TRIAZOLYL QUINOLINE DERIVATIVES

Abstract: New triazolyl quinoline derivatives and acid addition salts thereof (wherein R<1> stands for hydrogen, methyl, trihalogenomethyl or carboxy; R<2> is hydrogen, halogen, C1-4 alkyl, hydroxy, C1-4 alkoxy, phenoxy, amino, acetamino, C1-4 dialkylamino, acetyl, benzoyl, methylthio, carboxy, cyano, ethoxycarbonyl, nitro or trihalogenomethyl; R<3> represents hydrogen, C1-4 alkyl or C1-4 alkoxy; R<4> stands for hydrogen, methyl or ethyl and X stands for a valency bond or -S-). The new compounds of general formula (I) possess valuable analgesic, antiphlogistic and fungicidal effect and can be used both in therapy and agriculture.

Description: TRIAZOLYL QUINOLINE DERIVATIVES This invention reLates to new triazolyl quinoline derivatives, a process for the prepara¬ tion thereof and pharmaceutical and fungicidal com¬ positions containing the same. According to an aspect of the present invention there are provided new triazolyl quinoline derivatives and acid addition salts thereof (wherein R stands for hydrogen, methyl, trihalogeno- methyl or carboxy • 2 R is hydrogen, haLogen, C. r alkyl, hydroxy, C L alkoxy, phenoxy, a ino, acetamino, C . di IkyLaraino, acetyl, benzoyl, meth Lthio, carboxy, cyano, ethoxyca bony1, nitro or trihalogenomethyL; R * represents hydrogen, C ^ aLkyL or C . aLkoxy; R stands for hydrogen, methyL or ethyL and X stands for a valency bond or -3-) According to a further aspect of the present invention there is provided a process for the preparation of compounds of the general Formula (I) ι __ *** t Ix- (whe re in R , R , Er , R and X are as s tated above ) A 3770-77-ICY and acid addition salts thereof which comprises reacting a halogeno quinoline derivative of the general formula (ll) or (III) L 2 *■ $ (wherein R , R and R are as stated above) with a 1,2,∑_- riazole of the general Formula (l-V) or (V) HN N (v) US ' ^ N -^ R 4 _j. (wherein R is as stated above) in the presence or absence of a solvent, in the presence or absence of an acid or a base, at a temperature between 0 C and 200 °C and if desired isolating the product thus obtained in the form of the free base or an acid addition salt thereof. According to a feature of the process of the present * invention there is provided a process for the preparation of compounds of the general Formula (la) which comprises reacting a ^-chloro-quinoLine de¬ rivative of the general formula (II) with a 1,2 , k-triazole of the general Formula (IV) (wherein t 2 * _ -h R , R , R and R are as stated above). According to a further feature of the process of the present invention there is provided a process for the preparation of compounds of the general Formula (lb) _ _ which comprises react ing a -chloro-quinoline de¬ rivative of the general Formula ( l) with a 3- -mercapto-L , , - triazo Le of the general Formula • t l (V) (wherein R , R , R and R are as stated above). According to a still further feature of the process of the present invention there is provided a process for the preparation of compounds of the general Formula (Ic) which comprises reacting a 2-chloro-quinoline of the general Formula (ill) with a 1,2, -triazole of L 2 T the general Formula (IV) (wherein R , R , R and . R are as stated above). According to a still further feature of the process of the present invention there is - D - provided a process for the preparation of compounds of the general Formula (id) which comprises reacting a 2-chLoro-quinoline derivative of the general Formula (ill) with a 3-mercapto-L , 2 , 4--triazoLe of the getieraL Formula l __ ** t . (V) (wherein R , R , R and R are as stated above). The starting materials used in the process of the present invention are known compounds, The prior art references of the starting materials are as follows: ■^■-chloro-quino lines of the general Formula (ll) : "The Chemistry of Hecerocyclic Compounds" Vol. 32 Quinolines Part I pages 391 - 398; the references cited therein; Hungarian patent applications Ser. No. 3869/32 and 4-003/82. 2-chloro-quinolines of the general Formula (ill): "The Chemistry of Heterocyclic Compounds" Vol. 32 Quinolines Part I pages 387-390: J. Chem. Soc. P.I. 1981 1(5) 1537-15^3. LH-1 , 2 , 4-4-triazoles of the generaL For¬ mula (IV) : Hungarian patent application Ser. No. 4-370/83} DOS No. 2,802,^91; Chera. Ber. 1968., 101 (6) 2033-2036. 