HU196378B - Process for producing new 3(2h)-pyridazinone derivatives and pharmaceutical compositions comprising these compounds as active ingredient - Google Patents

Abstract

The novel compounds (and salts thereof) of the present invention are: R 1 is hydrogen, methyl, C 3-6 alkenyl, C 5 -C 6 cycloalkyl, benzyl, phenyl or trifluoroethyl, - / CH 2 / CO 2 R 3 general (m = 1-4, R5 is hydrogen or 1-5 carbon atoms) or - (C1-C6) alkyl substituted with hydroxyl or C2-6 alkyl (n = 2-6); R2 is chlorine bromine; Yi, Yz, Ya are halogen, C1-C5 alkyl, C2-C8 alkenyl, C1-C4 alkylthio, C2-C8 dialkylamino, -ORs, or -CO2Re wherein Rs is hydrogen, 1- C 8 alkyl or C 1-4 alkyl substituted at the terminus with phenyl and R 4 is hydrogen or C 1-5 alkyl; wherein Y 1 and / or Y 2 may also be hydrogen. According to the invention, the target product of formula (I) is prepared by reacting a compound of formula (II) with the corresponding compound of formula (III) (or an acid salt thereof) in which R1, Rz, Yi, Yz and Yj are defined. measured and Z is chlorine or bromine. (111) 196378 -1-

Description

The present invention relates to a novel 3 / 2H / -pyridazinone derivative which is antagonistic to a slow-reacting anaphylactic agent (SRS-A) which causes contraction of bronchial smooth muscle and is thus useful as an antiallergic agent. For the preparation of anti-allergic pharmaceutical compositions containing at least one of the active substances (2H) -pyridazinone derivatives.

Pathologically, SRS-A is essentially a pathogenic agent that causes acute allergies, e.g. bronchial asthma or allergic rhinitis (rhinitis).

Therefore, it is expected that a pharmaceutical composition capable of counteracting the pharmacological action of SRS-A, i.e., an antagonist of SRS-A, would be useful as an antiallergic agent.

To date, however, very few therapeutically active compounds have been reported which exhibit SRS-A antagonistic activity and their practical use has not yet been reported.

The pyridazinone derivatives already described in some sources have some similarities to the novel compounds of the present invention.

(a) Source: Chemical Abstracts, 78, 4639 dg, which refers to CA-784,639. patent. For the 3 / 2H / pyridazinone derivatives described in (a), the 2-position is hydrogen, (C 1 -C 8) -alkyl, (C 3 -C 8) -cycloalkyl or phenyl; at the 4-position a chlorine or bromine atom; the 5-position is benzylamino. However, source (a) refers only to the herbicidal efficacy of these compounds and no reference to its therapeutic use or pharmacological efficacy.

(b) Source: Chemical Abstracts, 62, 2773b, which refers to Bull. Soc. Chim. Francé Volume 9/1964 / 2124-32. pages published on your pages; the 3 / 2H / pyridazinone derivatives described therein are hydrogen or diethylarainoethyl at the 2-position; the 4-position is a chlorine atom; and at the 5-position is a benzylamino group. Neither source (b) mentions medicinal use nor pharmacological efficacy.

(c) Source: DE-1 670 169. Patent application filed November 5, 1970. The 3 / 2H / pyridazinone derivatives described in (c) have a hydrogen, aliphatic, cycloaliphatic, arylaliphatic or aromatic group at the 2-position, a chloro or bromo position at the 4-position and an aralkylamino group at the 5-position. Source (cl) discloses a process for the preparation of a group of pyridazinone derivatives which include the above mentioned compounds, as well as their use as agricultural chemicals, intermediates for the production of pharmaceuticals and paints, or as intermediates for the preparation of other compounds. no specific examples of such compounds are given, nor are such compounds specifically described.

In our research, we have prepared various compounds which have been tested for SRS-A antagonist activity and have been surprisingly found to have SRS-A antagonist activity - and thus useful as antiallergic agents - 3 / 2H / pyridazinone derivatives - and their pharmaceutically acceptable salts - which (I)

R 1 is hydrogen, methyl, C 3 -C 6 alkenyl, C 5 -C 6 cycloalkyl, benzyl, phenyl, 2,2,2-trifluoroethyl / -CH 2 CF 3 /, - / CH 2 / CO 2 R 3, wherein R 3 is hydrogen or C 1 -C 5 alkyl and m is an integer of 1 to 4 or - / CH 2 / nA where n is an integer of 2 to 6 and A is hydroxy or -N / R 4/2 wherein R4 is C1-C3 alkyl;

R2 is chlorine or bromine;

Y 1 and Y 2 are each independently hydrogen, halogen, C 1 -C 5 alkyl, C 2 -C 8 alkenyl, -OR 5 where R 8 is hydrogen, C 1 -C 8 alkyl or C 1 -C 4 alkyl substituted at the end of the chain, -CO2R6 wherein Re is hydrogen or C1-C5 alkyl, -N / R7 / 2, wherein R7 is C1-C4 alkyl, or -SRa, wherein R5 is 1 C4-C4 alkyl; and

Y 3 is halogen, C 1 -C 5 alkyl, C 2 -C 8 alkenyl, -OR 8, -CO 2 R 6, -N / R 7/2 or -SR a, wherein R 5 -R 8 are as defined above.

The preferred compounds of the formula (I) which may be prepared according to the invention will now be described in detail.

Several examples of the substituents R1, R2, Y1, Ya and Y1 in the formula (I) are provided, without limiting the scope of the novel compounds of the present invention as generally defined above to the examples. Symbols used in the following designations mean: n-normal, i-iso, 10 sec-secondary, t-tertiary.

Preferably, R ¹ is hydrogen, methyl, allyl, 2-butenyl, 2-pentenyl, 2hexenyl, cyclopentyl, cyclohexyl, benzyl, phenyl, carboxymethyl, 2-carboxy-15-ethyl- , 3-carboxypropyl, 4-carboxybutyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl,

1-propoxycarbonylmethyl, n-butoxycarbonylmethyl, i-butoxycarbonylmethyl, t-butoxycarbonylmethyl, n-pentoxycarbonylmethyl, 2-methoxy -carbonylethyl, 2-ethoxycarbonylethyl, 2-n-propoxycarbonylethyl, 2-i-propoxycarbonylethyl, 2-n-butoxycarbonylethyl, 3- methoxycarbonyl-propyl, 3-ethoxycarbonyl-propyl, 3-n-propoxycarbonyl-propyl,

3- i -propoxycarbonyl-propyl, 4-methoxycarbonyl-butyl, 4-ethoxycarbonyl-butyl, 2-hydroxyethyl, 3-hydroxypropyl,

4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-dimethylaminoethyl,

2-diethylaminoethyl, 2-di / n-propyl-aminoacetyl, 3-dimethylaminopropyl, 3-diethylaminopropyl, 3-di / n-propyl amido-propyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, and 2,2,2-trifluoroethyl.

R2 is chlorine or bromine. 40

Preferably, Y 1 and Y 2 are independently hydrogen, methyl, ethyl, η-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, n-pentyl, 45 i-pentyl, , vinyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl, fluorine, chlorine, bromine, iodine, hydroxy, methoxy -, ethoxy, n-propoxy, 50 i-propoxy, η-butoxy, i-butoxy, sec-bu toxic, η-pentoxy, n-hexyloxy, η-heptyloxy , n-octyloxy, benzyloxy, phenethyl-oxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 55-methylthio, ethylthio, η-propylthio, n- butylthio, i-butylthio, carboxy, methoxycarbonyl, ethoxycarbonyl, η-propoxycarbonyl, i-propoxycarbonyl, η-butoxycarbonyl, i-60-butoxycarbonyl, , n-pentoxycarbonyl, dimethylaraino, diethylamino, di / n-propylamino, or di / n-butylarino.

