BG60798B2 - New morpholine derivatives, method for their preparation, pharmaceutical forms containing these derivatives, and their use as antimycotics - Google Patents

Abstract

The compounds exhibit a fungicidal action and can be used as antimycotic agents, especially for combating sindidia allians. They have the general formula wherein r represents ethyl or phenyl. The invention also relates to salts and n-oxides of these compounds which are prepared by known methods.

Description

The invention relates to heterocyclic compounds of the general formula wherein R is ethyl or phenyl, and to salts and N-oxides of these compounds.

The invention also relates to a process for the preparation of compounds of formula I and their salts and N-oxides, to a fungicidal agent containing these compounds, to a method for preparing a fungicidal agent, and to its use.

DE-A-2 752 096 discloses compounds of which the compounds of formula I according to the invention differ in that they are cis-isomers.

The method of preparing the compounds of the invention is that

II

a) halide c formula

in which R has bromine or

B) or iodine,

CH ₂ -Y the values indicated above and

Y stands for chlorine, of formula

compound of formula

III

in which R has the above meanings and one of the two dotted lines means one additional bond is reduced, or

c) a compound of general formula

is reacted with a compound which introduces a carbonyl ion of the general formula

- 3 R \ ® c-ch ₃ H ₃ C ^Z

VI in which R has the meanings given above, or

d) a compound of formula

R CH ₃ H ₃ C. and 0¾ ^ A ^ -sub

VII

wherein R has the above meanings is reacted with a compound of formula III, under conditions suitable for the hydrogenation process, or in order to obtain an N-oxide compound of formula I is treated with hydrogen peroxide or peroxoacid, or for the purpose of to form a salt, a base of formula I is reacted with an acid in a known manner and converted to the corresponding salt.

Option a) of the process according to the invention is carried out by reacting a halide of formula II with an amine of formula III, preferably in an inert solvent, e.g. in ether, such as diethyl ether, tetrahydrofuran or dioxane, or in dimethyl sulfoxide, preferably in high boiling alcohol, such as ethylene glycol or glycerol, in the presence of a base such as e.g. triethylamine or in excess of an amine of formula III. The reaction mixture is adjusted preferably to a temperature in the range of 50 to 150 ° _C? during which the reaction takes place. It is particularly appropriate to use ethylene glycol as the solvent, whereby the reaction is carried out at 100-110 ° C.

In variant b) of the process according to the invention, a compound of formula IV is reduced. When a compound of formula IV is used as a compound in which

- 4 double bond is in the α-position with respect to the morpholine residue, the reduction can be carried out catalytically

or with formic acid.

Especially precious metal catalysts, such as platinum, palladium, optionally deposited on activated carbon, and rhenium-nickel, are suitable catalysts for the reduction. Preferably palladium on carbon is used. Suitable solvents for catalytic reduction are hydrocarbons such as benzene, toluene or xylene, as well as alcohols such as methanol or ethanol. Toluene is preferably used. A suitable temperature for carrying out the reaction is a temperature in the range from 0 to 50 ° C, preferably operated at room temperature. The reduction of enamines with formic acid is preferably carried out in the presence of solvents, with the formic acid being added dropwise at temperatures from 0 to 100 ° C, preferably at 50-70 ° C, and dropwise if necessary carried out under cooling. .

When using a starting compound of formula IV, wherein the double bond is in the α-position relative to the phenyl moiety, the reduction can be carried out catalytically. Platinum or palladium may preferably be used as a catalyst, and water or alcohol may be used as solvent. To avoid possible hydrolysis, at least one equivalent acid, preferably hydrochloric acid, is added to the reaction mixture.

The alkylation of a compound of general formula V in embodiment c) of the process according to the invention is carried out in the presence of a suitable amount of a Friedel Crafts catalyst. The most commonly used catalysis is used for this purpose.

fried l-krafts forests, e.g. aluminum chloride, ferric chloride, zinc chloride, bortrifluoride, tin chloride, hydrogen fluoride, sulfuric acid and phosphoric acid. For the purposes of the process of the invention, sulfuric acid is particularly preferred.

The use of an inert organic solvent medium in carrying out this method is optional but is still preferable. Inert organic solvents are particularly suitable alkanes such as hexane, cyclohexane, chlorinated hydrocarbons, such as chloroform, ethylenedichloride or methylene chloride, with methylene chloride being particularly preferred. The temperature for carrying out the alkylation reaction is not critical, but is generally in the range of 0 to 50 ° C, preferably between 18 and 20 ° C.

