Derivative 3(2h)-pyridazinone or their pharmaceutically acceptable additive salts of acids and pharmaceutical compositions on their basis

 

(57) Abstract:

Presents new 3(2H) -pyridazinone derivative of the formula I, where R1represents a hydrogen atom or a C1-4-alkyl; each R2and R3represents a hydrogen atom; X represents a chlorine atom or a bromine atom; Y1represents a hydrogen atom, a halogen atom, a nitro-group or1-4-alkoxygroup; Y2is1-4- alkoxygroup; And is1-5-alkylenes chain which may be substituted by a hydroxyl group; represents a carbonyl group or a methylene chain which may be substituted WITH1-4is an alkyl group; and R4represents a hydrogen atom, R5is Z-Ar, where Z represents a C1-5-alkylenes chain, and Ar is pyridyl, or R4and R5taken together with the adjacent nitrogen atom, form a 4-substituted pieperazinove ring of formula II, where R6represents a C1-4is an alkyl group which may be substituted by phenyl group which may be substituted by Y3where Y3is a halogen atom, amino group, N-formylamino or1-4-alkylcarboxylic; pyridium, quinoline or group of formulas is SUP>4and R5together with the adjacent nitrogen atom form a 4-substituted piperidine ring of formula IV, where R11- C1-4-alkyl which may be substituted by phenyl group. Compounds have bronchodilator activity, anti-allergic and/or antithrombotic activity, describes acceptable additive salt of the acid and / or pharmaceutical composition based on compounds of formula I. 2 S. and 1 C.p. f-crystals, 5 PL.

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The present invention relates to novel 3(2H)-pyridazinone derivatives and their pharmaceutically acceptable salts with bronchodilator activity, antiallergic activity and/or antithrombotic activity.

1) bronchodilating agents

In the treatment of chronic reversible obstructive respiratory diseases such as bronchial asthma, bronchitis and respiratory distress syndrome in adults, during attacks it is very important to ensure the restoration of breathing. For these purposes a bronchodilating agents. Most bronchodilatory funds currently used for clinical purposes can be broadly classified as stimulants, for example, SoC, what with long-term use, in the case of intractable diseases, their efficiency is reduced, and in the treatment of bronchial asthma requiring long introduction, is often observed even worsening of symptoms (The New England Journal of Medicine, vol. 321, p. 1517-1527, 1989).

On the other hand, theophyllinate drugs have limited use due to the narrow range of their harmlessness.

2) Antiallergic drugs

It is obvious that various chemical in vivo mediators involved in allergic reactions of immediate type, such as bronchial asthma, allergic rhinitis, urticaria and hay fever. One of the most important mediator is histamine, and so already for a long time antihistaminic agents are used as antiallergic agents. However, many anti-Allergy medications antihistamines type have adverse side effects on the Central nervous system, such as drowsiness. For the treatment of asthma preferably with both therapeutic and economic standpoint to use such medicinal products, which would have not only hypoallergenic, but also mean the e developed.

3) antithrombotic agents

It is known that platelets play an important role in thrombogenesis associated with a specific pathological condition and mediated platelet activation by stimulation of adhesion to vessel walls and aggregation. Thrombosis causes various thrombotic diseases, foremost among which are, for example, cerebral thrombosis, lung thrombosis, myocardial infarction, angina and occlusion of peripheral arteries; and to treat all these diseases, it is necessary to develop the needed medicines. During the development of preventive or therapeutic agent special attention was paid antithrombotic agent with activity aimed at the inhibition of platelet aggregation. So, for example, has been widely investigated the effect of aspirin, followed clinically developed ticlopidin and Cilostazol. However, it would be highly desirable to obtain a more potent agent than with these drugs.

In addition to the aforementioned thrombotic disease associated with platelets and other various diseases. Examples of such diseases are jade, metadatecelexa, mainly using antithrombotic agent with activity, regulating the function of platelets, recently conducted various studies ("Journal of the Royal College of Physicians, vol. 7, N 1, p. 5-18, 1972; "Clinics Japan (Nihon Rinsho)", vol. 4, N 6, p. 130-136, 1988; Anticancer Research, vol. 6, p. 543-548, 1986).

Below will be described the relationship derivatives of 5-aminoalkylindole - or-aminocarbonylmethyl-substituted, benzylamino-3(2H)-pyridazinone formula (I) and their pharmaceutically acceptable salts of the present invention with the compounds disclosed in published materials.

The type compounds, which replaced benzylamino associated with 3(2H)-pyridazinone ring in position 5 and which are relatively similar to the compounds of the present invention are disclosed in the following works.

a) In the publication of Japanese patent N 41455/1994, in EP-186817B or in U.S. patent 5098900 (denoted hereinafter by the reference material (a)) discloses compounds, representing 3(2H)-pyridazinone derivatives, where position 2 is the lower alkyl group in position 4 is a chlorine atom or a bromine atom in position 5 is benzylamino having a benzene ring substituted by the Deputy, thrupp and aminocarbonyl group; also disclosed pharmaceutical use of these compounds as anti-MPC-A-agents (MPC-A-slow-reacting substance of anaphylaxis) and their pharmacological activity.

(b) In the publication of unexamined Japanese application 030769/1987, EP201765B or in U.S. patent 4 892 947 (denoted hereinafter by the reference material (b)) reveals the connection that represents the 3(2H)-pyridazinone derivatives, where position 2 is the hydrogen atom in position 4 is a chlorine atom or a bromine atom in position 5 is benzylamino having a benzene ring substituted by such Deputy as alkyloxy-phenylalkylamine and dialkylamino, and in the 6 position is a carbon atom; and the pharmaceutical use of these compounds as anti-MPC-A-agents and their pharmaceutical activity.

c) In the publication of unexamined Japanese application N 301870/1988, EP275997B or in U.S. patent 4978665 (denoted hereinafter by the reference material (c)) reveals the connection that represents the 3(2H)-pyridazinone derivatives, where position 2 is a hydrogen atom or lower alkyl group in position 4 is a chlorine atom or a bromine atom in position 5 is benoxaprofen and dialkylamino, and at position 6 is a halogen atom, a nitro-group, amino group or alkoxygroup; and pharmaceutical use of these compounds as anti-MPC-A-agents and their pharmaceutical activity.