3( 5)-τnercapto-L ,2 , - triazoles of the general Formula (V): Liebigs. Ann. Chem. 637 , 133 135-1 5 (i960). The new compounds of the general Formula (i) possess valuable biological properties and exhibit useful analgesic and antiphlogistic effect. Some representatives of the compounds of the general Formula (i) are highly active against phytopathogenie fungal pests according to both in vivo and in vitro tests. It has been found that the reaction between — and 2-chloro-quinoline derivatives of the general Formula (il) or (ill), respectively, comprising only electron repulsing substituents (e.g. methyl or methoxy groups) and lH-1,2,4— -triazoles or 3(5)-"πercapto-lH-l,2, -triazoles of the general Formula (IV) or (V) , respectively, is autocatalytic whereby the hydrochloric acid formed in the course of the reaction acts as catalyst. The reaction can also be catalysed by other acids, particularly strong mineral or organic acids or acidic salts (e.g. sulfuric acid, trifluoroacetic acid or ammonium chloride) . It is preferred to carry out the reaction in the presence of the said acidic compounds - particularly hydrochloric acid - which can be used in the range of from catalytic to stochiometrical amount. If less basic chloro quinolines comprising electron attracting group or groups (e.g. chlorine, trifluoromethyl) are used, such catalysis is not observed. In this case, however, the reaction may be facilitated by carrying out the same in the presence of an organic or inorganic base (e.g. triethyl araine, potassium carbonate or sodium hydroxide) used in stochiometrical or higher amount. This pertains also to the case if the 1H-1,2, —triazole or 3(5)-mercapto-lH-l,2,4—triazole derivative is used in the form of an alkali salt (e.g. sodium salt) thereof. It has been found furtheron that the mercapto group is more reactive than the - H- 5 -group of the triazole ring. The reaction (preparation of compounds of the general Formulae (la), (lb), (ic) and (id)) may be carried out preferably in the presence of a polar organic solvent (e.g. ethanol, acetone, ]_o acetonitrile, dimethyl formamide, dimethyl sulfoxide etc). As reaction medium an apolar organic solvent (e.g. benzene, toluene, chloro benzene, dichloro benzene) may also be used and one may also work in the absence of an organic solvent in the 15 melt. The reaction of the present invention may be carried out at a temperature between 0 C and 200 °C, preferably in the range of 20 - 150 °C. The reaction temperature is selected under taking 0 into consideration the properties of the reactants and the method used. It is sifficient to react the chloro quinoline component with a iiolar equivalent amount of the 1H-1,2,---I—triazole or 3(5)-mercapto-l,2 , - 5 -triazole but the reactions generally take place more rapidly and completely if the starting mate¬ rial of the general Formula (IV) or (V) is used in a 1-2 molar equivalent amount. According to a form the realization of the 0 process of the present invention the reaction com¬ ponents are melt and the reaction having been terminated the product formed is isolated. Accord¬ ing to the said embodiment of the process the product is formed in the form of the hydrochloride 5 thereof. The direct reaction product is treated with an apolar organic solvent (e.g. ether, chloro¬ form, benzene, hexane) or crystallized from a polar solvent (e.g. ethanol, methanol, acetonitrile, dimethyl formaraide) or a mixture of polar and apolar solvents. The free base of the general Formula (l) may be isolated by cooling the reaction mixture, dissolving in water or a mixture of water and ethanol - preferably under adding a mineral or organic acid - and precipitating the product by adding an organic or inorganic base. The crude product may be crystallized from a mixture of a polar organic solvent and water or polar and apolar organic solvents. According to a further embodiment of the process of the present invention the reaction partners are reacted in the presence of an apolar organic solvent (e.g. benzene, toluene, xylene, hexane, carbon tetrachloride, chloro benzene, dichloro benzene etc). The reaction having been completed the product precipitated in the form of the