It is preferred, especially when sulfuric acid is used to carry out the process, that the product obtained after the reaction, in the form of a salt, is extracted with an inert organic solvent, such as e.g. methylene chloride. If desired, the free amine can be obtained using a suitable base such as sodium hydroxide solution, potassium hydroxide solution, sodium carbonate, potassium or calcium hydroxide.

Preferred compounds that provide carbonyl ions of general formula VI are the corresponding tertiary alcohols, such as 2-methyl-2-butanol or tertiary chlorides, such as 2-chloro-2methylbutane.

The reaction of a substituted cinnamic aldehyde of formula VII with cis-2,6-dimethylmorpholine of formula III is carried out under hydrogenation conditions, e.g. using palladium catalysts in methanol medium.

- 6 To obtain the N-oxide of a compound of formula I, this compound is treated with hydrogen peroxide or peroxoacid. When using hydrogen peroxide as an oxidizing agent, suitable solvents for the reaction are alcohols such as methanol, ethanol or isopropanol, the latter being particularly preferred. Suitable reaction temperatures are from 0 to 50 ° C, and it is particularly preferred to carry out the reaction at 40 ° C. Suitable peroxoacids that can be used in this method are e.g. peracetic, perbenzoic, meta-chloroperbenzoic and peradipic acids. Suitable solvents for the use of these acids are preferably halogenated hydrocarbons such as methylene chloride, chloroform or ethylene chloride. Suitable temperatures for carrying out the oxidation are the same as described using hydrogen peroxide.

The compounds of formula I form salts with organic and inorganic acids. Salts of physiologically acceptable acids are the most suitable salts of the compounds of formula I. These are preferably hydrohalic acids, such as e.g. hydrochloric and hydrobromic acids, then phosphoric and nitric acids, in addition mono- and dicarboxylic acids, as well as hydroxycarboxylic acids, such as e.g. acetic, maleic, succinic, fumaric, tartaric, citric, salicylic, sorbic and lactic acids, and finally sulfonic acids, such as 1,5-naphthalene-disulfonic acid. The preparation of such salts is carried out in the manner known for this purpose.

The starting compounds of formula II and VI are known. The starting compounds of formulas III and IV are known as mixtures,

- 7 containing cis / trans isomers. The starting cis-compounds of formulas III and IV were prepared by methods analogous to those for the preparation of the cis / trans mixture.

The starting compounds of formula IV, in which the double bond is in the α-position with respect to the morpholine residue, can be obtained e.g. by reacting respectively substituted phenyl-2-methyl-propionaldehyde with cis-2,6-dimethylmorpholine. Hydrogenation of the compound thus obtained in the form of

la IV it is appropriate to carry out an in situ.

The starting products of formula IV, in which the double bond is in the α-position with respect to the phenyl moiety _? can be obtained e.g. however, by substituting a halide corresponding to a compound of formula II, there is, in the α-position relative to the phenyl moiety, a double bond, with cis-2,6-dimethylmorpholine.

The compounds of general formula V can be prepared by mixing a compound of formula

with a compound of general formula III and catalytic hydrogenation of this mixture.

Preferably an organic solvent is used as a solvent, e.g. alcohol, such as methanol. The temperature is not critical, but is preferably in the range of 0 to 50 ° C.

Conventional catalysts may be used for catalytic hydrogenation, e.g. platinum, rhenium-nickel or palladium, preferably using 5% palladium on charcoal.

Compounds of the invention in which the morpholine moiety is linked via the propylene chain to the p-substituted

The phenyl moiety contains an asymmetric carbon atom and can exist in the form of racemic mixtures or as optical antipodes. The latter can be obtained from the racemates obtained by separation with optically active acids, e.g. with (+) -camphoric acid, (+) -camphor-10sulfonic acid, N, N'-dibenzoyltartaric acid (in L- or D-form), L (+) -tartaric acid, O (-) - tartaric acid, L (+) glutamic acid-4-sulfonate, b (-) - malic or D (+) malic acid. This separation is carried out according to known techniques for this purpose.

