CS226050B2 - 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 1-substituted 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives having fungicidal activity which can be used as active substances 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 / SO ₂ -A OTIL 10 (I)

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, 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 alkyloxycarbonyl) aminosulfonyl, or C 1 -C 4 phenylalkyl carbon 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 - (1,4) - (di) substituted pyrrolidine-2,5-dione possess antimicrobial effects (South African Patent No. 701,624).

Compounds of a similar structure, but which are derivatives of N- (2,6-disubstituted phenyl) -pyrrolidine-2,5-dione substituted in the 3-position, are described in the German publication.

No. 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 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 ingredients used and therefore new antimicrobial active ingredients are being sought.

It has now been found that the novel 3-cycloalkylsulfonylpyrrolidine-2,5-dione substituted in the 1-position of formula (I), which can be prepared by the method of the invention, exhibit antimicrobial, especially fungicidal activity, even against such microorganism strains which have 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 formula I

R

SO., - A (I) where

A and R are as defined above, characterized in that to the cycloalkylsulfonylsuccinic acid poloamide of formula VIII ch ₂ -ch-so ₂ -a (VIII)

0 = 6 C = O and I wherein one of B and D is hydroxyl and the other is -NH-R, and

R and A are as defined above and act as a water-binding agent.

The dehydration of cycloalkylsulfonylsuccinic acid amides of the general Formula VIII can preferably be carried out in an excess of a water-binding agent.

As water-binding agents, phosphorus pentoxide, phosphorus trichloride, acetyl chloride, or acetic anhydride may be used. The reaction is preferably carried out in an inert organic solvent. It is particularly preferred that the same compound, for example acetic anhydride, is used as solvent and water-binding agent. The reaction can be accelerated by heating the reaction mixture. In general, the reaction is carried out at a temperature in the range of from 20 to 140 ° C, preferably in the range of from 90 to 95 ° C.

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 filtering off any by-products which have formed and, for example, pouring the reaction mixture on ice, whereupon the product thus formed 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 resulting 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 acid anhydride is a group having an alkyl moiety having 1 to 4 carbon atoms.

The starting compounds of formula (VIII) may be prepared from 4-substituted amino-4-oxobutenyl acids and cycloalkylthiols. (The preparation of 4-substituted amino-4-oxobutenyl acids has been described in the literature, for example in J. Org. Chem. 26, p. 2037 (> 961) or Wtss. Z. Univ. Halle, XXV 76M, £, p. 5 (1976)). The product resulting from the addition reaction of 4-substituted amino-4-oxobutyl acid and cycloalkylthiols is then oxidized with an oxidizing agent, preferably hydrogen peroxide or potassium permanganate, at a temperature ranging from 0 to 50 ° C.

tt

Said release of the substance is a commercially available product.

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 and 144 and 288 hours of incubation period. The results obtained are shown in Tables I and II.

The following microorganisms were used in the tests:

Saccharomyces cerevisiae OKI 1282 1

Candida albicans CBS.562 ”2

Candida tropicalis CBS.433 2

Aspergillus niger CBS.12648 5

Aspergillus niger CCM.P-330 20

Aspergillus fumigatus CBS.11325 5

Aspergillus flavus CBS.24765 7

Penicillium digitatum CBS.31948 7

Penicillium digitatum CCM.F-382 8

Penicillium chrysogenium CBS.19646 9

Penicillium chrysogenium CCM.F-362 10

Microsporum gypseum var. vinosum CBS.10064 11

Sporotriohum schenkii CBS-34053 12

Trichophyton rubrum CBS.30339 13

Trichophyton mentagrophytes CBS.50148 14

Epidermophyton flocoosum OKI / IV 15

Fusarium graminocorum DSM.11802 16

Fusarium oxysporum DSM.10975 17

Fusarium moniliforme DSM.11778 18

Fusarium culmorum DSM.11425 19

Candida krusei 79 / K47

Cryptococous neoform. 78 / K16 22

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

The meaning of abbreviations following the names of microorganisms:

CBS .: Centralbureau voor Schimmelcultures, Bern, The Netherlands

CCM .: Czechoslovak Collection of Microorganisms, J.V. Purkyně University, Brno, ČSSR DSM .: Deutsche Sammlung für Mikroorganismen, Institution für Mycologie, Berlin-Dahler,

West Berlin

OKI .: Orszégo-s Kozegészeégtani Intézet, Budapest.