hydrochloride is filtered, if necessary crystallized and converted into the free base as described above. According to a still,further embodiment of the process of the present invention the reac¬ tion partners are reacted in a polar organic solvent (e.g. ethanol, ethylene glycol, acetonitrile, acetone, ethyl methyl ketone, dimethyl formamide, dimethyl sulfoxide, glacial acetic acid). The product is isolated in the form of the free base or a salt formed with a mineral acid. According to a preferred embodiment of the process of the present invention the reaction is accomplished in a polar organic solvent (e.g. - 0 - ethanol, ethylene gLycol, acetonitrile, acetone, methyl ethyl ketone, dimethyl formamide), prefer¬ ably in the presence of hydrochloric acid. The acidic medium may be either provided by introducing an acid (preferably hydrochloric acid) to the reaction or by using the chloro quinoline component in the form of a salt (preferably hydrochLoride) thereof. The product formed in the form of a salt may be isolated from the reaction mixture according to one of the methods set forth above. According to a further preferable form of realization of the present process of the in¬ vention the reaction is accomplished in a polar organic solvent, in the presence of a molar equivalent or larger amount of a strong base (e.g. triethyl amine, potassium carbonate, sodium carbonate etc). The above reaction may also be carried out by using the triazole or mercapto triazole of the general Formula (TV) or (v) , respectively, in the form of an alkali (e.g. sodium or potassium) salt thereof. The structure of the new compounds pre- pared by the process of the present invention is characterized and con irmed by means of N R, I?R and MS spectrum and the purity of the product is determined by thin layer, gas and liquid chroma- tography. The compounds of the general Formula (i) possess valuable physiological properties and eliminate or efficiently relieve induced pain and inflammation processes. The significant advantage of the compounds of the general Formula (i) is that in analgesic and antiphlogistic dose range lcerative activity is observed not at all or but to a Very small extent. Thus the orally administered compounds of the general Formula (l) efficiently reduce acute inflammatory processes. According to the method of ¥inter [Proc. Soc. Exp. Biol. Med. Ill, 54 (1962)] carrageenin oedema is induced and evaluated on male Wistar rats fasted for 16 hours (body weight l6θ - 180 g). Percental inhibition is calculated from the average oedema values of the groups treated with the test compound on the one hand and with carrier (carboxy methyl cellulose, CMC; control) on the other. ED p .- values are •determined by means of regression analysis of the inhibition Values. The test compounds are adminis¬ tered through a stomach canule in the form of a 1 < ?o carboxy methyl cellulose (CMC) suspension, one hour before introducing the carrageenin injec¬ tion. The carrageenin oedema inhibiting effect of the test compounds are summarized in Table I. The protecting effect of the test com¬ pounds against adjuvant induced arthritis is shown in Table II. According to the method of Newbold 0.1 nil of Freund complet adjuvant (Difco Lab. Mich. USA) is injected to the plantar- surf ce of the right hind paw of male Wistar rats weighing l6θ - - 200 g. The volume of the hind paws is measured before and 21 days after the administration of the adjuvant with the aid of a mercury plethysmometer. The test compound is administered to the test animals for two weeks in a daily oral dose of 25 mg/kg. In Table II the "percental inhibition of the growth of paw volume" relates to the value determined on the 21st day. In the adjuvant arthritis test, considered to be the best model test of rheumatoidal arthritis, the compounds of the present invention inhibit articular deformations more effectively than the reference substances Naproxen and Phenylbutazon. The tests show furthermore that the compounds of the present invention are active not only in healing morphological deformations but effect in a desirable and useful manner the functional condition and fitness of the feet, moreover the general physical state and condition of the animals, too. The anaLgesic