SE447730B - MORPHOLINE DERIVATIVES, PROCEDURES FOR PREPARING THEREOF, AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH SUCH ASSOCIATIONS FOR USE AS ANTIMYCOTICS - Google Patents

Description

447 730 a) reacting a halide of the formula wherein R has the meaning given above and Y represents chlorine, bromine or iodine, with a compound of the formula e1 I CIH3 HN lll ° '_ CH3 or b) reducing a compound of the formula IV (IH3 wherein R has the meaning given above and one of the two dashed lines forms an additional bond, or c) converts a compound of the general formula Q / Vxá CH3 447 73ÜMhW.

J - 3 .. _. With a compound emitting a carbonium ion of the general formula wherein R is as defined above, or d) reacting a compound of formula VII CHO wherein R is as defined above, under hydrating conditions with a compound of formula III , or for the preparation of an N-oxide, a compound of formula I treats with hydrogen peroxide or peracids, or, for the preparation of a salt, transfers a base of formula I with an acid in a manner known per se to a salt.

According to process variant a) a halide of formula II is reacted with an amine of formula III, suitably in an inert solvent, for example in an ether such as diethyl ether, tetrahydrofuran or dioxane or in dimethyl sulphoxide, preferably in a higher boiling alcohol such as ethylene glycol or glycerin. in the presence of a base such as, for example, triethylamine or an excess of an amine of formula III. The mixture is preferably reacted in a temperature range between 50 and 150 ° C. Particularly preferred as the solvent are ethylene glycol and a temperature of 100 to 110 ° C.

According to process variant b), a compound of formula IV is reduced.

When a compound is used as starting material for formula IV in which the double bond is in the α-position to the morpholine residue, the reduction can take place catalytically or with formic acid.

Precious metal catalysts such as, for example, platinum, palladium - possibly on carbon and 447,730 in Raney nickel - are particularly suitable as catalysts. Preferably, palladium is used on carbon. Suitable solvents for the catalytic reduction are hydrocarbons such as benzene, toluene or xylene, as well as alcohols such as methanol or ethanol. Toluene is preferred. As reaction temperatures, a range between 0 and 50 ° C is preferably chosen, preferably room temperature. The reduction of the enamine with formic acid is preferably carried out in the absence of a solvent, until the enamine is added dropwise at a temperature of 0 - 10 ° C, preferably 50 - 70 ° C formic acid, if required under cooling.

When using a starting material of formula IV, wherein; If the double bond is in the Q position to the phenyl residue, the reduction can take place catalytically. Platinum or palladium are preferably used as catalysts, water or alcohol being used as solvent. To avoid possible hydrogenolysis, at least one equivalent of acid, preferably hydrochloric acid, is added to the reaction mixture.

The alkylation of the compound of the general formula V according to process variant c) takes place in the absence of a suitable amount of a Friedel-Crafts catalyst. Suitable catalysts are the known Friedel-Crafts catalysts such as e.g. aluminum chloride, iron chloride, zinc chloride, boron trifluoride, tin chloride, hydrogen fluoride, sulfuric acid and phosphoric acid. For the purpose of the present invention, sulfuric acid is particularly suitable. The use of an inert organic solvent is not mandatory but is preferred. Suitable inert solvents are especially alkanes such as hexane, cyclohexane, chlorinated hydrocarbons such as chloroform, ethylene dichloride and methylene chloride, with methylene chloride being particularly preferred. The temperature of the alkylation reaction is not critical but is generally between 0 and 5000, preferably between 18 and 2090. Preferably and especially when using sulfuric acid, after completion of the reaction the product obtained is extracted in salt form with an inert organic solvent such as methylene. chloride. If desired, the free amine can be obtained with a suitability of .z- fl- IL-: ä-v. ~ 447,730 base such as sodium hydroxide, potassium hydroxide, soda, potash or calcium hydroxide.

Preferred compounds which give off the carbonium ion of the general formula VI are the corresponding tert. alcohols such as 2-methyl-2-butanol or tert. chloride such as 2-chloro-2-methylbutane.

The reaction of the substituted cinnamaldehyde of formula VII with cis-2,6-dimethylmorpholine of formula III takes place under hydrogenating conditions, for example using a palladium iodine catalyst e.g. and methanol.

