: solvents such as aromatic mate (e.g. xylene), chlorinated aromatics (e.g. chlorobenzenes), paraffins (e.g. petroleum fractions), alcohols (e.g. methanol, butanol), ketones (e.g. cyclohexanone), amines (e.g. ethanol in, dirnethylformamide) and water; Carriers such as natural stone powder (eg kaolins, clays, talc, chalk) and synthetic stone powder (eg highly disperse silica, silicates); Emulsifiers such as nonionic and anionic emulsifiers ren (for example polyoxyethylene fatty alcohol ethers, alkylsulfonates and arylsulfonates) and dispersants such as lignosulfite waste liquors and methylcellulose ^'.

The alkali, alkaline earth, ammonium salts of aromatic sulfonic acids, e.g. Lignin, phenol, naphthalene and dibutylnaphthalenesulfonic acid, as well as 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., .Z..B,. ".. encapsulation -., .. impregnation and homogeneous granules. can be produced by binding the active ingredients to solid carriers. Solid carriers are mineral soils such as silica gel, silicas, silica gels, silicates, talc, kaolin, limestone, lime, chalk, boluses, 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 cereal flour, tree bark, wood and nutshell flour, 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 an inventive

Compound I, 70 parts by weight of xylene, 10 parts by weight of the adduct of 8 to 10 moles of ethylene oxide and 1 mole of oleic acid-N-monoethanolamide, 5 parts by weight of calcium salt of dodecylbenzenesulfonic acid, 5 parts by weight of the additive - 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 ol 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 cyclo-hexanol, 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 adduct 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 and 10 parts by weight of the sodium salt, ground in a hammer mill a lignin sulfonic acid from a sulfite waste liquor and 7 parts by weight of powdered silica gel; by finely distributing the mixture in water you get a spray mixture;

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 con- densates, 2 parts by weight of silica gel and 48 parts by weight of water, which 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 of a phenolsulfonic acid-urea-formaldehyde -Condensates and 50 parts by weight of a paraffinic mineral oil. ^• - ^{• •}

Of particular importance are the compounds I for controlling a multitude of fungi ^'in various crops such as wheat, rye, barley, oats, rice, maize, lawns, cotton, soybeans, coffee, sugar cane, grapevines, fruit and ornamental plants and vegetables, such like cucumbers, beans and squash, 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, üncinula necator on vines, Pucciniaiz species on cereals, Cotton and grass, Ustilago species on cereals and sugar cane, Venturia inaegualis (scab) on apples, Helminthosporium species on cereals, Septoria nodorum on wheat, Botrytis cinerea (.grey mold) - strawberries, vines, ornamental plants and vegetables, Cercospora arachidicola on peanuts, Pseudocercosporella herpotrichoides on wheat, barley, Pyricularia oryzae on rice, Phytophthora infestans on potatoes and tomatoes, Fusarium and Verticillium species on various plants, Plasmopara viticola on vines, AI ternaria 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.

The agents according to the invention can also be present in the use form as fungicides together with other active ingredients, e.g. with herbicides, insecticides, growth regulators, fungicides or even with fertilizers.

When mixed with fungicides, the fungicidal spectrum of activity 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, but not to limit, the possible combinations:

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, N'-polypropylene-bis- (thio-carbamoyl) -disulfide;