Preferably Y3 is methyl, ethyl, η-propyl, ϊ-propyl, η-butyl, i-butyl, sec-butyl, η-pentyl, i-pentyl, vinyl, 1-propenyl -, 1-butenyl, 1-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl, fluorine, chlorine, bromine or iodine, hydroxy, methoxy, ethoxy, n-propoxy, i-propoxy, η-butoxy, i-butoxy, sec-butoxy, η-pentoxy, n-hexyloxy, η-heptyloxy, n-octyloxy, benzyloxy , phenethyloxy, 3-phenylpropyl-χχί-, 4-phenylbutyloxy, methylthio, ethylthio, n-propylthio, η-butylthio, i-butylthio, carboxyl, methoxy. carbonyl, ethoxycarbonyl, η-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, ß-butoxycarbonyl, n-pentoxycarbonyl, dimethylamino, diethyl- amino, di (n-propyl) amino or di (n-butyl) amino.

The process for the preparation of the novel compounds of formula (I), the synthesis of which is illustrated in Scheme 1, will now be described. In Scheme 1, R 1, R 2, Y 1, Y 2 and Y a are as defined, Z is chlorine or bromine.

As shown in Scheme 1, the novel 3 / 2H / pyridazinone derivatives of formula (I) are prepared by reacting one of the starting materials, a 3 / 2H / pyridazinone derivative of formula (II), with the parent compound of formula (III). with a benzylamine derivative or an acid salt thereof in an inert solvent and optionally in the presence of a dehydrohalogenating agent.

The solvent may be an ethereal solvent, e.g. diethyl ether, isopropyl ether tetrahydrofuran (THF) or 1,4-dioxane; an amide solvent, e.g. N, N-dimethylformamide (DMF), Ν, Ν-dimethylacetamide or N-methylpyrrolidone, dimethylsulfoxide (DMSO); an alcoholic solvent, e.g. methanol, ethanol and 1-propanol; a hydrocarbon solvent, e.g. toluene or benzene; a ketone solvent, e.g. acetone or methyl ethyl ketone; an organic amino solvent, e.g. pyridine or trialkylamine; and water, or a mixture of two or more of these.

In this reaction, where the 4-position substituent of the starting material of formula (II) / R 2 / is chlorine or bromine, in addition to the target product (1) which is substituted at the 5-position with a benzylamino group, it will be formed. is also a compound of formula (R1, Z, Y1, Y2 and Y3 are as defined above) which is the muscle of the target product of formula (I). The yield of the target product (1) and the by-product (IV) depends on the polarity of the solvent used. If it's big, like in the case of water, lower alcohol, ether, amide or DMSO, the yield of the target product (1) will be high. However, if a hydrocarbon solvent, e.g. If toluene or benzene is used, there is a tendency to increase the yield of the by-product IV. Therefore, the use of said highly polar solvents or a mixture of water and an organic solvent is preferred for the efficient production of the target product of formula (1), the most preferred of which is the particular reagent.

The target compound of formula (I) can be readily isolated and purified by fractional crystallization or silica gel column chromatography.

As the dehydrohalogenating agent, an inorganic base, e.g. potassium carbonate, sodium carbonate or sodium bicarbonate, or an organic base, preferably a tertiary amine, e.g. Ν, Ν-dimethylaniline, Ν, Ν-diethylaniline, trimethylamine, triethylamine, pyridine or methylethylpyridine. As a phase transfer catalyst, a quaternary amine, e.g. of triethyl benzyl ammonium chloride.

The reaction temperature may range from 10 ° C to the boiling point of the solvent used in the reaction mixture.

The molar ratio of the starting materials may be selected according to the particular circumstances; The amount of benzylamine derivative (III) used is generally from 1 to 5 moles, preferably from 1 to 3 moles, per mole of pyridazinone derivative (11).

One of the starting materials, the 3 / 2H / pyridazinone derivative of formula (11), may be prepared by known methods, e.g. 257 (Flow Chart 2) in Advances in Heterocyclic Chemistry, 9 (1968), p. 257 or Chemical Abstracts, 62, 2772g (Flow Chart 3).

In Schemes 2 and 3, R 1, R 2 and Z are as defined above, while Ru is benzyl, alkenyl or alkyl optionally substituted by halogen, hydroxy, amino or ester and Hal is chloro, bromo or iodo.

In the general synthesis of Scheme 2, the starting material of formula (11) is prepared by reacting a hydrazine derivative or an acid salt thereof with a mucochloric acid or mucobromic acid in a ring-closure reaction. In the synthesis shown in Scheme 3, a compound of formula (11) of formula (11) having a substituent at the 2-position can be prepared; that is, it is an alternative process for the preparation of the compound of formula (117) by reacting a 4,5- (dichloro or dibromo) -3 / 2H / pyridazinone

With a halide of the formula Ru-Hal, wherein Ru and Hal are thus either the syntheses according to Scheme 2 or Scheme 3 for the preparation of the starting material of formula A / 117 already described: and the synthesis according to Scheme 3 is generally advantageous when the appropriate hydrazine starting material is difficult to obtain commercially or is difficult to obtain economically.

Alternatively, when the other starting material, benzylamine derivative of formula (III), Yi, Yz and Ya, is difficult to obtain commercially, it may be prepared by any of the syntheses shown in Scheme 4. In the formulas herein, Y1, Y2 and Y3 are as defined above, R is hydrogen or alkyl.

In any of the three types of syntheses 4A, 4B, 4C in Scheme 4, the desired benzylamine derivative 111 is treated with a reducing agent treated with an intermediate aldoxime prepared by the corresponding aldehyde is reacted with the appropriate hydroxylamine or alkoxyamine for the 4A / synthesis, with the appropriate Utril for the 4B / synthesis and with the appropriate amide for the 4 / C / synthesis.

Any of the syntheses 4 / A / 4 / B / 4 / C may be used, either as starting material or commercially derived from a commercially available product.

The reduction of aldoxime can also be accomplished by two known reduction methods. According to the / 1 / reduction method, Raney nickel (nickel-aluminum alloy) is used in an alkali metal hydroxide, e.g. in the presence of sodium hydroxide, according to the reduction procedure (2 / '), sodium tetrahydroboroborate is used in the presence of an acid, such as acetic acid, trifluoroacetic acid or Lewis acid. The Y1 substituent is present on the phenyl ring, and also for reasons of economy and chemical stability, for example, the / 1 / reduction process is suitable if the Y1, Y2, Y3 groups are stable alkyl or relatively stable reducing agents. substituted by alkoxy, while the process of reduction of / 2 / is relatively mild and is suitable when the substituent of Y 1, Y 2 or Y 3 is relatively unstable, such as a halogen, olefin, ester or amide.

Generally, benzylamine derivatives react with air in the presence of ι 3 carbon dioxide to form carbonate. Therefore, in most cases, isolation is preferably effected by treating the benzylamine derivative with an acid salt, e.g. in the form of its hydrochloride or sulfate. The hydrogen chloride of the benzylamine derivative can itself be reacted with the 4,5-di / chloro or bromo - (- 3 / 2H) -pyridazinone.

If one, two, or all of the substituents · Υι, Υϊ, Y3 in the desired product of formula (1), wherein Re is C 1--C5 alkyl, the target product can be readily prepared by esterification of the corresponding carboxylic compound or a salt thereof with a sulfuric ester of the formula (Re6 / C2-C5) substituted with an alkyl group - (R6 is C1-C5-alkyl), e.g. in the presence of sodium hydroxide, potassium hydroxide, sodium / bi / carbonate or potassium / bi / carbonate, or with an organic amine or an alcohol of the formula R 10 (Re is as defined), an acidic catalyst, e.g. in the presence of sulfuric acid or hydrochloric acid.

In addition to the target products obtained in the detailed preparation examples described below, further examples of the new 3 / 2H / pyridazionone derivatives of formula (I) according to the invention are given in Table 1 using the following symbols: n-normal, i-iso, cyc- cyclo, Me-methyl, Et-ethyl, Pr-propyl, B-butyl, Pen15-pentyl, Hex-hexyl, Oct-octyl, Ph-phenyl and the structure is referred to as cis, trans.

