CS274277B2 - Fungicide and method of its active substance production - Google Patents

Abstract

As active substance, the fungicide agent contains the compound of the general formula I, where R1 stands for the hydrogen atom, methyl group, trihalogenmethyl group, or carboxy group, R2 stands for the hydrogen atom or halogen, alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, phenoxy group, amine group, acetamino group, dialkylamino group with 1 to 4 carbon atoms in alkyl groups, acetyl-, benzyl-, methylthio-, carboxy-, cyano-, ethoxycarbonyl-, nitro- or trihalogenmethyl group, R3 stands for the hydrogen atom, alkyl group with 1 to 4 carbon atoms, or alkoxy group with 1 to 4 carbon atoms, R4 stands for the hydrogen atom, methyl- or ethyl group and X stands for the valence bond or group -S-, and/or its addition salt with acids. The preparation method of active substance of the general formula I lies in the fact that the halogen derivate of quinoline of the general formula II or III, where R<1>, R<2>, R<3> have the above mentioned meanings, reacts with 1, 2, 4- triazole of the general formula IV or V, where R4 has the above mentioned meanings, with the temperature in the range from 0 to 200 degrees C, possibly in the presence of the dissolvent and acid or base, whereupon the so created product is possibly isolated in the form of free base or addition salt with acid.<IMAGE>

Description

The invention relates to a fungicidal composition comprising the active ingredient in admixture with suitable inert solid or liquid carriers or diluents, as well as a process for the preparation of compounds which form the active ingredient in the fungicidal composition.

The principle of the fungicidal composition according to the invention consists in that it contains, in admixture with suitable inert or liquid carriers or diluents, the novel triazolylquinoline derivatives of the formula I as active ingredient.

in which it is hydrogen, methyl, trihalomethyl or carboxy, f? ₂ is hydrogen or halogen, (C1-C4) alkyl, hydroxy, (C1-C4) alkoxy, phenoxy, amino, acetamino, dialkylamino (C1-C4) alkyl, acetyl, benzoyl, methylthio, carboxy, , ethoxycarbonyl, nitro or trihalomethyl,

R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, hydrogen, methyl or ethyl; and

X is a valence bond or a -S- group, or acid addition salts thereof.

Summary of the novel derivatives triazolylchinolinu above formula I in which Rp _R2, R, R₁ and X have the above meanings, and their addition salts with acids, characterized in that the halo-substituted quinoline derivative of the formula II or III

wherein R p R ₂ and R p are as defined above, reacted with the 1,2,4-triazole of formula IV or V

HN-N

LU

R

HN-N

(V) (IV) wherein the above meaning is given, in the presence or absence of a solvent and in the presence or absence of an acid or base, at a temperature ranging from 0 to 200 ° C and optionally recovered as the free base of its addition salt with acid.

In one embodiment of the process of the invention, compounds of Formula Ia are prepared

R ₃ by reacting the 4-chloroquinoline derivative of the formula II with 1,2,4-triazole of formula IV, wherein in the above formulas, R p R _2> R and R as defined above.

In another embodiment of the process of the present invention, compounds of Formula Ib are prepared

by reacting a 4-chloroquinoline derivative of the general formula II with a 3-mercapto-1,2,4-triazole of the general formula V, wherein in the above formulas Rp, Rp and Rj are as defined above.

According to yet another embodiment of the process of the present invention, compounds of Formula 1c are prepared

by reacting a 2-chloroquinoline of formula III with a 1,2,4-triazole of formula IV, wherein in the above formulas Rp, Rp, Rj and R6 are as defined above.

In yet another embodiment of the process of the present invention, compounds of Formula Id are prepared

(Id) by reacting a 2-chloroquinoline derivative of the general formula III with a 3-mercapto-1,2,4-triazole of the general formula V, wherein R @ 1, R @ ₂ , R @ 3 and R @ 4 are as defined above.

The starting materials used in the process of the invention are known compounds. Reference is made to the following references in which the starting materials are described:

4-Chloroquinolines of formula II:

The Chemistry of Heterocyclic Compounds, Vol. 32, Quinolines, Part I, pp. 391-398; references cited in this literature;

2-chloroquinolines of formula III:

The Chemistry of Heterocyclic Compounds, Vol. 32, Quinolines, Part I, pp. 387- 390; J. Chem. Soc. P.I. 1981 1 (5) 1537-1543.

1H-1,2,4-Triazoles of formula IV:

DOS 2,802,491; Chem. Ber. 1968, 101 (6) 2033-2036.

3 (5) -Mercapto-1,2,4-triazoles of general formula V:

Liebigs. Ann. Chem. 637, 133, 135-165 (1960).

The novel compounds of the formula I exhibit valuable biological properties and have a useful analgesic and anti-inflammatory effect. Some representatives of the compounds of formula I are highly effective against phytopathogenic fungal pests, as confirmed by both in vivo and in vitro assays.

It has been found that the reaction between a 4- or 2-chloroquinoline derivative of formula (II) or (III) containing only electron-repellent substituents such as methyl or methoxy, and 1H-1,2,4-triazole or 3 (5) -mercapto- 1H-1,2,4-triazole of general formula

IV or V is autocatalytic, wherein the hydrochloric acid formed during the reaction acts as a catalyst. The reaction can also be catalyzed by other acids, particularly strong mineral or organic acids or acid salts (e.g. sulfuric acid, trifluoroacetic acid or ammonium chloride). The reaction is preferably carried out in the presence of these acidic compounds, in particular hydrochloric acid, which can be used in an amount ranging from catalytic to stoichiometric.

Using less basic chloroquinolines which contain one or more electron-attracting groups (e.g. chlorine, trifluoromethyl), this catalysis is not observed.