· »

For intraperitoneal administration, the LDjq 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 (µg / ml)

Microorga-1-phenyl-3-cyclohexylaulfonyl-1- (p-tolyl) -3-cyclohexylsulphonism poly-pyrrolidin-2,5-dionyl-pyrrolidine-2,5-dione used in hour-hour tests

48 72 144 288 24

11 1 II 50 50 - - 25 25 - - - «2« 75 100 ALIGN! - - - 25 50 - - - ^W 3 ^W 150 150 - - - 100 ALIGN! 150 - - - 4 - - 75 150 150 - - 25 75 75 n ^ n - - 50 150 150 - - 50 150 150 6 - - 100 ALIGN! 200 250 - - 150 250 - - - 10 25 25 - - 10 10 10 G - - 25 50 75 - - 25 25 75 ny tt - - 50. 75 75 - - 50 75 75 10 - - 75 200 200 - - 75 150 150 115 - - 10 10 10 - - 10 25 25 12 - - 10 10 > 0 - - 5 10 25 13 - - 2.5 10 10 - - 2.5 5 5 14 - - 5 10 10 - - 2.5 2.5 5  15 Dec - - 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 May - - 150 200 250 - - 100 ALIGN! 150 250

Microorga- 1- (p-chlorophenyl) -3-cyclohexyl-1- (p-chlorophenyl) -3-cyclohexylnism

tests (minimal concentration (Qig / ml) hours hours

48 72 144 288 24

1 75 75 - - - 10 25 - - - ”2” 50 50 - - - 10 25 - - - -3- 75 75 - - - - - - - - -4 « - - 75 150 150 - - 25 50 75 - - 50 150 200 - - - - - - - 75 150 200 - - - - - »Ιγ« - - 10 25 50 - - 10 10 10 8 - - 10 50 50 - - - - - «Ζ ^ Μ - - 50 75 150 - - - - - «10- - - 75 150 200 - - - - -

Table I - continued

Micro-1- (p-chlorophenyl) -3-cyclohexyl-1- (p-chlorophenyl) -3-cyclohexylism po-sulfonyl-pyrrolidine-2,5-dione sulfonylpyrrolidine-2,5-dione used in tests for minimal inhibitory concentration of tyags (ml) hours hours

24 48 72 144 288 24 48 72 144 288 11 - 10 25 25 - - - - 12 ” - - 50 75 100 ALIGN! - - 5 25 25 13 - - 2.5 10 10 - - 1 2.5 2.5 14 - - 2.5 10 25 - - 2.5 2.5 5 15C - - 1 2.5 10 - - 2.5 5 5 17 - - 50 75 75 - - - - - 18 - - 75 150 200 - - - - - 20 May - - 78 150 150 - - - - - 21 10 10 - - - - - - - - 22nd 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 µg / ml of environment after 24 and 48 hours of observation for the most important budding fungi propagating;

Mushroom Minimum inhibitory concentration .mu.g / ml 24 hours 48 hours Candida benhamii 25 75 Candida guilliermondii 5 10 Candida humicola 5 25 Candida (79 / K47) 2.5 10 Candida lipolytic 5 10 Candida parapsilosis 10 50 Candida pseudotropic 2.5 10 Candida valida 5 , 0 Candida vini 1 5 Cryptococcus Neoform (78 / K16) 1 , 0

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

1- (p-tolyl) -cyclohexylsulfonylpyrrolidine-2,5-dione and 1-phenylcyclohexylsulfonylpyrrolidine-2,5-dione are also active against the following phytopathogenic fungal species: Botrytis cinerea, Ascochyta pisi, Cercospora beticola, Taphrina deformans, Phytophthora Sclerotinia sclerotiorum, Verticillium alsoatrum, Verticillium dahliae and Venturia.

The novel 1-substituted 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives of the formula I can be used as active ingredients of fungicidal agents, because of their potent fungicidal activity. One or more compounds of the formula I are formulated with customary 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.

β

¢ ¢ 9

Η

I Ό ηιΑ ί? <\ Γ ϋ i

Η Η & S áfe & 5 ·

SÉ?