Yl ^Y! (I)

Y3

Table 1.

Ri R2 Yi Yi Y3 Pen-cyc cl 2-OMe 4-OMe H Pen-cyc cl 2-OMe H H Pen-cyc cl 4-OMe H H CH2CH = CH2 cl 4-Me H H CH2CH = CH2 cl 3-Me H H -CH2CH = CH cl 2-Me H H CH2CH = CH2 cl 2-OMe H H CH2CH = CH2 cl 4-OMe H H Me cl 3-0-n-Bu H H Me cl 3-0-n-Bu 4-OMe H CH2CH = CH2 cl 3-OH H H Pen-cyc cl 3-OH H H Me cl 2-n-Pr H H - / CH2 / 3 OH cl 4-CH = CH-n-Pen cis H H CH2CH = CH2 cl 3-Et 4-OMe H CH2CH = CH2 Br 3-Et 4-OMe H -CH2CH CWhen cl 2-Me 4-Me H CH2CH = CH2 Br 2-Me 4-Me H CH2CH = CH2 cl 2-OMe 4-OMe H CH2CH = CH2 Br 2-OMe 4-OMe H Pen-cyc Br 2-OMe 4-OMe H Pen-cyc Br 4-OMe H H Pen-cyc cl 3-OMe 4-OMe H Pen-cyc Br 3-OMe 4-OMe H H cl 4-Me-CH = CH H H

cis

-511

Ri RZ Yi yz Ya H Br 4-CH = CH-Me cis H H H cl 4-CH = CH-Et cis H H H Br 4-CH = CH-Et cis H H H cl 4-CH = CH-n-Pr cis H H H Br 4-CH = CH-n-Pr cis H H H cl 4-CH = CH-n-Pr transport H H H Br 4-CH = CH-n-Pr transport H H H cl 3-OEt 4-SMe H H Br 3-OEt 4-SMe H H cl 3-0-n-Pr 4-SMe H H Br 3-0-n-Pr 4-SME H H cl 3-0-n-Bu 4-SME H H Br 3-0-n-Bu 4-SMe H H cl 3-O-n-Pen 4-SMe H H Br 3-0-n-Pen 4-SMe H H Br 3-0-n-Hex 4-SMe H H cl 3-O-n-Oct 4-0Me H H Br 3-0-n-0ct 4-OMe H H cl 3-O-i-Pr 4-OMe H H Br 3-O-i-Pr 4-OMe H H cl 3-0-sec-Bu 4-OMe H H cl 3-0-i-Bu 4-OMe H H Br 3-0-sec-Bu 4-OMe H H Br 3-O-i-Bu 4-OMe H H cl 3-0-sec-Pen 4-OMe H H Br 3-0-i-Pen 4-OMe H H Br 3-0-n-Pr 4-Cl H H cl 3-0-n-Pr 4-Cl H H Br 3-0-n-Bu 4-Cl H H cl 3-0-N-Bu 4-Cl H H Br 3-OEt 4-0 Et H H cl 3-OEt 4-OEt H H Br 3-0-n-Pr 4-OEt H

The novel active compounds of the formula I can be administered parenterally, preferably by subcutaneous, intravenous, intramuscular or intraperitoneal injection, in the form of an ointment, suppository or aerosol, or orally, e.g. in the form of tablets, capsules, granules, dragees, pills, syrups, liquids, emulsions or suspensions.

In a pharmaceutical composition for treating a living organism (medical or veterinary) containing the active ingredient of the formula (I) according to the invention, the concentration of the active ingredient is generally 0.1 to 99.5 s%, preferably 0.5 to 95 sX. in relation to its total weight. The pharmaceutical composition may contain other pharmacologically or veterinary active compound (s) other than the active ingredient (1) of the present invention, but several different active ingredients (1) of the present invention may be combined in the pharmaceutical composition.

The clinical dosage of the active ingredient of formula (I) according to the present invention will depend on the age, weight, sensitivity, symptoms, etc. of the patient. Generally, an effective daily dose is 0.003 to 1.5 g, preferably 55 to 0.01 to 0.6 g, per adult patient. Dosage outside this range may be used as required.

The pharmaceutical composition containing the active ingredient of the formula (I) according to the invention may be formulated in different ways depending on the route of administration, in accordance with the methods generally used in pharmaceutical preparation.

When preparing tablets, capsules, granules or dragees for oral administration,

The material used is -613 e.g. sugar, lactose, glucose, starch or mannitol; a binder such as syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose or polyvinylpyrrolidone; starch, carboxymethylcellulose or its calcium salt, crystalline cellulose powder or poly (ethylene glycol) as disintegrants; preferred polishing agents are talc, magnesium or calcium stearate or colloidal silica; a preferred lubricant is sodium laurate or glycerol.

For injection, solutions, emulsions, suspensions, syrups or aerosols, the active ingredient may be formulated with water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol or polyethylene glycol; as a surfactant, a sorbitol fatty acid ester, a polyoxyethylene / sorbitol fatty acid ester, a polyoxyethylene / fatty acid ester, a hydrogenated castor oil (musk) or a polyoxyethylene ether of lecithin; as a suspending agent, a carboxymethyl sodium salt or a cellulose derivative, e.g. methyl cellulose or natural rubber, e.g. tragacanth or gum arabic, as a preservative paraoxybenzoic acid ester, benzalkonium chloride or a salt of sorbic acid (2,4-hexadienoic acid). Suitable for making cones is e.g. poly (ethylene glycol), lanolin or cocoa butter.

PHARMACOLOGICAL EXAMPLES

A. Examination of the antiallergic effect.

It is already known that the major constituents of the SRS-A substance include components that act as significant mediators of acute allergies, e.g. in bronchial asthma to induce tracheal constriction (bronchoconstriction), namely leukotriene-C, leukotriene-D4 and the like (hereinafter LTC4 and LTD4, respectively). Accordingly, the SRS-A antagonist activity can be evaluated by performing one of the following tests:

testing the SRS-A antagonist effect in a sensitized guinea pig;

Testing for LTC4 antagonist activity;

Study of LTD4 antagonist activity.

The procedure and results of such tests performed by the inventors are described below. Fisons Limited's FPL-55712 is used as a control agent to evaluate the efficacy of the test drug samples; the structure of this known active ingredient is represented by the formula (FPL).

A / l test: LTC4 and LTD4 antagonism in guinea pig trachea.

An isolated guinea pig trachea is prepared as a spiral ribbon; the preparations are suspended at a load of 1 g in 10 ml organic baths and incubated for one hour prior to use. a contraction reaction is obtained with LTO4 at 2 x 10 g / ml after the maximal histamine reaction (10 * M). Samples of the active compound to be tested are dissolved in 100% DMSO and added to the organic baths at a final concentration of 10 * ⁵ or 10 * ⁶ g / ml one minute before the addition of LTC4 and LTD4. The contractile reaction for LTC4 and LTU4 is compared with the result of a control test in which twisted trachea is tested for the absence of a drug sample. LTC1 or LTD4-induced contraction is expressed as a percentage of the maximal histamine response. Antagonism / Ant is defined by the following equation:

1.0% contraction in the presence of active ingredient

Ant /% / = - X 100% contraction in the absence of active ingredient

Tables 2 and 3, respectively, illustrate LTC4 and LTD4 antagonism at 10 x ⁵ g / mL drug samples.

Table 2

Compound number LTC4-Ant /% / 3 97 10 29 13 81 FPL-55 712 100

-715

Table 3

Dry. LTD.- Dry. LTD.- Dry. LTD "- S. Ant /% / S. Ant /% / S. Ant /% / 1 49 12 73 23 31 2 93 13 79 24 43 3 82 14 35 25 63 4 49 15 51 26 46 5 71 16 24 27 20 6 53 17 20 28 67 7 53 18 18 29 61 8 36 19 22 30 100 9 26 20 19 31 51 10 20 21 20 32 100 11 47 22 72 FPL-55 712 97

Test A / 2: LTD. antagonism in guinea pig trachea.