To prepare the N-oxide of the compound of formula I, a compound of formula I is treated with hydrogen peroxide or a peracid. Alcohols such as methanol, ethanol or isopropanol are used as solvents when hydrogen peroxide is used as the oxidizing agent, the latter being preferred. Preferred reaction temperatures are between 0 and 50 ° C, especially 40 ° C.

As peracids, for example, peracetic acid, perbenzoic acid, metachloroperbenzoic acid or peradipic acid can be used. Halogenated hydrocarbons such as methylene chloride, chloroform or ethylene chloride preferably serve as solvents for the peracids. As reaction temperatures, the same as described above is suitable for the reaction with hydrogen peroxide.

The compounds of formula I form salts with inorganic and organic acids. As salts for the compounds of the formula I, salts with physiologically tolerable acids are particularly suitable. This preferably includes hydrohalic acids, such as e.g. hydrochloric acid and hydrobromic acid, in addition phosphoric acid, nitric acid, as well as mono- and bifunctional carboxylic acids and hydroxycarboxylic acids such as e.g. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid and finally sulfonic acids such as 1,5-naphthalene-disulfonic acid. The preparation of such salts takes place in a manner known per se.

The starting materials of formula II and VI are known compounds. »---- -.... .-.... - »-» -,. -.._-, .., ...-.....-- ~ --_....;.-... v.q.wv -.-. v .. “-..._.« ..-- »wq. ~ v ~ n-vvu-vuun ~ 447 730 The starting materials III and IV are known as cis / trans mixtures.

Cis starting materials III and IV can be obtained analogously to the processes for producing the cis / trans slopes.

The starting materials of formula IV, wherein the double bond is present. can be obtained, for example, by reacting a correspondingly substituted phenyl-2-methylpropionaldehyde with cis-2,6-dimethylmorpholine. The hydrogenation of the compound of formula IV thus obtained preferably takes place in situ. The starting materials of formula IV, in which the double bond is in the form of the phenyl residue, can be obtained, for example, by reacting a halide, corresponding to formula II, which, however, in the position of the phenyl residue has a double bond, with cis-2,6 ~ dimethylmorpholine.

The compounds of general formula V can be prepared by mixing and catalytically hydrogenating a compound of general formula CH 3 / VI 11 cHo with a compound of general formula III.

The solvent used is preferably an organic solvent, e.g. an alcohol such as methanol. The temperature is not critical but is usually between 0 and 50 ° C.

In the catalytic hydrogenation, the usual hydrogenation catalysts such as e.g. platinum, Raney nickel or palladium with 5% palladium on carbon being particularly preferred.

The compounds of the invention contain in the propylene chain connecting the morpholine residue with the β-substituted phenyl residue an asymmetric C atom and can therefore occur in the form of. .. -_._... -_.-_.-..__..-..._...._...- .. ~ .. - "- ~ '- f * 447 730- .- * 7 ___-_ "racemates and in the form of the optical antipodes. The latter can also be obtained from the racemates formed by cleavage with optically active acids, for example with (+) - camphoric acid, ( +) - camphor-10-sulfonic acid, 0,0'-dibenzoyltartaric acid (L- or D-form), L (+) - tartaric acid, D (-) - tartaric acid, L (+) - glutamic acid 4-sulfonate , L (-) - malic acid or D (+) - malic acid This cleavage can take place according to the usual cleavage methods.

The compounds according to the invention have a fungicidal effect and can therefore be used for controlling fungi in agriculture or in the horticultural industry. The compounds of the invention; d is particularly suitable for controlling true powdery mildew fungi such as Erysiphe graminis (cereal powdery mildewqq), Erysiphe cichoracearum (cucumber powdery mildew), Podosphaera leucotricha (apple powdery mildew). Sphaerotheca pannosa (rose flour), Oidium tuckeri '(wine flour); rust diseases such as those of the genus Puccinia, Uromyces and Hemileia, especially Puccinia graminis (cereal black rust), Puccinia coronata (oat crown rust), Puccinia sorghi (corn rust), Puccinia striiformia (yellow rust on wheat), Puccinia recondyula (brown rust, appendicus) (creeping bean rust) and against Hemileia vastatrix (coffee rust) and Phragmidium mucronatum (rose rust).