effect of the compounds of the present invention is tested according to the hot (5 C) plate test on male and female CFLP strain mice weighing 18 - 22 g. The point of time of the appearence of the deterring reaction (Abwehrreaktion) is determined and related to the latent time measured on the control group (WooI e and McDonald 19 -4). At least 10 animals are used per dose. The test compounds are administered orally 60 minutes before the test in the form of a 1 methyl cellulose suspension. The results are summarized in Table III. The test is carried out on separated male Wistar rats weighing 180 - 210 g and fasted for 16 hours. The test compounds are suspended in 1 carboxy methyl cellulose and administered orally in a dose of 10 ml/kg. Five hours after treatment the animals are sacrificed and their stomachs are placed into a 2.5 formaline solution. The number and rate of punctiform haemorrhage and ulcers is evaluated according to the following scale: 0 = no lesion; 1 = some punctiform haemorrhage ( ^ 10) ; 2 = diffuse haemorrhage or small ulcer ( 2 mm); 3 = two or more minor small ulcer ( * 2 mm) ; 4 = one or more large ulcer ( > 2 mm). In a dose of 25 mg/kg and 100 mg/kg the compounds of the present invention do not exhibit ulcerogenic effect. In acute test the ' W5--< n J value of Naproxen and Indomethacin amounts to 20.8 mg/kg and 6.3 mg/kg p.o., respectively. The acute toxicity of the compounds of the general Formula (i) is determined according to the method of Litch ield - Wilcoxon on male and female rats of CFLP strain. The LD_„ values D O vary between 500 and 2000 mg/kg p.o. According to a further aspect of the present invention there are provided pharmaceutical compositions comprising in an effective amount at least one compound of the general Formula (i) . 1 2 3 4 •. (wherein R , R , R , R and X are as stated above) or a pharmaceutically acceptable acid addition saLt thereof as active ingredient in admixture with suitabLe inert soLid or liquid pharmaceutical carriers. The pharmaceutical compositions may be prepared in a manner known per se by admixing at least one compound of the general Formula (i) or a pharmaceutic lly acceptable acid addition salt thereof with suitable inert solid or liquid pharmaceutical carriers. The compounds of the present invention may be used in therapy preferably for the treat- ment of various rheumatic diseases, particularly rheumatoi al arthritis, spondylitis, osteortrosis and gout. The active ingredient may be finished by known methods of pharmaceutical industry in forms suitable for enteral or parenteral adminis- tration (.e.g. tablets, capsules, dragees, injec- tions etc.). The pharmaceutical compositions of the present invention may optionally comprise one or more further biologically active materials in addition to the compound of the general Formula (i) • The compositions comprise carriers and exci- pients generally used in therapy. The dose of the compounds of the generaL Formula (l) Varies between wide ranges and depends on several factors (e.g. body weight, age and con- dition of the patient etc). The dose amounts generally to 10 - 200 mg/kg body weight (enteral administration) and to 1 - 50 mg/kg (parenteral administration). The above ranges are, however, just of an informative character. The compounds of the general Formula (l) possess considerable antifungal activity, too, and are active against phytopathogenic fungal strains and diseases. The compounds of the general Formula (i) are particularly effective against powdery mildew. In Table IV the activity of some compounds of the general Formula (TV) against Erysiphe graminis f. sp. tritici strain are disclosed. The following test method is used: Glasshouse conditions: temperature 20 C; relative humidity 80 > • strength of illumination 6000 lux. The test plants (MV-9 Automn wheat) are cultivated in pots (diameter 20 cm) in a 1: 1 mixture of sand and perlite. The average number of plants per pot amounts to 180, the height of the plants is 6-7 cm. About 8 ml of the aqueous suspension of the test compound is applied onto the plants with the aid of a sprayer. The rate of infectedness is determined after 8 days. Activity is calculated from the percental inhibition values. As control commercial - Ik - products