CS226049B2 - Method of preparing 3-cycloalkylsulphonylpyrrolidine-2,5-dione derivative substituted in position one - Google Patents

Description

The present invention relates to a process for the preparation of I-substituted 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives having fungicidal activity, which can be used as active ingredients in fungicidal compositions together with customary auxiliaries and salts thereof.

The novel derivatives produced by the process according to the invention can be represented by the general formula I

(I) where

AND

R is C 5 -C 10 cycloalkyl and is hydrogen, C 1 -C 6 alkyl, phenyl optionally substituted by at least one C 1 -C 4 alkyl, nitro, hydroxyl, carboxyl, aminosulfonyl, halogen , (C 1 -C 4) alkoxy, (C 1 -C 4) acyloxy, (C 2 -C 5) alkoxycarbonyl, (C 1 -C 4) acyl group (C 2 -C 5) alkoxycarbonyl; or a phenylalkyl radical having 1 to 4 carbon atoms in the alkyl moiety.

As mentioned above, these novel 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives substituted at the 1-position exhibit significant fungicidal properties and are useful in the control of disease-causing parasitic fungi in humans, animals and plants. It is already known that derivatives of N- (3,5-dihalophenyl) -3,4- (di) substituted pyrrolidine-2,5-dione are characterized by:

226049 2 with antimicrobial effects (South Africa Patent Specification 701,624). Compounds of a similar structure, but which are derivatives of N- (2,6-disubstituted phenyl) -pyrrolidine-2,5-dione substituted at the 3-position, are described in German Patent Publication 2,143,601.

These compounds exhibit antimicrobial activity.

The addition reaction of N-arylmaleimide with phenylsulfonic acid is described in an article published in Bull. of the Chem. Soc. of Japan, 48 (12), pp. 3,675-3,677 [1975]).

The paper only describes this reaction, but does not mention the usefulness of the obtained compounds.

After some time, the microbes become resistant to the active ingredients used and therefore new antimicrobial active ingredients are being sought.

It has now been found that the novel 1-substituted 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives of formula (X) which can be prepared by the process of the present invention exhibit antimicrobial, antifungal activity, even against strains of microorganisms which have already become resistant to conventional fungicidally active substances.

Process according to the invention for the preparation of said novel 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives, substituted in the 1-position, of the general formula I / SO ₂ -A

0 = 1 ^ J = O (I)

R where

A and R are as defined above, characterized in that the 3-halopyrrolidine-2,5-dione substituted in the 1-position of formula VII

R where

R is as defined above and

X represents a halogen atom, for example chlorine, bromine or chlorine, reacted with an alkali metal 3ulfinate of formula VI

Me-C-SO-A <VI} where

A is as defined above and

Ke is an alkali metal, preferably in an inert, polar, aprotic solvent, for example dimethylformamide.

The reaction of the 3-halopyrrolidine-2,5-dione of formula VII with an alkali metal sulfinate of formula VI takes place using equimolar amounts of the reactants at a temperature in the range of 15 to 35 ° C for 30 to 120 minutes.

The compounds of formula (I) formed in the reaction are precipitated from the reaction mixture and can be isolated by filtration or centrifugation or remain in solution. In the latter case, the reaction mixture is generally worked up by separating any by-products which may be formed. by filtration and the reaction mixture is poured onto ice, for example, whereupon the precipitated product is isolated. Alternatively, the volatiles and solvent are removed from the reaction mixture by distillation and the residue is purified, for example, by recrystallization. However, the end products can of course be isolated and purified by other methods customary in organic chemistry.

In this specification, a lower alkyl group, a lower alkoxy group, a lower alkenoalkyl group, a lower alkanecarboxylic acid and a lower alkanecarboxylic acid enhydride means a group containing an alkyl moiety of 1 to 4 carbon atoms.

The starting compounds of the formulas (VI) and (VII) used in the process of the invention are known or can be prepared according to literature procedures.

Sulfinic acid salts of formula (VI) may be prepared by methods known in the literature (J. Amer. Che. Soc., 61, p. 3 089 [1938], Org. Synth. Clll vol. I, p. 492 [1943], J. Org. Chem., 17, 1529 [1952]). The 3-halopyrrolidine-2,5-diones substituted in the 1-position of formula VII can be prepared by methods known in the literature (e.g., Obščej. Chimii, 26, p. 208 [1956], J. Org. Chem., 28 , P. 1963 and South African Patent Publication No. 70.01624).

Said starting materials are commercially available products.

The fungicidal activity of the novel compounds of the formula I was determined as follows:

Sabouraud broth was inoculated with a suspension containing 10 germs in 1 ml and the minimum inhibitory concentrations were determined after 24, 48, 72, 144 and 288 hours of incubation. The results obtained are shown in Tables I and II.