An isolated guinea pig trachea is formed as a spiral band; preparations were suspended at a load of 1 g in a 10 ml organic bath containing 5 pmoles of indomethacin and incubated for one hour prior to use. 30 A contractile reaction was obtained for 2 x 10 ^-3 g / ml LTD after the maximum histamine reaction (ΙΟ * ⁴ M). Samples of the active ingredient were dissolved in 100% DMSO and added to the organic baths at a final concentration of 35-10 g / ml for 30 minutes in LTD. before adding. The contractile reaction obtained for LTD is compared with the result of a control test in which a twisted trachea is tested without the presence of a drug sample. LTD4-induced contraction is expressed as a percentage of the maximal histamine response. Antagonism / Ant / is defined by the following equation:

1.0% contraction in the presence of drug 5q

Ant /% / = - X 100% contraction in the absence of active ingredient

The antagonistic activity of 10 @ g / ml of drug samples is shown in Table 4, with the asterisk (*) denoted by the results obtained in the A / 1 test, while the other results are obtained by the A / 2 test. g 0

Table 4

Compound Sami Ant /% / Compound number Ant /% / 30 * 78 44 20 32 * 64 45 23 34 * 49 46 38 35 * 42 47 31 36 * 70 48 28 37 * 87 49 42 38 * 80 50 30 39 * 87 52 22 40 99 53 37 41 87 54 44 42 96 55 54 43 78 FPL-55 712 75 *, 94 Test A / 3: Efficiency » anaphylactic broncho-

in passively sensitized guinea pig.

Male guinea pigs weighing 350-450 g were passively sensitized by intravenous (i.v.) injection of 0.125 ml rabbit antiEA / egg albumin / serum / Cappel Laboratories one or two days prior to the experiment. Antigen-induced anaphylactic bronchoconstriction was modified by Konzett and Rossler [Arch. Exp. Path. Pharmac., 195 (1940), 71]. Sensitized guinea pigs are anesthetized with 1.5 g / kg urethane injection administered intraperitoneally. A cannula was inserted into the right cervix for the administration of all active ingredients, and a cannula into the trachea to determine total lung resistance. 'Ten-8η guinea pigs' were artificially ventilated using a small veterinary ventilator (Shinano's Model SN-480-7) at a stroke volume of 4.5 ml at a rate of 50 rpm. The change in lung resistance was measured with a Nihon Kohden TP-602T pressure transducer fitted to the trachea with a T-tube. The increase in airflow volume is expressed as a percentage of the maximum bronchial constriction that occurs when the trachea is constricted. After surgical preparation, the animals are pretreated, which consists of administering 0.2 [mu] g / kg indomethacin 10 minutes prior to the [0.1 or 10 mg / kg dose] test and 2 mg / kg 6 minutes prior to the EA test. pyrilamine and 0.1 mg / kg propranolol 5 minutes before. The drug samples to be tested are administered intravenously or orally prior to the EA test. The percentage of broncho-constriction inhibition (Inh) is determined according to the following formula:

1.0 - max. construct in the presence of /% / active ingredient

Inh /% / = - X 100 max. in the absence of construct /% /

Maximum bronchial constriction occurs 30 minutes after performing the EA test. During the test, drug samples were administered intravenously to four animals, or six animals orally.

(a) Intravenous test:

The 2 mg / kg drug sample is suspended or dissolved in 3% Tween 80 and administered intravenously 1 minute before the 10 mg / kg EA test.

The construction reaction obtained in the control test without active ingredient gave a value of 73 £ 9% (mean £ standard deviation, n = 4), against which the known agent (FPL-55712) showed a 27% inhibitory effect. The inhibitory effect (Inh) obtained with the active substance samples tested is shown in Figure 5-1. Table.

5-1. spreadsheet

Compound number Inh /% / 3 31 12 31 13 19 25 27 FPL-55 712 27

b, oral test:

Samples of the active ingredient were suspended in 5% Arabic Gum solution, followed by oral administration as described in Figure 5-2. 2 hours before the 0.2 mg / kg EA test. The reaction value for the control test without active ingredient is 62% to 6%.

No significant inhibition was observed in the oral administration of 100 mg / kg of the control agent FPL-55712, the inhibitory effect obtained with the active compound samples of formula (I) being tested in Figures 5-2. Table.

5-2. spreadsheet

Compound number Dose [Mg / kg] Inh /% / 30 50 65 32 50 71 36 50 68 38 30 53 38 50 62

B. Toxicity study

B / l test.

The lethal dose was determined in four-week-old male mice of ddY strain seven days after intraperitoneal administration of drug samples. The results are shown in Table 6.

Table 6

Compound number Dose [Mg / kg] Fatal Dose Number of deaths number of experiments 3 200 0/2 400 0/1 12 200 0/2 400 0/1 13 200 0/2 400 0/1 B / second test. It's deadly dose ddY tribal four weeks old male mice determined and seven days the after oral administration of samples of material.

The results are shown in Table 7.

-919

Table 7

Compound Dose Deadly dose number [Mg / kg] deaths number

number of experiments

38 400 0/3 800 0/3

From the experimental results it is evident that the 3 / 2H / pyridazinone derivatives of the general formula (I) according to the invention exhibit outstanding antagonistic activity against SRS-A and its major constituents, LTCi and LTDi, both in vitro and in vivo. Therefore, the compounds of formula (I) of the present invention have been shown to be useful as prophylactic and therapeutic agents for various SRS-A-induced allergic complaints, e.g. bronchial asthma, allergic rhinitis and urticaria.

The invention will now be explained in more detail by means of preparation examples. Examples R1 to R13 illustrate the preparation of intermediates, Examples 1 to 7 illustrate the preparation of target products. Of course, the invention is not limited to the production of the specific products specifically stated in the examples. Symbols used in the Examples and the accompanying tables have the following meanings: NMR magnetic resonance spectrum; MS: mass spectrum; (Only the typical absorbances from NMR, the major peaks from MS and the typical peak fractions are reported); Me-methyl; Et, ethyl; Pr propyl; Bu butyl; Pen is pentyl; Hex-hexyl; Hep-heptyl; Ph-phenyl; cyc-cyclodextrin; n standard; i-isopropyl; t-t; cis-cis.

Rl. example

Preparation of 3,4-Dimethoxybenzylamine Hydrochloride.

A mixture of 24.06 g of 3,4-dimethoxybenzazaldehyde, 14.28 g of hydroxyamine sulfate, 7.25 g of sodium hydroxide, 300 ml of methanol and 250 ml of water is added and the mixture is stirred under reflux. while boiling for one hour. After the mixture has cooled, 14.5 g of sodium hydroxide is added and after dissolution, 40 g of Raney nickel (Ni-Al alloy) are gradually added under ice-cooling. After completion, the ice bath was removed and the mixture was stirred at room temperature for one hour. The reaction mixture was filtered, methanol was removed from the filtrate under reduced pressure, and the residue was extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and the solvent was distilled off to give a colorless oil having a NMR (CDCl3):

δ: 6.77 (3H, s); 3.81, 3.80 (each 3H, s);

3.75 (2H, s); 1.58 / 2H, s, which disappeared when D2O was added.

The resulting oily residue was diluted with diethyl ether (100 mL) and treated with 25 mL of a solution of 6N hydrochloric acid in 1,4-dioxane under ice-cooling. The precipitated solid was filtered off and washed with ether; 29.36 g of 3,4-dimethoxybenzylamine hydrochloride are obtained in the form of a colorless powder.

Further benzylamine derivatives and their hydrochloride salts may be prepared using the appropriate beuzaldehyde starting materials as described, e.g. 4-i-propyl, 3-ethoxy, 4-ethoxy, 3-n-propoxy, 3-ethoxy-4-methoxy, 3-n-propoxy-4-methoxy, 3-n-butoxy 4-methoxy, 3-n-pentoxy-4-methoxy, 3-n-hexyloxy-4-methoxy, 3-n-heptyloxy-4-methoxy, 3-phenethyloxy-4 methoxy or 3,1,5-trimethoxy.