Fundazol 50 WP and Karathene LC 50 are used. According- to a further feature of the present invention there are provided fungicidal compositions comprising as active ingredient in an effective amount at least one compound of the ι 4 general Formula (l) (wherein R , R , R , R and X are as stated above) or an acid addition salt there¬ of in admixture with suitable inert solid or liquid carriers or diluents. The said fungicidal compositions are prepared by methods known per se. Table I Antiphlogistic effect on carrageenin induced oedema on rats Test com- Dose Percental ED_ ^ D O pound No. mg/kg p.o. inhibition mg/kg p.o. of paw volume 12.5 29 61 25.0 37 60.9 LOO.O 58 12.5 18 25.0 51 62 50.0 59 38.4 100.0 69 12.5 15 25.0 27 64 50.0 59.1 100.0 65 Table :I (cc •ntd •) Test com¬ Dose n Percental ED_. 50 pound No. mg/kg inhibition mg/kg p.o. p.o. of paw volume 12.5 27 25 33 69 50 52 35.0 100 86 12.5 26 lh 25 55 25-7 50 69 12.5 21 25 63 83 50 70 28.1 100 72 12.5 29 25 ho 107 50 70 30.6 100 7 12.5 10 19 25 10 H-5 108 50 10 6ι 38.5 100 10 70 12.5 10 10 25 10 H-2 110 50 10 k6 51.4 100 10 6ι - 16 - Table I (contd. ) Test com¬ Dose n Percental 50 pound No. mg/kg inhibition mg/kg p.o. p.o. of paw volume 25 10 21 Phenylbu- 50 15 42 tazon 100 15 45 100.9 200 15 66 12.5 15 33 25 15 49 Naproxen 50 15 64 28.7 100 15 71 1 10 28 2 10 40 Indomethacin 4 10 7 4.1 8 10 64 12 10 67 n = number of the test animals Table II Inhibitory effect on adjuvant induced arthritis on rats Test com¬ Dose n Percental inhibition of the pound No. mg/kg growth of paw volume, on the p.o. 21st day 46 25 10 28.1 61 25 10 38.2 62 25 10 40.3 Table II ( contd . ) Test com¬ Dose n Percental inhibition of the pound No. mg/kg growth of paw volume, on the p.o. 21st day 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 Phenylbu- tazon 50 15 18.5 Naproxen 12.5 15 16.8 25 15 28.4 n = number of the test animals Table III Hot plate te.st : on mice Test com¬ Dose Lengthening of reaction pound No. mg/kg p.o. time in 25 7 46 50 18 100 38 Table III ( contd . ) Test com¬ Dose 1 Lengthening of reaction pound No. mg/kg p.o. time in 25 20 61 50 22 100 26 12. 5 17 25 19 62 50 30 100 38 25 17 64 50 39 100 44 25 13 69 50 24 100 30 25 19 74 50 26 100 43 25 16 83 50 28 100 59 25 34 107 50 41 100 88 25 34 108 50 46 100 46 Table III ( contd . ) Test com¬ Dose Leingthening of reaction pound No. mg/kg p.o. time in % 25 21 110 50 34 100 52 25 25 138 50 37 100 82 Phen Ibu- 100 29 tazon 150 42 200 44 12. 5 25 25 31 Naproxen 50 45 100 49 Table IV In vitro antifungal effect on Erysiphe graminis test organism Test < 20m- Concentrat: Ion Inhibition 1 ED DO pound No. ,ug/ml ug/ml 37.5 50.6 50 72-6 75 83-0 1 100 85.3 32.9 150 36.8 200 90.1 400 99.6 25 42.1 50 70.9 100 82.0 8 150 84.1 31.1 200 91-9 400 98.8 25 20.3 50 42.8 10 100 76.4 56.9 200 2 -7 400 90.1 25 49.2 50 71.6 6 100 85.1 27.9 200 89.5 400 99-k Table IV ( contd . ) Test com¬ Concentration Inhibition % ED. 50 pound No. •ug/m1 Λig/ml / 25 40.8 50 67.7 22 100 79.8 31.2 200 93-0 400 96.9 12.5 24.9 Karathane 25 46.2 LC 50 50 72.7 27.4 100 87-9 50 55-3 Chinoin fun- 100 72.6 41.2 dazol 50 WP 200 89- 1 400 94.6 Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the said Examp¬ les. Example 1 4-(lH-l,2,4-triazole-l-yl)-7-chloro- -quinoline A mixture of 1.98 g of 4,7- ichloro- -quinoline, 1,38 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100 C for 6 hours, whereupon the reaction mixture is poured into 100 ml of water and neutralized with 1 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered and recrystallized from ethanol. Thus 1.6l g of the desired product are obtained, yield Example 2 4-(lH-l,2,4-triazole-l-yl)-2,8-dimethyl- -quinoline A mixture of 1.91 S of 2,S-dimethyl-4- -chloro-quinoline and L.38 g of 1,2,4-triazole is melt 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 and 20 ml of water. The precipitated product is filtered. Thus 1.97 o of the desired compound are obtained, yield 88 * ?