The following organisms were used in the tests:

Saccharomyces cerevisiae, OKI 1282 1

Candida albicans, CBS.562 ”2

Candida tropicalis, CBS.433

Aspergillus niger CBS.12648 5

Aspergillus niger CCM.F-330 20

Aspergillus fumigatus CBS.11325 5

Aspergillus flavus CBS.24765 6

Penieillium digitatum CBS.31948 7

Penicillium digitatum CCM.F-382 8

Penieillium chrysogenium CBS.19646 9

Penicillium chrysogenium CCM.F-362 10

Microsporum gypseum var. vinosum CBS.10064 11

Sporotrichum schenkii CBS.34035. 12

Trichophyton rubrum CBS.30339 13

Trichophyton mentagrophytes CBS.50148 14Γ

Epidermophyton floccosum OKI / IV 15

Fusariuijj graminocorum DSM., 1802

Fusarium oxysporum DSM.10975 17

Fusarium moniliforme DSM.11778 18

Fusarium culmorum DSM. 11425 19 “.

Candida krusei 79 / K47

Cryptococcus neoíořm. 78 / K16

In the tables below, the quotation marks are used instead of the names of the micro-organisms.

The meanings of the abbreviations following the names of microorganisms:

CBS .: Centralbureau voor Schimmelcultures, Bern, The Netherlands.

CCM .: Czechoslovak Collection of Microorganisms, J. E. Purkyně University, Brno, & SSR.

DSM: Deutsche Sammlung Forum Micro-organisms, Institution Forum Mycologie, Berlin-Dahlen,

West Berlin

OKI. 5 'Qrszágo s Kozegászságtani Intázet, Budapest.

For intraperitoneal administration, the LD 50 of N-phenyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione is 382 mg / kg in female mice and 461 mg / kg in male mice.

When administered orally, the compounds of formula I do not exhibit toxic properties.

Table I

Minimum inhibitory concentration (Qug / ml)

Microorga-1-phenyl-3-cyclohexylsulfonyl-1- (p-tolyl) -3-cyclohexylsulfonism used for pyrrolidin-2,5-dionyl-pyrrolidin-2,5-dione used in hour-hour tests

24 48 72 144 288 24 48 72 144 288 II j 11 50 50 - - 25 25 - 11 2 « 75 100 ALIGN! - - - 25 50 - - - 11 ₃ 11 150 150 - - - 100 ALIGN! 150 - - - 11411 - - 75 150 150 - - 25 75 75 5 - - 50 150 150 - - 50 150 150 -6 - - 100 ALIGN! 200 250 - - , 50 250 - 11 y 11 - - 10 25 25 - - 10 10 10 8 - - 25 50 75 - - 25 25 75 ΗφΙΙ - - 50 75 75 - - 50 75 75 10 - - 75 200 200 - - 75 150 150 11 - - 10 10 10 - - 10 25 25 12 - - 10 10 50 - - 5 10 25 13 - - 2.5 10 10 - - 2.5 5 5 14 - - 5 it 10 - - 2.5 2.5 5  1 5 - - 2.5 5 5 - 5 5 5 16 - - 50 100 ALIGN! 100 ALIGN! - - 50 50 50 17 - - 50 75 75 - - 150 200 200 1Θ - - 100 ALIGN! 150 1 50 - - 10c 150 150 19 ” - - 50 50 100 ALIGN! - - 75 1 50 150 20 May - - 150 200 250 - - 100 ALIGN! 150 250

Table 1 - continued

Micro-organism used in the tests 1- (p-fluorophenyl) -3-cyclohexylsulfonyl-pyrrolidine-2,5-dione 1- (p-chlorophenyl) -3-cyclohexyl- sulfonypyrroliin-2, , 5-dione 144 288 24 minimal inhibitory concentration 24 (/ ig / ml) clock clock 144 288 48 72 48 72 1 75 75 - - - 10 25 - - »2 ^M 50 50 - - - 10 25 - - - 3 75 75 - - - - - - - - 4 - - 75 150 150 - - 25 50 75 II CJII - - 50 150 200 - - - - - 6 - - 75 150 200 - - - - - 7 ” - - 10 25 50 - - , 0 , 0 10 8 - - 10 50 50 - - - - - «9 II - 50 75 150 - - - - - 10 ” - - 75 150 200 - - - - - 11 - - 10 25 25 - - - - - 12 - - 50 75 100 ALIGN! - - 5 25 25 13 - - 2.5 10 10 - - 1 2.5 2, 14 - - 2.5 10 25 - - 2.5 2.5 5  1 5 - - 1 2, 5 10 - - 2.5 5 5 17 - - 50 75 75 - - - - - 18 - - 75 150 200 - - - - - 20 May - - 75 1 50 150 - - - - - 21 10 10 - - - - - - - - 22nd 25 25 - - • - -

Table II on pages 6 and 7.

