CS226048B2

CS226048B2 - Method of preparing 3-cycloalkylsulphonylpyrrolidine-2,5-dione derivatives substituted in position one

Info

Publication number: CS226048B2
Application number: CS825368A
Authority: CS
Inventors: Jenoe Dr Seres; Erika Varkonyi; Sandor Dr Virag; Gabor Dr Kulcsar
Original assignee: Chinoin Gyogyszer Es Vegyeszet
Priority date: 1979-07-17
Filing date: 1982-07-13
Publication date: 1984-03-19
Also published as: CS226050B2; CS226049B2

Description

The present invention relates to a process for the preparation of 1-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 / ^S 2 ^A

0 = ^ 1 ^ = 0

N

AND

R where

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, amino sulfonyl, halogen, C 1 -C 4 alkoxy, (C 1 -C 4) acyloxy, (C 2 -C 5) alkoxycarbonyl, (C 1 -C 4) acyl group or C (C 5 -C 5) alkoxycarbonyl, or (C 1 -C 4) phenylalkyl radical alkyl moieties.

As mentioned above, these novel 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives substituted in 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 (1,4) - (di) substituted pyrrolidine-2,5-dione are characterized by antimicrobial agents (South African Patent No. 701,624).

Compounds of a similar structure, but which are derivatives of N- (2,6-disubstituted phenyl) -3-substituted pyrollidin-2,5-dione, are described in German publication no.

143 601.

These compounds exhibit antimicrobial activity.

The coupling reaction of N-aryl maleimide with phenylsulfonic acid is described in an article in Bull. of the Chem. Soc. of Japan, 48, (12), p

677 (1975). The article only describes this reaction, but does not mention the usefulness of the obtained compounds.

After some time, the microbes become resistant to the active substances used, and therefore, new antimicrobially active substances are sought.

It has now been found that the novel 1-substituted 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives of formula (I) which can be prepared by the process according to the invention are characterized by an antimicrobial, in particular fungicidal action, even against such microorganism strains which have already become resistant to the usual 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 / SO3 - and

O = _<n J = O (I)

AND

R where

A and R are as defined above, characterized in that the 1-substituted pyrroline-2,5-dione of formula II

R where

R is as hereinbefore defined, reacting additively with a cycloalkylsulfinic acid of formula V

HO-SO-A (V) where

A is as defined above, preferably in a mixture of water with a lower alkanol.

Said reaction is preferably carried out by first dissolving or suspending the compound of formula (II) in a mixture of water with a lower alkanol and adding to this mixture, with stirring, preferably at a temperature in the range of 0-25 ° C, cycloalkylsulfinic acid of formula (7). of said reaction conditions, the reaction is complete after a few hours and the product of formula (I) is formed from the reaction mixture.

The compounds of formula (1) 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 filtering off any by-products which have formed and, for example, pouring the reaction mixture over ice, 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 alkanoyl group, a lower alkanecarboxylic acid and a lower alkanecarboxylic anhydride is a group containing an alkyl moiety of 1 to 4 carbon atoms.

The starting compounds of the formulas (II) and (V) used in the process according to the invention are known or can be prepared by methods described in the literature. The 1-substituted 3-pyrroline-2,5-dianes represented by the general formula (II) can be prepared by reacting maleic anhydrides with the appropriate amine and treating the resulting 4-substituted amino-4-oxybutenyl acid (Wiss. S. Univ Halle XXV76M, p.

0 976] β J. Org. Chem., 26, p. 2037 096]. Sulfinic acids of formula V and their salts can be prepared by methods known in the literature (J. Aaer. Chem. Soc., 61, p. 3 089 0939], Org. Synth. Coll., Vol. I, p. 492 01943] , J. Org. Chem., 17.

529 0952] and literature cited above).

Said starting materials are commercially available products.

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

Sabouraud broth was inoculated with a suspension containing 10 germs in 1 ml, and 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

Candida tropicalis CBS.433

Aspergillus niger CBS.12648

Aspergilus niger CCM.F-330

Aspergillus fumigatus CBS.11326

Aspergillus flavus CBS.24765

Penicillium digitatum CBS.31948

Penicillium digitatum CCM.F-382

Penicillium chrysogenium CBS.19646 - Penicillium chrysogenium CCM.F-362 Microsporum gypseum var. vinosum CBS.10064 Sporotrichoma schenkii CBS.34035 Trichophyton rubrum CBS.30338 Trychophyton mentagrophytes CBS.50148 Epidermophyton floceosum OKI / IV.