_, ra.p.: 99 - 100 °C Example 3 4-(lH-l,2,4-triazole-l-yl)-2-.meth l-6- -methoxy-quinoline A mixture of 2.44 g of 2-methyl-4-chloro- -6-methoxy-quinoline-hydrochloride , I.38 g of 1,2 , 4-triazole and 10 ml of dimethyl formamide is stirred at 80 C for 3 hours whereupon the reac¬ tion mixture is poured into 100 ml of water and neutralized with 2 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered. Thus 2.09 S of the desired compound are obtained, yield 87 , mp. : 117 - 118 °C. Example 4 4-(lH-l,2,4-triazole-l-yl)-2-methyl-6,8- -d ichlor -quino line A mixture of 2.46 g of 2 -met y 1-4, 6, 8- -trichloro-quinoline, 1.82 g of the sodium salt of 1,2 , 4-triazole and 10 ml of dimethyl formamide is stirred at 100 C for 2 hours whereupon the reε.ction mixture is poured into 100 ml of water. The precipitated product is filtered. Thus 2.59 o of the desired compound are obtained, yield 93 7°. Mp. : 220 - 222 °C. Example 5 4-(lH-l,2,4-triazole-l-yl)-2,8-bis-tri- fluorome hy1-quinoline A mixture of 3.0 g of 4-chloro-2 ,8- -bis-trifluoromethyl-quinoline, I.38 g of 1,2,4- -triazole, 1.38 g of potassium carbonate and 30 ml of acetone is heated to boiling for 23 hours whereupon the reaction mixture is poured into 100 ml of water. The precipitated product is filtered, dissolved in 5 ml of ethanol, whereupon 5 ml of wa¬ ter are added. The precipitated product is filtered. Thus 2.42 g of the desired compound are obtained, yield: 73 , mp. : 106 - 107 °C. Example 6 4-riH-l,2,4-triazole-3(5)-yl-5(3)- -mer capto]-2-tr ichlorome th 1-8 -chloro- quinoline A mixture of 3.1ό g of 2-trichloromethyl- -4,8-dichloro-quinoline, 1.48 g of the sodium salt of 3(5 )-mercapto-l,2 , 4-triazole and 10 ml dimethyl- formamide is stirred at 100 C for 18 hours. The reaction having been completed the reaction mixture is poured into water, the precipitated product is filtered and recrystallized from ethanol. Thus 2.1 g of the desired compound are obtained, yield 55 "hi M.p. : 188 - 183 °C Example 7 4-r5(3)-ethyl-lH-l,2,4-triazole-3(5)-yl- -mercapto]-2 , 8-dimethyl-quinoline A mixture of 1.32 g of 4-chloro-2, 8-di- raethyl-quinoline, 1.55 S of 3( ) -mercapto-5(3 ) - -ethyl-l,2,4-triazole and 20 ml of ethanol is stirred at 30 °C for 20 hours. The reaction mixture is poured into 50 ml of water, neutralized with 1 ml of concentrated ammonium hydroxide and the precipitated product is filtered. Thus 2.4l g of the desired compound are obtained, yield 85 °&, mp. : 176 - 177 °C Example 8 2-(lH-L,2,4-triazole-l-yl)-3-methyl- -quinoline A m- cture of I.78 g of 2-chloro-3-methyl- -quinoline and O.69 g of 1,2,4-triazole is melt and allov, * ed to stand at 120 C for 4 hours. The melt is cooled, then dissolved in 10 ml of ethanol, poured into 20 ml of water and neutralized with 1 mL of concentrated ammonium hydroxide, fhe precipitated product is filtered. Thus 1.49 g of the desired compound are obtained, yield 71 ^. Mp. : 80 - 81 °C. Example 9 2-(lH-l,2,4-triazole-l-yl)-4-methyl- -quinoline hydrochloride A mixture of L.78 g of 2-chloro-4-methyL- -quinoline, O.76 g of 1,2,4-triazole and 10 ml of chloro benzene is stirred at 100 °C for 7 hours. The reaction mixture is cooled, the precipitated product is filtered, dissolved in 5 ml of ethanol and precipitated by adding 10 ml of ethyl ether. The precipitated product is filtered. Thus 1.72 g of the desired compound are obtained, yield 70 . Mp. : 193 - 94 °C. Example 10 2-(lH-l,2,4-triazoLe-L-yL)-7-chLoro-3 . 8- -diraethyi-quinoiine A mixture of 2.26 g of 2 ,7-dichLoro-3,8- -dimethyL-quinoiine, L,L g of the sodium saLt of L,2,4-triazoLe and L0 mL of dimethyL formamide is stirred at LOO C for 25 hours. The reaction mixture is poured into L00 mL of water and the precipitated product is fiLtered. Thus 2.48 g of the desired compound are obtained, yieLd 96 °.O. Mp. : L47 - - L48 °C. ExampLe LL- 2- ( 3-methyL-LH- L , 2 , 4-triazo ie- L-yL ) -4 , 6- -bis -t rich Lor omethyL-quino Line A mixture of 3. 99 g of 2-chloro-4 , 6-bis- -trichloromethyl-quinoline , L.26 g of the sodrurn saLt of 3-methyL-L , 2 , 4-triazo Le and L0 mL of dimethyL formamide is stirred at 100 C for 20 hours. The reaction mixture is poured into 100 ml of water, the precipitated product is filtered and re¬ crystallized from 10 ml of ethanol. Thus 2.76 g of the desired compound are obtained, yield 62 . M.p. : I69 - 170 °C. Example 12 2-r5(3)-methyl-lH-l,2,4-triazole-3(5)- -y 1-mer capt o 1 - 3 -me t hy 1-qu ino L ine - hydrochioride A mixture of L.78 g of 2-chLoro-3-methyL- -quinoline, I.38 g of 3(5)-mercapto-5 (3 )-methyl- -1, ,4-triazole and 10 ml of chloro benzene