FI91065C - Process for the preparation of novel therapeutically useful triazolylquinoline derivatives - Google Patents

Description

i 91065

Process for the preparation of new therapeutically useful triazolylquinoline derivatives

Divided by application 870028 5

The invention relates to the preparation of novel triazolylquinoline derivatives of the formula I and their acid addition salts, wherein Rx is hydrogen, methyl, trihalomethyl or carboxy, R2 is hydrogen, halogen, C1-4 alkyl, hydroxy, C N-alkoxy, amino, acetamino, C 1-4 dialkylamino, acetyl, carboxy, ethoxycarbonyl, nitro or trihalomethyl, R 3 is hydrogen, C 1-4 alkyl or C 1-4 alkoxy, R 4 is hydrogen, methyl or ethyl and X is a valence bond or -S-, Silia provided that R4 is not methyl when Rx, R2 and R3 are simultaneously hydrogen. Nail compounds have an analgesic effect.

The compounds of the formula I and their acid addition salts can be prepared by reacting a haloquinoline derivative of the formula "vi rT N% 35 (II) (III) 2 in which R1, R2 and R3 have the same meaning as above" With 1,2,4-triazole of formula

^ πιν J-— ^ MM-N

lp I or i o.

(IV) (V) wherein R <is as defined above, with or without a solvent 1MsnM, at a temperature of 0 to 200 ° C, and if desired, the product obtained is isolated in the form of a free emulsion or an acid addition salt.

Thus, to prepare compounds of formula rSr

20 p N-N

(la) C == D -R | The 4-chloroquinoline derivative of formula II is reacted with a 1,2,4-triazole of formula (IV) (wherein R 1, R 2, R 3 and R 4 are as defined above).

For the preparation of compounds of formula 30

N-M

S-10 I (ib) 91065 A 4-chloroquinoline derivative of formula (II) is reacted with a 3-mercapto-1,2,4-triazole of formula (V) (wherein R1, R2, R3 and R4 are such as yllM).

5 For the preparation of compounds of formula

fy P

10 J> 1 | .. (! c)

ί? ^ Ν M —- M

The 2-chloroquinoline of formula (III) is reacted with 1,2,4-triazole of formula (IV) (wherein R 1, R 2, R 3 and R 4 are as defined above).

For the preparation of compounds of formula 20 n

U? > A ° A

Μ N% R 3 The 2-chloroquinoline derivative of formula (III) is reacted with 3-mercapto-1,2,4-triazole of formula (V) (wherein R 1, R 2, R 3 and R 4 are as defined above).

The compounds used in the process are known and compounds and are described in the following publications: 4-Chloroquinolines of general formula (II): "The Chemistry of Heterocyclic Compounds", Vol. 32 Quinolines, Part I, pp. 391-398; references cited therein; Hungarian-35 patent applications 3869/82 and 4003/82.

4

2-Chloroquinolines of General 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 general formula (IV); Hungarian Patent Application 4370/83, DE Application No. 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).

It has been found that the reaction of 4- and 2-chloroquinoline derivatives of general formula (II) or of formula (III) having electron-only substituents (e.g. methyl or methoxy groups) and of general formula (V) ) or 1H-1,2,4-triazoles of formula (V) or 3 (5) -mercapto-1H-1,2,4-triazoles, respectively, is autocatalytic such that the hydrochloric acid formed during the reaction acts as a catalyst. Other acids, especially strong mineral acids or organic acids or acid salts (e.g. sulfuric acid, trifluoroacetic acid and ammonium chloride) also catalyze the reaction. The reaction is preferably carried out in the presence of said acidic compounds, in particular chloro-5-hydrochloric acid, the use of which varies from catalytic to stoichiometric.

When using less alkaline quinolines with an electron-withdrawing group or groups (e.g. chlorine trifluoromethyl), no such catalysis is observed. In such a case, however, the reaction can be promoted by carrying it out in the presence of an organic or epa-30 organic base (e.g. triethylamine, potassium carbonate or sodium hydroxide) having a stoichiometric kSyt or higher. This applies to the case of myOs using a 1H-1,2,4-triazole or 3 (5) -mercapto-1H-1,2,4-triazole derivative in the form of an alkali salt 35 (e.g. sodium salt).