R2. example

Preparation of 4-diethylaminobenzylamine hydrochloride.

A mixture of 8.80 g of 4-diethylaminobenzaldehyde, 4.59 g of O-methylhydroxylamine hydrochloride, 11.87 g of pyridine and 80 ml of ethanol is refluxed for one hour with stirring. The solvent was distilled off under reduced pressure and water was added to the residue. The mixture was extracted with benzene. The extract was washed twice with water and then with a saturated aqueous solution of sodium chloride and dried over sodium sulfate, followed by distillation of the solvent; This gives 10.30 g of 0-methyl aldoxime as a pale yellow oily substance, which has a NMR spectrum of 11a (CDCl3):

7.87 (1H, s); 7.34, 6.54 / 2H each,

AB q /; 3.85 (3H, s); 3.33 (4H, q); 1.15 / 6H, t /

Sodium tetrahydroborate (7.6 g) was suspended in THF (200 mL), dissolved in THF (10 mL) and trifluoroacetic acid (22.8 g) was added dropwise to the suspension (3) with stirring and ice-cooling. After completion of the dropwise addition, the ice bath was removed, the reaction solution was stirred for one hour at room temperature, and then 10.30 grams of O-methyl aldoxime obtained as described above was added. Unchanged heat11

At -1021, the mixture is reacted for 1 hour and then refluxed for 2 hours. After cooling, water is added to the reaction mixture under ice-cooling to decompose the excess reducing agent. After distilling off the THF, the resulting residue was extracted with dichloromethane. The extract was washed first with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and then the solvent was distilled off. To the residue was added 25 ml of 6N hydrochloric acid in dioxane while cooling with ice. The mixture was concentrated under reduced pressure. The resulting solid was treated with methanol-ether; Thus, 11.13 g of ⁴ "15-diethyl-amino-benzylamine hydrochloride as a colorless powder. NMR (CDCl3) of the free amine;

&Amp; 7.06, 6.56 (each 2H, ABq); 3.66 (2H, 20 s); 3.27 (4H, q); 1.55 / 2H, s, which disappeared when D2O was added /; 1.11 / 6H, t /.

Additional benzylamine derivatives and their hydrochloride salts may be prepared using the appropriate benzaldehyde starting materials as described herein, e.g. 3-hydroxy-4-methoxy, 3-benzyloxy, 3-benzyloxy-4-methoxy or 4-methylthio.

R3. example

Preparation of 4- (cis-1-heptenyl) -benzylamine hydrochloride, 1.86 g of trifluoroacetic acid in 25 ml of THF are added dropwise with stirring and ice-cooling, to give 617 mg of sodium chloride. tetrahydroborate] and 100 ml of THF. After completion of the dropwise addition, the ice bath was removed and the reaction mixture was stirred for one hour.

A solution prepared by treating triphenyl-n-hexylphosphonium bromide in the presence of n-butyl 45-lithium and hexamethylphosphoric triamide with the Wittig reagent and 4-cyanobenzaldehyde in THF was added dropwise to the reaction mixture. and the resulting 4- (cis-1-heptenyl) -benzonitrile (3.09 g) is dissolved in 3 mL of THF. The resulting reaction mixture was stirred at room temperature for three hours. Ice pieces were added to the reaction mixture to decompose the excess reducing agent, then the solvent was evaporated and the residue was extracted with benzene. The extract was washed first with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and then distilled off to give a pale yellow solid. The product was dissolved in ethyl ether (80 mL) and 3 mL of a solution of 6N hydrochloric acid in 1,4-dioxane was added under ice-cooling. The solid precipitate was filtered off and washed with ethyl ether to give 3.47 4-cis-55

-1-heptenyl / benzylamine hydrochloride was obtained as a pale yellow solid. NMR (CDCl3) of free amine:

δ 7.17 (4H, s); 4.33 (1H, d, J = 10.8 Hz); 3.78 (2H, s).

R4. example

Preparation of 4-chlorobenzylamine hydrochloride.

A mixture of 11.58 g of acetic acid and 30 ml of 1,4-dioxane is added dropwise over 30 minutes with ice-cooling and stirring to 7.30 g of sodium tetrahydroborate, 6.00 g of 4-chlorobenzamide and 100 ml of , Containing 4-dioxane. After completion of the dropwise addition, the reaction mixture was refluxed for 2 hours with stirring. After the mixture has cooled, ice pieces are gradually added to decompose the reducing agent and the solvent is distilled off under reduced pressure. The residue was extracted with chloroform, the extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled to a concentration of about 80 ml. The evaporated solution was cooled with ice and added dropwise to 10 ml of a 6N solution of hydrogen chloride in dioxane. The solid precipitate was treated with methanol-ether; This gives 3.16 g of 4-chloro-l-benzylamine hydrochloride as a colorless powder.

NMR (CDCl3) of free amine:

7.38 (4H, s); 4.16 (2H, s); 1.55 / 2H, s, which

Disappeared when D2O was added.

R5. example

Preparation of 4,5-dichloro-2-allyl-3 / 2H / -pyridazinone.

(1)

16.4 g of 4,5-dichloro-3 (2H) -pyridazinone,

To a mixture of 14.5 g of allyl bromide in 60 ml of DMF was added dropwise 4.3 g of sodium hydride (55% suspension in mineral oil) at 15 ° C to 20 ° C and the reaction mixture was added at 20 ° C to 25 ° C. at room temperature for 2 hours. The reaction mixture was cooled, poured into cold water (200 mL) and extracted with 5: 1 hexane: benzene. The organic phase is dried and the solvent is distilled off. The resulting crude crystals were recrystallized from n-hexane to give 10.3 g of 4,5-dichloro-2-allyl-3 / 2H / pyridazinone, m.p. 45 ° C.

-1 123

R6. example

Preparation of 4,5-dichloro-2-benzyl-3 / 2H / pyridazinone.

(2)

R5. Prepared as described in Example 1b

7.5 g of 4,5-dichloro-2-benzyl-3 / 2H / pyridazinone, m.p. 86 ° C after recrystallization from n-hexane; constituents of the reaction mixture: 8.2 g of 4,5-dichloro-3 / 2H / pyridazinone,

6.4 g benzyl chloride, 2.2 g sodium hydride and 40 ml DMF.

R7. example

Preparation of 4,5-dichloro-2-cyclopentyl-3 / 2H / -pyridazinone.

(3)

R5. The reaction mixture was prepared using the following procedure: 16.5 g of 4,5-dichloro-3 / 2H / pyridazinone, 22.8 g of cyclopentyl bromide, 4.3 g of sodium hydride and 60 ml of DMF; 4.5 g of product are obtained, m.p. 56-57 ° C after recrystallization from 1:10 methanol / water.

R8. example

Preparation of 4,5-dichloro-2- (2,2,2-trifluoroethyl) -3 / 2H / pyridazinone.

(4)

R5. The reaction mixture was prepared by the following procedure: 16.5 g of 4,5-dichloro-3 / 2H / pyridazinone, 17.9 g of 2,2,2-trifluoroethyl bromide, 4.3 g of sodium hydride and 60 mL DMF; 15.3 g of product are obtained, m.p. 62 DEG C. after recrystallization from n-hexane.

9. example

Preparation of 4,5-dichloro-2-carboxymethyl-3 / 2H / -pyridazinone.

(5)

12.4 g of 4,5-dichloro-3 (2H) -pyridazinone,

A mixture of 14.6 g of iodoacetic acid, 20.7 g of potassium carbonate and 100 ml of DMF was stirred at 50 ° C for four hours. After completion of the reaction, the solvent was distilled off and 60 ml of 10% aqueous sodium hydroxide solution and 100 ml of benzene were added. Shake vigorously. The benzene phase is removed, the aqueous phase is acidified with 10% hydrochloric acid, then extracted with 100 ml of ethyl acetate and dried. The solvent was distilled off, and the crude crystals thus obtained were recrystallized from ethyl acetate: ethyl ether: petroleum spirit (1: 1: 1) to give 3.26 g of product, m.p. 175-177 ° C.