The following are the minimum inhibitory concentrations of 1- (p-tolyl) -3-cyclohexylsulphonylpyrrolidine-2,5-dione per µg / ml medium after 24 and 48 hours of observation for the most important budding pathogenic fungi.

Mushroom Minimum inhibitory concentration yug / ml 24 hours 48 hours Candida benhamii 25 75 Candida guilliermondii 5 10 Candida humicola 5 25 Candida Krusei (79 / K47) 2.5 10 Candida lipolytic 5 10 Candida parapsilosis 10 50 Candida pseudotropic 2.5 10 Candida valida 5 10 Candida vini 1 5 Cryptococcus Neoform (78 / K16) 1 10

These minimum inhibitory concentrations completely inhibit the growth of these microorganisms. Sabouraud's broth was used as culture medium.

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1- (p-tolyl) -cyclohexylsulfonylpyrrolidine-2,5-dione and 1-phenylcyclohexylsulfonylpyrrolidine-2,5-dione are also effective against the following phytopathogenic fungi: Botrytis cinerea, Ascochyta pisi, Cereospora betioola, Xaphrine deformansest, Phytophththora deformans Sclerotinia sclerotiorum, Verticillium alsoatrum, Verticillium dahliae and Venturia.

The novel derivatives of the 1-substituted 3-cycloalkylsulfonylpyrrolidine-2,5-dione of the formula I can be used as active ingredients of fungicidal agents, because of their potent fungicidal activity. One or more compounds of Formula I are formulated with conventional fillers, diluents, stabilizers, and / or flavoring agents and / or other excipients. Solid, liquid and semi-solid compositions can be prepared. Solid compositions include tablets, capsules, dragees, powders, and pills. The tablets may optionally be divided. »

Dragee and capsule coatings may optionally be color coded according to the active ingredient content.

The liquid compositions may be in the form of liquids for brush application, for cladding, or may be in the form of sprays, pickling agents, injectable compositions or aerosols. Semi-solid compositions may be formulated with ointments, pastes or creams.

The above-mentioned fungicidal compositions comprise as active ingredient 1 to 80% of a compound of formula I or a salt thereof, wherein R and A are as defined above, and up to 20% silicic acid, up to 10% surfactant, 1 to 20% mineral filler, up to 5% mica, up to 10% protective colloids, up to 80% starch, up to 50% glycerol, up to 15% water, up to 99% inert atoxic organic solvent and up to 60% aerosol propellant.

The preparation of the compounds of formula (I) is explained in more detail below, and in other examples the preparation of fungicidal compositions containing the compounds of formula (I) is explained in more detail.

Example 1

1-phenyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione

To a solution of 1-phenyl-3-bromopyrrolidine-2,5-dione (2.54 g, 0.01 mol) in DMF (50 mL) at 30 ° C was added a solution of cyclohexylsulfinate (1.7 g, 0.01 mol) with stirring. sodium. The mixture was stirred at 30 ° C for a further 2 hours. The mixture was diluted to 10-fold with water and the title compound was filtered off. After washing and drying, 2.63 g (82% yield) of the title compound of melting point 148-151 ° C are obtained.

The following compounds can be prepared in a similar manner:

1-ethyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 47.6%, mp 113-120 ° C;

1-n-hexyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 39.8%, mp 127-130 ° C

1- (2-chlorophenyl) -3-cyclohexylsulphonylpyrrolidin-2,5-dione, 71.4% yield, m.p. 153-155 ° C;

1- (3-nitrophenyl) -3-cyclohexylsulphonylpyrrolidine-2,5-dione, 92% yield. mp 145-146 ° C

1- (4-acetylphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 79.1%, mp 203-206 ° C;

1- (4-Aminosulfonylphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, 71.8% yield, mp 208-210 ° C

1- (4-methoxyphenyl) -3-cyclohexyl-8-phenyl-pyrrolidine-2,5-dione yield 85.7%, mp 139-140 ° C;

1- (4- (N-Sthoxycarbonylaminosulfonyl) phenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 42.6%, mp, 15-118 ° C,

1-benzyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 84%, mp, 60-62 ° C;

1-phenyl-3-cyclohexylsulphonylpyrrolidine-2,5-dione, 60.2% yield, mp, 58-59 ° C (after recrystallization from ethanol);

1- (p-tolyl) -3-cyclopentylsulfonylpyrrolidine-2,5-dione, yield 86.1%, m.p. 178-180 ° C (after recrystallization and ethanol);

1- (3,4-methylenedioxyphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, 91.8% yield, mp, 86-88 ° C;

1- (4-methyl-3-carbonylphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 46.7%, mp 184-188 ° C;

1- (4-Methyl-2-hydroxymethylphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, 86.2% yield, m.p. 174-177 ° C;

