CS255242B1 - Substituted 5-amino-6- (4-pentyloxyphenyl) -3 (2H) -pyridazinones - Google Patents

Abstract

The solution relates to substituted 5-amino-6-(4-pentyloxyphenyl)-3(2H)-pyridazinones of the general formula I where R is a hydrogen atom, cyclohexyl group, 2-hydroxyethyl group, tetrahydrofurfuryl group, 4-chlorobenzyl group or 4-methoxybenzyl group. These substances show anthelmintic activity against the model helminths Hymenolepis nana and Nippostrongylus brasiliensis.

Description

wherein R represents a hydrogen atom, cyclohexyl, 2-hydroxyethyl, tetrahydrofuryl, 4-chlorobenzyl or 4-methoxybenzyl.

These new, as yet undescribed substances show useful ani helminthic activity:. u x .1. a · ί t, especially against the model helminths Hymenolepis nana and Nippostrongylus brasiliensis.

Compounds of general formula I can be prepared according to the invention by reacting 5-Lccm- n· (4-pentyj - ·- , .onyl)-3 (2H)-pyridazinone Czechoslovak Patent No. AO No. 255 243 with an amine of general formula H^NR, in which R .ic.í the same as in formula I, preferably in the medium of water or an organic solvent, such as nv ta: bo acetonitrile, at a temperature of 80 to 190 ° C, preferably at a temperature of 140 to 180 ^U C.

Evaluation of anthelmintic efficacy against the model helminth Hymeno.b>p.ís nana;

The tests were Orovedeuy on male mice of the H n strain weighing 10 to 13 g in groups of 7 kur- ·,. Two of the three control groups were invaded, untreated, the third invadovec.á, treated with 1 ·ηί·. ' rán.í.m preparation - p;perazine salt n ^; - osamid - against which the effectiveness was i í. -. · < oc rov-úivána.

The test was performed by gavage orally with 500 Hymeno 1 eggs of monkeys, 0.15 ml/mouse. The compounds of general formula 1 were applied on the 13th and 14th days after invasion by gavage at a dose of 150 mg/ ^kg of live weight (in the form of a homogenate in Doríman's reagent). The mice were killed on the 3rd day after application and after determining the total number of taseranic worms, the anthelmintic efficacy was determined by calculating the Steward method indirectly. The standard was also applied

·. u uo invasion in a dose of 150 my, kg ¹ z, wt., which, converted on the basis of nicdcmainid - 4 - j ,u dose of 4.05.10 mol.kg zh. wt.

iíodnoc·. ní anthelmintic efficacy against the model helminth Nippostrongylus brasiliensisTests were performed on male rats of the Black head strain weighing 120 to 140 g. in groups of 6. Two of the three control groups were invaded untreated, the third was treated with a standard preparation - levamisole, against which the efficacy was compared•-inu. The rats were invaded with 500 motile larvae of Nippostrongylus brasiliensis subcutaneously in the dorsal region between the shoulder blades. On the 8th day after invasion, compounds of general formula 1 were always applied once in a dose of 150 mg.kg ^-1 ž. wt., levamisole was also applied in the same dose, which, calculated per its molecule, corresponds to 7.34.10 ^-4 mol.kg ¹ ž. wt. The substances were administered orally to rats by gavage as homogenate in Dorfman's reagent and the experiment was terminated on the 12th day by killing the animals and performing a helminthological dissection of the small intestine. From the total number of worms in the intestine, the anthelmintic efficacy of the evaluated substances was calculated using the indirect activity method according to Steward.

The anthelmintic activity of the compounds of general formula I against the model helminths Hymenoleniš n.«na (H.n.) and Nippostrongylus brasiliensis (N.b.), expressed in percentage by the indirect activity method according to Steward, is shown in the following table.

Substituent in formula I P Dose mol.kg w.. wt. Efficiency in % against Example of execution H,n. N.b. H 5, 49.1 V ⁴ 56 14 1 cyclohexyl 4,22.Í0~* 18 60 2 tetrahydrofurfuryl 4,20.10 ^-4 6 4 0 3 CH _? CH _? OH 4.73.10 ^-4 54 40 4 Cn _? C ₆ H ₄ Cl~(4) 3.77.10 ^-4 „ Δ 75 34 _{CH2C6H4OCH3- ( 4 )} 3.81.10 ⁵⁷ Q 6 The method of preparing the substances according to the invention is simple and provides reap Line products in satisfactory yields, . More details result from the following examples done. Examples of invention only illustrative, not limiting.