ρ ο 9-1 λ

Ο V Ρ43 φ ο ϋΗ I 34 I >> <\ ι ο * -> I I <*))

Ο

I £

η η ο Η Η & 7 φΙΑ Λ * Ο CM Η I υ · ο I Η (ΊΗ

Q0

CM i

Ό

Ο

Λ §

<Μ (Μ t * 0? § §

Φ Η Λ Ό Ο Η «Α

34 * Ο 1 1 β <* 1Η 1 Ό > » ~ Η β CM Η Η • Η C- >> ο Ό β β Ο Φ β 43 Μ> »ο α β ι ΡΗ 5 1 ο 0.9-1 «3 Φ ν α CM

I I Ο Η Μ Ο β X X X X X 0 0 0 0 0 0 0 P P P SP

0 Ο Ο <ΙΛ Ο Ο ΙΛ ΙΛ -

I KS ΟΑ ΙΑ KS ΙΑ li \ t- t- (Μ

I l I CV Ο Ο ΙΑ ΙΑ (CVΑ ΙΑ CVJ | 1 Ο Ο ΙΑ ΙΑ Ο Ο

ΙΑ (Λ CJ ť- Ο ΙΑ | | ΙΑ Ο ΙΑ ΙΑ LA Ο f * Ο (Μ t * · · · s eatsCJPO ^ iA CJ t— ίο ο ο

Η Η 2ό Μ ►> I Μ * ϋΐΛ * - 1 * >> σϊ <Μ β 1 1 Η * β β Ό Η Η Ο >> 0 43 CM βΗ fr-

ΦΗ sl

PH §Š>

I o

0.9-1

*; J * - n φ

Λ o β

-3> s * O o 1

I IA m · i CM

Β β >> H Η Ό OH PH and 2 ^Ύ Ι

Φ β

Ρ β

Φ

Ο β

ο

Η β

Κ)

Η

JB

-3: -3.

Ό

Ο 00 43 · * | | ΟΑ Ο ΟΑ Ι CM ΙΑ t- Ο | I ΙΛ ο ΟΑ ΙΑ ΙΑ-- - * ΙΑ Ο | I | I | I CM Ο

CM řø φ

>> >> O ο ι I ΙΑ <η * ι CM ua

9 Ο Η ΡΗ ¹ 9 4 &

• Β «σ

S 5

I I

X Ο 0 & 0θ. »Β β CXJ3 Ο 01 ο Ο β ^ Φ β μ 34 μ Η Μ ΗΗ> Ν Φ and β βρ

I | ΟΟ ΟΑ ΙΑ ΙΑ ΟΑ ΙΑ CM CM CM * ΙΑ ΙΑ | | | | | | cm e7 what phi

O

Cb phi <0

CM

E?

Φ phí o

d> »c o I H *« «* O wA

S CM

IN! and

O * H ΗΌ fí fd ϋΗ

AS ¹ b * - Cb

E? β Φ o fdfd 0 * 0 rd I 44 A *

O CM? Á '-' • O Η fd

Φ í d b b b b b d d d d f f >> Of Of Of Of Of Of Of Of Of í Of Of Of

Ύ * 3 - O O A O CM CM CM

CM t00

CM

CD fí

P fí

Φ o

fí o

fí

M £

• rd • H fí fí rl &

Φ phi o O fd s3V >> and o *

I CM m I I ph

>>> o <fí fí rd fí ► >>> P o. Φ rd

S £

I 3 · - w

I I ω O -rd hDQ.> Phi phi Cbfi o0o o 3> 5 phi a p p phi CO H 0) S phi 3P

A A | | | I | |

CM t *

A O I I I I I fr- A

A O I t I I I I CM A | O O A O A A A A CM A CM fr—

I | O O A A A O

A 0 CM <M C \ l A t | A A A O O A fr- C * - * - - CM

A t fr CM £ \ \ \ CM CM CM CM CM CM CM CM CM CM CM CM CM - »

WHAT co

CM rd >>

X

Φ fí

O rd phi> »o

F c »o»--* * * * * * * * P * * * * * * s s s s & s s &

• id

Ό

O phí o

phi + »phi

Φ

O phí o

fí | o O A A A o A A fr- τΑ A A A CM A fr- CM CM tlil

A O O fr- A A

I rd g · o

* d rd fi • rd fi c

>>

X

Φ fí

O rd ph >>

o <* 1 ph

I o

A5 a

♦ fd f • rd a

>> 1 >> fíA fí Φ - • rd «Η CM Ό O 1 O fí fí fí P · Η • rd rd CH 1 O Cbfí fí 1 >> - Q.

• rd · Η fí '>> fí O P o O-d Φ fí ** P Λ 3 03 rd O Φ a o.p

O O O A

CM -

The dragee coating as well as the capsules may optionally be color coded according to the active ingredient content.

The liquid compositions may take the form of liquids for brush application, for cladding, or they may be in the form of sprays, stains, injectables, 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 56 slime, up to 10 56 protective collides, up to 80% starch, up to 50% glycerol, up to 15% V8dy, up to 99% inert atoxic organic solvent and up to 60% aerosol propellant.