The compounds of the invention have fungicidal activity and can accordingly be used to control fungi in agriculture and horticulture. The compounds are particularly suitable for combating mana-causing fungi, such as e.g. Erysiphe graminis (Cereal Mana), Erysiphe cichoracearum (Cucumber Mana), Podosphaera leucotricha (Apple Mana), Sphaerotheca pannosa (Rose Mana), Oidium tuckeri (Vine Mana); in plant diseases caused by fungi, such as those caused by Gattungen Puccinia, Uromyces and Hemileia, especially Puccinia graminis (cereals), Puccinia coronata, Puccinia sorghi, Puccinia striiformia, Puccinia recondita, Uromyces fabae, and appendiculatus, also in Hemileia vastatumc and Phragminiumc.

In addition, these compounds are active against the following phytopathogenic fungi: Ustilago avenae, Venturia inaequalis, Cercospora arachidicola, Ophiobolus graminis, Septoria nodorum and Marssonina rosae. Some of the compounds in this group have pronounced side effects against different species of the following groups: Rhizoctonia, Tilletia, Helminthosporium and also

so in some cases against Peronospora, Coniophora, Lenzites, Corticium, Thielaviopsis and Fusarium.

In addition, the compounds of the invention of formula I act against phytopathogenic bacteria, e.g. Xanthomonas vesicatoria, Xanthomonas oryzae and other Xanthomonaden, and also against various Erwinia species, e.g. Erwinia tracheiphila.

Above all, the active substances of the invention are suitable for combating fungal infections due to their fungistatic and fungicidal action, for example to combat Genera Candida, Trichophyten or Histoplasma. They are particularly active against various types of Candida, such as. Candida albicans and are suitable e.g. for the topical treatment of infections on the skin surface and on mucus-secreting skin surfaces, especially of the genital tract, such as for the treatment of vaginitis caused by Candida.

When used topically, the active ingredient may be formulated in a suitable therapeutically active preparation, e.g. in the form of creams, suppositories, suppositories, ovules and other suitable forms.

The preparation of pharmaceutical agents can be accomplished in known ways by mixing the active substance with other organic and inorganic inert carriers and / or excipients such as water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol, petroleum jelly, preservative, stabilizing, crosslinking or emulsifying agents, salts for altering the osmotic pressure or buffers.

The dosage is carried out according to individual requirements, however, a preferred dosage requires that the pharmaceutical preparation is administered daily on 1-2 tablets containing 50-100 mg of the active substance for several days. Creams most often contain 0.3 to 5%, e.g. 0.5 to 2% and preferably 0.5 to 1% of the active substance. The following test results of the compounds, as well as the data given in the table, also provide the necessary information to a person skilled in the art in order to be able to evaluate the dosage of the active substance.

The activity of the compounds of the invention against Candida albicans was tested in rats by the vaginal candidate method described in Path. Microbiol. 23: 62-68 (1960), yielding the following results:

Compound

Conc. in% _? at which ED 50 "activity of cis-4- [3- (p-tert-amyl phenyl) occurs -

-2-methylphenyl] -2,6-dimethylmorpholine cis-4- / 3- [p- (a, a-dimethylbenzyl) phenyl] -2-methyl propyl / -2,6-dimethylmorpholine

0.01

0.01

Example 1,

230 g of 3- (p-tert-amylphenyl) -2-methyl-propionaldehyde and 137 g of cis-2,6-dimethylmorpholine are heated in 1000 ml of toluene with a separator under a nitrogen atmosphere for 16 hours, until water is stopped. into the back flow. At room temperature and under nitrogen atmosphere, the reaction mixture was stirred

17.5 g of 5% palladium on charcoal were added and hydrogenation was carried out until hydrogen was consumed. The catalyst was removed by filtration and the toluene was evaporated in vacuo. Distillation of the residue afforded pure cis-4- [3- (p-tertylphenyl) -2-methylpropyl] -2,6-dimethylylmorpholine with a boiling point of 120 ° C / 0.1 mm Hg.

Example 2.

In a similar manner to that described in Example 1, reaction of 3- [p- (a, α-dimethylbenzyl) -phenyl] -2-methylpropionaldehyde with cis-2,6-dimethylmorpholine and hydrogenation gave the cis-4- / 3- [p- (a, a-Dimethylbenzyl) -phenyl] -

2-methylpropyl / -2,6-dimethyl-morpholine with a boiling point of 162 ° C / 0.04 mm Hg.

Example 3.