In this case, however, the reaction may be facilitated by carrying out in the presence of an organic or inorganic base (e.g., triethylamine, potassium carbonate or sodium hydroxide) used in stoichiometric or higher amounts. This also applies to the use of the 1H-1,2,4-triazole or 3 (S) -mercapto-1H-1,2,4-triazole derivative in the form of an alkali salt (e.g. sodium salt).

It has further been found that the mercapto group is more reactive than the -NH- group of the triazole ring.

The reaction (i.e., the preparation of compounds of formulas Ia, Ib, Ic and Id) may preferably be carried out in the presence of a polar organic solvent (e.g. ethanol, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, etc.). A non-polar organic solvent (e.g., benzene, toluene, chlorobenzene or dichlorobenzene) may also be used as the reaction medium and may be operated in the absence of an organic solvent - in the melt.

The reaction of the present invention can be carried out at a temperature in the range of 0 to 10 ° C

2.0 ° C, preferably between 20 ° C and 150 ° C. The reaction temperature is chosen taking into account the properties of the reagents and the method used.

It is sufficient that the chloroquinoline moiety is reacted with a molar equivalent amount of 1H-1,2,4-triazole or 3 (S) -mercapto-1,2,4-triazole, but reactions generally proceed faster and more fully when starting materials are reacted. of the formula IV or V is used in an amount of one to two times the molar equivalent.

In one embodiment of the process of the invention, the reactants are melted and the product formed is isolated after completion of the reaction. In this embodiment, the product is obtained as the hydrochloride. The direct reaction product is treated with a non-polar organic solvent (e.g. ether, chloroform, benzene or hexane) or crystallized from a polar solvent (e.g. methanol, ethanol, acetonitrile or dimethylformamide) or a mixture of polar and non-polar solvents.

The free base of formula (I) may be isolated by cooling, dissolving in water or a mixture of water and ethanol, preferably with the addition of a mineral or organic acid, and precipitating the product by addition of an organic or inorganic base. The crude product may be recrystallized from a mixture of a polar organic solvent and water or a polar and non-polar organic solvent.

According to another embodiment of the process according to the invention, the reactants are reacted in the presence of a non-polar organic solvent (for example benzene, toluene, xylene, hexane, carbon tetrachloride, chlorobenzene, dichlorobenzene and the like). After completion of the reaction, the product precipitates in the form of the hydrochloride and is filtered off, optionally recrystallized and converted into the free base as described above.

According to yet another embodiment of the process of the invention, the reactants are reacted in the presence of a polar organic solvent (e.g. ethanol, ethylene glycol, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide or glacial acetic acid). The product is isolated in the form of a free base or a salt formed with a mineral acid.

In a preferred embodiment of the process of the invention, the reaction is carried out in a polar solvent (for example ethanol, ethylene glycol, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide) and preferably in the presence of hydrochloric acid.

The acidic medium can be provided either by adding an acid (preferably hydrochloric acid) to the reaction mixture or by using a chloroquinoline component in the form of a salt (preferably hydrochloride). The salt product can be isolated from the reaction mixture by any of the above methods.

According to a further preferred embodiment of the process according to the invention, in a polar organic solvent, in the presence of a molar equivalent or a strong base (e.g. triethylamine, potassium carbonate, reaction carbonate, a larger amount of sodium, etc.) is carried out.

The above reaction can also be carried out by using the triazole or mercaptotriazole of formula IV or V in the form of an alkali salt (e.g. sodium or potassium salt).

The structure of the novel compounds prepared by the process of the invention is characterized or confirmed by NMR, IR and MS, and the purity of the product is determined by thin layer chromatography or gas chromatography.

The compounds of formula I also have valuable physiological properties and eliminate or effectively reduce the induced pain and inflammatory processes. An essential advantage of the compounds of formula I is that ulcerative activity is not observed at all or only to a very limited extent at a dose in the dosage range when administered as an analgesic or anti-inflammatory agent.

When administered orally, the compounds of the formula I effectively suppress acute inflammatory processes. This is confirmed by the results of the Winter test (Proc. Soc. Exp. Biol.

Copper. 111, 544 (1962). In this test, edema-induced carrageenin was induced in male Wistar rats (160-180 g) that were left without food for 16 hours.

Percent inhibition is calculated from the average edema values of the groups of rats either treated with the test compound or given vehicle only (carboxymethylcellulose (CMC); control). ED 50 values were determined by regression analysis of the inhibition values. Test compounds were administered by gavage as a 1% carboxymethylcellulose (CMC) suspension one hour prior to the carrageenin injection. The inhibitory effect of the test compounds on carrageenin edema is summarized in Table I.

The protective effect of the test compounds against adjuvant-induced arthritis is shown in Table II. Using the Newbold method, male Wistar rats weighing 160-200 g are injected into the plantar surface of the right hind paw with 0.1 ml of Freund complet adjuvant (Difco Lab. Stir. USA). Using a mercury plethysmometer, the volume of the hind legs is measured before and 21 days after adjuvant administration. The test compound is administered orally to test animals for two weeks at a daily dose of 25 mg / kg. The percent inhibition of paw volume growth in Table II refers to the value measured on day 21.

In the adjuvant-induced arthritis assay, which is considered to be the best model of rheumatoid arthritis, the compounds of the invention inhibit articular deformation more effectively than reference agents (naproxen and phenylbutazone). Tests further show that the compounds of formula I not only effectively cure morphological deformities, but also have a desirable and useful effect on the functional and fitness of the shed and even the general physical state of the animals.