The following examples illustrate the preparation of the compounds of formula (I) and the following examples illustrate the preparation of fungicidal compositions containing the compounds of formula (I).

Example 1

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

2.39 g (0.01 mol) of 2-cyclohexylsulfonyl-4-phenylamino-4-oxobutanoic acid are dissolved in a mixture of 20 ml of acetic anhydride with 0.82 g (0.01 mol) of anhydrous sodium acetate and the resulting solution is heated 1 hour at 100 ° C. The reaction mixture was then poured onto crushed ice, the precipitated solid was filtered off and the acid removed by washing. This gives 2.79 g (86% yield) of the title compound, m.p. 149-151 ° C. After recrystallization from methanol, the melting point of the product is in the range of 150-152 ° C.

Minimum inhibitory concentration for Trichophyton mentagrophytes: 2.5 µg / ml, for Epidermophyton floccosum: 1.0 µg / ml.

The following compounds can be prepared in a similar manner:

1-ethyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 47.6 56, mp 118-120 ° C;

1-n-hexyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 39.8 56, mp 127-130 ° C;

1- (2-chlorophenyl) -3-cyclohexylsulphonylpyrrolidine-2,5-dione, yield 1.456, m.p. 153-155 ° C;

1- (3-nitrophenyl) -3-cyclohexylsulphonylpyrrolidine-2,5-dione, yield 92 56, mp 145-146 ° C;

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

1- (4-aminosulfonylphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 71.8, mp 208-2010 ° C;

1- (4-methoxyphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 85.7 56, mp 139-140 ° C;

1- [4- (N-ethoxycarbonylaminosulfonyl) phenyl] -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 42.6 56, mp 115-118 ° C;

1-benzyl-3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 84 56, melting point 160-162 ° C;

1-phenyl-3-cyclopentylsulfonylpyrrolidine-2,5-dione, yield 60.2 56, mp 158-159 ° C (after recrystallization from ethanol);

1- (p-tolyl) -3-cyclopentylsulfonylpyrrolidine-2,5-dione, yield 86.1 56, mp 178-180 ° C (after recrystallization from ethanol);

1- (3,4-methylenedioxyphenyl and ^{Lenii phen ox} y y ¹⁾ '3-cyklohexylsulfonylpyrrolldin-2,5-dione, yield 91.8%, mpt 186-188 ° C;

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

1- (4-methyl-2-hydroxymethylphenyl) -3-cyclohexylsulfonylpyrrolidine-2,5-dione, yield 86.2%, mp 174-177 ° C.

A fungicidal composition comprising as an active ingredient a compound of formula (X) 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 2.00 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 Dehymlus F ^x 8.00 g Cetiol V ³ '10.00 g white petrolatum 10.00 g distilled water 100.00 g

The obtained homogeneous mixture is filled into crucibles or tubes.

(x)

Substances marked with 'have the following chemical composition:

Miglyol 812: a mixture of glycerol esters of C8-C12 fatty acids.

This additive promotes homogenization of the ingredients. Manufacturer: Chemisohe Werke, Witten GmbH, Witten, Germany

Cetiol V: decyl oleate - Manufacturer ^ Dehydat, Dtisseldorf, Germany

Dehymuls F: mixture of aliphatic esters, emulsifier. Manufacturer: Dehydat, Dtisseldorf, Germany.

Example B

Backfill

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

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 mixture is filled into dusting containers.

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 822 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-cyclohexylsulfonylpyrrolidine-2,5-dione was used as the test substance. The test results are shown in the table below.

Claims (3)

A process for the preparation of 3-cycloalkylsulfonylpyrrolidine-2,5-dione derivatives substituted in the 1-position of the general formula I / SO ₂ -A ο = οο (I) wherein ^R 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, acyloxy C 1 -C 4, C 2 -C 5 alkoxycarbonyl, C 1 -C 4 acyl or C 2 -C 5 -alkyloxycarbonyl, or C 1 -C 4 phenyl alkyl moieties, and salts thereof, characterized in that the cycloalkylsulfonylsuccinic acid poloamide of formula (VIII) CH 2 ' O = C AND B • CH · I C = O AND D ₂ -a (VIII), wherein one of B and D represents a hydroxyl group and the other represents a group of the formula -NH-R, and R and A are as defined above, acts with a water-binding agent. 2. The process according to claim 1, wherein the dehydration is carried out with acid anhydride. 3. A method according to acetic anhydride points,