Fusarium graminocorum DSM.11802 Fusarium oxysporum DSM.10975 Fusarium moniliforme DSM.11778 Fusarium culmorum DSM.11425 Candida krusei 79 / K47

Cryptococcus neoform. 78 / K16

Γ γ tl 8

10! 11 11 12 13 14 15 16 17

22nd

In the tables below, the numbers in quotation marks are given instead of the names of the micro-organisms.

Meaning of abbreviations given with the names of microorganisms:

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

CCM.i Czechoslovak Collection of Microorganisms, JE Purkyně University, Brno, Czechoslovakia.

DSM .: Deutsche Sammlung fiir Microorganism, Institution fiir Mycologle, Berlin-Dahlem,

West Berlin

OKI .: Orsságos Kosegássságtani Intézet, Budapest, Hungary.

For intraperitoneal administration, the LD 50 of N-phenyl-3-cyclohexylsulphonylpyrrolidine-2,5-dione was 382 mg / kg in female mice and 46 mg / kg in male mice.

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

Table 1

Minimum inhibitory concentration (jug / ml)

Micro-, -phenyl-3-cyclohexylsulphonyl-1- (p-tolyl) -3-cyclohexylsulphonism used for the pyrrolidine-2,5-dione-pyrrolidine-2,5-dione used in the hour-hour test

24 48 72 144 288 24 48 T2 144 288 1 »1 M 50 50 25 25 «2 H 75 »00 - - - 25 50 - - - «2” 150 150 - - - 100 ALIGN! 150 - - - - «4« - - 75 150 150 - - 25 75 75 - - 50 150 150 - - 50 150 150 6 - - 100 ALIGN! 200 250 - - 150 250 - - - 10 25 25 - - 10 10 10 8 - - 25 50 75 - - 25 25 75 - - 50 75 75 - - 50 75 75 10 - 75 200 200 - - 75 150 150 Ml - - 10 10 10 * - 10 25 25 12 - - 10 10 50 - - 5 10 25 13 - - 2.5 10 10 - - 2.5 5 3 14 - - 5 10 10 - - 2.5 2.5 5 , 5 ^H - - 2.5 5 5 - 5 5 5 16 - - 50 100 ALIGN! 100 ALIGN! - - 50 50 50 17 - - 50 75 75 - - 150 200 200 18 - - 100 ALIGN! 150 150 - - 100 ALIGN! 150 150 19 Dec - - 50 50 100 ALIGN! - - 75 150 150 20? - - 150 200 250 - - 100 ALIGN! 150 250

Table 1 - continued

2-Corro-1- (p-fluorophenyl) -3-cyclohexyl-1- (p-chloroperiyl) -3-cyclohexylmethylsulfonylpyrrolidine-2,5-dione sulfonylpyrrolidine-2,5-dlon ¹ tests of minimum inhibitory concentration (Mg (ml) hours hours

24 48 72 144 288 24 48 72 144 288 N | M 75 75, - 10 25 - • «2« 50 50 - - - 10 25 - - - 75 75 - - - - - - - - * 4 « - - 75 150 150 - - 25 50 75 - - 50 150 200 - - - - - - - 75 150 200 - - - - - ”7 - - 10 25 50 - - 10 10 10 8 - - 10 50 50 - - - - - W £ H - - 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 15 Dec - - 1 2.5 10 - - 2.5 5 5 10 - - 50 75 75 - - - - - 18 - - 75 150 200 - - - - 20 May - - 75 150 150 - - - - - 21 10 10 - - - - - - - - «22 ** 25 25 * - - - - - - -

Table II, see pages 6 and 7.

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

Mushroom minimal inhibitory concentration 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 Candidapseudotropic 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. Sabourad's broth was used as culture medium.

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1- (p-tolyl) -cyclohexylsulphonylpyrrolidine-2,5-dione and 1-phenyleyclohexylsulphonylpyrrolidine-2,5-dione are also active against the following phytopathogenic fungal species: Botrytis cinerea, Ascnchyta plel, Ceroospora beticola, Taphrthora deformans, Phytophora deformans Sclerotinia sclerotiorum, Vertieillium alsoatrum. Verticillium dahliae and Venturia.

The novel 1-substituted 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives of the general 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.