(d) In 091/16314, EP482208A or in U.S. patent 5202323 (denoted hereinafter by the reference material (d)) reveal connections, representing a 3(2H)-pyridazinone derivatives, where position 2 is a hydrogen atom or lower alkyl group in position 4 is a chlorine atom or a bromine atom in position 5 is benzylamino having a benzene ring substituted by such Deputy as alkyloxy-phenylalkylamine, where the benzene ring may be substituted by an alkyl group or a halogen atom, -alkiloksikarbonilalkilamidov and - aminocarbonylmethyl, and at position 6 is accelerograph having any functional group in a-position; and the pharmaceutical use of these compounds as anti-thrombotic agents, cardiotonic agents, vasodilating factors and anti-MPC-A-agents agents and their pharmaceutical activity.

As a result of extensive studies, the authors of this izobreteny is acceptable salt, different from all of the compounds disclosed in the above reference materials (a) to(d) are a valuable vasodilator, anti-allergic and/or antithrombotic means; moreover, these compounds have particularly high activity when administered orally, which allows their use as active ingredients in the preventive or therapeutic drugs for treatment of these respiratory diseases, allergic reactions of immediate type and/or thrombotic diseases. This conclusion was the basis of the present invention.

Thus, the present invention relates to 3(2H)-pyridazinone compounds of formula (I) and their pharmaceutically acceptable salts; the method of production of these compounds and to pharmaceutical compositions containing these compounds as the active ingredient:

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in which R1is a hydrogen or C1-4- alkyl; each of the radicals R2and R3is a hydrogen atom; X is a chlorine atom or bromine; Y1is a hydrogen atom, a halogen atom, a nitro-group or C1-4- alkoxy; Y2is C1-4- alkoxy; A is C1-5alkylene chain which may be substituted C1-4- alkyl, and (a) R4is a hydrogen atom, R5is a group of Z-Ar, in which Z is C1-5alkalinous chain, and Ar is pyridium, or (b) R4and R5form together with the adjacent nitrogen atom a 4-substituted pieperazinove ring of the formula:

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in which R6is C1-4- alkyl, whereby alkyl may be substituted by phenyl which can be substituted for Y3where Y3is a halogen atom, amino, N-formylamino or C1-4- alkylcarboxylic, pyridium, chinaillon or a group of the formula:

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in which R9is C1-4- alkyl or benzyl which may be substituted by a halogen atom, or (c) R4and R5form together with the adjacent nitrogen atom a 4-substituted piperidine ring of the formula:

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in which R11is C1-4- alkyl which can be substituted by phenyl, and pharmaceutically acceptable acid additive salt.

Below will be described in more detail radicals R1, R2, R3, R4, R5, A, B, X, Y1and Y2in the compound of formula (I) according to the present invention. Specific examples of the radical R1include hydrogen, methyl, et is is a hydrogen atom. Each of the radicals R2and R3is a hydrogen atom.

X may be a chlorine atom or a bromine atom.

Y1may be, for example, a hydrogen atom, chlorine atom, bromine atom, iodine atom, nitro group, methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, sec-butoxy or tert-butoxy.

Y2may be, for example, a methoxy group, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, sec-butoxy and tert-butoxy.

A is alkalinous chain with the total number of carbon atoms from 1 to 5. This chain can be substituted by a hydroxyl group and may be, for example, the type of connection, such as methylene, ethylene, propylene, butylene or pentile. The most preferred linear Allenova group containing from 1 to 4 carbon atoms.

B may be a carbonyl linking group or a methylene chain.

R4and R5can have the following values:

(a) R4is a hydrogen atom, a R5is a group of the formula Z-Ar, in which Z is C1-5alkalinous chain, and Ar is a group of pyridyl,

(b) R4and R5form together with the neighboring nitrogen atom to which they are bound, a 4 can be substituted by phenyl, which, in turn, can be substituted for Y3and Y3is a halogen atom, amino group, N-formylamino or C1-4- alkylcarboxylic; pyridium, chinaillon or a group of the formula:

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in which R9is C1-4- alkyl or benzyl which may be substituted by a halogen atom.

Specifically, the radical R6may be benzyl, containing halogen atom, substituted at any arbitrary position ortho-, meta - or para-position of the benzene ring, pyridylmethyl, kinalimutan and benzimidazolylthio containing a benzyl group which may be substituted by a halogen atom in a benzene ring or substituted C1-4the alkyl in N-position.

(c) the Radicals R4and R5form together with the adjacent nitrogen atom a 4-substituted piperidine ring of the formula:

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in which R11is C1-4- alkyl, in which alkyl group may be a substituted phenyl group.

Specific examples of R11include benzyl.

Preferred examples of radicals R4and R5include the above 4-substituted piperazine-1-yl and 4-substituted piperidine-1-yl.

Niteclub is obreteniyu.

The above compound in which R4and R5form together with the neighboring nitrogen atom to which they are bound, a 4-substituted pieperazinove ring of the formula:

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in which R14is a group of the formula:

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in which Y4is a hydrogen atom, halogen atom, amino group, N-formylamino or C1-4- alkylcarboxylic

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or

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in which R15is benzyl which may be substituted by a halogen atom.

The compounds of formula (I) can exist as optical isomers and stereoisomers, based on the availability of 1-5 asymmetric carbon atoms.

The compounds of formula (I) of the present invention can be converted into a pharmaceutically acceptable non-toxic salts with the appropriate acid, if necessary. The compounds of formula (I) can be used for the purposes of the present invention either in free form or in the form of pharmaceutically acceptable salts. Such salts can be, for example, salts of mineral acids such as hydrochloride, hydrobromide, sulfate, bisulfate, nitrate, phosphate, phosphate or monopotassium phosphate), organic acid salts such as formate, acetate, propionate, succina the Oli sulfonic acid (such as methanesulfonate, bansilalpet or toluensulfonate). These salts can be obtained corresponding to the standard methods.

In table. I shows typical examples 3(2H)-pyridazinone derivative of the formula (I) of the present invention and its pharmaceutically acceptable salts. However, it should be noted that the present invention is not limited to these specific examples.

In table. I n means normal, i means ISO, t stands for "tertiary", Me means methyl group, Et means ethyl group, Pr means through the group, Bu means boutelou group, and Ph denotes phenyl group. In table.I Q - Q42 represent a group having the formula shown at the end of the description.

The following describes methods of producing compounds of the present invention.

3(2H) - pyridazinone derivatives of the formula (I) of the present invention and their pharmaceutically acceptable salts can be obtained by the methods illustrated in the following reaction schemes (1) to (7).