To 1223 g of cis-4- (2-methyl-3-phenylpropyl) -2,6 dimethylmorpholine 4 l methylene chloride at minus (-) temperature

4941 g of concentrated sulfuric acid was added dropwise at 5 ° C for about 45 minutes and finally 520 g of 2-methyl-2-butanol was added dropwise over 60 minutes. Water was added to the reaction mixture under ice-cooling and the aqueous phase was repeatedly extracted with methylene chloride. The organic extracts were washed first with sodium hydroxide solution and then with water, then dried, the solvent was evaporated and the oily residue obtained was distilled in vacuo to give cis-4- [3- (p-tertylphenyl) -2- methylpropyl] -2,6-dimethyl-morpholine with a boiling point of 120 ° C / 0.1 mm Hg.

The starting cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethyl-morpholine used in this example can be obtained as follows: 1000 g α-methyl-cinnamic aldehyde, 10 l methanol and

789 g of cis-2,6-dimethylmorpholine is mixed with 50 g of 5% palladium on carbon under a nitrogen atmosphere. It is then hydrogenated by cooling with water at 30 ° C to stop hydrogen uptake, the catalyst is separated by filtration, the methanol is distilled off under reduced pressure, and then the crude cis-4- (2-methyl-3-phenylpropyl) obtained - 2,6-Dimethylmorpholine was distilled. The product with 99% purity has a boiling point of 109 ° C / 0.055 mm Hg.

Example 4.

20.0 g of p- (a, α-dimethylbenzyl) -a'-methyl-cinnamic aldehyde and 9.6 g of cis-2,6-dimethylmorpholine were mixed in 60 ml of methanol under argon with 1 g of 5% palladium on carbon and then hydrogenates until it stops absorbing hydrogen. The catalyst-liberated reaction solution was evaporated under reduced pressure, chromatographed on alumina (grade II) with chloroform as eluent and finally distilled under high vacuum. Cis-4- / 3- [p- (a, α-dimethylbenzyl) phenyl] -2-methylpropyl / -2,6-dimethylmorpholine was obtained at a temperature of

boiling 162 ° C / 0.04 mm Hg.

Example 5.

In a manner similar to that described in Example 4, starting from p- (tert-amylphenyl) -α-methyl-cinnamic aldehyde and cis-

2,6-dimethylmorpholine, the compound cis-4- [3- (tert -amylphenyl) -2-methylpropyl) -2,6-dimethyl morpholine is obtained.

Example 6

To a solution of 22.7 g of cis-2,6-dimethylmorpholine in 70 ml of ethylene glycol was slowly added dropwise at 125 ° C 44.3 g of 3- (p- (tert-amylphenyl) -2-methyl-propyl bromide and the reaction mixture was stirred in After 48 hours at this temperature, 2N hydrochloric acid was added after cooling, and the neutral portions were extracted with ether, and then the alkaline solution was made basic with 5N sodium hydroxide solution.

base, extracted with ether, the ether extracts washed with water, dried over sodium sulfate and evaporated. Distillation gave pure cis-4- [3- (p-tert-amylphenyl) -

2-methylpropyl] -2,6-dimethyl-morpholine with a boiling point of 120 ° C / 0.1 mm Hg.

Example 7.

To a solution of 22.7 g of cis-2,6-dimethylmorpholine in 60 ml of ethylene glycol was slowly added dropwise at 125 ° C 61.8 g of 3- [p- (a, a-D methylbenzyl) -phenyl] -2-methylpropyl bromide and the reaction the mixture was stirred at this temperature for 48 hours. The development of the mixture was carried out in a manner similar to that described in Example 6. Distillation gave pure cis-4- / 3- [p- (a,? -Dimethylbenzyl) -phenyl] -2methylpropyl] -2,6-dimethyl-morpholine with a boiling point of 162 ° C / 0.04 mm Hg.

Example 8.

286 g of cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6 dimethylmorpholine was dissolved in 500 ml of absolute ethanol and at room temperature 500 ml of a 28% ethanol solution of hydrogen chloride was added dropwise. . The homogeneous solution was dried in a rotary evaporator and the resulting residue was recrystallized from 100 ml of water. The crystalline product was washed with water and dried in a vacuum oven at 55 ° C. Cis-4- [3- (p-tert-amylphenyl) - hydrochloride is obtained

2-methylpropyl] -2,6-dimethyl-morpholine, in the form of white, slightly hygroscopic crystals, m.p. Mp 204-206 ° C.

Example 9.