In addition, these compounds also have an effect on the following phytopathogenic fungi: 'Ustilago avenae (fly agaric), Venturia inaequalis (apple scab), Cercospora arachidicola (peanut leaf spot disease), Ophiobolus graminis (cereal foot disease), Septoria nodorum (wheat brown) or wheat brown Marssonina rosae (rose spot disease). Individual substances from this class of compounds have pronounced side effects against various species of the following genera: Rhizoctonia, Tilletia, Helminthosporium and also partly against Peronospora, Coniophora, Lenzites, Corticium, Thielaviopsis and Fusarium.

In addition, the compounds of the formula I also act against phytopathogenic bacteria such as, for example, Xanthomonas vesicatoria, Xanthomonas oryzae and other xanthomonads, as well as against various species of Erwinia, e.g. Erwinia tracheiphila.

Above all, however, the active compounds according to the invention are suitable due to the fungistatic and fungicidal effect for controlling infections caused by fungi and yeasts, for example Genera Candida, trichophytes or histoplasma. They are particularly effective against candidate species such as Candida albicans and are preferably suitable for local therapy of superficial infections of the skin and mucous membranes, especially in the genital area, for example Vaginitis, especially caused by Candida. The choice of application form is local, so that the active substance can be used as a therapeutically active preparation in the form of ointments, suppositories, suppositories, ovules and other suitable forms.

The pharmaceutical preparations can be prepared in a manner known per se by mixing the active substance with customary organic or inorganic inert carriers and / or excipients such as water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol. petroleum jelly, preservatives, stabilizers, wetting or emulsifying agents, salts for altering the osmotic pressure or buffer substances.

Dosages are made according to individual requirements, however, an application of 1 to 2 tablets daily, containing_S9 - 100 mg of active substance for a few days constitutes a preferred dosage.

The ointment suitably contains 0.3 - 5%, preferably 0.5 - 2%, especially 0.5 - 1% active substance. The experimental report below and the results given in the tables also provide the person skilled in the art with the necessary information for the dosage of the active substance.

The compounds of the invention are tested for the effect against Candida albicans in that of Path. Microbiol. volume 23: (1960) p. 62 - 68 described Vaginal Candidiasis test in rats whereby the following results were obtained: ^ '. ~~ t- * ~ .'- t "'.: '<Fl r1u-. ~ .-:' ~ m. - 447 730 Compound concentration in% at which an "ED 50" effect occurred cis-4- [3- (p-tert.amylphenyl) -2-methylphenyl] - 0.01 2,6-dimethylmorpholine cis-4- / 3 ~ [ P '(u, dimethylbenzyl) -phenyl] -2- 0.01 methylpropyl / -2,6-dimethylmorpholine. DE-OS 27 52 096 describes i.a. the two compounds 4- [3- (p-tert-amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine and 4-1-1β- (NAN-dimethyl-benzyl) -phenyl] -2- methyl-propyl-2,6-dimethyl-morpholine. The compounds obtained according to this patent form cis / trans mixtures, while the compounds according to the present application constitute cis compounds.

The present cis compounds, i.e. the compounds of formula I and their acid addition salts and N-oxides, have an antifungal effect, which is surprisingly much higher than the antifungal effect of the cis / trans mixtures known from DE-OS 27 52 096. For example, comparative experiments determined that the cis / trans mixtures in vaginal candidiasis tests on rats (Path. Microbiol. 23: 62-68 (1960)) are effective (ED 50) against Candida albicans at a concentration of 0.1 S , while the above table shows that the cis compounds of formula I are active (ED 50) already at a concentration of 0.01%.

The invention is further illustrated by the following examples in which the temperature refers to degrees Celsius.

Example 1 230 grams of 3- (p-tert-amylphenyl) -2-methylpropionaldehyde and 137 grams of cis-2,6-dimethylmorpholine were heated at reflux in 1000 ml of toluene in a water trap under nitrogen gasification for 16 hours until the water cleavage was completed. At room temperature, 17.5 grams of 5% palladium on carbon are added under nitrogen gasification and then the reaction mixture is hydrogenated to complete hydrogen uptake, the catalyst is filtered off and the toluene is evaporated in vacuo. Pure distillation of the residue gives pure cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorphane, boiling point 120 ° / 0.1 Torr.