The reaction scheme (1)

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where R1, R2, R3, R4, R5X, Y1, Y2A and B are the same as they have been defined above.

A method of obtaining in sootvetst-aminoalkylindole - or-aminocarbonylmethyl-substituted benzylamino derivative of the formula (III) or salts thereof optionally in the presence of dehydrohalogenating agent in an inert solvent to obtain compounds of formula (I) of the present invention.

In the above reaction scheme (I) isomer of the provisions of the compounds of formula (I), i.e. a compound of formula (IV) having oxybenzaldehyde substituted in 4-position:

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where R1, R2, R3, R4, R5X, Y1, Y2A and B are the same as defined above, is formed as a by-product. The ratio of the produced compounds of formulas (I) and (IV) depends mainly on the polarity of the solvent used.

For example, if the solvent has a high degree of polarity, the content of compounds of formula (I) of the present invention will be more high. Therefore, as a solvent suitable for the efficient production of the compounds of formula (I) of the present invention, which at the same time will contribute to the suppression of side reactions leading to the formation of compounds of formula (IV) can be used ethereal solvent (such as tetrahydrofuran or 1,4-dioxane), an amide solvent (such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, or N-organic), acetonitrile, dimethyl sulfoxide, an alcohol solvent (such as methanol, ethanol or propanol), organic amine solvent (tritely. For isolation and purification of the compounds of formula (I) of the present invention of the above-mentioned mixtures of compounds of formula (I) and compounds of formula (IV) can be used known essentially methods of organic synthesis, such as fractional recrystallization, or various types of chromatography on silica gel.

In the reaction between the compound of formula (II) and the compound of the formula (III) formed hydrogen chloride or bromovalerate. To increase access to the reaction system may be added dehydrohalogenating agent, which captures the specified halogenation.

For these purposes may be used any dehydrohalogenating agent, unless it has an adverse effect on the reaction and has the ability to capture halogenation. As such dehydrohalogenating agent may be used an inorganic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate; or an organic base, such as N,N-dimethylaniline; N,N-diethylaniline, trimethylamine, triethylamine, N,N-dimethylaminoethanol, N-methylmorpholine, pyridine, or 2,6-dimethyl-4-N,N-dimethylaminopyridine.

Alternativamente derivative of the formula (III). As a result, in many cases, can be increased yield of the desired compound.

The reaction temperature may be generally from 10oC to the boiling point of the solvent used in the reaction.

The molar ratio of starting compounds can be, but not necessarily, installed in advance. However, in General, benzylamine derivative of the formula (III) or its salt can be used in an amount of from 1 to 10 M, and preferably from 1.2 to 5 M by 1 M 4.5-dihalogen-3(2H)-pyridazinone derivative of the formula (II).

4,5-dihalogen-3(2H)-pyridazinone derivative of the formula (II) may be obtained using standard organic reactions, or by using the following conventional method of obtaining compounds of this type. So, for example, a connection in which the Deputy Y1in the 6-position is a hydrogen atom, can be obtained by the method described in (a) and (b); and the connection, in which Deputy Y1is a halogen atom, a nitro-group, amino group, or alkoxygroup, can be obtained by the method described in (c).

- Aminoalkylindole - or - aminocarbonylmethyl-substituted benzylamine derivative of the formula (III) job described in (a).

(a). Scheme (A)

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where hal is a leaving group such as chlorine atom, bromine atom, iodine atom, methysulfonylmethane, or p-toluensulfonate, R represents a halogen atom, a hydroxyl group, a C1-4is an alkyl group, or a C1-4-alkoxygroup, and R2, R3, R4, R5, Y2A and B are the same as defined above.

Scheme (B)

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where T represents aminosidine group, such as benzyloxycarbonyl group, tert-butoxycarbonyl group, formyl group, acetyl group, benzoline group, methoxycarbonyl group or ethoxycarbonyl group; R2, R3, R4, R5, Y2, A, B, R and hal are as defined above.

Scheme (C)

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where R9represents a hydrogen atom or a lower alkiline group, and R2, R3, R4, R5, Y2, A, T and hal are as defined above.

Scheme (D)

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where R10represents a hydrogen atom or a C1-4is an alkyl group; hal represents the data if there is a Deputy, having a similar or lower ability to cleavage than "hal" in the pre-selected combination; a R2, R3, R4, R5, Y2, A, T and hal are as defined above.

Diagram (E)

Scheme (E)

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where D represents C1-4-alkylenes group, and R2, R3, R4, R5, Y2and hal are as defined above.

The reaction scheme (A) illustrates the method in which the starting compound is used hydroxycarbonyl derivative (IX), and in which, first, the compound of formula (VIII) is reacted with a phenolic centre with the introduction of the corresponding side allocsize, and then the carbonyl group is converted into the amino group with the help of reduction reaction. Reaction scheme (B) illustrates the method in which the reactions were carried out in a different order compared to the reaction scheme (A). The reaction scheme (C) illustrates the method in which the starting compound used is N-protected hydroxymethylamino derivative of the formula (X), which is an intermediate compound in the method illustrated in reaction scheme (B), and in which a side chain phenolic part of this with the hunger of his restored the product of formula (Illb), having restored section of the amide bond of the compounds of formula (IlIa). Reaction scheme (D) illustrates a method of obtaining omega-aminoethylethanolamine derivative of the formula (Illc), i.e., benzylamino derivative of the formula (III) containing branched methylene chain, where B is a substituted lower alkyl group. Reaction scheme (E) illustrates a method of obtaining compounds of formula (IIId), i.e., benzylamino derivative of the formula (III) in which A represents a methylene chain having a hydroxyl group.

Using readily available and manufactured by industry source products, or products obtained from products, from the above methods (A) - (E) it is easy to choose any suitable method to use.

For the reaction hydroxycarbonyl derivative (IX) with compound (VIII) in scheme (A) use terms, which are usually widely used for the alkylation of phenols. This reaction usually occurs relatively quickly when using inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, or potassium bicarbonate in a ketone solvent (such as acetone, Amid or N-organic, an alcohol solvent (such as methanol, ethanol or n-propanol), or in water or in mixtures of these solvents, at temperatures of from 40 to 150oC.

Subsequent reaction for the conversion of the carbonyl group (formyl group or ketone group) aminomethyl group can be carried out by the condensation reaction, which is subjected to the amine of the formula RNH2pick imino-compounds, which, in turn, is subjected to reaction recovery. In this method imino-compound can be formed in the reaction system and subjected to the subsequent reaction of recovery without highlighting it. In some cases this method may be more preferable from the viewpoint of increasing output and reducing material costs.