The analgesic effect of the compounds of this invention was tested by the hot plate test (56 ° C) on male and female CFLP strain mice weighing 18-22 kg. The point at which the defensive reaction occurred is correlated with the latency measured in the control group (Woolfe and McDonald 1944). At least ten animals are used per dose. Test compounds are administered orally 60 minutes before the start of the test as a 1% methylcellulose suspension. The results are summarized in Table III. The test was performed on separate male Wistar rats weighing 180-210 g, who were left without food for 16 hours. Test compounds are suspended in a 1% carboxymethylcellulose suspension and administered orally at a dose of 10 ml / kg.

Five hours after treatment, the animals are sacrificed and their stomachs are placed in a 2.5% formalin solution. Punctiform haemorrhage and ulcers are evaluated according to the following scale:

= no damage;

= some extent of punctiform hemorrhage (less than 10%);

= diffuse hemorrhage or small ulcer (less than 2 mm);

= two or more small ulcers (less than 2 mm);

= one or more large ulcers (greater than 2 mm).

At 25 mg / kg and 100 mg / kg, the compounds of the formula I do not show an ulcerogenic effect. In the acute test, the UD-g for naproxen is 20.8 mg / kg and for indomethacin 6.3 mg / kg, both when p.o.

The acute toxicity of the compounds of formula I was determined by the Litchfield-Wilcoxon method on male and female CFLP rats. The LD 50 values range from 500 to 2000 mg / kg p.o.

The pharmaceutical preparations can be prepared by methods known per se by admixing at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof with suitable inert solid or liquid pharmaceutical carriers.

The compounds of the formula I act against various rheumatic diseases, in particular rheumatoid arthritis, spondylitis, osteortrotitis and gout. The active ingredient may be formulated by conventional methods in the pharmaceutical industry into dosage forms suitable for enteral and parenteral administration (for example, tablets, capsules, dragees, injections, etc.). The pharmaceutical preparations may contain one or more other biologically active substances in addition to the compound of formula (I). Drugs contain carriers and excipients commonly used in therapy.

and

The dosage of the compounds of formula I varies within a wide range and depends on several factors (for example, body weight, age, patient condition, etc.). The usual dose is 10 to 200 mg / kg body weight for enteral administration and 1 to 50 mg / kg body weight for parenteral administration. However, the above ranges are for information only.

The compounds of formula (I) also exhibit considerable antifungal activity and are effective against phytopathogenic fungal strains and diseases. The compounds of formula I are particularly effective against powdery mildew. Table IV shows the activity of some compounds of formula IV against Erysiphe graminis f.sp. tritici.

The following test melodies shall be used:

Greenhouse conditions: temperature of 20 ° C, relative humidity 80%, light intensity 6 000 lux. The test plants (winter wheat MV-9) are grown in pots of 20 cm diameter in a 1: 1 perlite mix. The average number of plants per pot is 180, the height of the plants is 6 to 7 cm. About 8 ml of an aqueous suspension of the test compound is sprayed onto the plants.

The degree of infection is determined after eight days. Activity is calculated from percent inhibition values. Commercially available Fundazol 50 WP and Karathene LC 50 are used as controls.

Accordingly, the present invention also provides fungicidal compositions, characterized in that they contain as an active ingredient an effective amount of at least one compound of the formula I, wherein R 1, R 1, R 1, R 3 and X are as defined above, or acid addition salts in admixture with suitable inert solid or liquid carriers or diluents.

These fungicidal compositions are prepared by methods known per se.

Table I

Antiphlogistic effect on edema induced by carrageenin in rats

Tested compound number Dose mg / kg after. n Percentual inhibition buckle volume ^ED 50 mg / kg po 61 12.5 25.0 100.0 29 37 58 60.9 62 12.5 25.0 50.0 100.0 18 51 59 69 38.4 64 12.5 25.0 50.0 100.0 15 Dec 27 Mar: 44 65 59.1 69 12.5 25 50 100 ALIGN! 27 Mar: 33 52 86 35.0

Table I - continued

Tested compound number Dose mg / kg after. n Percentual inhibition buckle volume ^ED 50 mg / kg po 12.5 26 74 25 55 25.7 50 69 12.5 21 25 63 83 50 70 28.1 100 ALIGN! 72 12.5 29 25 40 107 50 70 30.6 100 ALIGN! 74 12.5 10 19 Dec 25 10 45 108 50 10 61 38.5 100 ALIGN! 10 70 12.5 10 10 25 10 42 110 50 10 46 51.4 100 ALIGN! 10 61 25 10 21 50 15 Dec 42 Phenylbutazone 100 ALIGN! 15 Dec 45 100.9 200 15 Dec 66 12.5 15 Dec 33 25 15 Dec 49 Naproxen 50 15 Dec 64 28.7 100 ALIGN! 15 Dec 71 1 10 28 2 10 40 Indomethacin 4 10 47 4.1 8 10 64 12 10 67

number of test animals

Table II

Inhibits adjuvant-induced arthritis effect in rats

Tested compound number Dose mg / kg after. n Percentage growth inhibition buckle volume 21. den 46 25 10 28.1 61 25 10 38.2 62 25 10 40.3 64 25 10 40.6 67 25 10 32.8 69 25 10 35.2 83 25 12 46.7 85 25 12 28.4 107 25 12 17.8 108 25 12 35.2 109 25 12 36.7 110 25 12 32.1 138 25 10 35.2 Phenylbutazone 50 15 Dec 18.5 Naproxen 12.5 15 Dec 16.8 25 15 Dec 28.4

n = number of test animals

Table III

Hot plate test on mice

Tested compound number Dose mg / kg after.· Extension of reaction time in% 25 7 46 50 18 100 ALIGN! 38 25 20 May 61 50 22nd 100 ALIGN! 26

