CS253350B1 - Ester derivatives with the effect of insect development regulators and their method of production - Google Patents

Abstract

Ester derivatives with the effect of insect development regulators and a method for their production. The substances have the general formula I in which the general symbols have the meaning given in the definition. They are characterized by high values of biological activities, as well as high stability against environmental influences. In the case of wider use, the substances that are the subject of this invention may have great economic importance.

Description

The subject of the invention are ester derivatives with the effect of insect development regulators and a method of their production. These are substances imitating the effect of insect juvenile hormone.

At present, a large number of such substances, also known as juvenoids, have been described (K. Sláma et al.: Insect Hormones and Bioanalogues, Springer-Verlag, Wien-New York 1974; or L. I. Gilbert et al.: The Juvenile Hormones, Plenum Press, New York 1976). A common feature of the action of juvenoids, which are otherwise chemically very diverse compounds, is the occurrence of developmental disorders in insects, ultimately leading to the extinction or a strong suppression of the population of harmful insects. Their advantage is a relatively high specific efficacy on certain insect species with very low toxicity to vertebrates and a wide spectrum of biological activity, which includes sterilizing and ovicidal effects, molting disorders and disruption of developmental cycles.

The substances that are the subject of this invention are lycopenes of a new structural type, derived from a known intermediate (AO 195 530, 206 421 and 243 567). They are characterized by higher activity against some species of insects, e.g. against the wax moth (Galleria melione11a) or the housefly (Musea domestica) and also by higher stability against environmental influences (temperature, air humidity and acidity, etc.).

These facts are essential in both laboratory and field experiments in terms of extending the time for which substances are capable of existing in a biologically active form, i.e. chemically unchanged, and also having better absolute values of measured biological activity.

In real natural conditions, the developmental stage of harmful insects that is sensitive to the effect of the substances that are the subject of this invention always occurs over a wider period of time due to the uneven development of the insect population in nature, and it is necessary for the active substance to act for several weeks.

The economic benefit of the substances that are the subject of this invention is due to their high efficiency and higher stability compared to previously prepared compounds.

The subject of the invention are ester derivatives with the effect of insect development regulators of the general formula I.

where y is an integer of value one or two,

Z represents a group of the general formula -O-(CH ₂ ) _n -O-, in which n is an integer of value two or three,

R stands for a group of the general formula

R ¹ O

2 in which m is an integer from one to three, R represents methyl or ethyl and R represents alkyl, alkenyl or alkynyl with up to 5 carbon atoms, A represents hydrogen, methyl, ethyl, hydroxyl, OCOCH, or a group of the formula

X

The invention also provides a method for producing a juvenoid of general formula I.

According to a known procedure, first of all, from a cyclic ketone of the general formula VI

AND

-{CH ₂ )y (VI) in which A and ay have the meanings given above, and a nitrogenous base, preferably pyrrolidine, prepares an enamine of the general formula VII (Ch ₂ ), (VII) in which A and ay have the meanings given above. The compound of the formula VII is then reacted with a methoxybenzyl halide of the general formula VIII

OCH, (VIII) where X represents chlorine or bromine, gives a methoxybenzylcycloalkanone of general formula IX

AND

-(CH ₂ ) y

OCH, (IX)

O where A and y have the above meanings and which then by any of the common methods of dealkylation, e.g. by the action of hydrogen bromide or sodium ethyl mercaptan, provides the free ketophenol of general formula II

AND

O where A and y have the meanings given above (AO No. 206,421).

The essence of the method according to the invention is that the ketophenol of the general formula II

A (ch ₂ ) _in

OH(II)

in which A and y have the meanings given above, is reacted with a substance of formula III

R-X (III) where R and X have the meanings given above, to form a compound of general formula IV

AND

O (IV) where ^A, y and R have the meanings given above, which upon reaction with a substance of general formula V

HO-(CH ₂ ) _n -OH (V) will give the final product of general formula I.

The following examples are provided to clarify the nature of the invention without limiting it in any way.

Example

Preparation of (2 Z)—2—(4-)3-ethoxycarbonyl-2-methyl-2-propen-1-yloxy(benzyl)-1-cyclohexanone ethylene acetal (I, A=H, Z=-O(CH ₂ ) ₂ 0-, y=2, m=1, R ¹ =CH ₃ , R ₂ =C ₂ H ₅ )

First, a known intermediate, 2-(4-hydroxybenzyl)-1-cyclohexanone (AO number 195,530), was prepared.