Nitroderivatives, such as dinitro- (1-methylheptyl) phenylcrotonate, 2-sec. -Butyl-4, 6-dinitrophenyl-3, 3-dimethylacryla, 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-phthalimi- _^ dophosphonothioate, 5-amino-l - [bis- (dimethylamino) phosphinyl] -3-phenyl-1, 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-dichlorofluoromethylthio-N ', N'-dimethyl-N -phenyl-sulfuric acid diamide, 5-ethoxy-3-trichloromethyl-1, 2, 3-thiadiazole, 2-rhodanmethylthiobenzothiazole, 1, 4-dichloro-2, 5-dimethoxybenzene, 4- (2-chlorophenylhydrazono) -3 -methyl-5-isoxazolone, pyridine-2-thione-l-oxide, 8-hydroxyquinoline or its copper salt, 2, 3-dihydro-5-carboxanilido-6-methyl-l, -oxathiin, 2, 3- dihydro-5 carbox-anilido-6-methyl-l, -oxathiin-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- carboxanilide, 2, 5-dimethyl-furan-3-carboxylic acid cyclohexylamide, N-cyclohexyl-N-methoxy-2, 5-dimethyl-furan-3-carboxamide, 2-methyl-benzoic acid anilide, 2-iodine benzoic acid anilide, N-formyl-N-morpholine-2, 2, 2-trichloroethyl acetal, piperazin-1, 4-diylbis- (1- (2, 2, 2-trichloroethyl) -formamide, 1- ( 3, -Dichloranilino) -1-formylamino-2, 2, 2-trichloroethane, 2, 6-dimethyl-N-tridecyl-morpholine or its salts, 2, 6-dimethyl-N-cyclododecyl-morpholine or its salts, N- [3- (p-tert-butylphenyl) -2-methylpropyl] cis-2, 6-dimethylmorpholine, N- [3- (p-tert-butylphenyl) -2 -methylpropyl] -piperidine, 1- [2- (2,4-dichlorophenyl) -4-ethyl-l, 3-dioxolan-2-yl-ethyl] -1H-1,2, -triazole 1- [2 - (2,4-dichlorophenyl) -4-n-propyl-l, 3-dioxolan-2-yl-ethyl] -1H-1,2,4-triazole, N- (n-propyl) -N- (2nd , 4, 6-trichlorph enoxye-thyl) -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-dimethyl-a ino- -hydroxy-6-methyl-pyrimidine, bis- (p-chlorophenyl) - 3-pyridinomethanol, 1,2-bis (3-ethoxycarbonyl-2-thioureido) benzene, 1,2-bis (3-methoxycarbonyl-2-thioureido) benzene, [2- (4-chloro phenyl) 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- (phenylace-, tyl) .alanine methyl ester, 5-methyl-5-vinyl-3- (3 ,,. 5-dichloro-. phenyl) -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-1-methyl) -benzhydryl alcohol, N- (3rd -Chlor-2, 6-dinitro-4-trifluoromethyl-phenyl) -5-trifluoromethyl-3-chloro-2-aminopyridine, 1- ((bis- (4-fluorophenyl) methylsilyl) ethyl) - 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 artery, angina pectoris, arrhythmia, acute / chronic ni enver say, chronic heart failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, Migraines, 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-related 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 in the usual way. (subcutaneous, intavenous, intramuscular, intraperotonic). 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 applied 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 mixed with the usual pharmaceutical auxiliaries such as tablet binders, fillers. Substances, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants are processed (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:

example 1

One equivalent of Neorustmicin B 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 oxi 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 by chromatography.

Claims

claims

1. Neorustmicin B 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-Cg-alkyl, phenyl or substituted

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

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

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

_R 1 -C (= 0) R ⁴ ; R ² = NOR ⁵ ;

_R 3 -C (= 0) R ⁶ ;

3. Neorustmicin B 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 ⁵ ;

4. Neorustmicin B derivatives according to claim 1, wherein the radicals have the following meanings: l -C (= 0) R ⁴ ; R ² = 0;

R ³ -H;

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

R ¹ -H; R ² = 0; 10 "R ^3" -C (= 0) R ⁶ ;

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

15 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 fungicidal activity.

20 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. Process for combating harmful fungi in plants, characterized in that the harmful fungi and their habitat. or the plants, surfaces, materials or spaces to be kept free from them are treated 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. 30

10. Pharmaceutical compositions containing as active ingredients at least one compound of formula I according to claims 1 to 5.

35 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 40 with antifungal activity, characterized by the

Use of compounds of formula I according to claims 1 to 5.

45