R1Q. example

Preparation of 4,5-dichloro-2- (2-hydroxyethyl) -3- (2H) -pyridazinone.

(6)

16.5 g of 4,5-dichloro-3 (2H) -pyridazinone, 15 g

A mixture of 2-bromoethanol, 16.5 g of potassium carbonate, 1.5 g of sodium iodide and 60 ml of DMF was stirred at 60 ° C for 4 hours. The solvent was distilled off, and ethyl acetate (80 mL) and water (80 mL) were added. The mixture was shaken vigorously and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting oily material was subjected to silica gel column chromatography (developer: ethyl acetate) to obtain 8.7 g of product as a pale yellow oily substance.

RII. example

Preparation of 4,5-dichloro-2- (3-hydroxypropyl) -3 (2H) -pyridazinone.

(7)

The RIO. except that the reaction mixture contains

16.5 g of 4,5-dichloro-3 (2H) -pyridazinone, 16.7 g

3-bromo-1-propanol, 16.6 g of potassium carbonate, 1.5 g of sodium iodide and 70 ml of DMF and 1: 1 v / v benzene / ethyl acetate for silica gel column chromatography of the resulting oily reaction product rabbit and the product obtained

13.7 grams of pale yellow oily substance.

R12. example

Preparation of 4,5-dichloro-2- (2,2-dimethylaminoethyl) -3- (2H) -pyridazinone.

(8)

The RIO. except that the reaction mixture contains 41.0 dg of 4,5-dichloro-3 / 2H / pyridazinone, 40.4 g of 2,2-dimethylaminoethyl chloride, 64.5 g of potassium. carbonate, 42.1 g of sodium iodide and 80 ml of DMF and silica gel column chromatography of the resulting oily reaction product with a 5: 1 by volume mixture of chloroform and methanol to give 7.72 g of the product.

-1225 pale yellow oily substance.

R13. example

Preparation of 4,5-dichloro-2- [2- (t-butoxycarbonyl-ethyl) -3 / 2H] -pyridazinone.

(9)

The RIO. except that the reaction mixture contains

19.3 g of 4,5-dichloro-3 (2H) -pyridazinone, 29.4 g

2- tert -butoxycarbonyl / ethyl bromide, 19.3 g of potassium carbonate, 1.75 g of sodium iodide and 60 ml of DMF, and the eluent benzene and ethyl acetate used for silica gel column chromatography of the resulting oil. 1: 1 by volume and the product obtained

8.1 grams of pale yellow oily substance.

Example 1

Preparation of 4-Chloro-5- (3-methoxybenzylamino) -2-cyclopentyl-3 / 2H-pyridazinone.

[3rd s. compound (10)

0.75 g of 3-methoxybenzylamine, 0.5 g of 4,5-dichloro-2-cyclopentyl-3 / 2H / pyridazinone, 0.4 g of potassium carbonate, 5 ml of 1,4-dioxane and The mixture is refluxed with stirring for seven hours. The solvent was distilled off under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The extract was washed sequentially with 2% dilute aqueous hydrochloric acid, water, and then with a saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The solvent was distilled off to obtain a pale yellow oil which crystallized from diethyl ether / n-hexane; This gives 250 mg of the target product in the form of colorless crystals, m.p. 113-115 ° C and NMR (CDCl 3):

5: 7.54 (1H, a); 4.53, 4.43 (fall: 2H, each s); 3.77 (3H, s); 2.24-1.52 (9H, m /).

Example 2

Preparation of 4-chloro-5- (3,4-dimethoxybenzylamino) -2- (2-N, N-dimethylaminoethyl) -3,2H) -pyridazinone.

(Compound 8, Formula 11)

500 mg of 4,5-dichloro-2- / 2-N, N-dimethylaminoethyl / -3 / 2H-pyridazinone, 1.29 g of 3,4-dimethoxybenzylethanine hydrochloride, A mixture of 18 g of potassium carbonate, 6 ml of 1,4-dioxane and 18 ml of water is refluxed for 7 hours with stirring. The 1,4-dioxane is distilled off under reduced pressure and the residue is extracted with chloroform. The chloroform layer was dried over sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developer: chloroform: methanol = 5: 1) and then crystallized from a mixture of acetone and n-hexane; 270 mg of the target product are obtained in the form of a yellow crystalline solid, m.p. 180-182 ° C and NMR (CDCl 3):

δ 7.55 (1H, s); 6.82 (3H, s); 5.04 (1H, broad s); 4.47, 4.37 (fall: 2H, each s); 4.21 (2H, t); 3.84 (6H, s); 2.66 (2H, t);

2.25 (6H, s).

Mass Spec [m / e]: 330 (M + -HC), 296, 150, 71 (100%).

Example 3

Preparation of 4-Chloro-5- (3-n-pentoxy-4-methoxybenzylamino) -2- [2- (t-butoxycarbonyl) ethyl] -3,2H-pyridazinone.

[16th s. Compound (12)

1.43 g of 4,5-dichloro-2- [2- (t-butoxycarbonyl)

ethyl] -3 / 2H-pyridazinone, 3.8 g of 3-n-pentoxy-4-methoxybenzylamine hydrochloride, 2.69 g of potassium carbonate, 25 ml of 1,4-dioxane and The mixture was refluxed with stirring for 8 hours, then the 1,4-dioxane was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed first with dilute hydrochloric acid, then with water and dried over sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (developer: benzene: ethyl acetate = 2: 1); 1.56 g of product are thus obtained in the form of a pale yellow viscous substance having a NMR (CDCl3):

<5: 7.53 (1H, s); 6.82 (3H, s); 5.18 (1H, broad s); 4.48, 4.38 (fall: 2H, each s); 4.30-3.80 (4H, m); 3.83 (3H, s); 2.70 (2H, s); 2.00-1.10 (6H, m); 1.40 (9H, s); 0.93 (3H, t).

Mass Spec [m / e]: 479 (M +), 388, 207 (100%), 137.

Example 4

Preparation of 4-chloro-5- (3,4-dimethoxybenzylamino) -2- (carboxymethyl) -3,2H) -pyridazinone.

[10th s. Compound (13)

178 mg of 4,5-dichloro-2-carboxymethyl-3 (2H) -1327

Pyridazinone, 1018 g of 3,4-dimethoxybenzylamine hydrochloride, 1.11 g of potassium carbonate, 2 ml of 1,4-dioxane and 20 ml of water are heated under reflux for seventeen hours. Most of the 1,4-dioxane is distilled off under reduced pressure and dilute hydrochloric acid is added to the residue to adjust the pH to about 2.0. The residue was then extracted with ethyl acetate, and the extract was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. The solvent was distilled off and the resulting slightly yellowish oily material was purified by silica gel column chromatography (developing solvent: chloroform: methanol = 8: 1). The solvent was distilled off, and the resulting slightly yellowish viscous material was crystallized from a mixture of methanol and diethyl ether; 119 mg of the target product are obtained in the form of a colorless crystalline solid, m.p. 168-171 ° C, NMR (CDCl3 + DMSO):

<5: 7.54 (1H, s); 6.79 (3H, s); 5.9 / 5.4 (1H, m); 4.74 (2H, s); 4.49, 4.39 (total): 2H, each a; 3.82 (6H, s).

Mass Spectrum [m / e]: 353 (M +) = 318, 151 (100%).

Example 5

Preparation of 4-Chloro-5- (3,4-dimethoxybenzylamino) -2- (2-N, N-dimethylaminoethyl) -3,2H / pyridazinone hydrochloride.

[9th s. compound, formula (14)]

150 mg of 4-chloro-5- (3,4-dimethoxybenzylamino) -2- (2-N, N-dimethylaminoethyl) -3- (2H) -pyridazinone obtained according to Example 2 and to a solution of 10 ml of chloroform are added 2 ml of a solution of 6N hydrogen chloride in 1,4-dioxane under ice-cooling. After standing for two hours at room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in 5 ml of water and filtered. The filtrate was subjected to rapid-freeze drying; 120 mg of the target product are thus obtained as hygroscopic yellow crystals.