91065 5

In addition, it has been found that the mercapto group is more reactive than the -NH- group of the thiazole ring.

The reaction (preparation of compounds of general formulas (Ia), (Ib), (Ic) and (Id)) can be preferably carried out in a polar, organic solvent (e.g. ethanol, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc. .) present. A non-polar, organic solvent (e.g., benzene, toluene, chlorobenzene, dichlorobenzene) 10 can be used as the reaction medium, and myOs can be used in the molten state without an organic solvent.

The reaction of the present invention can be carried out at a temperature of 0 to 200 ° C, preferably 20 to 150 ° C. The reaction mode is selected based on the properties of the reactants and the method used.

It is sufficient to react the chloroquinoline component with a molar equivalent of 1H-1,2,4-triazole or 3 (5) -mercapto-1,2,4-triazole, but the reaction is generally faster and more complete if the general formula 20 (IV) or ( V) 1-2 molar equivalents of valent is used.

According to one embodiment of the process of the present invention, the reaction components are melted and the product formed is isolated after the reaction is complete.

According to said embodiment of the process, the product is obtained in the form of the hydrochloride. The resulting reaction product is treated with a non-polar, organic solvent (e.g., ether, chloroform, benzene, hexane) or crystallized from a polar solvent (e.g., ethanol, methanol, acetonitrile, dimethyl, dimethylformamide), or polar and polar solvents. a mixture.

The free base of general formula (I) can be isolated by cooling the reaction mixture, dissolving in water or a mixture of water 35 and ethanol, preferably by adding mineral acid 6 or an organic acid, and precipitating the product by adding an organic or inorganic base. The pure product can be crystallized from a mixture of a polar, organic solvent and water or polar and non-polar organic solvents.

According to a further embodiment of the process of the present invention, the reactants are reacted in a non-polar organic solvent (e.g. benzene, toluene, xylene, hexane, carbon tetrachloride, chlorobenzene, dichlorobenzene, etc.). Upon completion of the reaction, the product precipitated as the hydrochloride is isolated by filtration, crystallized if necessary, and converted to the free base form as described above.

According to a further embodiment of the process of the present invention, the reactants are reacted in a polar, organic solvent (e.g., ethanol, ethylene glycol, acetonitrile, acetone, ethyl methyl ketone, dimethylformamide, dimethyl sulfoxide, dimethyl sulfoxide). The product is isolated as the free base or as a salt with mineral acid.

According to a preferred embodiment of the present invention, the reaction is carried out in a polar organic solvent (e.g. ethanol, ethylene glycol, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide), preferably in the presence of hydrochloric acid.

The acidic diluent is 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 the hydrochloride). The product obtained in the form of a salt can be isolated from the reaction mixture by any of the methods described above.

II

According to a further preferred embodiment of the process of the present invention, the reaction may be carried out in a polar organic solvent at a molar equivalent weight of a strong base (e.g., triethylamine, potassium carbonate, sodium carbonate, etc.) or at a higher rate.

The reaction described above can also be carried out with the triazole or mercaptotriazole of the general formula (IV) or the formula (V) of kSyt-tMe, respectively, with its alkali salt (e.g.

10 sodium or potassium).

The structure of the novel compounds prepared by the process of the present invention has been characterized and verified by NMR, IR and MS spectra, and the purity of the product has been determined by thin layer, gas and liquid chromatography.

The compounds of general formula (I) have valuable physiological properties and are able to effectively eliminate or alleviate the pain and inflammatory processes. A significant advantage of the compounds of general formula (I) is that the analgesic and anti-inflammatory dosage there is no or very little ulceration of the ear.

Thus, orally administered compounds of general formula (I) are effective in acute inflammatory processes. According to the method of Winter (Proc. Soc. Exp.