To a solution of 60 g of 30% hydrogen peroxide in 60 ml was added dropwise to 21 g of cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6 dimethylmorpholine on cooling with a mixture of acetone-dry ice. acetic anhydride so that the reaction temperature does not exceed 50 ° C and then the reaction mixture is allowed to react for another 16 hours at room temperature. The reaction was monitored by thin layer chromatography (hexane.ether = 1: 1). In order to decompose excess peroxide, the reaction mixture was cooled to minus 10 ° C and 200 ml of 40% potassium hydroxide solution was added. After stirring for 20 hours, the reaction mixture was diluted with water and then extracted with chloroform until complete recovery of the product. The combined chloroform extracts were washed to neutral, dried and evaporated. Recrystallization of the residue from 100 ml of pentane gave pure cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine-4-oxide.

The following examples illustrate the preparation of pharmaceutical preparations:

Example 10.

Tablets for vaginal administration are prepared by known methods using the following composition:

Cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine50 mg

Tech. calcium phosphate 2H2O 400 mg

Compression Starch (STA-RX1500) 261 mg

Milk sugar (spray dried) 100 mg Polyvinylpyrrolidone25 mg

Citric acid5 mg

Magnesium stearate 6 mg

- 15 Example 11,

An ointment of the following composition is prepared:

Cis-4- / 3- [p- (a, α-dimethylbenzyl) -phenyl] -

2-methylpropyl / -2,6-dimethylmorpholine 0.7 Mr Rücker Cetyl alcohol 3.6 Mr Rücker Lanolin 9.0 Mr Rücker Vaseline, white 79 .: 5 g Paraffin oil 7.4 Mr Rücker 100 • θ g Example 12, Cream with the following composition is prepared: Cis-4- [3- (p-tert-amylphenyl) -2-methyl- propyl] -2,6-dimethylmorpholine 0.7 g Polyoxyethylene arate 3-3 g Stearyl alcohol 8.0 g Hard paraffin oil 10.0 g Vaseline, white 10.0 g Carboxyvinylpolymer (CARBOPOL 934 Ph) 0.3 g Sodium base (purest) 0.07 g Distilled water TO 100.0 g

Claims (11)

Compounds of the general formula wherein R is ethyl or phenyl, as well as salts and N-oxides of these compounds. 2. Cis-4- [3- (p-tert-amyl phenyl) -2-ethyl ethyl] -2,6-dimethylmorpholine and its salts and N-oxides. 3. Cis-4- / 3- [p- (α, α-dimethylbenzyl) -phenyl] -2-methylpropyl] - 2,6-dimethylmorpholine and its salts and N-oxides. Use of compounds according to claims 1 to 3 as antimycotic agents. 5. A process for the preparation of compounds of the general formula wherein R is ethyl or phenyl, as well as salts and oxides of these compounds, characterized in that a) a halide of formula - 17 II in which R has the above meanings and Y represents chlorine, bromine or iodine, reacts with a compound of the formula CH ₃ / - \ HN 0 н CH ₃ or B) a compound of formula wherein R is as defined above and IV one of the two dotted lines means an additional connection is reduced, or c) a compound of general formula is reacted with a compound which introduces a carbonyl ion of general formula - 18 R \ © C-CH3 H ₃ C ^Z VI in which R has the meanings given above, or d) a compound of formula VII in which R has the above meanings is reacted with a compound of formula III under conditions suitable for the hydrogenation process, or in order to obtain the N-oxide a compound of formula I is treated with hydrogen peroxide or peroxoacid, or for the purpose of to form a salt, a base of formula I is reacted with an acid in a known manner and converted to the corresponding salt. A method according to claim 5, characterized in that a compound of formula IV in which the double bond is in the α-position with respect to the morpholine residue is reduced catalytically or with formic acid. The method of claim 5, wherein the compound of formula IV, wherein the double-strand is in the α-position relative to the phenyl moiety is catalytically reduced. A method according to claim 5, 6 or 7, characterized in that the resulting racemate is separated into optically active antipodes. A method for the preparation of a pharmaceutical agent, characterized in that at least one of the compounds according to claims 1 to 3 is mixed with a pharmaceutically acceptable, non-toxic, inert, commonly used solid or liquid carrier, and process to an appropriate form. A pharmaceutical agent comprising at least one of the compounds according to claims 1 to 3, together with a non-toxic inert carrier. Pharmaceutical agent according to claim 10, characterized in that it is used to combat infections caused by pathogenic fungi or yeast.