Table III - continued

Tested compound number Dose mg / kg after. Extension of reaction time in% 12.5 17 25 19 Dec 62 50 30 100 ALIGN! 38 25 17 64 50 39 100 ALIGN! 44 25 13 69 50 24 100 ALIGN! 30 25 19 Dec 74 50 26 100 ALIGN! 43 25 16 83 50 28 100 ALIGN! 59 25 34 107 50 41 100 ALIGN! 88 25 34 108 50 46 100 ALIGN! 46 25 21 110 50 34 100 ALIGN! 52 25 25 138 50 37 100 ALIGN! 82 100 ALIGN! 29 Phenylbutazone 150 42 200 44 12.5 25 25 31 Naproxen 50 45 100 ALIGN! 49

Table IV

Antifungal effect on test organism Erysiphe graminis in vitro

Tested »] number Koncontrnou µg / ml l uh .i i uc 0. 0 ™ 50 µg / ml 37.5 50.6 50 72.6 75 83.0 1 100 ALIGN! 85.3 32.9 150 86.8 200 90.1 400 99.6 25 42.1 50 70.9 100 ALIGN! 82.0 8 150 84.1 31.1 200 91.9 400 98.8 25 20.3 50 42.8 10 100 ALIGN! 76.4 56.9 200 92.7 400 90.1 25 49.2 50 71.6 6 100 ALIGN! 85.1 27.9 200 89.5 400 99.4 25 40.8 50 67.7 22nd 100 ALIGN! 79.8 31.2 200 93.0 400 96.9 12.5 24.9 Karathane 25 46.2 LO 50 50 72.7 27.4 100 ALIGN! 87.9 50 55.3 Chinoin fun- 100 ALIGN! 72.6 41.2 dazol 50 WP 200 89.1 400 94.6

Further details relating to the present invention are given in the following examples. The examples are illustrative only and do not limit the scope of the invention in any way.

Example 1

4- (1H-1,2,4-Triazol-1-yl) -7-chloroquinoline

A mixture of 1.98 g of 4,7-dichloroquinoline, 1.38 g of 1,2,4-triazole and 10 ml of dimethylformamide is stirred for 6 hours at IDO, after which the reaction mixture is poured into 100 ml of water and neutralized with 1 ml. concentrated ammonium hydroxide solution. The precipitated product is filtered off and recrystallized from ethanol. Thus 1.61 g of the desired compound are obtained, yield 70%, mp 169-170 ° C.

Example 2

- (1H-1,2,4-Triazol-1-yl) -2,8-dimethylquinoline

A mixture of 1.91 g of 2,8-dimethyl-4-chloroquinoline and 1.38 g of 1,2,4-triazole is melted at 120 ° C and stirred for 2 hours. The solidified melt is dissolved in a mixture of ethanol and water. The solution is poured into a solution of 0.84 g of sodium bicarbonate in 200 ml of water. The precipitated substance was filtered off. Thus 1.97 g of the desired compound are obtained, yield 88%, mp 99-100 ° C.

Example 3

4- (1H-1,2,4-Triazol-1-yl) -2-methyl-6-methoxyquinoline

A mixture of 2.44 g of 2-methyl-4-chloro-6-methoxyquinoline hydrochloride, 1.38 g of 1,2,4-triazole and 10 ml of dimethylformamide is stirred for 3 hours at 80 ° C, after which the reaction mixture is poured into 100 ml. ml of water and neutralized with 2 ml of concentrated ammonium hydroxide. The precipitated product is filtered off. Thus 2.09 g of the desired compound are obtained, yield 87%, mp 117-118 ° C.

Example 4

4- (1H-1,2,4-Triazol-1-yl) -2-methyl-6,8-dichloroquinoline

A mixture of 2.46 g of 2-methyl-4,6,8-trichloroquinoline, 1.82 g of 1,2,4-triazole sodium salt and 10 ml of dimethylformamide was stirred at 100 ° C for 25 hours. into 100 ml of water. The precipitated product is filtered off. Thus 2.59 g of the desired compound are obtained, yield 93%, m.p. 220-222 ° C.

Example 5

4- (1H-1,2,4-Triazol-1-yl) -2,8-bis-trifluoromethylquinoline

A mixture of 4-chloro-2,8-bis-trifluoromethylquinoline (3.0 g), potassium carbonate (1.38 g) and acetone (30 ml) was heated to boiling for 23 hours and then poured into water (100 ml). The precipitated product is filtered off, dissolved in 5 ml of ethanol and then 5 ml of water are added. The precipitated product is filtered off. Thus 2.42 g of the desired compound are obtained, yield 73%, mp 106-107 ° C.

Example 6

4- (1H-1,2,4-Triazol-3 (5) -yl-5 (3) -mercapto) -2-trichloromethyl-8-chloroquinoline

A mixture of 3.16 g of 2-trichloromethyl-4,8-dichloroquinoline, 1.48 g of 3 (S) -mercapto-1,2,4-triazole sodium salt and 10 ml of dimethylformamide was stirred at 100 ° C for 18 hours. .

After completion of the reaction, the reaction mixture is poured into water and the precipitated product is filtered off and recrystallized from ethanol. Thus 2.1 g of the desired compound are obtained, yield 55%, m.p. 188-193 ° C.