Biol. Med 111, 544 (1962)) carrageenan edema is induced and develops in Wistar male rats fasted for 16 hours (body weight 160-180 g). Percent inhibition is calculated from the mean Edema values of the groups treated with the test compound on the one hand and the vehicle on the other hand (control with carboxymethylcellulose or CMC). ED50 values are calculated using regression analysis of inhibition values. Test compounds are administered by gavage as a 1% carboxymethylcellulose (CMC) suspension one hour before the 8 carrageenan injection. The inhibitory effect of test compounds on carrageenan Edema is shown in Table I.

The protective effect of the test compounds against adjuvant-induced arthritis is shown in Table II.

5 According to the Wewbold method, 0.1 ml of Freud's complete adjuvant (Difco Lab. Mich. USA) is injected into the soles of the right hind paw of Wistar male rats, weighing 160-200 g. The volume of the hind paws is measured before and 21 days after administration of the excipient in mercury-10 tysmometres. The test compound is administered orally to the experimental animals for two weeks at a dose of 25 mg / kg pSiv. In Table II, column "Percent inhibition of paw volume growth" means the measured value of 21. pSivfinS.

In the adjuvant-induced arthritis test, which is considered to be the best test model for rheumatoid arthritis, the compounds of the present invention inhibit joint deformities more effectively than the comparators naproxen and phenylbutazone. The tests further show that the compounds of the present invention are effective not only in improving morphological deformations, but also in influencing the condition and function of the feet in a desired and useful manner, and in addition to the general physical condition and condition of myOs.

The analgesic effect of the compounds of the present invention was tested in a hot plate test (56 ° C) on male and female mice of the 5CFLP strain, weighing 18-22 g. The time of onset of the control reaction (Abwehr reaction) was determined compared to the delay time measured in the control group (Woolfe and McDonald 1944). At least 10 animals per dose were used. Test compounds were administered orally 60 minutes before the test in the form of a 1% methylcellulose suspension. A summary of the results is shown in Table III. The test was performed on different Wistar male rats weighing approximately 91065 9,180-210 g and fasted for 16 hours. Test compounds were suspended in 1% carboxymethylcellulose and administered orally at a dose of 10 ml / kg.

For five hours, the organs of the treatment fraction were killed and their stomachs were placed in 2.5% formalin solution. The number and appearance of punctate bleeding and ulcers were assessed according to the following scale: 0 - no damage 1 = a few punctate bleeding (<10) 10 2 diffuse bleeding or small ulcer (<2 mm) 3 = two or more small ulcers (< 2 mm) 4 = one or more large ulcers (> 2 mm)

At doses of 25 mg / kg and 100 mg / kg, the compounds of the present invention do not cause ulcers. In the acute test, the UD50 values for naproxen and indomethacin were 20.8 mg / kg and 6.3 mg / kg orally, respectively.

The acute toxicity of the compounds of general formula (I) was determined according to the method of Litchfield and Wilcoxon on male and female strains belonging to the CFLP strain. LD50 values ranged from 500 to 2000 mg / kg orally.

The pharmaceutical compositions may be prepared in a manner known per se by mixing at least one compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof and suitable inert solid or liquid pharmaceutical carriers.

The compounds of formula (I) can be used advantageously in therapy for the treatment of various rheumatic diseases, in particular rheumatoid arthritis, vertebral inflammation, osteoarthritis and gout. The active ingredient may be formulated for enteral or parenteral administration (e.g. tablets, capsules, granules, injections, etc.) by methods known to the pharmaceutical industry. The pharmaceutical compositions may optionally contain one or more other biologically active substances in addition to the compound of formula (I). The compositions contain carriers and excipients conventionally used in therapy.

The dosage of the compounds of formula (I) will vary within wide limits and will depend on many factors (e.g. the weight, age and condition of the patient, etc.). Dose levels are generally 10 to 200 mg / kg body weight (enteral administration) and 1 to 50 mg / kg (parenteral administration). The above-mentioned areas are, of course, indicative only.