A mixture of 2-(4-hydroxybenzyl)-1-cyclohexanone (3 g), ethyl 4-bromoseneacetate (4.3 g) and anhydrous potassium hydroxide (7.9 g) in 2-butanone (25 ml) was heated to reflux for 5 h. The reaction mixture was cooled to 20 °C, diluted with water (30 ml) and extracted with ether (80 ml). The ethereal solution was dried over sodium sulfate, the ether was evaporated and the crude residue was chromatographed on 50 times silica gel. Elution with petroleum ether with 20% ether separated the two isomers resulting, yielding 1.9 g of (2Z)-2-(4-)3-ethoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone and 2.5 g of the (2E)-isomer; total yield 90.5 4. Constants: (2Z)-isomer: ¹ H-NMR spectrum: 2.02 (dt; 0.6, 0.6, 1.6 Hz), (2E)-isomer: 1 H-NMR spectrum: 2.12 (dt; 0.7, 0.7, 1.5 Hz).

A solution of (2Z)-2-(4-)3-ethoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone (0.5 g) in benzene (50 ml) was refluxed in the presence of ethylene glycol (10.5 ml) and 5 mg of p-toluenesulfonic acid while distilling off the water of reaction for 2 h. The reaction mixture was cooled to 20 °C, diluted with water and extracted with benzene. After drying with sodium sulfate and evaporation of the solvent, the crude product was purified by chromatography on a silica gel column eluting with a mixture of petroleum ether with 30% ether. 0.5 g (95%) of (2Z)-2-(4-)3-ethoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal (I, A=H, y=2, Z=-O(CH,),O-, m=1, R ¹ =CH,,

1 of 1

R =C ₂ Hg). Constants: H-NMR spectrum: 5.81 (m; 1.6, 1.6, 1.6, 1.6, 1.6 Hz), 2.02 (dt; 0.6,

0.6, 1.6 Hz), IR spectrum: 1714, 1650, 1611, 1588, 1512, 1240, 1216, 1090, 1042 cm ^-1 .

Example 2

Preparation of (2E)-2-(4-)3-ethoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal (I, AH, y=2, Z=-O(CH ₂ ) ₂ 0-, R ¹ =CH3, R ² =C2H _s )

By the procedure given in Example 1, 1.5 g (95%) of (2E)-2-(4-)3-ethoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal was obtained from 1.5 g (2E)-2-(4-)3-ethoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone. Constants: 1H-NMR spectrum: 6.06 (m; 1.5, 1.5, 1.5, 1.5, 1.5 Hz), 2.18 (dt; 0.7, 0.7, 1.5 Hz), IR spectrum: 1,720, 1,674^ 1,611, 1,584,

512, 1240, 1229, 1156, 1090, 1046 cm ^-1 . —

Example 3,

Preparation of (2Z)-2-(4-)3-isopropoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal (I, AH, y-2, Z=-O(CH ₂ ) ₂ O-, R ¹ =CH3, m=1, R ² -CH(CH3> ₂ )

By the procedure given in Example 1, both isomers (2Z)-2-(4-)3-isopropoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone and the corresponding (2E)-isomer are first prepared from 2-(4-hydroxybenzyl)-1-cyclohexanone in a total yield of 90%. Constants: 1H-NMR spectrum: (2Z)-isomer:

2.02 (dt; 0.6, 0.6, 1.6 Hz), (2E)-isomer: 2.14 (dt; 0.7, 0.7, 1.5 Hz).

Furthermore, by the procedure described in Example 1, 0.5 g (90 4) (2Z)-2-(4-)3-isopropoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone was obtained from 0.5 g (2Z)-2-(4-)3-isopropoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone.

-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal. Constants: IR spectrum: 1,715, 1,650, 1,583, 1,513, 1,242, 1,217, 1,090 cm ^-1 .