02

Example 7

4- (5 (3) -Ethyl-1H-1,2,4-triazol-3 (5) -ylmercapto) -2,8-dimethylquinoline

A mixture of 1.32 g of 4-chloro-2,8-dimethylquinoline, 1.55 g of 3 (S) -mercapto-5 (3) -ethyl-1,2,4-triazole and 20 ml of ethanol was stirred for 20 hours at 30 ° C. The reaction mixture is poured into 50 ml of water, neutralized with 1 ml of concentrated ammonium hydroxide solution and the precipitated product is filtered off. Thus, 2.41 g of the desired compound are obtained, yield 85%, m.p. 176-177 ° C.

Example 8

2- (1H-1,2,4-Triazol-1-yl) -3-methylquinoline

A mixture of 1.78 g of 2-chloro-3-methylquinoline and 0.69 g of 1,2,4-triazole is melted and allowed to stand for 4 hours at 120 ° C. The melt is cooled, dissolved in 10 ml of ethanol, poured into 20 ml of water and neutralized with 1 ml of concentrated ammonium hydroxide solution. The precipitated product is filtered off. Thus 1.49 g of the desired compound are obtained, yield 71%, m.p. 80-81 ° C.

Example 9

2- (1H-1,2,4-Triazol-1-yl) -4-methylquinoline hydrochloride

A mixture of 2-chloro-4-methylquinoline (1.78 g), 1,2,4-triazole (0.76 g) and chlorobenzene (10 ml) was stirred at 100 ° C for 7 h. The reaction mixture is cooled, the precipitated product is filtered off, dissolved in 5 ml of ethanol and reprecipitated by addition of 10 ml of diethyl ether. The precipitated product is filtered off. Thus 1.72 g of the desired compound are obtained, yield 70%, mp 193-194 ° C.

Example 10

2- (1H-1,2,4-Triazol-1-yl) -7-chloro-3,8-dimethylquinoline

A mixture of 2.26 g of 2,7-dichloro-3,8-dimethylquinoline, 1.1 g of 1,2,4-triazole sodium salt and 10 ml of dimethylformamide was stirred at 100 ° C for 25 hours. The reaction mixture is poured into 100 ml of water and the precipitated product is filtered off. Thus 2.48 g of the desired compound are obtained, yield 96%, mp 147-148 ° C.

Example 11

2- (3-Methyl-1H-1,2,4-triazol-1-yl) -4,6-bis-trichloromethylquinoline

A mixture of 3.99 g of 2-chloro-4,6-bis-trichloromethylquinoline, 1.26 g of 3-methyl-1,2,4-triazole sodium salt and 10 ml of dimethylformamide was stirred at 100 ° C for 20 hours. The reaction mixture is poured into 100 ml of water and the precipitated product is filtered off and recrystallized from 10 ml of ethanol. Thus, 2.76 g of the desired compound are obtained, yield 62%, m.p. 169-170 ° C.

Example 12

2- (5 (3) -Methyl-1H-1,2,4-triazol-3 (5) -yl-mercapto) -3-methylquinoline hydrochloride

A mixture of 1.78 g of 2-chloro-3-methylquinoline, 1.38 g of 3 (S) -mercapto-5 (3) -methyl-1,2,4-triazole and 10 ml of chlorobenzene is stirred for 2 hours at a temperature of Mp 100 ° C. The reaction mixture was cooled, the precipitated product was filtered off and washed with diethyl ether. Thus 2.8 g of the desired compound are obtained, yield 96%, m.p. 190-192 ° C.

Example 13

2- (1H-1,2,4-Triazol-3 (S) -ylmercapto) -4,8-dimethylquinoline hydrochloride

A mixture of 1.92 g of 2-chloro-4,8-dimethylquinoline and 1.21 g of 3 (S) -mercapto-1,2,4-triazole is melted and the melt is allowed to stand for one hour at 120 ° C. The reaction mixture was cooled, 5 ml of hot ethanol was added, cooled and the precipitated product was filtered off. Thus 1.90 g of the desired compound are obtained, yield 65%, m.p. 201-202 ° C.

Example 14

4- (1H-1,2,4-Triazol-1-yl) -2, B-dimethyl-5-chloroquinoline

A mixture of 2.26 g of 4,5-dichloro-2,8-dimethylquinoline, 1.38 g of 1,2,4-triazole and 0.1 g of 96¾ sulfuric acid was stirred at 70 ° C for 3 hours. The reaction mixture was poured into 50 ml of water and neutralized with 1 ml of concentrated ammonium hydroxide solution. The precipitated product is filtered off and washed with water. Thus 2.0 g of the desired compound are obtained, yield 77.4%, mp 117-118 ° C.

Example 15

4- (5 (3) -methyl-1H-1,2,4-triazol-3 (5) -ylmercapto) -2-methyl-7,8-dichloroquinoline

A mixture of 2.46 g of 2-methyl-4,7,8-trichloroquinoline, 1.38 g of 3 (S) -mercapto-5 (3) -methyl-1,2,4-triazole and 10 ml of dimethylformamide was added for 8 hours. The mixture was stirred at 100 ° C for one hour. The reaction mixture is poured into 100 ml of water, neutralized and the precipitated product is filtered off. Thus, 3.10 g of the desired compound are obtained, yield 95%, mp 156-158 ° C.

Example 16

2- (1H-1,2,4-Triazol-1-yl) -3-methyl-7-ethylquinoline

A mixture of 2.05 g of 2-chloro-3-methyl-7-ethylquinoline, 1.05 g of 1,2,4-triazole hydrochloride,

0.69 g of 1,2,4-triazole and 10 ml of dimethylformamide are stirred for 6 hours at 100 DEG C. The reaction mixture is poured into 100 ml of water, neutralized and the crude product is recrystallized from a mixture of ethanol and hexane. Thus 1.52 g of the desired compound are obtained, yield 64%, m.p. 72-73 ° C.