is stirred at 100 C for 2 hours. The reaction mixture is cooled, the precipitated product is filtered and washed with diethyl ether. Thus 2.8 g of the desired compound are obtained, yield 96 , mp. : 190 - 192 °C, Example 13 2-riH-1.2,4-triazole-3(5)-yl-mercapto]- -4,8-dimethyl-quinoline-hydrochloride A mixture of 1.92 g of 2-chloro-4, 8- -dime thy 1-quino line and 1.21 g of 3(5)-mercapto- -1,2 ,4-triazole is melt and allowed to stand at 120 C for an hour. The cooled reaction mixture is treated with 5 ml of hot ethanol, cooled and filtered. Thus I.90 g of the desired compound are obtained, yield 65 . Mp. : 201 - 202 °C. Example l4 4- ( 1H-1 , , 4-tr iazo le-l- 1 ) -2 , 8-d imeth 1- -5-ohloro-quinoline A mixture of 2.26 g of 4,5-dichloro-2 , 8- -dimethyl-quinoline, I.38 g of 1,2 , 4-triazole and 0.1 g of 96 sulfuric acid is stirred at 70 °C for 3 hours. The reaction mixture is poured into 50 ml of water and neutralized with 1 ml of a concentrated ammonium hydroxide solution. The precipitated 5 product is filtered and washed with water. Thus 2.0 g of the desired compound are obtained, yield 77.4 ?i>. Mp. : 117-118 °C. Example 15 L0 4-r5(3)-methyL-LH-L,2,4-triazole-3(5)- -yi-mercapto]-2-methyL-7,8-dichioro- -quinoLine A mixture of 2.46 g of 2-methy1-4,7,8- -trichloro-quinoline, I.38 g of 3(5)-mercapto-5(3)- 15 -raethyl-1,2,4-triazole and 10 ml of dimethyl form¬ amide is stirred at 100 C for 8 hours. The reaction mixture is poured into 100 ml of water, neutralized and the precipitated product is filtered. Thus 3.10 g of the desired compound are obtained, yield 95 / ■->• 0 Mp. : 156 - 158 °C. Example 16 2-(LH-L,2,4-triazoLe-L-yL)-3-methyL- -7-ethy 1-quinoline 5 A mixture of 2.05 g of 2-chloro-3-methyl- -7-ethyL-quinoLine, L.05 g of 1,2 , 4-tr iazole- -hydrochloride , 0.69 g of 1, 2,4-triazole and 10 ml of dimethyl formamide is stirred at 100 C for 6 hours. The reaction mixture is poured into 100 ml 0 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 . Mp. : 7 - 73 °C . 5 Example 17 2-[lH-l, 2 , 4-triazole-3 (5 )-yl-mercapto]- -4-me th 1-quino line A mixture of 1.78 g of 2-chloro-4- -methyl-quinoline , 1.21 g of 3(5)-mercapto-l, 2 , 4- -triazole and 10 ml of dimethyl formamide is st irred at 40 C for 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 98 , m. p. : 96 - 98 °C . Example 18 3-f5(3)-ethyl-lH-l,2,4-triazole-3(5)- -yl-mercapto]-3.8-dimethyl-quinoline 1.91 g of 2-chloro-3jS-dimethyl-quinoline and 1-55 g of 3(5)-mercapto-5(3)-ethyl-l,2,4- -triazole are reacted in an analog ous manner to Example 16. The crude product is recrystallized from a mixture of chloroform and ethanol. Thus 1-93 g of the desired compound are obtained, yield 68 . Mp. : 190 - 192 °C. Further compounds are prepared in an analoguous manner to the process described in the preceeding Examples. The compounds are disclosed in the following Table V. The number appearing in the column "method" relates to the number of the Example used for the preparation of the compound in caption. Tahlc V Compounds of the 'ϊonoi'ul ' ui'iuula (lu) Compound K, R. R. . Mo I hoc! Yielu Mp. No. Compound of the general Formula (lb) Compounds of the tyonorul Formula (ic) .( ' υmpυuuda υl" the you oral Formula. .( d)

Claims: - kZ - What we claim is: 1. Triazolyl quinoline derivatives of the general Formula (l) (wherein R1 stands for hydrogen, methyl, trihalogeno¬ methyl or carboxy; R is hydrogen, halogen, C, £, alkyl, hydroxy, C j i alkoxy, phenoxy, amino, acetamino, C dialkylamino, acetyl, benzoyl, methylthio, carboxy, cyano, ethox car- bony1, nitro or trihalogenomethyl; R represents hydrogen, C . alkyl or C . alkoxy; R stands for hydrogen, methyl or ethyl and X stands for a valency bond or -S- ) and acid addition salts thereof. 2. Compounds according to Claim 1 of the general Formula (la) (la) - 43 - 1 3 '+ (wherein R , R , R and R are as stated in Claim l) and acid addition salts thereof. 3. Compounds according to Claim 1 of the general Formula (lb) (wherein R are as stated in Claim l) and acid addition salts thereof. k. Compounds according to Claim 1 of the general Formula (ic) 1 3 - wherein R , R , R and R are as stated in Claim 1) and acid addition salts thereof. 5. Compounds according to Claim 1 of the general Formula (id) (wherein R 1, R*2, and R k are as stated in Claim l) and acid addition salts thereof. 