A fungicidal composition comprising as an active ingredient a compound of formula (I) and is prepared as follows:

Example A

Ointment

In a blender, a homogeneous mixture is prepared from the following ingredients:

Active ingredient of the formula 1 2.0 g propyl (p-hydroxybenzoate) 0.06 g methyl (p-hydroxybenzoate) 0.14 g crystalline magnesium sulfate 0.30 g white wax (cera alba) 1.00 g glycerol 5.00 g Miglyol 812 ^X 8.00 g liquid paraffin 8.00 g Dehymuls F * 8.00 g Cetiol V * 10.00 g white petrolatum Ιβ, ΦΟ g distilled water 100.00 g

The obtained haemogenic ointment is filled into crucibles or tubes.

Substances marked with ^x ^ have the following chemical compositions:

Miglyol 812: a mixture of glycerol esters and fatty acids of 8 to 12 carbon atoms. This additive promotes homogenization of the ingredients. Manufactured by: Chemieche Werke Witten GmbH, Witten MSB.

Cetiol V: decyl oleate, manufacturer: Dehydat, Diiseeldorf, MSB.

Dehymuls F: mixture of aliphatic esters, emulsifier. Producer: Dehydat, Diisseldorf, MSB.

Example B

Backfill

The homogeneous powder mixture is prepared from the following finely powdered substances:

Active ingredient of the formula 1 2.00 g colloidal silicon dioxide 1.00 g magnesium stearate 1.00 g zinc oxide 2.00 g white clay (alumina) 5.00 g magnesium carbonate 10.00 g maatek 79.00 g

The powder mixture is filled into a dusting container.

Example C

Aerosol agent

A mixture of the following is prepared:

Active substance of the formula I 0.80 g anhydrous alcohol 11.00 g Miglyol 812 12.00 g methylene chloride 17.60 g

The resulting mixture is filled with aerosol vials which are provided with a button valve and filled with an aerosol propellant, for example a mixture of halogenated hydrocarbons.

With the compositions described in Examples A to C, the assay was repeated to determine the inhibitory ability against microorganisms. 1- (p-tolyl) -3-cyclohexylsulphopylpyrrolidine-2,5-dione was used as test substance. The test results are shown in the table below.

Table

Microorganism used in the test Ointment Aerosol Backfill clock 24 clock minimal 24 inhibitory concentration (yug / ml) 24 clock , 44 48 72 144 48 72 48 72 144 II 25 25 - - 2.5 5 - - 25 50 - - «2« 25 75 - - 25 75 - - 50 75 - - ”3 '* 25 50 - - 25 50 - - 50 75 - - «4« - - 50 75 - 25 50 - - 50 50 I, fjh - - 50 100 ALIGN! - - 50 50 - - 75 , 00 ii - - , 0 10 - - 2.5 , 0 - - 10 10 ncpi - - 10 75 - - 25 50 - - 25 50 12 - - 25 75 · - - 10 25 - - 10 10 13 - - , 0 50 - - 1 5 - - 5 10 14 - - 10 25 - - 1 2.5 - - 10 25 21 10 25 - - 2.5 10 - - 25 25 - - 22 ” 25 50 - - , 0 25 - - 25 25 - - .., 5 » - - 5 , 0 - - 2.5 2.5 - - 10 10 11 - - 10 25 - - , 0 10 - - 10 25 18 - - 100 ALIGN! 100 ALIGN! - - 50 50 - - 75 100 ALIGN! 17 - - 75 75 - - 25 25 - - 75 , 00

Claims (3)

A process for the preparation of 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives substituted in the 1-position of the general formula 1 R (I) wherein A represents a C 5 -C 10 cycloalkyl group and R is hydrogen, C 1 -C 6 alkyl, phenyl optionally substituted by at least one C 1 -C 4 alkyl, nitro, hydroxyl, carboxyl, aminosulfonyl, halogen, C 1 -C 4 alkoxy, acyloxy C 1 -C 4, C 2 -C 5 alkoxycarbonyl, C 1 -C 4 acyl or C 2 -C 5 alkoxycarbonyl, or C 1 -C 4 phenyl phenyl parts, as well as their salts, characterized in that the 3-halopyrrolidine-2,5-dione substituted in the 1-position of the general formula Til X I I (VXD ί R where R is as defined above and X represents a halogen atom, for example chlorine, bromine or iodine, reacted with an alkali metal aulfinate of formula VI Me-O-SO-A (VI) wherein A has the meaning given above and Ke is an alkali metal. 2. The process of claim 1 wherein the reaction of the compound of formula VII with the compound of formula VI is carried out in an inert, polar, aprotic solvent. 3. The process according to claim 1, wherein the inert, polar, aprotic solvent is dlmethylformamide.