Example 2 In, for example, 1 in an analogous manner, by reacting 3- [β- (α, α-flmethylbenzyl) -phenyl] -2-methylpropionaldehyde and cis-2,6-dimethylmorpholine and hydrogenation cis-4- / 3- [ p- (α, α-dimethylbenzyl) -phenyl] -2-methylpropyl / -2,6-dimethylmorpholine with a boiling point of 1620 / 0.04 Torr.

Example gel 3 To 1223 grams of cis-4- (2, methyl-3-phenylpropyl), 2,6-dimethylmorpholine in 4 liters of methylene chloride is dropped at -5 ° within 45 minutes 4941 grams of concentrated sulfuric acid and then within 60 minutes S20 grams 2 -methyl-2-butanol. The reaction solution is placed under ice-cooling with water and the aqueous phase is extracted several times with methylene chloride. The organic extracts are washed with sodium hydroxide and then with water, dried, evaporated and the oily cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine is distilled in vacuo. boiling point 120 ° / 0.1 Torr. The cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine used as starting material can be obtained as follows: 1000 grams of methylmethylcannaldehyde, 10 liters of methanol and 789 grams of cis-2.6 -dimethylmorpholine is placed under a nitrogen atmosphere with 50 grams of 5 percent palladium on carbon. It is then hydrogenated under water cooling at the 30 ° reaction mixture until complete hydrogen uptake, the catalyst is filtered off, the methanol is distilled off under reduced pressure and then the crude 3 cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine is distilled. The 99 2% pure product boils at 1090 / 0.055 Torr.

2 (Dimethylbenzyl) -phenyl] -2-methylpropyl bromide and stirred for 48 hours 447,730 μl Example 4 20.0 grams of p- (α, ordimethylbenzyl) -α'-methylcinnamaldehyde and 9.6 grams of cis-2,6-dimethylmorpholine are added 1 60 ml of methanol under argon gassing with 1 gram of 5% palladium on carbon and then hydrogenated to complete hydrogen uptake. The reaction solution liberated from the catalyst is evaporated under reduced pressure, chromatographed with chloroform on alumina (activity stage II) and then distilled in a high vacuum. Cis-4- [3- [β- (α, α-dimethylbenzyl) -phenyl-2-methylpropyl] -2,6-dimethylmorpholine with a boiling point of 162 ° / 0.04 Torr are obtained. _ - _: _., Example 5 In analogy to the data in Example 4, starting from p- (tert.-amylphenyl) -α'-methylcinnamaldehyde and cis-2,6-dimethylmorpholine, cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine.

Example 6 To a solution of 22.7 grams of 2,6-cis-dimethylmorpholine in 70 ml of ethylene glycol is slowly added dropwise at 125 DEG C. 44.3 grams of 3- (p-tert-amylphenyl) -2-methylpropyl bromide and stirred for 48 hours. temperature. After cooling, the mixture is added with 2N hydrochloric acid and the neutral part is extracted with ether. Then the hydrochloric acid solution is made alkaline with Sn sodium hydroxide solution, extracted with ether, the ether extract is washed with water, dried over sodium sulphate and evaporated. Pure cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine, boiling point 1200 / 0.1 Torr, is obtained by distillation.

Example gel 7 To a solution of 22.7 grams of 2,6-cis-dimethylmorpholine in 80 ml of ethylene glycol is slowly added dropwise at 125 DEG C. 51.8 grams of 3- [p- (a, a at this temperature. The work-up is carried out analogously to Example 5. pure cis-4- [3- [p- (α, c-dimethylbenzyl] phenyl] -2-methylpropyl] -2,6-dimethylmorpholine is obtained, b.p. 62 ° / 0.04 Torr. 447 730 12 Example 8 266 grams of cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine, 1,500 ml of absolute ethanol are dissolved and at room temperature, 500 ml of a 28% hydrogen chloride ethanol are added dropwise. The homogeneous solution is evaporated on a rotary evaporator to dryness and the residue is recrystallized from 100 ml of water.