11 91065

Table I

11

Anti-inflammatory effect in carrageenan-induced odeema in the rat

Test compound - Dose Paw volume - ED

5 teen mg / kg po. percent inhibition nig / kg po.

12.5 29 61 25fo 37 60.9 LOO ^ 0 53 10 L2.5 13 25 r 0 51 62 50.0 59 33, ¾ 100.0 69 15 12 »5 15 25.0 27 6¾ 50.0 months 59.1 100.0 65 12.5 27 20 25 33 69 50 52 35.0 100 86 12.5 26 7¾ 25 55 25.7 25 50 69 12.5 21 25 63 83 50 70 28.1 30 _ ™ _If_ 12 r 5 29 25 ^ 0 107 50 70 30.6 100 7¾ 12

Table I (continued)

Test Compound- Dose Paw Volume- ED ^ Q

tea "mg / kg n den percent- ,, no no. polar inhibition 9/9 P · 5 12,5 10 19 25 10 * + 5 108 50 10 6l 38,5 100 10. 70

12.5 10 LO

10 '25 LO 42 LL0' 50 10 46 51.4 __100 10 61_

25 - LO 2 L

15 Phenylbut 50 L5 Hz

tatsoni L00 L5 45 L00.9 200 L5 06 12.5 L5 33

Naproxen L5 49 20 50 L5 64 23.7

LOO L5 7L

L LO 28 2 LO 4θ

Indometa- .n 4 LO 47 4.L

25 sum '1 8 LO 64 L2 LO 67___ n = number of experimental animalsSra li 13 91065

Table II

Inhibitory effect on adjuvant-induced arthritis in rats

Test dose Dose Inhibition of paw volume as a percentage of 5 mg / kg on day 21 no.

i »6 25 10 2S, L

61 25 LO 3S, 2 62 25 LO ^ 0.3 1 0 64. 25 10 4o, 6 67 25 10 32.3 69 25 10 35t2 83 25 '12 46.7 15 35 25 12 23.4

107 25 12 17iS

108 25 12 35 f 2 109 25 12 3o, 7

110 25 12 32, L

20 L3S 25 10 35.2

Phenylbutazone 50 15 iSf5

Naproxen 12.5 15 l6.8 25 15 23 r 4 n = number of test animals

Table III

14

Hot plate test with mouse

Test portion Dose Extension of reaction time b mg / kg tymå% nr_po. _ 25 7 46 50 L8 100 33 10 ”25 20 61 50 22 L00 26 * 12.5 17 25 L9 15 62 50 30 LOO 38 25 17 64 50 39 100 44 2 0 _ 25 13 69 50 24 100 30 25 19 25 74 50 26 100 43 2 5 l6 S3 50 23 100 59 30 _ 25 34 107 50 4i 100 S3 25 34 35 io3 50 46 100 46

Table III (cont'd)

Test vehicle Dose Response to tea No. mg / kg prolongation% _E2__ 5 25 21- LLO 50 ^ 100 52 IT 25 10 138 50 57 100 32

Eenylyl- 100 2 9

tatsoli UZ

1.1, ZOO ^ _ 15 12.5 25

Neproxen 2 5 51- 50 ^ 5 100 ^ 9 16

The following examples illustrate the invention.

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 was stirred for 6 hours at 100 ° C and then the reaction mixture was poured into 100 ml. water and neutralized with 1 ml of concentrated ammonium hydroxide solution. The precipitated product was isolated by filtration and recrystallized from ethanol. 1.61 g of the desired product are obtained, yield 70%, m.p. 169 -170 eC.

Example 2 4- (1H-1,2,4-triazol-1-yl) -2,8-dimethylquinoline

A mixture of 1.91 g of 2,8-dimethyl-4-chloro-15-quinoline and 1.38 g of 1,2,4-triazole was melted at 120 ° C and stirred for 2 hours. the powdered melt was dissolved in a mixture of ethanol and water. The solution was poured into a solution of 0.84 g of sodium bicarbonate and 20 ml of water. The precipitated product was isolated by filtration. There was thus obtained 1.97 g of the desired compound, yield 88%, m.p. 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-methyl toxicquinoline hydrochloride, 1.38 g of 1,2,4-triazole and 10 ml of dimethylformamide were stirred for 3 hours at 80 ° C and then the reaction mixture was poured into 100 ml of water and neutralized with 2 ml of stable ammonium hydroxide solution. The precipitated product was isolated by filtration. There was thus obtained 2.09 g of the title compound, yield 87%, m.p. 117-118 eC.