Example 6

Preparation of 4-chloro-5- (3-n-pentoxy-4-methoxybenzylamino) -2- (2-hydroxyethyl) -3,2H) -pyridazinone.

[14th s. compound, (formula 15)]

400 mg of 4,5-dichloro-2- (2-hydroxyethyl) -3- [24 H] -pyridazinone, 1.49 g of 3-n-pentoxy-4-methoxybenzylamine hydrochloride, 1.05 g. A mixture of potassium carbonate (g), 1,4-dioxane (5 ml) and water (15 ml) was heated at reflux for 8 hours, then 1,4-dioxane was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed first with dilute chloride, then with water, and dried over sodium sulfate. The solvent was distilled off and the resulting residue was purified by silica gel column chromatography (developer: ethyl acetate); This gives 250 mg of the target product as a pale yellow viscous oily substance having a NMR (CDCl3):

?: 7.59 (1H, s); 6.83 (3H, s); 5.44 (1H, broad s); 4.50, 4.40 (fall: 2H, each s); 4.40-3.50 (6H, m); 3.83 (3H, s);

2.10-1.10 (6H, m); 0.93 (3H, t).

Mass spectrum [m / e]: 395 (M +), 360, 207 (100%), 137.

Example 7

Preparation of 4-Bromo-5- [3-n-pentoxy-4-methoxy-benzylamino] -3 [2H] -pyridazinone.

/ 39th s. chemical, (formula 16)]

1.52 g of 4,5-dibromo-3 / 2H / pyridazinone,

A mixture of 3-n-pentoxy-4-methoxybenzylamine (4.01 g) and ethanol (60 ml) was heated at reflux for seven and a half hours, then the ethanol was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed first with dilute hydrochloric acid, then with water and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was crystallized from ethyl acetate / diethyl ether; 1.42 g of the target product are obtained in the form of a pale yellow crystalline solid, m.p. 148-150 ° C and NMR (CDCl3):

?: 7.51 (1H, s); 6.82 / 3H, s / 5.28 / 1H, broad a; 4.51, 4.41 (div. 2H, each s); 3.97 (2H, t); 3.84 (3H, s); 2.05-1.05 '' 6H, m /; 0.96 / 3H, t /.

Mass spectrum [m / e]: 395 (M +), 316 (100%), 207, 137.

In accordance with one of the examples described above, additional target products are prepared and are summarized in Table 8. The left side of Table 8 gives the number of the compound and the right side the number of the preparation example for which the corresponding target product was prepared.

-1 429

Table 8

Dry. s. Ri R2 Yl Y2 Y3 mp (° C, NMR (CDCl 3) δ Example s. 1 Me Cl 4 -i-Pr H H 161-161.5 7.46 (1H, a), 4.51, 4.41 (div. 2H, all s, 3.68 (3H, s), 1.25 (6H, d) 1 2 -CHzCH = CH2 Cl4-C1 H H 142-142.5 7.47 (1H, s), 1

6.26-5.56 (1H, m),

4.70 (2H, d), 4.57, 4.47 (div. 2H, all s) 3 Pen-cyc cl 3-OMe H H 113-115 see Example 1 1 4 Me cl 3-0 Et H H 138.5 7.47 (1H, s) 4.54, 4.44 (div. 2H, all s), 3.72 (3H, s), 1.41 (3H, t) 1 5 Me cl 3-O-n-Pr H H 111.5 7.49 (1H, s) 4.56, 4.46 (div. 2H, all s), 3.74 (3H, s), 1.08 (3H, t) 1 6 CH2CH = CH2 cl 3-OMe 4-OMe H 141-142.5 7.57 (1H, s) 1

6.16-5.65 (1H, m),

4.71 (2H, d), 4.51, 4.41 (div. 2H, all s), 3.86 (6H, s) 7 Me Cl 3 -OCH 2 Ph H H 119-120 7:45 (1H, s) 7.37 1 (5H, s), 4.54, 4:44 (div. 2H, all s), 3.72 (3H, s) 8 - <CH2) 2N (Meh. Cl 3 OME 4-OMe H 180-182 see See Example 2 2 9 - (CH2) 2N (Me) 2.HCl Cl 3 OME 4-OMe H hygroscopic. powder see See Example 5 5 10 -CH2CO2H Cl 3 OME 4-OMe H 168-171 see See Example 4 4 11 CH2CF3 Cl 3 OME 4-OMe H 168-169.5 7.62 (1H, s), 4.72 1 (2 H, d, J = 8.4 Hz), 4:52, 4.44 (sec. 2 H), 3.87 (6H, s) 12 Me Cl 3-0-n-Pr 4-OMe H 156-156.5 7:44 (1H, s), 4.45, 1 4:35 (split 2H, all s), 3.81 (3H, s), 3.69 (3H, s), 1:02 (3H, t, 13 Me Cl 3-OEt 4-OMe H 157.5-158 7:54 (1H, sl, 4.50, 1 4:40 (Division 2H, all . s), 3.86 (3H, s), 3.74 (3H, s); 1.45 (3H, t, 14 - (CHzizOH Cl 3-0-n-Pen 4-OMe H Visc. Italians 7:59 (1H, s), 4.50, 6

-1 531

Dry. s. Ri Ra Υι Y2 Y3 c-p (° C) NMR (CDCl3)? Example s. divine material 4.40 (total 2H, all e), 3.83 (3H, s), 0.93 (3H, t) 15 - (CH2) 3OH cl 3-O-n-Pen 4-OMe H, 1C5 7.60 (1H, s), 4.53, 4.43 (total 2H, all s), 3.83 (3H, s), 0.92 (3H, t) 1 16 - (CH2) -Bu 2CO2t cl 3-O-n-Pen 4-OMe H v'.sk. Italians if it is material see Example 3 3 17 -CH2CO2H cl 3-O-n-Pen 4-OMe H, 174-175 7.55 (1H, s), 3.78 (3H, s), 0.91 (3H, t) 4 18 - (CH2) 2CO2H cl 3-O-n-Pen 4-OMe H, 161-163 Ms (m / e): 351 (M + 1-CH 2 CH 2 CO 2 H) *, 207 (100%) 4 19 Me cl 3-OMe 4-OMe 5-OMe 145.5 7.51 (1H, s), 4.52, 4.42 (total 2H, all s), 3.82 (9H, s), 3.72 (3H, s) 1 20 - (CH2) 3OH cl 3-OMe 4-OMe 5-OMe 127-129 7.64 (1H, s), 4.54, 4.44 (total 2H, all s), 3.84 (9H, s), 3.54 (2H, t) 1 21 - {CH2) 2N (Me) 2 cl 3-OH 4-OMe H is semi-solid material 7.52 (1H, s), 4.44, 4.34 (total 2H, all s), 3.86 (3H, s), 2.39 (6H, s) 2 22 CH2CH = CH2 cl 4-SMe H H 148 7.52 (1H, s), 4.80 1

(2Η, d), 4.53,

4.43 (total 2H, all s), 2.47 (3H, s)

23 -CH2CO2H cl 4-CH = CH-n-Pen (cis) Η H semisolid material 7.50 (1H, s), 6.30 (1H, d, J = 11.4 Hz) 5.20-5.85 (3H, m), 4.41 (2H, broad s), 2.0-2.8 (2H, m) 4 24 Me cl 4-CO2-n-Bu Η H 120-122 7.47 (1H, s), 4.70, 1 4.60 (total 2H, mind s), 3.75 (3H, s), 1.00 (3H, t) 25 H cl 4-N (Me) 2 Η H 280 (CDCl₃ + DMSO-d₆): 2 / decay 7.52 (1H, s), temperature 4.46, 4.35 (total

2H, all s), 2.87 (6H, s)