The dragee coating and capsules 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 fungicidal compositions comprising as active ingredient 1-80% of a compound of formula I or its _salt wherein R and A are as defined above, and up to 20% silica, up to 10% surfactant 1 to 20% of a mineral filler, up to 5% slime, up to 10% protective cocoids, 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 the formula I as well as the preparation of fungicidal compositions containing the compounds of the formula I are explained in more detail below, but the scope of the invention is not limited to these examples.

Example 1

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

A solution of 0.296 g (0.002 mol) of cyclohexylsulfinic acid in 100 ml of water was added with stirring at 15 ° C to a solution of 0.346 g (0.002 mol) of 1-phenyl-pyrroline-2,5-dione in 100 ml of ethanol. The reaction mixture was then stirred at 15 ° C for 10 hours. The precipitated product is filtered off and washed with water. This afforded 0.475 g (74% yield) of the title compound, mp 149-151 ° C.

In a manner similar to that described above, the following compounds can be prepared:

1-ethyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 47.6%, mp 118-120 ° C;

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

1- (2-chlorophenyl) -3-cyclohexylsulphonylpyrrolidine-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, 79.1% yield, mp 203-206 ° C;

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

1- (4-methoxyphenyl) -3-cyclohexylsulphonylpyrrolidine-2,5-dione, 85.7% yield, mp 139-140 ° C

1- Q - (N-ethoxycarbonylaminosulfonyl) phenyl] -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 42.6%, mp 115-118 ° C;

1-benzyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 84%, mp 160-162 ° C;

1-phenyl-3-cyclopentylsulfonylpyrrolidine-2,5-dione, yield, 60.2%, mp 158-159 ° C (after recrystallization from ethanol),

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

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

1- (3,4-methylenedioxyphenyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, 91.8% yield, m.p. 186-188 ° C);

1- (4-methyl-2-hydroxymethylphenyl) -3-cyclohexyl-3-sulfonylpyrrolidine-2,5-dione, yield 86.2%, mp, 74-77 ° C.

A fungicidal composition comprising as an active ingredient a compound produced by the process of the invention is prepared as follows:

Example A

Ointment

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

Active ingredient of the formula I 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 Myglyol 812 ⁺ 8,00 g liquid paraffin 8,00 g Dehymuls F ⁺ 8,00 g Cetiol V ⁺ 10,00 g white petrolatum 10,00 g distilled water 100,90 g

The obtained homogeneous ointment is filled into crucibles or tubes.

Substances marked with * have the following chemical composition:

Myglyol 812: a mixture of glycerol esters of C8-C12 fatty acids. This additive promotes homogenization of the ingredients. Manufacturer: Chemische Werke Witten GmbH, Witten, Germany

Cetiol V: decyl oleate, manufacturer: Dehydat, Diisseldorf, Germany

Dehymuls F: mixture of aliphatic esters, emulsifier. Manufacturer: Dehydag, Diisseldorf, Germany.

Example B

Backfill

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

Active ingredient of the formula I 2.00 g colloidal silica 1.00 g magnesium stearate 1.00 g zinc oxide 2.00 g white clay (alumina) 5.00 g magnesium carbonate 10.00 g talc- 79.00 g

The powder blend is filled into gelatine containers.

Example C

Aerosol agent

An active ingredient of the formula I as described below is prepared from 0.80 g anhydrous alcohol. 11.00 g Mlglyol 812 12.00 g methylene chloride 17.60 g

The resulting mixture is filled with aerosol vials, which are provided with a push-button valve and filled with aerosol propellant, for example by the emission of halogenated hydrocarbons,

With the compositions described in Examples A to C, the assay was repeated to determine the Inhibitability to Microorganisms. 1- (p-Tolyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione was used as test substance. The test results are shown in the table below.

Table

Mikroorganis-.,

Claims

SUBJECT OF THE INVENTION

A process for the preparation of 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives substituted in the 1-position of the general formula I) = k, J = O (I)

R where

A represents a C 5 -C 10 cycloalkyl group and

R is hydrogen, C 1 -C 6 alkyl, phenyl optionally substituted with at least one C 1 -C 4 alkyl, NH 4, 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 or C (C 5 -C 5) alkoxycarbonyl, or (C 1 -C 4) phenylalkyl radical in the alkyl moiety as well as their salts, characterized in that the 1-substituted pyrroline-2,5-dione of formula II

0 =

R (II) wherein

R is as hereinbefore defined, reacting additively with a cycloalkylsulfonic acid of formula V

HO-SO-A (A) where

And has the above meaning,

2. The process of claim 1 wherein the reaction is carried out in a mixture of water with a lower alkanol.