Example].

5-Amino-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone

a) A mixture of 1.70 g (5 mmol) of 5-bromo-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone and 15 ml of 25% aqueous ammonia is heated in an autoclave at 150 °C for 14 h. After cooling, 0.83 g (60%) of the product is obtained by suction, which, after purification by chromatography on a silica gel column and crystallization from ethanol and methanol, gives a substance with a melting point of 217 to 225 °C and an elemental molecular weight of C 1! j ,j ’! / >b) A mixture of 1.70 g (5 mmol) of 5-bromo-6- (4-pentyloxyphenyl)-3 (2H) -pyridazinone and 10 ml of a methanolic solution containing 3.2 g of ammonia is heated in an autoclave to a temperature of 150 °C for .15 h. After cooling, the reaction mixture is treated in the same way as in example la), whereby 0.0 g (65%) of a substance is obtained, which after purification according to point a) has a melting point of 218 to 226 °C and the above-mentioned elemental composition.

Example 1 and 2

5-cyclohexy 1 amino-6-(4-pontyloxyphene 1)-3(2H)-pyr ide? z i no.:

Direction 9 g (76// mmol) of 5-bromo- 6 - {4-f ·οη·>·γ : o .·< . ivv;-, /-3 ( 2H j -gr.r id nzinone and 7.82 g (78.8 mmol) of amiícviyk iphexane in 156 ml of ton.i. tril.u is heated in an autoclave at a temperature of 170 °C for .18 h. After cooling, ..di/1 .i m ,v.uká 6.5? g (67 %} of the product, which after crystallization from ethanol gave a substance with a melting point of .. 188.1 to 189.3 o: composition ^21^29^3^2’

Example 3

5-tetrahydrofluorouraylamino-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone

A mixture of 3.3 g (10 mmol) of 5-bromo-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone and 2.4 g (23.7 mmol) of tetrahydrofurfurylamine in 50 ml of acetonitrile is heated in an autoclave at a temperature of 170 °C for 13 h. After cooling, 2.72 g (76%) of the product are obtained by suction filtration, which, after crystallization from ethanol, gives a substance with a melting point of 158.2 to 160 °C and a composition of 1/4

Example 4

5-(2-hydroxyethylamino)-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone

A mixture of 13.49 g (0.04 mol) of 5-bromo-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone and 5.5 g (0.09 mol) of 2-aminoethanol in 150 ml of acetonitrile is heated in an autoclave to a temperature of 170 C.

for 31 h. After cooling, 10.82 g (85%) of the product was obtained by suction filtration, which, after crystallization from 50% aqueous ethanol, gave a substance with a melting point of 198-199 °C and a composition of ^C |7 ^H 23 ^N 3°3'

Example 5

5-(4-Chlorobenzylamino)-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone

A mixture of 10.11 g (0.03 mol) of 5-bromo-6-(4-pentyloxyphenyl)“3(2H)“pyridazinone and 16.9 g (0.119 mol) of 4-chlorobenzylamine in 150 ml of acetonitrile is heated in an autoclave to a temperature of 170 °C for 29 h. After cooling, 8.61 g (72%) of the product is obtained by suction, which after crystallization from ethanol gives a substance with a mp of 205.5 to 206.4 °C and the composition ^C 22 ^H 24 ^C ' ^t ' ^N 3 ^O 2 *

Example 6

5-(4-Methoxybenzylamino)-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone

A mixture of 3.37 g (0.01 mol) of 5-bromo-6-(4-pentyloxyphenyl)-3(2H)-pyridazinone and 4.05 g (0.029 mol) of 4-methoxybenzylamine in 50 ml of acetonitrile is heated in an autoclave at 170 °C for 16 h.

After cooling, 2.65 g (67%) of product was obtained by suction filtration, which, after crystallization from 60% aqueous ethanol, gave a substance with a melting point of 215.1 to 217.5 °C and a composition of C^H^N^O^.

Claims (1)

SUBJECT OF THE INVENTION Substituted 5-amino-6- (4-pentyloxyphenyl) -3 (2H) -pyridazinones of formula I NHR wherein R is hydrogen, cyclohexyl, 2-hydroxyethyl, tetrahydrofurfuryl, 4-chlorobenzyl or 4-methoxybenzyl.