-1 633

Dry. s. Ri R2 Y1 Y2 Y3 mp (° C) NMR (CDCl3) Example s. 26 Me cl 4-N (Et, 2 H H 158 7.50 (1H, s), 4.37, 4.27 (div. 2H, all s), 3.65 (3H, s). 1.13 (6H, t) 2 1 27 Me cl 4-CO2H H H 275 (DMSO-d6): 7.68 (1H, 4.71, 4.61 (split 2H, all s), 3.64 (3H, s) S), 1 Dry. s. Ri R2 Yi Y2 Y3 3.p. (° C) Ms (m / e) Example s. 28 H cl 4-OMe H H 215-216 265 (MN, 121 (100%) 7 29 H Br 3-O-n-Pr H H 1.64-166.5 258 <M '-Br, 100%) 7 30 H Br 3-O-n-Pr 4-OMe H 169-171 367 (M * J, 179 (100%) 7 31 H cl 3-O-n-Pr H H 177-179 293 (M ') i 258 (100%) 7 32 H cl 3-O-n-Pr 4-OMe H 'i.53-154 323 (MN, 179 (100%) 7 33 H cl 4-OEt H H .65-167 279 (MN, 135 (100%) 7 34 H cl 3-O-n-Bu 4-OMe H 206-207 337 (M *>, 193 (100%) 7 35 H cl 3-OEt 4-OMe H : .73-174 309 (MN, 165 (100%) 7 36 H Br 3-OEt 4-OMe H 170-174 353 (M *), 165 (100%) 7 37 H cl 3-O-n-Pen 4-OMe H 156-158 351 (MN, 207 (100%) 7 38 H Br 3-O-n-Bu 4-OMe H 194-197 381 (M *), 193 (100%) 7 39 H Br 3-O-n-Pen 4-OMe H 148-150 see Example 7 7 40 H cl 3-O-n-Hex 4-OMe H 113-117 365 (MN, 221 (100%) 7 41 H Br 3-O-n-Hex 4-OMe H 126-127.5 409 (MN, 221 (100%) 7 42 H cl 3-O-n-Hep 4-OMe H 97-99 379 (M *), 235 (100%) 7 43 H Br 3-O-n-Hep 4-OMe H 124-125 355 (M *), 121 (100%) 7 44 Ph cl 4-OMe H H 134.5-136 341 (MN, 121 (100%) 1 45 PhCH 2 cl 4-OMe H H 130-133 355 (MN, 121 (100%) 1 46 Pen-cyc cl 3-OEt 4-OMe H 155.5-157 377 (MN, 165 (100%) 1 47 CH2CH = CH2 cl 3-O-n-Pr 4-OMe H 137 363 (MN, 179 (100%) 1 48 CH2CH = CH2 cl 3-OEt 4-OMe H 136-107.5 349 (MN, 165 (100%) 1 49 Ph cl 3-OEt 4-OMe H 153-165 385 (MN, 165 (100%) 1 50 PhCH 2 cl 3-OEt H H 135-137 369 (MN, 106 (100%) 1 51 CH2CH = CH2 cl 3-OMe H H 133-104 305 (MN, 270 (100%) 1

-1 735

Dry. s. Ri RZ Yi Y2 yj M.p. (° C) Ms (m / e) Example s. 52 H cl 2-Me 4-Me H 255-258 263 <M '), 119 (100%) 7 53 H Br 2-Me 4-Me H 245-252 307 (M '), 119 (100X) 7 54 H cl 3-OCH 2 Ph 4-OMe H 190-191 371 (M '), 91 (100%) 7 55 H Br 2-OCH2Ph 4-OMe H 194-197 415 IM '), 91 (100%) 7 56 H cl 3 OCH2CH2Ph 4-OMe H. 190-191 385 (M * 1, 105 (100%) 7 57 H Br 3 OCH2CH2Ph . 4-OMe H 154-155 429 (M *), 105 (100%) 7 58 H cl 3-OMe 4-OMe H 190-192 295 (M *), 151 (100%) 7 59 H Br 3-OMe 4-OMe H 198-200 339 (M ')> 151 (100%) 7

Hereinafter, examples are provided of medicaments containing the active compounds of formula (I).

Finishing Examples 1 & 2 / Tablets /

Active ingredient / 1. finishing example

No. 2 Compound 2, Finishing 2

5. Finishing Example 6 / Soft Capsule /

Active ingredient / 5. for finishing example 25 no. Compound 6 in Preparation Example 6; compound / 10 g

Marine Oil 35 g Example 38 compound / 10 g

Lactose 20 g

Starch 4 g

Starch for pulp 1 g

Magnesium stearate 100 mg

Carboxymethylcellulose calcium 7 g

Total weight: 42.1 g

The ingredients listed above are mixed in the usual way and sugar coated tablets (dragees) are prepared containing 50-50 mg of active ingredient.

Finishing Examples 3 & 4 / Capsule /

Active ingredient / 3. finishing example

No. 3 Compound 4 Finishing Example 4 Total: 45 g 30

The ingredients listed are mixed in the usual manner into a soft capsule.

and finishing example 8 / ointment /

Active ingredient / 7. finishing example no. Compound 8, Finishing Example 8 compound / 1.0 g

Olive oil 20.0 g

White Vaseline 79.0 g Danish no. compound / 10 g

Lactose 20 g

Crystalline cellulose powder 10 g

Magnesium stearate 1 g

Total: 41 g

Total: 100.0 g

The ingredients listed are mixed in a conventional manner into a 1% ointment.

Preparation Examples 9 and 10 (aerosol suspension) / A / Active ingredient / 9. in the finishing example 50 No. 2. Compound 10, Preparation Example 10 compound 0.25%

Isopropyl myristate 0.10%

Ethanol 26.40%

The ingredients listed above are mixed in the usual manner and filled in an amount of 50-50 mg of active ingredient in each gelatin capsule.

60: 40% mixture of B / 1,2-dichloro-tetrafluoroethane and pentafluoroethane

1% klór73.25

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The A / A composition is mixed first, the resulting solution mixture is placed in a valve vessel and the 8 / filler is injected through a valve nozzle at a manometric pressure of 2.46 to 2.81 kg / cm ² to form 5 aerosol suspensions.

Claims (2)

A process for the preparation of novel 3 / 2H / pyridazinone derivatives of the general formula (1) and their pharmaceutically acceptable salts, wherein: R 1 is hydrogen, methyl, C 3 -C 6 alkenyl, C 5 -C 6 cycloalkyl, benzyl, phenyl, 2,2,2-trifluoroethyl / -CH 2 CF 3 /, - / CH 2 / CO 2 R 3. wherein R3 is hydrogen or C1-C5 alkyl and m is an integer from 1 to 4, or - / CH2 / nA wherein n is an integer from 2 to 6 and A is hydroxy or -N An amino group of formula (R4 / 2) wherein R4 is C1-C3 alkyl; R2 is chlorine or bromine; Y 1 and Y 2 are each independently hydrogen, halogen, C 1 -C 5 alkyl, C 2 -C 8 alkenyl, -OR 5 wherein R 8 is hydrogen, C 1 -C 8 alkyl, or C 1 -C 4 alkyl substituted at the end of the chain. , -CO2R6 wherein Re is hydrogen or (C1-C5) alkyl, N / R7 / 2 wherein R? is C 1 -C 4 alkyl, or -SR 6 where Re is C 1 -C 4 alkyl; and Y3 is halogen, C1-C5 alkyl, C2-C8 alkenyl, -OR5, -CO2R8, -N / R7 / 2 or -SRe, wherein R5-Ra is as defined above, wherein: The 3 / 2H / pyridazinone derivative of formula (11) - wherein R 1 and R 2 are as defined in the preceding disclosure and Z is chlorine or bromine - is reacted with the corresponding benzylamine derivative of formula II 'or an acid salt thereof; Y2 and Y3 have the meanings given in 1 object. 2. A process for the preparation of an anti-allergic pharmaceutical composition, characterized in that one or more of the active compounds of the general formula I according to claim 1 - R, R 2, Υι, Y 2 and Y 3 are as defined in claim 1 - or with other excipients and / or other known active ingredients in a pharmaceutical composition.