II

91065 17

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-trichloro-5-quinoline, 1.82 g of the sodium salt of 1,2,4-triazole and 10 ml of dimethylformamide was stirred for 25 hours at 100 ° C and then the reaction mixture was poured into 100 ml of water. The precipitated product was isolated by filtration. There was thus obtained 2.59 g of the desired compound, yield 93%, m.p. 220-222 ° C.

Example 5 4- (1H-1,2,4-triazol-1-yl) -2,8-bistrifluoromethylquinoline

A mixture of 3.0 g of 4-chloro-2,8-bistrifluoromethylquinoline, 1.38 g of 1,2,4-triazole, 1.38 g of potassium 15 carbonate and 30 ml of acetone was heated to reflux. hours and then the reaction mixture was poured into 100 ml of water. The precipitated product was isolated by filtration, dissolved in 5 ml of ethanol and then 5 ml of water were added. The precipitated product was isolated by filtration. There was thus obtained 2.42 g of the desired compound, yield 73%, m.p. 106-107 ° C.

Example 6 4- [1H-1,2,4-triazol-3 (5) -yl-5-5 (3) -mercapto] -2-trichloromethyl-8-chloroquinoline A mixture of 3.16 g 2-Trichloromethyl-4,8-dichloroquinoline, 1.48 g of the sodium salt of 3 (5) -mercapto-1,2,4-triazole and 10 ml of dimethylformamide were stirred for 18 hours at 100 ° C. After completion of the reaction, the reaction mixture was poured into water, and the precipitated product was isolated by filtration and recrystallized from ethanol. There was thus obtained 2.1 g of the desired compound, yield 55%, m.p. 188-183 eC.

18

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-dimethyl-5-quinoline, 1.55 g of 3 (5) -mercapto-5 (3) -ethyl-1,2,4-triazole and 20 g of ml of ethanol, was stirred for 20 hours at 30 ° C. The reaction mixture was poured into 50 ml of water, neutralized with 1 ml of stable ammonium hydroxide, and the precipitated product was isolated by filtration. N3in gave 2.41 g of the desired compound, yield 85%, m.p. 176 - 177 eC.

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 was melted and allowed to stand at 120 ° C for 4 hours. The melt was cooled, then dissolved in 10 ml of ethanol, poured into 20 ml of water and neutralized with 1 ml of severe ammonium hydroxide. The precipitated product was isolated by filtration. 1.49 g of the desired compound were obtained, yield 71%, m.p. 80-81 ° C.

Example 9 2- (1H-1,2,4-Triazol-1-yl) -4-methylquinoline hydrochloride

A mixture of 1.78 g of 2-chloro-4-methylquinoline, 0.76 g of 1,2,4-triazole and 10 ml of chlorobenzene was stirred for 7 hours at 100 ° C. The reaction mixture was cooled, the precipitated product was isolated by filtration, dissolved in 5 ml of ethanol and an additional 10 ml of ethyl ether was precipitated. The precipitated product was isolated by filtration. There was thus obtained 1.72 g of the desired compound, yield 70%, 30 m.p. 193 - 194 eC.

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-dimethyl-35-quinoline, 1.1 g of 1,2,4-triazole sodium salt and 11,91065 19 10 ml of dimethylformamide was stirred for 25 hours at 100 ° C: in. The reaction mixture was poured into 100 ml of water and the precipitated product was isolated by filtration. NSin gave 2.48 g of the desired compound, yield 96%, m.p. 147 - 148 eC.