The crystallizate is washed with water and dried in a vacuum drying cabinet at 550; The hydrochloride of cis-4- [3- (p-tert.-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine is obtained as white slightly hygroscopic crystals, m.p. 204 DEG-206 DEG C. Example: To 21 grams of cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine is added dropwise under the acetone-dry rinse a solution of 60 ml of precursor hydrogen peroxide in 60 ml of acetic anhydride so that the reaction temperature does not exceed 500 and then the mixture is left to react further for 16 hours at room temperature. The batch is tested by thin layer chromatography (hexane ether 1: 1). To destroy the excess peroxide, the reaction mixture is cooled to -10 ° and added with 200 ml of 40% potassium hydroxide. After stirring for 20 hours, the mixture is diluted with 500 ml of water and extracted exhaustively with chloroform.

The combined chloroform extracts are neutral washed, dried and evaporated. By recrystallization of the residue from 100 ml of pentane, pure cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine-4-oxide is obtained.

The following examples describe the preparation of pharmaceutical preparations: 9 Example 10 i 5 Vaginal tablets of the following composition are prepared in the usual manner: 447 730, - 13 cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl ] -2,6-dimethylmorpholine 50 mg sec. calcium phosphate 2H20 400 mg direct pressable starch sTA-Rxlsoo 261 mg milk sugar (spray dried) 100 mg polyvinylpyrrolidone 25 mg citric acid 5 mg magnesium stearate 6 mg 847 mg Example ll An ointment of the following composition is prepared: cis-4- / 3- [p- ( n, ardimethylbenzyl) -phenyl] -2-methylpropyl / -2,6-dimethylmorpholine 0.7 g cetyl alcohol 3.6 g wool fat 9.09 petroleum jelly, white 79.3 g paraffinic acid 7.4 g 100.0 g A cream of the following composition is prepared: cis-4- [3- (ether-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine 0.7 grams of polyoxyethylene stearate 3.3 grams of stearyl alcohol 8.0 grams of viscous paraffin oil 10.0 grams of Vaseline, white 10.0 grams of carboxyvinyl polymer CARBOPOL 934 Ph 0.3 grams of Na

Claims (10)

447f7zo M PATENTKRAV 1. Compounds of the general formula R cH3 Ha H G 3 CH3 CH3 wherein R represents ethyl or phenyl, and salts and N-oxides of these compounds. Cis-4- [3- (p-tert.-Amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine and its salts and its N-oxide as a compound according to claim 1. Cis-4- [3-Ip- (dimethyl-benzyl) -phenyl] -2-methyl-propyl] -2,6-dimethyl-morpholine and its salts and its N-oxide as a compound according to claim 1. Compounds according to any one of claims 1 to 3 for use as antifungals. 5. A process for the preparation of compounds of the general formula R cH3 CHa H36 C H3 9-447 730 wherein R represents ethyl or phenyl, and of salts and N-oxides thereof, characterized in that a) a halide is reacted with formula R CH3 g H30 cH3 || Wherein R has the meaning given above and Y represents chlorine, bromine or iodine, with a compound of the formula CH 3 HN 1H CH 3 or b) reduces a compound of the formula IV CH 3 wherein R has the meaning given above and one of the two dashed lines form a further bond, or c) reacting a compound of the general formula _ ae, 447 730 CH3 CH3 CH3 'with a compound which gives off a carbonium ion of the general formula e1 R \ g-CH vi HSC / 3 wherein R has the meaning given above or d) react a compound of the formula F * CH 3 C H 3 c H 3 VII / cHo wherein R has the meaning given above, under hydrating conditions with a compound of the formula III, or that for the preparation of a N-oxide treats a compound of formula I with hydrogen peroxide or lower acids, or for the preparation of a salt in a manner known per se, a base of formula I is transferred with an acid in a salt. 6. A process according to claim 5, characterized in that a compound of formula IV is reduced catalytically or with formic acid, wherein the double bond is in the position of the morpholine residue. 7. A process according to claim 5, characterized in that a compound of formula IV is catalytically reduced, wherein the double bond is in the position of the phenyl radical. IYà 447 730 u 8. A method according to claim 5, 6 or 7, characterized in that a obtained racemate is split into the optical antipodes. Pharmaceutical preparations containing at least one of the compounds mentioned in claims 1 to 3 and non-toxic inert carrier materials, for use as antifungals for the control of infections caused by pathogenic fungi or yeast species. Pharmaceutical preparations according to claim 9 for use in controlling Candida albicans.