Example 4

Preparation of (2E)-2-(4-)3-isopropoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal (I, A=H, y=2, Z=-O(CH ₂ ) ₂ 0-, m=1, R ^X =CH3, R ² =-CH(CHj)2)

By the procedure given in Example 1, 1 g (90%) of (2E)-2-(4-)3-isopropoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone is obtained from 1 g of (2E)-2-(4-)3-isopropoxycarbonyl-2-methyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal. Constants: IR spectrum: 1,719, 1,673, 1,612, 1,586) 1,512, 1,242, 1,228, 1,158 cm' ¹ ,

Example 5

Preparation of (2E)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propenyloxy(benzyl)-1-cyclohexanone ethylene acetal (I, A=H, y=2, Z=-O(CH ₂ ) ₂ O-, m=1, R ¹ =C2H5, R ² =-CH2=CH ₂

By the procedure given in Example 1, both (2Z)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propenyloxy(benzyl)-1-cyclohexanone and the corresponding (2E)-isomer were first prepared from 2-(4-hydroxybenzyl)-1-cyclohexanone in a total yield of 85%. Constants: ^b H-NMR spectrum: (2Z)-isomer: 4.12 (t; 0.6, 0.6 Hz), (2E)-isomer: 4.20 (t 0.7, 0.7 Hz).

Furthermore, by the procedure given in Example 1, 1 g (2E)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propenyloxy (benzyl)-1-cyclohexanone was obtained from 1 g (2E)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propenyloxy (benzyl)-1-cyclohexanone ethylene acetal. Constants: IR spectrum: 1,720,

675, 1612, 1584 cm ^-1 .

Example6

Preparation of (3E)-2-(4-)4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy(benzyl)-4-acetoxy-1-cyclohexanone ethylene acetal (I, A=-OCOCH ₃ , y-2, Z=-O (CH.,) ₂ O-, m=2, R ¹ =CH3, R ² =-CH2CECH)

By the procedure given in Example 1, both {3Z)-2-(4-)4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy(benzyl)-4-acetoxy-1-cyclohexanone and the corresponding (3E)-isomer were first prepared from 2-(4-hydroxybenzyl)-1-cyclohexanone in a total yield of 85%. Constants: (3Z)-isomer: ^b H-NMR spectrum: 2.04 (dti 0.6, 0.6, 1.6 Hz), (3E)-isomer: ^b H-NMR spectrum: 2.16 (dt; 0.7, 0.7, 1.5 Hz).

Furthermore, by the procedure given in Example 1, 0.5 g of (3E)-2-(4-)4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy(benzyl)-4-acetoxy-1-cyclohexanone is obtained from 0.5 g of (3E)-2-(4-)4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy(benzyl)-4-acetoxy-1-cyclohexanone ethylene acetate. Constants:

IR spectrum: 1720, 1674, 1611, 1240 cm ^-1 .

Example 7

Preparation of (3E)-2-(4-)4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy(benzyl)-4-tetrahydropyranyloxy-1-cyclohexanone-1,3-propenyl acetal (I, A=0THP, y=2, Z=-0(CH ₂ ) ₃ 0-, m=2, R ¹ =CH3, R ² =-CH2C=CH)

By the procedure given in Example 1, both (3Z)-2-(4-)4-propargyloxycarbonyl-3-methyl-3“buten-1-yloxy(benzyl)-4-tetrahydropyranyloxy-1-cyclohexanone and the corresponding (3E)-isomer are first prepared from 2-(4-hydroxybenzyl)-1-cyclohexanone in a total yield of 85%. Constants: (3Z)-isomer: ^b H-NMR spectrum: 2.05 (dt; 0.6, 0.6, 1.6 Hz), (3E)-isomer: ^b H-NMR spectrum: 2.14 (dt; 0.7,

0.7, 1.5 Hz).

Furthermore, by the procedure given in Example 1, 0.5 g (90%) <3E)-2-(4-)4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy(benzyl)-4-tetrahydropyranyloxy-1-cyclohexanone was obtained from 0.5 g (3E)-2-(4-)4-propargyloxycarbonyl-3-methyl-3-buten-1-yloxy(benzyl)-4-tetrahydropyranyloxy-1-cyclohexanone-1,3-propenyl acetal. Constants: IR spectrum: 1,719, 1,680, 1,612, 1,243 cm ^-1 .

Example 8

Preparation of (2E)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy(benzyl)-1-cyclopentanone-1,3-propenyl acetal (I, A=H, y=1, Z=-O(CH ₂ ) ₃ 0-, m=1, R ¹ =C2H5, R ² =-CH2CH=CH ₂ )

By the procedure given in Example 1, both (2Z)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy(benzyl)-1-cyclopentanone and the corresponding (2E)-isomer were first prepared from 2-(4-hydroxybenzyl)-1-cyclopentanone in a total yield of 87%. Constants: (2Z)-isomer: ¹ H-NMR spectrum:

2.03 (dt; 0.6, 0.6, 1.6 Hz), (2E)-isomer: ¹ H-NMR spectrum: 2.11 (dt; 0.7, 0.7, 1.5 Hz).