In this case, the primary amine as one of benzylamine derivatives of the formula (III), where R2is a hydrogen atom, can be carried out using as RNH2such amine, ammonia, hydroxylamine or O-alkylhydroxylamines, with subsequent recovery of the thus obtained imine.

For this recovery is widely used reaction hydrogenation with IRS upon receipt iminovogo connections use the O-alkylhydroxylamines, this reaction can be carried out using a metal hydride such as trattoreusatocalabria sodium [NaBH3(OCOCF3)] or bis-methoxyethoxymethyl sodium [NaAlH2(OCH2CH2OCH3)2] (Chemical and Pharmaceutical Bulletin, vol. 26, p. 2897-2898, 1978).

The last of these recovery methods may sometimes be preferable to obtain a compound that belongs to benzylamino derivative of the formula (III), and which contains Y2and R4or R5halogen atom or a benzyl group, which is relatively unstable in terms of recovery by hydrogenation. To obtain the secondary amine, representing benzylamine derivative of the formula (III) in which R2represents a C1-4is an alkyl group, as RNH2can be used the corresponding primary alkylamine formula R2NH2and then in reduction reaction of iminovogo derivative, obtained by means of the condensation reaction, as a reducing agent can be added to not only reducing agent described in the above method of obtaining the primary amine, but also much softer metal is UB>), which are the most suitable and widely used reducing agents.

In the reaction scheme (B) benzylamine formula (III) are obtained by reactions carried out in a different sequence compared to the reactions in the reaction scheme (A).

In accordance with this, the transformation of the carbonyl group in the aminomethyl group and the reaction of alkylation of phenolic parts can be held in the appropriate reaction conditions described for Scheme (A). In this method, the required stage of introducing a protective group for atom benzylimidazole. For this purpose, as a protective group of the formula T can be used a protective group of a wide range, which are commonly used for amino groups in peptide synthesis, such as benzyloxycarbonyl group, t-butoxycarbonyl group, formyl group, acetyl group, benzoline group, methoxycarbonyl group and ethoxycarbonyl group. When selecting a specific group of these various protective groups don't have any hard constraints. However, in some cases, the correct choice of protective groups or conditions for its removal depends on the types of substituents Y2, B, R4and R5. For example, dlinnuy group, in some cases it is necessary to choose substituents and reaction conditions so that the reaction of removing the protective group can be conducted with a high degree of efficiency and selectivity even when using instead of the catalytic hydrogenation of another method. To obtain benzylamine formula (III), where B represents a carbonyl chain, in many cases, it is preferable to use benzyloxycarbonyloxy group or t-butoxycarbonyl group, because the removal of such protective groups can be more easily Nagykanizsa conditions. This can be used in the standard reaction conditions, which are usually used for introduction and removal of various protective groups of the specified type.

The reaction scheme (C) illustrates a method in which, using as a starting compound, hydroxybenzylated formula (X), protected by a protective group T, Paladino increasing the ether side chain, resulting in the receive connection of the formula (IlIa), where B represents a carbonyl chain, and a compound of the formula (IlIb), where B is a linear methylene chain, obtained by recovering carbonyl; moreover, these compounds is e, if R9is a hydrogen atom, can be used methods of condensation by dehydration, which usually are widely used for peptide synthesis. If the amine is relatively rich in its nucleophilic nature, there may be used an ester, where R9represents a lower alkyl group, and in this case, usually, use conditions of heating in an inert solvent. To obtain benzylamine formula (IIIb) as a reducing agent may be used a metal hydride, such as alumalite lithium. The reaction of alkylation of phenolic portion and the reaction of removing the protective group in the other stages can be carried out in accordance with the methods described for the corresponding reactions in schemes (A) and (B).

Reaction scheme (D) illustrates a method of obtaining aminoethylethanolamine derivative of the formula (Illc), where a - carbon of an amino group at the end of the phenolic side chain is a methylene chain, a substituted linear or lower alkyl. Stage of introduction of the radical of an amino group can be carried out in a standard reaction conditions that are typically used in the substitution reactions of the alkylamine with alkylhalogenide.

The reaction scheme (2)

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where R1'represents a C1-4is an alkyl group, hal represents a chlorine atom, a bromine atom, or iodine atom, and R2, R3, R4, R5X, Y1, Y2A and B defined above.

The reaction scheme (2) illustrates the method of obtaining substituted in the 2-position pyridazinones product of the formula (I-b) as compounds of the present invention by reaction of compounds of formula (I-a), which is a compound of the present invention of formula (I) where, in the 2-position of pyridazinone is a hydrogen atom, a halogen derivative of formula R1'-hal.

For this reaction using an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, or lithium hydroxide; an organic base such as triethylamine or tri-n-Propylamine; or a metal hydride or ORGANOMETALLIC compound, such as sodium hydride or n-utillity.TBE solvent can be used ketone solvent (such as acetone, methyl ethyl ketone or diethylketone), amide solvents (such as formamide, N,N-dimethylformamide, or N,N-dimethylacetamide), an alcohol solvent (such as methanol or ethanol), water or a mixture of these solvents. If you use a metal hydride, preferably an ethereal solvent.

In case you are using an inorganic or organic base, the reaction temperature may be from 0oC to the boiling point of the solvent. If in this reaction uses a metal hydride or ORGANOMETALLIC compound, the reaction temperature may be in the range from -78oC to 60oC.

The molar ratio of the starting compounds may be optional, pre-installed. Typically, however, the reactive derivative of formula R1'- hal can be used in the ratio of 1 to 5 M per 1 M of the compounds of formula (I-a).

For isolation and purification of the desired product can be used standard methods of organic synthesis, such as recrystallization, chromatographia different types on silica gel and distillation.

The reaction scheme (3)

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where R1the scheme I (3) illustrates the method in which 5- -/ carboxyaniline)benzylamine derivative or 5-alkoxycarbonylmethyl)benzylamine derivative of the formula (V) is subjected together with aminoven compound of formula (VI) reaction of condensation by dehydration or dealcoholization, resulting in a gain amide derivative of the formula (I-c).

If R9is a hydrogen atom, the condensation reaction can be carried out in accordance with conventional condensation methods commonly used in peptide synthesis. For example, the condensation reaction may be carried out by the method using the acid chloride method using mixed acid anhydride, and a method using a condensing agent, such as di-cyclohexylcarbodiimide, carbonyldiimidazole, and N-hydroxysuccinimide; and suitable condensation method can be selected depending on the reactivity of the amine of formula (VI). As the reaction conditions can be used for such reactions conditions.