Example 17

2- (1H-1,2,4-triazol-3 (S) -ylmercapto) -4-methylquinoline

A mixture of 2-chloro-4-methylquinoline (1.78 g), 3 (S) -mercapto-1,2,4-triazole (1.21 g) and dimethylformamide (10 ml) was stirred at 40 ° C for 3 hours. The reaction mixture is poured into 100 ml of water, neutralized and filtered. Thus, 2.37 g of the desired compound are obtained, yield 90%, m.p. 96-98 ° C.

Example 18

3- (5 (3) -Ethyl-1H-1,2,4-triazol-3 (5) -ylmercapto) -3,8-dimethylquinoline

1.91 g of 2-chloro-3,8-dimethylquinoline and 1.55 g of 3 (S) -mercapto-5 (3) -ethyl-1,2,4-triazole were reacted in a manner analogous to Example 16. Crude the product was recrystallized from a mixture of chloroform and ethanol. Thus 1.93 g of the desired compound are obtained, yield 68%, m.p. 190-192 ° C.

Other compounds were prepared in a manner analogous to that described in the preceding Examples. The prepared compounds are listed in the following Table V. The number in the method column indicates the number of the example in which the method used to prepare the corresponding compound in the table is described.

Table V

Compounds of formula (Ia)

Compound number ^R 1 ^R 2 ^R 3 ^R 4 Method Yield (¾) Melting point ° C 1 H 7-C1 H H 1 70 169-170 2 H 8-CH ₃ H H 1 81 142-144 3 H 8-CFj H H 4 75 146-147 4 2-CKj H H H 3 57 88-89 5 2-CH-j 6-CH 3 H H 3 71 110-112 6 2-CH 2 8-CH 3 H H 1 88 98-100 7 _2-CH3 6-0CH ₃ H H 3 87 117-118 8 2-CH 2 8-OCHj H H 3 68 179-180 9 2-CH 2 6-Cl H H 3 58 173-175 10 2-CH 2 8-C1 H H 4 97 142-144 11 2-CH 2 7-CFj H H 4 93 68-70 12 2-CH 2 8-CFj H H 4 86 154-156 13 2-CH 2 6-OH H H 1 40 238-240 14 2-CH 2 6-COCH3 H H 1 28 189-190 15 Dec 2-CH 2 7-COOCH H H 1 49 184-186 16 2-CH 2 8-CH H H 4 57 208-210 17 2-CH 2 5-C1 8-CH 3 H 1 88 113-115 18 2-CH 2 6-Cl 8-CH 3 H 4 50 173-175 19 Dec 2-CH 2 7-C1 8-CH 3 H 4 98 147-149 20 May _2-CH3 5-C1 8-C1 H 1 74 123-124 21 2-CH 2 6-Cl 8-C1 H 4 93 220-222 22nd 2-CH 2 7-C1 8-C1 H 4 93 168-170 23 _2-CH3 5-C1 8-0CH ₃ H 1 59 188-190 24 _2-CH3 5-CH 3 _7-CH3 H 1 59 119-121 25 _{2-CH3 5-CH3} 8-CH 3 H 1 64 120-122 26 2-CH 2 _6-CH3 8-CH 3 H 1 66 129-131 27 Mar: 2-CH 2 7-CH 3 8-CH ₃ H 1 62 128-130 28 2-CH 2 5-CH 3 8-NHCOCH ₃ H 1 57 232-234 29 2-CH 2 5-CH 3 8-NH ₂ H 1 35 205-207 30 2-CCl _{3 6-CH3} H H 4 50 102-104 31 2-CClj 8-CH 3 H H 4 61 130-132 32 2-CClj 8-OCHj H H 4 31 169-170 33 2-CClj 8-C1 H H 5 40 133-135

Table V - continued

Compound number ^R 1 r ₂ ^R 3 ^R 4 Method Yield (¾) Melting point ° C 34 2-CClj 6-CCIj H H 5 47 162-163 35 2-CClj 8-CClj H H 5 50 157-158 36 2-CCl ₃ 8-CFj H H 5 47 132-133 37 2-CCl ₃ 6-C1 8-C1 H 5 73 157-159 38 2-CF 3 8-CFj H H 5 73 106-107

Compounds of formula 1b

Compound number ^R 1 ^R 2 ^R 3 ^R 4 Method Yield (%) Melting point ° C 39 H 7-C1 H H • 7 77 161-162 40 2-CH 2 H H H 7 66 181-182 41 _2-CH3 6-CH 3 H H 7 59 167-169 42 _2-CH3 8-CH 3 H H 7 71 143-145 43 2-CH 2 6-OCHj H H 7 98 191-192 44 2-CH 2 8-0CH ₃ H H 7 77 186-187 45 2-CH 2 6-C1 H H 7 68 194-195 46 2-CH 2 8-C1 H H 7 88 199-200 47 2-CH 2 7-CF ₃ H H 7 76 205-207 48 2-CH 2 8-CFj H H 7 42 183-184 49 _2-CH3 5-C1 8-CH 3 H 7 78 184-186 50 _2-CH3 6-C1 8-CH 3 H 7 66 197-199 51 2-CH 2 7-C1 8-CH ₃ H 7 79 168-170 52 2-CH 2 6-C1 8-C1 H 7 65 206-207 53 2-CH 2 7-C1 8-C1 H 7 87 199-200 54 2-CClj 6-CH 3 H H 15 Dec 72 127-129 55 2-CCl ₃ 8-CH 3 H H 6 40 166-168 56 2-CCIj 8-C1 H H 6 55 188-189 57 2-CCl ₃ 8-CCl ₃ H H 6 18 129-130 58 2-CCl ₃ 8-CF ₃ H H 6 50 190-192 59 2-CClj 6-C1 8-C1 H 6 48 214-215 60 2-CF 3 8-CFj H H 6 24 208-210