Example 11 2- (3-Methyl-1H-1,2,4-triazol-1-yl) -4,6-bistrichloromethylquinoline

A mixture of 3.99 g of 2-chloro-4,6-methylquinoline, 1.26 g of the sodium salt of 3-methyl-1,2,4-triazole and 10 ml of dimethylformamide was stirred for 20 hours at 100 ° C. . The reaction mixture was poured into 100 ml of water, the precipitated product was isolated by filtration and recrystallized from 10 ml of ethanol. 2.76 g of the desired compound were obtained under N3, yield 62%, m.p. 169-170 ° C.

Example 12 2- [5 (3) -Methyl-1H-1,2,4-triazol-3 (5) -ylmercapto] -3-methylquinoline hydrochloride

A mixture of 1.78 g of 2-chloro-3-methylquinoline, 1.38 g of 3 (5) -mercapto-5 (3) -methyl-1,2,4-triazole and 10 ml of chlorobenzene was stirred. 2 hours at 100 ° C.

The reaction mixture was cooled, the precipitated product was isolated by filtration and washed with diethyl ether. 2.8 g of the desired compound were obtained, yield 96%, m.p. 190 - 192 eC. Example 13 2- [1H-1,2,4-Triazol-3 (5) -yl mercapto] -4,8-dimethylquinoline hydrochloride

A mixture of 1.92 g of 2-chloro-4,8-dimethylquinoline and 1.21 g of 3 (5) -mercapto-1,2,4-triazole was melted and allowed to stand at 120 ° C for one hour. . The cooled reaction mixture was treated with 5 mL of hot ethanol, cooled and isolated by filtration. There was thus obtained 1.90 g of the desired compound, yield 65%, m.p. 201 - 202 eC.

20

Example 14 4- (1H-1,2,4-Triazol-1-yl) -2,8-dimethyl-5-chloroquinoline

A mixture of 2.26 g of 4,5-dichloro-2,8-dimethyl-5-quinoline, 1.38 g of 1,2,4-triazole and 0.1 g of 90% hydrochloric acid was stirred for 3 hours at 70 ° C. C. The reaction mixture was poured into 50 ml of water and neutralized with 1 ml of thick ammonium hydroxide solution. The precipitated product was isolated by filtration and washed with water. There was thus obtained 2.0 g of ha-10 lute compound, yield 77.4%, m.p. 117 - 118 eC. 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-trichloro-15-quinoline, 1.38 g of 3 (5) -mercapto-5 (3) -methyl-1,2,4-triazole and 10 ml of dimethylformamide, stirred for 8 hours at 100 ° C. The reaction mixture was poured into 100 ml of water, neutralized and the precipitated product was isolated by filtration. There was thus obtained 3.10 g of the desired compound, yield 95%, 20 m.p. 156-158 ° C.

Example 16 2- (1H-1,2,4-Triazol-1-yl) -3-methyl-7-ethyl-quinoline

A mixture of 2.05 g of 2-chloro-3-methyl-7-ethyl-25-quinoline, 1.05 g of 1,2,4-triazole hydrochloride, 0.69 g of 1,2,4-triazole and 10 ml of dimethylformamide , stirred for 6 hours at 100 ° C. The reaction mixture was poured into 100 ml of water, neutralized, and the crude product was recrystallized from a mixture of ethanol and hexane. There was thus obtained 1.52 g of the desired compound, yield 64%, m.p. 72 - 73 eC.

Example 17 2- [1H-1,2,4-Triazol-3 (5) -yl-mercapto] -4-methyl-quinoline

A mixture of 1.78 g of 2-chloro-4-methylquinolin-35, 1.21 g of 3 (5) -mercapto-1,2,4-triazole and 10 ml of dimethyl 91065 21 style formamide was stirred for 3 hours. At 40 ° C. The reaction mixture was poured into 100 ml of water, neutralized and isolated by filtration. NSin gave 2.37 g of the title compound, yield 98%, 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 (5) -mercapto-5 (3) -ethyl-1,2,4-triazole rea-10 Gold were administered in the same manner as in Example 16. The crude product was recrystallized from a mixture of chloroform and ethanol. NS gave 1.93 g of the title compound, yield 68%, m.p. 190 - 192 eC.