If as an amine of formula (VI) amine is used, which is rich in its nucleophilic nature, the condensation reaction will proceed even with Slovan any solvent without any particular restrictions, unless it is inert to this reaction. In many cases, this reaction can be carried out in the absence of solvent. The reaction temperature may vary from room temperature to 200oC, but mostly it is from the 50oC to 150oC.

The reaction scheme (4)

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where R1, R2, R3, R4, R5X, Y1, Y2A , B and hal are defined above.

The reaction scheme (4) illustrates the method for obtaining compounds of the present invention of formula (I) by reaction of compounds of formula (VII) with a halogen derivative of the formula (VIII).

For this reaction can be used mainly inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, or lithium hydroxide; or an organic base such as triethylamine or tri-n-Propylamine.

As the solvent for this reaction can be used ketone solvent such as acetone, methyl ethyl ketone, or diethylketone), amide solvents (such as formamide, N,N-dimethylformamide, or N,N-dimethylacetamide) alcohol solvent (such as methanol or atani 0oC to the boiling point of the solvent.

The reaction scheme (5)

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where R1, R2, R3, R4, R5, R10X, Y1, Y2, A and hal are as defined above, and R7represents a hydrogen atom or a C1-4is an alkyl group.

The reaction scheme (5) illustrates a method of obtaining amine derivative of the formula (I-d) as the compounds of the present invention by reaction of compounds of formula (IX) obtained by the method described above for reaction scheme (4), with aminoven compound of formula (VI).

This reaction can be carried out by the method described for reaction scheme (4).

The reaction scheme (6)

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where R2'represents a C1-4is an alkyl group, and R1, R2, R3, R4, R5X, Y1, Y2A , B and hal are as defined above.

The reaction formula (6) illustrates the method for obtaining compounds of the present invention, in which R2is C1-4alkyl group, by reaction of compounds of formula (I-e) (which is a compound of the present invention of formula (I), where R2is is of good results as the organic solvent can be used amide solvent, such as dimethylformamide; ether solvent such as tetrahydrofuran or diethyl ether; or an aprotic organic solvent, such as n-hexane, benzene, or toluene; and the base may be used a metal hydride such as sodium hydride; n-utility, diisopropylamide lithium or sodium amide.

When carrying out the reaction in the presence of base, the reaction temperature may be in the range from -78oC to 10oC, and when carrying out the reaction using alkylidene the reaction temperature may range from -15oC to 70oC.

Reaction scheme (7)

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where R1, R2, R3, R4, R5X, Y1,Y2A , B and hal are as defined above.

Reaction scheme (7) illustrates a method of obtaining compounds of formula (I) of the present invention by the reaction of 3(2H)-pyridazinone formula (XI) containing the group - other2in the 5-position, with benzylguanine derivative of the formula (XII) in the presence of a base.

The reaction conditions for this reaction may be the same as for the reaction scheme (6).

3(2H)-pyridazinone of the present invention, Furla injection (subcutaneous, intravenous, intramuscular or intraperitoneal), ointments, suppositories or aerosols; or oral way in the form of tablets, capsules, granules, pills, syrups, liquid solutions, emulsions, or suspensions.

The above pharmaceutical composition contains a compound of the present invention in amounts of about 0.1 to 99.5 wt. percent, and preferably from about 0.5 to 95 wt.% based on the total weight of the composition.

With the connection of the present invention or the composition comprising the compound of the present invention, can be mixed with other pharmacologically active compounds.

The compound of the present invention can be manufactured in the form of various preparations suitable for injection, in accordance with the standard method commonly used for the manufacture of pharmaceutical preparations.

So, for example, tablets, capsules, granules or pills for oral administration can be obtained with filler, such as sugar, lactose, glucose, starch or mannitol; a binder such as syrup, Arabian gum, gelatin, sorbitol, tragacanth gum, methyl cellulose, or polyvinylpyrrolidone; dezintegriruetsja the ical pulp, or polyethylene glycol; agent to reduce friction, such as talc, magnesium stearate or calcium or silica; or a lubricant such as sodium laurate, or glycerin.

Injections, solutions, emulsions, suspensions, syrups, or aerosols can be obtained by using a solvent for the active ingredient, such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol, or polyethylene glycol; surfactants, such as complex arbitrator fatty acids, complex polyoxyethylenesorbitan fatty acids, complex polyoxyethylenated fatty acids, simple polyoxyethylenated hydrogenating castor oil or lecithin; a suspending agent, such as sodium carboxymethyl cellulose, a derivative of cellulose, such as methylcellulose, or natural rubber, such as tragacanth gum or avarissa gum; or preservative, such as ester, peroxybenzoyl acid, benzylaniline, or salt of sorbic acid.

Similarly can be made suppositories, for example, using polyethylene glycol, lanolin or coconut oil.

Most of Prani, the examples of the preparation of compositions and sample tests).

Below is a more detailed description of the present invention with reference to examples (including comparative examples, the examples of the preparation of compounds, examples of the preparation of compositions and sample tests). However, it should be noted that the present invention is not limited to these specific examples. In the comparative examples, examples of receipts or table. II abbreviations "NMR" and "MS" means spectroscopy using the method of nuclear magnetic resonance and mass spectroscopy, respectively. If it is not specifically mentioned, the NMR was measured in deuterium chloroform.

In the MC-data table. II, are only the main peaks or peaks characteristic fragments.

Comparative example 1

N-Benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine

< / BR>
A mixture containing 150 g of isovanillin, 93,2 g of sodium hydroxide, 99 g of hydroxylamine sulfate, 600 ml of ethanol, and 1500 ml of water, was heated under reflux with stirring for 30 minutes, and then cooled to a temperature of 40oC. After adding 93,2 g of sodium hydroxide, to the mixture for 30 minutes was added 180 g of Raney catalyst. The resulting mixture is displaced is. iltram and wash solutions were combined and then added of 53.6 g of sodium hydroxide. Then, to the mixture drop by drop) was added 186 g benzyloxycarbonylamino, cooling while the ice. This mixture was stirred for 4 hours. To the resulting reaction solution was added hydrochloric acid until then, until the pH does not become equal to 1-2, and then was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, then dried with anhydrous sodium sulfate. The solvent is then drove away. The obtained residue was led from diethyl ether, and received 95,11 g N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine in the form of white crystals.