6. A process for the preparation of triazolyl quinoline derivatives of the general Formula (l) (wherein stands for hydrogen, methyl, trihalogeno¬ methyl or carboxy; R " stands for hydrogen, halogen, C . alkyl, hydroxy, C. L .r alkoxy, phenoxy, a ino, acetamino, C , dialkylamino, acetyl, benzoyl, methylthio, carboxy, cyano, ethoxycarbony1, nitro or trihalogeno¬ methyl; R- represents hydrogen, C , alkyl or C . alkoxy; R stands for hydrogen, methyl or ethyl and X stands for a valency bond or -S-) and acid addition salts thereof which comprises reacting a halogeno quinoline derivative of the general Formula (ll) or ( II) 1 2 3 (wherein R , R and R are as stated above) with a 1,2 , 4-triazole of the general Formula (TV) or (V) - k6 - (wherein R is as stated above) in the presence or absence of a solvent, in the presence or absence of an acid or a base, at a temperature between 0 C and 200 C and if desired, isolating the product thus obtained in the form of the free base or an acid addition salt thereof. 7. A process according to Claim 6 for the preparation of compounds of the general Formula (la) which comprises reacting a -chloro- -quinoline derivative of the general Formula (ll) with a 1,2, -triazole of the general Formula (IV " ) 1 2 3 k (wherein R , R , R J and R are as stated in Claim 6). 8. A process according to Claim 6 for the preparation of compounds of the general Formula (lb) which comprises reacting a 4-chloro- -quinoline derivative of the general Formula (ll) with a -me-reapto-1,2,.{.-triazole of the gene- 1 ' ** ** ! k ral Formula (V) (wherein R , R~ , R and R are as stated in Claim 6.). 9. A process according to Claim 6 for the preparation of compounds of the general Formula (ic) which comprises reacting a 2-chloro- -quinoline of the general Formula (il ) with a 1,2, -triazole of the general Formula (IV) ( here - 2 3 in R , R , R and R are as stated in Claim 6). 10. A process according to Claim 6 for the preparation of compounds of the general For¬ mula (id) which comprises reacting a 2-chloro- -quinoline derivative of the general Formula (ill) with a 3-rπercapto-l, , -triazole of the general 1 3 k Formula (V) (wherein R , R , R and R are as stated in Claim 6.). 11. Pharmaceutical compositions comprising in an effective amount at least one compound of the 1 3 4 general Formula (i) (wherein R , R , R , R and X are as stated in Claim l) or a pharmaceutically acceptable acid addition salt thereof as active ingredient in admixture with suitable inert solid 5 or liquid pharmaceutical carriers. 12. A process for the preparation of pharmaceutical compositions according to Claim 11 which comprises admixing at least one compound of the general Formula (i) or a pharmaceutically 10 acceptable acid addition salt thereof with suit¬ able inert solid or liquid pharmaceutical carriers. 13. Fungicidal compositions comprising as active ingredient in an effective amount at least one compound of the general Formula (l) - 1 2 3 4 ID (wherein R , R , R , R and X are as stated in Claim l) or an acid addition salt thereof in admixture with suitable inert solid or liquid carriers or diluents. 14. A process for the preparation 0 of fungicidal compositions according to Claim 13 which comprises admixing at least one compound of the general Formula (I) or an acid addition salt thereof with suitable inert solid or liquid carriers or diluents. 5 15« A method for combating fungal diseases which comprises applying an effective amount of a fungicidal composition according to Claim 13 onto the plants, parts or environment thereof or the pests or the objects to be protected. 30 16. Compounds of the general Formula (i) and acid addition salts thereof whenever prepared by the process according to any of Claims 6-10. 17. A process as substantially disclosed herein with particular reference to the Examples. 35

Inventors: FRANK LASZLO, KORODI FERENC, POCSAI EMMA, SALAMON ZOLTAN, SANDOR JOZSEF, TEREBES ERZSEBET, FRANK, LASZLO, KORODI, FERENC, POCSAI, EMMA, SALAMON, ZOLTAN, SANDOR, JOZSEF, TEREBES, ERZSEBET
Applicants: ALKALOIDA VEGYESZETI GYAR
Application year: 1986
Main classification: C07D401
IPC codes: A01N3, A01N43, A61K31, A61P25, A61P29, C07D249, C07D401, C07D521