The other compounds were prepared according to the methods described in the previous Examples. The compounds are shown in Table V below. The number in the "Method" column means the number of the example used to prepare the compound.

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Claims (10)

A process for the preparation of novel therapeutically useful triazolylquinoline derivatives of formula I and acid addition salts thereof, Ρ0ΡΧΛ K3 in which formula R3 is C 1-4 alkoxy, amino, acetamino, C 1-8 dialkylamino, acetyl, carboxy, ethoxycarbonyl, nitro or trihalomethyl, R 3 arate, C 1-4 alkyl or C 1-4 alkoxy, R 4 arate, methyl or ethyl and X ar a valence bond or -S-, provided that R 4 is not methyl, since R 1, R 2 and R 3 simultaneously denote vate, may be -subscribed, that a halogenoquinoline derivative of the formula N * 3 (II) (III) was in Rx, R2 and R3 denotes the same as above, reacted with a 1,2,4-triazole of the formula πΝ-Μ Η Ν-Μ or C) (IV) ( V) wherein R 4 denotes as above the presence of a solvent or without it and in the presence of an acid or base or without them, at a temperature of 0 to 200 ° C and, if desired, the resulting product is isolated in the form of a free base or an acid addition salt. 2. A process according to claim 1, characterized in that a compound of the formula 20 p rbY D, 1-N <1a) is prepared from - R (R 3 wherein R x, R 2, R 3 and R above, or an acid addition salt thereof. 3. A process according to claim 1, characterized in that a compound of formula I 91065 N-Μ is prepared. A process according to claim 1, characterized in that a compound of formula cLd is prepared. IN Wherein R 3, R 2, R 3 and R 4 are the same as above, or an acid addition salt dd. 5. A process according to claim 1, characterized in that a compound of the formula is prepared. R, Λ'Ύ'Λ '' H- 'K3 is in R1, R2, R3 and R4 denotes the same as above, or an acid addition salt thereof. 5 V \ (Ib) qp U Kl 10 wherein Rx, R2, R3 and R4 denote the same as above, or an acid addition salt dOrav. A process according to claim 1, characterized in that 4- (1H-1,2,4-triazol-1-yl) -7-chloroquinoline, 4- (1H-1,2,4-) is prepared. triazol-1-yl) -2-methyl-6-methoxyquinoline, 4- [1H-1,2,4-triazol-3 (5) -ylmercapto] -2-methyl-8-chloroquinoline, 4- [5 (3) -methyl-1H-1,2,4-triazole-3 (5) -ylmercapto] -7-chloro-quinoline, 4- [5 (3) -methyl-1H-1,2,4-triazole -3 (5) -ylmercapto] -2-methyl-quinoline, 4- [5- (3) -methyl-1H-1,2,4-triazole-3 (5) -ylmercapto] -2,8-dimethylquinoline, 4- [5 (3) -methyl-1H-1,2,4-triazole-3 (5) -ylmercapto] -2,8-dimethyl-7-chloroquinoline, 2- (1H-1,2, 4-triazol-1-yl) -3-methylquinoline, 2- [1H-1,2,4-triazol-3 (5) -ylmercapto] -3,6-dimethylquinoline, or 2- [1H-1,2 , 4-triazole-3 (5) -ylmerkapto] -3,7-dimethylquinoline. 7. A process according to claim 2, wherein a 4-chloroquinoline derivative of formula (II) is reacted with a 1,2,4-triazole of formula (IV). 8. A process according to claim 3, wherein a 4-chloroquinoline derivative of formula (II) is reacted with a 3-mercapto-1,2,4-triazole of formula (V). 9. A process according to claim 4, characterized in that a 2-chloroquinoline of formula (III) is reacted with a 1,2,4-triazole of formula (IV). 10. A process according to claim 5, characterized in that a 2-chloroquinoline derivative of formula (III) is reacted with a 3-mercapto-1,2,4-triazole of formula (V). II