NMR: 7,34 (s, 5H), 6,79 (s, 3H), 5,78 (s, 1H), 5,12 (Shir. s, 2H), 4.25 in (d, 2N), of 3.84 ( s, 3H).

MS (m/z): 287 (M+), 196, 152, 137, 91(100%).

Comparative example 2

t-Butyloxycarbonyl-3-hydroxy-4-methoxybenzylamine

< / BR>
A mixture containing 150 g of isovanillin, 91 g of sodium hydroxide, 89 g of hydroxylamine sulphate, 500 ml of ethanol and 1300 ml of water, was heated under reflux for 1 hour under stirring, and then cooled to a temperature of 40oC. After adding 91 g of sodium hydroxide to the mixture was gradually added 150 g catalista was filtered and washed with 150 ml of ethanol and 150 ml of water. The filtrate and wash solutions were combined and neutralized under cooling with concentrated hydrochloric acid until then, until the pH does not become equal to 8. After adding 1 ml of acetonitrile to the mixture at room temperature for one hour drop was added 215 g of di-t-BUTYLCARBAMATE. This mixture was stirred over night. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. The solvent is then drove away. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/benzene, 1:5), and received 126 g t-butyloxycarbonyl-3-hydroxy-4-methoxybenzylamine in the form of an oily substance.

NMR: 6,54-6,85 (m, 3H), 6,14-6,47 (Shir. s, 1H), 4.92 in-of 5.34 (m, 1H), 4.09 to (d, 2H), 3,25 (s, 3H), of 1.44 (s, N).

MS (m/z) : 153 (M+- 100), 137 (100%).

Comparative example 3

N-Benzyloxycarbonyl-3-ethoxycarbonylmethoxy-4-methoxybenzylamine

< / BR>
A mixture containing 20 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 17,43 g ethylbromoacetate, 17,43 g of potassium carbonate and 200 ml of 2-butanone, was heated under reflux, while stirring, overnight. Then the mixture was cooled to room temperaturein. The obtained residue was extracted with chloroform, then the organic layer was washed with water and saturated aqueous sodium chloride, then dried with anhydrous sodium sulfate. After removal of the solvent, the obtained residue was led from diethyl ether/ n-hexane, resulting in received 17,83 g N-benzyloxycarbonyl-3-ethoxycarbonylmethoxy-4-methoxybenzylamine in the form of white crystals.

NMR: 7,33 (s, 5H), 6,85 (s, 3H), 5,12 (s, 2H), 4,63 (s, 2H), 4.26 deaths (d, 2H), 4,25 (square, 2N), of 3.84 (s, 3H), of 1.26 (t, 3H).

MS (m/z): 373 (M+), 282, 239 (100%), 210, 164, 136, 91.

In a similar way there were obtained compounds such

as:

N-Benzyloxycarbonyl-3-ethoxycarbonylmethoxy-4-methoxybenzylamine;

NMR: 7,25-of 7.55 (m, 5H), 6,72-7,06 (m, 3H), 5,14 (s,2H), 3,71-to 4.52 (m, 10H), 1,90 is 2.80 (m,4H), of 1.24 (t, 3H); and

N-Benzyloxycarbonyl-3-ethoxycarbonylmethoxy-4-methoxybenzylamine.

Comparative example 4

N-Benzyloxycarbonyl-3-carboxymethoxy-4-methoxybenzylamine

< / BR>
A mixture containing 23,56 g N-benzyloxycarbonyl-3-ethoxycarbonylmethoxy-4-methoxybenzylamine, 7,29 g of sodium hydroxide, 300 ml of methanol, and 30 ml of water was stirred for one hour at a temperature of 60oC. the Reaction solution neutralizable diluted hydrochloric acid, and this mixture was extracted with chloroform. The extract layer was washed with water and saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. After that, the solvent drove away. The obtained residue was led from diethyl ether/n-hexane, and received 21,55 g N-benzyloxycarbonyl-3-carboxymethoxy-4-methoxybenzylamine in the form of white crystals.

NMR: 7,34 (s, 5H), at 6.84 (s, 3H), 5,13 (s, 3H), to 4.62 (s, 2H), 4.25 in (d, 2H), 3,83 (s, 3H).

MS (m/z): 345 (M+), 254, 210 (100%), 91.

In a similar way there were obtained the following compounds:

N-Benzyloxycarbonyl-3-carboxyphenoxy-4-methoxybenzylamine; and

N-Benzyloxycarbonyl-3-carboxymethoxy-4-methoxybenzylamine.

Comparative example 5

N-Benzyloxycarbonyl-3-(2,C-epoxypropoxy)-4-methoxybenzylamine

< / BR>
A mixture containing 2 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 20 ml of dimethylformamide, 1.4 g of potassium carbonate and 1.4 g of epibromohydrin, was stirred overnight at a temperature of 60oC. After removal of the solvent under reduced pressure the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with an aqueous solution of potassium carbonate, and then nassen what I got 2.6 g N-benzyloxycarbonyl-3-(2,3-epoxypropoxy)-4-methoxybenzylamine in the form of an oily substance.

NMR: to 7.32 (s, 5H), for 6.81 (s, 3H), of 5.0-5.5 (m, 3H), 3,9-4,6 (m, 7H), and 3.8 (s, 3H).

MS (m/z): 343 (M+), 252, 208, 19 (100%).

Comparative example 6

N-Benzyloxycarbonyl-3-(4-methylpiperazin-1-yl)carbonyloxy - 4-methoxybenzylamine

< / BR>
A mixture containing 5 g of N-benzyloxycarbonyl-3-carboxymethoxy-4-methoxybenzylamine, 1,67 g of triethylamine, and 40 ml of tetrahydrofuran, cooled with ice, and then, one drop was added to 1.79 g of ethylchloride dissolved in 10 ml of tetrahydrofuran. The resulting mixture was stirred for 2 hours. Then to the reaction solution was added 1.65 g methylpiperazine dissolved in 10 ml of tetrahydrofuran, and the mixture was stirred for 4.5 hours at room temperature. After filtering off the precipitate, the filtrate was subjected to distillation under reduced pressure. To the obtained residue was added water, and the mixture was extracted with chloroform. The extract solution was washed with water and saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. After that, the solvent drove away. The obtained residue was led from ethyl acetate/diethyl ether/n-hexane, and received 3,53 g identified above compound in the form of white crystals.