Table V - continued

Compound number ^R 1 ^R 2 ^R 3 ^R 4 Method Yield (¾) Melting point ° C 61 H 7-C1 H ch ₃ 7 65 227-228 62 2-CH 2 H H ch ₃ 15 Dec 82 175-177 63 2-CH 2 _6-CH3 H CH ₃ 15 Dec 78 181-182 64 2-CH 2 8-CH ₃ H CHj 15 Dec 85 198-200 65 2-CH 2 6-OCHj H CHj 15 Dec 98 192-193 66 2-CH 2 8-OCHj H ch ₃ 15 Dec 98 186-187 67 2-CH-j 8-CF ₃ H CHj 15 Dec 96 180-182 68 2-CH 2 6-C1 8-CH 3 ch ₃ 15 Dec 99 207-208 69 2-CH 2 7-C1 b-ch ₃ ch ₃ 15 Dec 62 191-193 70 2-CH 2 6-C1 8-C1 CHj 15 Dec 38 209-211 71 _2-CH3 7-C1 8-C1 CHj 15 Dec 95 156-158 72 H 7-C1 H CHgCHi 7 79 154-156 73 2-CH 2 H H CH ₂ CH ₃ 7 44 135-137 74 _2-CH3 6-CH 3 H CH ₂ CH ₃ 7 36 171-172 75 2-CH 2 8-CH ₃ H CH ₂ CH ₃ 7 05 / 176-177 76 _2-CH3 6-0CH ₃ H CH ₂ CH ₃ 15 Dec 77 168-170 77 2-CH 2 8-OCHj H CH ₂ CH ₃ 7 30 171-173 78 _2-CH3 8-CF ₃ H CH ₂ CH ₃ 15 Dec 81 162-165 79 2-CH 2 6-C1 8-CH 3 CH ₂ CH ₃ 15 Dec 44 191-193 80 2-CH 2 7-C1 8-CH 3 CH ₂ CH ₃ 15 Dec 72 155-156 Bl _2-CH3 6-C1 8-C1 CH ₂ CH ₃ 15 Dec 85 177-178 82 2-CH 2 7-C1 8-C1 CH ₂ CH ₃ 15 Dec 32 172-174

Compounds of formula Ic

Compound number ^R 1 r ₂ ^R 3 ^R 4 Method Yield (%) Melting point ° C 83 3-CH ₃ H H H 16 71 79-80 84 3-CH _{3 6-CH3} H H 16 68 88-90 85 3-CH ₃ 7-CH 3 H H 16 87 79-80 86 3-CH 3 8-CH 3 H H 10 30 99-101 87 3-CH 3 6-CH ₂ CH ₃ H H 16 58 81-83

Table V - continued

Compound number ^R 1 r ₂ ^R 3 ^R 4 Method Yield (%) Melting point ° C 88 3-CH 3 7-CH ₂ CH ₃ H H 16 64 72-73 89 3-CH-j 8-CH ₂ CH ₃ H H 16 41 79-80 90 3-CH 3 6-0CH ₃ H H 10 75 87-89 91 3-CH-j 6-C1 H H 10 99 148-150 92 3-CH ₃ 7-C1 H H 10 98 119-120 93 3-CH-j 5-CH 3 7-CH 3 H 16 70 137-139 94 3-CH ₃ 6-CH 3 7-CH 3 H 16 62 117-119 95 3-CH 3 5-CH 3 8-CH 3 H 16 51 138-140 96 3-CH ₃ 6-CH 3 8-CH 3 H 16 84 126-128 97 3-CH 3 _7-CH3 8-CH 3 H 16 76 118-119 98 3-CH 3 6-C1 8-CH ₃ H 10 90 194-195 99 3-CH ₃ 7-C1 8-CH 3 H 10 96 147-148 100 ALIGN! 4-CH 3 H ' H H 16 99 111-113 101 _4-CH3 6-CH 3 H H 16 71 134-136 102 4-CH 3 7-CH 3 H H 10 66 134-135 103 4-CH 3 8-CH 3 H H 10 63 124-126 104 4-CH 3 6-0CH ₃ H H 10 71 124-126 105 4-CH 3 7-C1 H H 10 66 193-195 106 4-CClj 6-CClj H ch ₃ 11 62 169-170

Compounds of Formula Id

Compound number ^R 1 r ₂ ^R 3 ^R 4 Method Yield (¾) Melting point ° C 107 3-CH 3 H H H 17 62 144-145 108 3-CH 3 6-CH 3 H H 17 84 165-166 109 3-CH 3 _7-CH3 H H 17 99 170-171 110 3-CH ₃ 8-CH 3 H H 18 60 124-125 111 3-CH ₃ 6-OCHj H H 18 51 158-160 112 3-CH 3 6-C1 H H 17 80 188-190 113 3-CH 3 7-C1 H H 17 80 213-215 114 3-CH ₃ 6-C1 8-CH 3 H 18 60 190-192