Further, by the procedure given in Example 1, 0.5 g (90%) of (2E)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy(benzyl)-1-cyclopentanone is obtained from 0.5 g of (2E)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy(benzyl)-1-cyclopentanone-1,3-propenyl acetal. Constants: IR spectrum: 1,720, 1,680, 1,612, 1,245 cm ^-1 .

Example 9 'S..

Preparation of (2Z)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy(benzyl,-1-cyclopentanone-1,3-propenyl acetal (I, A=H, y-1, Z=-O(CH ₂ ) ₃ O-, m-1, R ¹ =C2H5, R ² =-CH2CH=CH ₂ )

By the procedure given in Example 1, 0.5 g (90%) of (2Z)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy(benzyl)-1-cyclopentanone prepared in Example 8 was obtained from 0.5 g (2Z)-2-(4-)3-propenyloxycarbonyl-2-ethyl-2-propen-1-yloxy-(benzyl)-1-cyclopentanone-1,3-propenyl acetal. Constants: IR spectrum: 1,719, 1,675, 1,610, 1,092 cm ^-1 .

Method of testing prepared substances:

The tests used are based on the morphogenetic effect of juvenoids, which manifests itself as inhibition of metamorphosis. Acetone solutions of the investigated substances are applied to the body surface using a microapplicator and their effect is evaluated after subsequent undressing, or after the trip of the control images. The measure of effectiveness is the proportion of affected individuals and the degree of inhibition of metamorphosis when all individuals in the test are affected. For comparison of different substances, the most practical expression of their effectiveness is in effective units affecting 50% of the tested individuals (ED-50). Doses are given in jtig of pure substance per individual. The following standard tests are used:

1. Dysdercus cingulatus - a bed bug (Heteroptera, Pyrrhocoridae), which is a significant pest of cotton in Asia. For the test, last instar larvae are used within 24 h after moulting, 2 μl of acetone solution are applied. The effect is manifested by development into intermediate forms between larva and adult.

2. Galleria mellonella - wax moth (Lepidoptera, Pyralidae) is a pest in beehives and in honeycomb and wax storage areas. Acetone solutions of juvenoids are applied at a dose of 2 ml to the larvae of the last instar after the end of the feeding (5th-6th day, total instar length 8 days). The effect is manifested by the development of intermediate forms between the larva and the pupa.

3. Musea domestica - house fly (Diptera, Muscidae) is a vector of some diseases. Juvenoids are applied at a dose of 1 µl per larva several hours before pupation. The effect is signaled by the fact that flies do not hatch and is verified by morphological analysis of individuals from the puparium. Undeveloped imaginal structures on the abdomen characterize juvenile action and distinguish them from a possible toxic effect. ED-50 is the dose that prevents the flight of flies from the puparium in half of the tested individuals.

Table

Biological efficacy of some substances that are the subject of this invention compared to a known substance (AO 195 530)

Substance No. Structure DYS GAL MUS 1 and 0 0.05 0.005 0.5 2 o ^z ^o 1_I „Q- 0 0.05 0.008 0.5 3 1_1 0.08 0.05 0.8 4 about 0.05 0.1 1 according to AO 195 530 1_1 0 about 0.1 inactive until: 0.3 1

Explanations:

DYS = Dysdercus cingulatus GAL = Galleria mellonella MUS = Musea domestica

Claims (2)

Ester derivatives having the effect of insect development regulators of the general formula I (i) in which y is the whole of Z is three, R is one or two, a group of the formula -O- (CH ₂ ) _n ^- O- wherein n is an integer of two or 2’m R ¹ O OR ^Z Wherein m is an integer of one to three, R is methyl or ethyl and R is alkyl, alkenyl or alkynyl of up to 5 carbon atoms, A is hydrogen, methyl, ethyl, hydroxyl, OCOCH4, or a group of formula and. o ό 2. A process according to claim 1 wherein the ketophenol of formula (II) - (CHjly OH (II) wherein A and y are as defined above, is reacted with a compound of formula III R-X (III) wherein R is as defined above and X is chlorine or bromine, to give a compound of formula IV A. (CH 2) 2 Z 2 -OR (IV) wherein A, y and R are as defined above, by reaction with a compound of Formula V HO- (CH _{2) n} -OH (V) yields the final product of Formula I. Severography, n. P., MOST Price 2,40 Kčs