NMR: of 7.25 (s, 5H), 6,78 ( CLASS="ptx2">

In a similar way there were obtained the following compounds:

N-Benzyloxycarbonyl-3-[4-(3-pyridylmethyl)-piperazine-1-yl] carbonyloxy-4-methoxybenzylamine

MS (m/z): 504 (M+), 92 (100%).

N-Benzyloxycarbonyl-3-(4-benzylpiperazine-1-yl)-carbonyloxy - 4-methoxybenzylamine;

NMR: 7,15-the 7.43 (m, 10H), 6,7-6,92 (m, 3H), 4,85-5,24 (m, 3H), to 4.62 (s, 2H), 4,22 (d, 2H), 3,4-of 3.96 (m, N in), 2.25 and 2.7 (m, 4H).

N-Benzyloxycarbonyl-3-[4-(4-terbisil)-piperazine-1-yl] carbonyloxy-4-methoxybenzylamine;

NMR: 6,60 is 7.50 (m, N), of 5.0-5.5 (m, 3H), to 4.62 (s, 2H), 4,22 (d, 2H), 3,22-3,95 (m, N), 2,2-2,7 (m, 4H).

N-Benzyloxycarbonyl-3-4-(3-pyridylmethyl)-piperazine-1-yl - Carboniferous-4-methoxybenzylamine;

MS (m/z): 532 (M+), 92(100%).

N-Benzyloxycarbonyl-3-(4-benzylpiperazine-1-yl)-Carboniferous - 4-methoxybenzylamine;

NMR: 7,0-7,40 (m, 10H), 6,60-of 6.90 (m, 3H), 5,50-5,51 (m, 3H), 3,22-4,37 (m, 13H), 2,0 of 2.68 (m, 8H); and

N-Benzyloxycarbonyl-3-(4-benzylpiperazine-1-yl)- carbonylmethyl-4-methoxybenzylamine;

NMR: / 7,0-to 7.35 (m, 10H), 6,60-to 6.80 (m, 3H), 5,0-of 5.50 (m, 3H), 3,20-4,32 (m, 13H), 1,1-2,48 (m, N).

Comparative example 7

N-Benzyloxycarbonyl-3-[{4-(4-forebesi)-piperazine-1-yl] - hydroxypropoxy}-4-methoxybenzylamine

< / BR>
A mixture containing 2.4 g of N-benzyloxycarbonyl the fridge over night with stirring. The resulting mixture was cooled to room temperature and then the reaction solution was concentrated under reduced pressure and extracted with chloroform. The organic layer was washed with an aqueous solution of potassium carbonate and dried with anhydrous sodium sulfate. The solvent is then drove away under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol=19:1) and obtained 2.6 g identified above connection.

NMR: 6,75-7,42 (m, 12H), of 5.0-5.5 (m, 3H), 4.26 deaths (d, 2H), 3,82-4,10 (m, 2H), of 3.77 (s, 3H), 3,20-of 3.60 (m, 3H), 2,20-to 2.85 (m, 10H).

MS (m/z): 537 (M+), 207 (100%), 109.

In a similar way there were obtained the following compounds:

N-Benzyloxycarbonyl-3-[{ 4-(2-chenailler)-piperazine-1-yl} - hydroxypropoxy]-4-methoxybenzylamine;

NMR: 7,03-to 8.12 (m, 11N), 6,60-6,87 (m, 3H), and 5.30-5,70 (m, 1H), of 5.05 (s, 2H), 3,22-4,37 (m, 11H), 2,22 is 2.80 (m, 10H).

N-Benzyloxycarbonyl-3-[{ 4-(4-aminobenzyl)-piperazine-1-yl} - hydroxypropoxy]-4-methoxybenzylamine:

NMR: 6,45-7,41 (m, 12H), 5,40-of 6.78 (m, 1H), 5,04 (s, 2H), 3,50-to 4.38 (m, 11N), 3,30 (c, 2H), 2,10 is 2.80 (m, 8H).

Comparative example 8

3-(4-Methylpiperazin-1-yl)-carbonyloxy-4-methoxybenzylamine

< / BR>
A mixture containing 3,26 g N-benzyloxycarbonyl-3-(4-IU is for 6 hours at 60oC in hydrogen atmosphere, and then over night at room temperature. Palladium-on-coal was filtered and then the filtrate is kept under reduced pressure, and received 2,45 g identified above compound in the form of a slightly brownish oily substance.

NMR: 6,88 (s, 3H), 4,74 (s, 2H), 3,50-4,10 (m, N), 2,29-of 2.58 (m, 7H), of 1.65 (s,2H).

MS (m/z): 293 (M+), 152, 299, 70 (100%).

In a similar way there were obtained the following compounds:

3-[4-(3-Pyridylmethyl)-piperazine-1-yl] carbonyloxy- -4-methoxybenzylamine;

MS (m/z): 370 (M+), 92 (100%).

3-(4-Benzylpiperazine-1-yl)-carbonyloxy-4-methoxybenzylamine;

MS (m/z): 369 (M+), 91 (100%).

3-[4-(4-forebesi)-piperazine-1-yl]carbonyloxy-4-methoxybenzylamine;

MS (m/z): 387 (M+), 109 (100%).

3-[4-(3-Pyridylmethyl)-piperazine-1-yl] Carboniferous-4 - methoxybenzylamine;

MS (m/z): 398 (M+), 92 (100%).

3-(4-Methylpiperazin-1-yl)-Carboniferous-4-methoxybenzylamine;

MS (m/z): 321 (M+), 99 (100%).

3-(4-Benzylpiperazine-1-yl)-Carboniferous-4-methoxybenzylamine;

MS (m/z): 397 (M+), 91 (100%).

3-[4-(4-forebesi)-piperazine-1-yl)-1-oxo-2-methylethoxy] -4-methoxybenzylamine;

MS (m (M+), 91 (100%).

Example obtain 1

4-Chloro-5-[3-(4-methylpiperazin-1-yl)-carbonyloxy-4-methoxybenzylamine]-3(2H)-pyridazinone

< / BR>
Mixture of 1.16 g of 3-(4-methylpiperazin-1-yl)- carbonyloxy-4-methoxybenzylamine, 0.5 g of 4,5-sodium dichloro-3(2H)-pyridazinone, and 0.46 g of triethylamine, 10 ml of ethanol, and 10 ml of water was heated under reflux overnight, stirring the while. The solvent is kept under reduced pressure and to the residue was added an aqueous solution of potassium carbonate. The resulting mixture was extracted with chloroform. The extract solution was washed with water and saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. After that, the solvent drove away. The obtained residue was purified by column chromatography on silica gel, and then were led out of chloroformmethanol ether, resulting in the received 0,61 g identified above compound in the form of white crystals.