Table V - continued

Compound number ^R 1 r ₂ ^R 3 ^R 4 Method Yield (¾) Melting point ° C 115 3-CH-j 7-C1 8-CH-j H 18 68 205-206 116 4-CH 3 H H H 17 98 96-98 117 4-CH 3 6-CH 3 H H 18 92 125-126 118 4-CH-j 7-CH 3 H H 18 74 134-136 119 4-CH 3 8-CH 3 H H 18 50 135-137 120 4-CH 3 6-OCHj H H 18 81 152-154 121 4-CH 3 7-C1 H H 18 83 158-160 122 3-CH-j H H CHj 17 84 211-212 123 3-CH 3 6-CH-j H CHj 18 74 215-216 124 3-CH-j 7-CH-j H CH-j 17 85 204-205 125 3-CH 3 8-CH 3 H CHj 18 74 212-213 126 3-CH 3 6-OCH-j H CHj 18 72 205-207 127 3-CH 3 6-C1 H CHj 18 79 213-215 128 3-CH-j 7-C1 H CHj 18 74 205-206 129 3-CH 3 6-01 8-CH-j CHj 18 40 226-227 130 3-CH 3 7-01 8-CH 3 CHj 18 87 228-230 131 4-CH 3 H H CH-j 17 78 172-174 132 4-CH-j 6-CH 3 H CHj 17 74 189-190 133 4-CH 3 7-CH 3 H CHj 18 59 172-174 134 4-CH 3 8-CH 3 H CHj 18 67 188-190 135 4-CH 3 6-QCH-j H CHj 17 86 192-193 136 4-CH 3 7-C1 H CHj 17 79 179-180 137 3-CH 3 H H CH ₂ CH ₃ 17 85 187-189 138 3-CH 3 6-CH 3 H CH ₂ CH ₃ 18 68 209-211 139 3-CH-j 7-CH-j H CH ₂ CH ₃ 17 57 145-146 140 3-CH 3 8-CH 3 H CH ₂ CH ₃ 18 68 190-192 141 3-CH 3 6-OCHj H CH ₂ CH ₃ 17 67 192-195 142 3-CH 3 6-C1 H CH ₂ CH ₃ 18 67 203-205 143 3-CH 3 7-C1 H CH ₂ CH ₃ 17 73 191-193 144 3-CH 3 6-C1 8-CH 3 CH ₂ CH ₃ 18 50 185-186 145 3-CH 3 7-C1 8-CH 3 CH ₂ CH ₃ 18 72 214-215 146 4-CH 3 H H CH ₂ CH ₃ 17 92 130-131 147 4-CH 3 6-CH-j H CH ₂ CH ₃ 18 37 132-133 148 4-CH 3 7-CH 3 H CH ₂ CH ₃ 18 60 117-118

Table V - continued

Compound number ^R 1 r ₂ ^R 3 ^R 4 Method Yield (%) Melting point ° C 149 4-CH 3 8-CH 3 H CH ₂ CH ₃ 18 63 154-156 150 4-CH 3 6-OCHj H CH ₂ CH ₃ IB 40 163-165 151 4-CH 3 7-C1 H CH ₂ CH ₃ 18 63 149-152

SUBJECT OF THE INVENTION

Claims (6)

SUBJECT OF THE INVENTION A fungicidal composition comprising the active ingredient in admixture with suitable inert solid or liquid carriers or diluents, characterized in that it comprises as active ingredient an effective amount of at least one compound of the formula I in which: R ^ represents a hydrogen atom, a methyl group, a trihalomethyl group or a carboxy group, R ₂ is hydrogen or halogen, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, phenoxy, amino, acetamino, C 1 -C 4 dialkylamino, acetyl, benzyl, methylthio- , carboxy, cyano, ethoxycarbonyl, nitro or trihalomethyl, R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, R1 is hydrogen, methyl or ethyl, and X is a valence bond or -S-, and / or acid addition salts thereof. 2. A method for preparing an active substance of the formula I, the fungicidal compositions referred to in paragraph 1 in which Rp _R2, R p and X have the meanings given in point 1, and its addition salts with acids, characterized in that the halogenated derivative of quinoline of formula II or III (II) (III) wherein R p of R ₂ and R 4 are as defined above, reacted with 1,2,4-triazole of formula IV or V wherein R 4 is as defined above, at from 0 to 200 ° C, optionally in the presence of a solvent and an acid or base, whereupon the product is optionally isolated as the free base or acid addition salt. 3. The method according to claim 2 for preparing compounds of formula Ia in which Rp _R2, R and R have the meanings given in point 1, and their addition salts with acids, characterized in that the 4-chloroquinoline derivative of the above formula II is reacted at a temperature in the range of 0 to 200 ° C, optionally in the presence of a solvent and an acid or a base, with the 1,2,4-triazole of the above-mentioned general formula IV, wherein R p R ₂ , R 2 and referred to in point 2. A process according to item 2 for the preparation of compounds of formula 1b (1b) wherein R ₂ , R 2 and R 2 have the meanings given in item 1, and their acid addition salts, characterized in that the 4-chloroquinoline derivative is of the above formula (II) is reacted at a temperature in the range of 0 to 200 ° C, optionally in the presence of a solvent and an acid or base, with the 3-mercapto-1,2,4-triazole of the above formula (V) ₂ , R1 and R2 have the meanings given in point 2. 5. A method according to claim 2 for preparing compounds of Formula lc (lc) in which Rp _R2, R and R have the meanings given in point 1, and their addition salts with acids, characterized in that 2-chloroquinoline above of formula (III) is reacted at a temperature in the range of from 0 to 200 ° C, optionally in the presence of a solvent and an acid or base, with the 1,2,4-triazole of formula (IV) above wherein Rp, Rp, R R and R ^ are referred to in point 2. 6. The process of item 2 for the preparation of compounds of formula Id wherein Rp, Rp, R5 and R5 are as defined in item 1, and acid addition salts thereof, characterized in that the 2-chloroquinoline derivative of the above formula III is used. reacted at a temperature in the range of 0 to 200 ° C, optionally in the presence of a solvent and an acid or a base, with the 3-mercapto-1,2,4-triazole of the above-mentioned general formula V, wherein R p R p referred to in point 2.