NMR: 12,66 (Shir. S., 1H), 7,44 (s, 1H), 6,78 (s, 3H), 5,43 (t, 1H), and 4.68 (s, 2H), 4,39 (d, 2H), of 3.77 (s, 3H), 3,30 of 3.75 (m, 4H), 2.0 to 2,60 (m, 7H).

MC (m/z ): 421 (M+), 386, 140, 99, 70 (100%).

Comparative example 9

4-Chloro-5-(C-carboxymethoxy-4-methoxybenzylamine)-3(2H)- pyridazinone

< / BR>
The mixture is potassium hydroxide, 10 ml of ethanol and 2 ml water was heated under reflux overnight, stirring the while. The reaction solution was neutralized by adding an aqueous solution of hydrochloric acid. The solvent is then drove away under reduced pressure. To the obtained residue was added water, and the mixture was extracted with chloroform. The extract solution was washed with water and saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. After removal of the solvent was received 212 mg identified above compound as a white solid.

MS (m/z): 281 (M+-CHCO2H), 246, 209, 159, 145 (100%), 116.

Example of getting 2

4-Chloro-5-[3-(C-pyridinedicarboxylate)-4-methoxybenzylamine -3(2H)-pyridazinone

< / BR>
A mixture consisting of 200 mg of 4-chloro-5-(3-carboxymethoxy-4-methoxybenzylamine)-3(2H)-pyridazinone, 65 mg of triethylamine and 10 ml of N,N-dimethylformamide, cooled with ice, and then added 88 mg of isobutylacetate. The resulting mixture was stirred at the same temperature for one hour and then was added 140 mg of 3-picolylamine. This mixture was stirred over night at room temperature. After removal of the solvent under reduced pressure, to the obtained residue DM solution of sodium chloride, and then was dried with anhydrous sodium sulfate. After that, the solvent drove away. The obtained residue was purified by column chromatography on silica gel (eluent:chloroform/methanol=9/1), and received 129 mg identified above compound as a white solid.

NMR: 8,35-8,58 (m, 2H), 7,81-of 8.33 (m, 1H), 7,72 (s, 1H), 7,45-of 7.60 (m, 2H), 6,88 (c, 3H), 6,40-to 6.80 (m, 1H), or 4.31-to 4.62 (m, 6N in), 3.75 (s, 3H).

MS (m/z): 429 (+), 394, 298, 137, 121, 107, 92 (100%).

Comparative example 10

N-Benzyloxycarbonyl-3-(3-chloropropoxy)-4-methoxybenzylamine

< / BR>
A mixture containing 20 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 14,43 g of potassium carbonate, 16,44 g bromochloromethane, and 200 ml of 2-butanone was heated under reflux with stirring for 16 hours. The resulting mixture was cooled to room temperature. Then the inorganic substance was filtered, and the filtrate was subjected to distillation under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was washed with water and saturated aqueous sodium chloride, then dried with anhydrous sodium sulfate. Then, the solvent drove away. The obtained residue was led from diethyl ether/n-hexane, and received 23,19 d, 2H), as 4.02 (t, 2H in), 3.75 (s, 3H), to 3.67 (t, 2H), 1,94-2,47 (m, 2H).

MS (m/z): 363 (M+), 316, 273 (100%), 228, 152, 137, 125, 91.

In a similar way there were obtained the following compounds:

N-Benzyloxycarbonyl-3-(2-chloroethoxy)-4-methoxybenzylamine; and

N-Benzyloxycarbonyl-3-(2-diethylaminoethoxy)-4-methoxybenzylamine.

Comparative example 11

N-Benzyloxycarbonyl-3-[3-(4-formylpiperazine-1-yl)propoxy] -4-methoxybenzylamine

< / BR>
Mixture of 23.1 g of N-benzyloxycarbonyl-3-(3-chloropropoxy)-4-methoxybenzylamine, 8.7 g of N-formylpiperazine, 13,16 g of potassium carbonate, 0.95 g of sodium iodide and 300 ml of N,N-dimethylformamide, was stirred for 16 hours at a temperature of 80oC. the resulting mixture was cooled to room temperature. Then the inorganic substance was filtered, and the filtrate is kept under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was washed with water and saturated aqueous sodium chloride, then dried with anhydrous sodium sulfate. After removal of the solvent was received 30,67 g identified above compound in the form of a slightly brownish oily substance.

NMR: of 7.97 (s, 1H), 7,32 (s,5H), for 6.81 (s, 3H), are 5.36 (Shir. so, 1H), 5,11 (s, 2H), 4.26 deaths (d, 2H), was 4.02 (t, by the procedure there were obtained the following compounds:

N-Benzyloxycarbonyl-3-(3-diethylaminopropyl)-4 - methoxybenzylamine;

N-Benzyloxycarbonyl-3-[2-(4-benzylpiperazine-1-yl)-ethoxy] -4-methoxybenzylamine;

N-Benzyloxycarbonyl-3-[2-(4-(4-Chlorobenzyl)-piperazine-1-yl] -ethoxy]-4-methoxybenzylamine;

N-Benzyloxycarbonyl-3-{ 2-[4-(4-forebesi)piperazine-1-yl] -ethoxy}-4-methoxybenzylamine;

N-Benzyloxycarbonyl-3-[3-(4-benzylpiperazine-1-yl)-propoxy] -4-methoxybenzylamine; and

N-Benzyloxycarbonyl-3-[3-(4-methylpiperazin-1-yl)-propoxy] -4-methoxybenzylamine.

Comparative example 12

3-[3-(4-Formylpiperazine-1-yl)-propoxy]-4-methoxybenzylamine

< / BR>
A mixture of 30.4 g of N-benzyloxycarbonyl-3-[3-(4 - formylpiperazine-1-yl)-propoxy-4-methoxybenzylamine, 3.1 g of 5% palladium-on-coal and 300 ml of ethanol was stirred for 9 hours at a temperature of 60oC in hydrogen atmosphere. After filtering off the palladium-on-charcoal, the filtrate is kept under reduced pressure, and received 17,99 g identified above compound in the form of a slightly brownish oily substance.

NMR: 8,03 (s, 1H), 6,86 (s, 3H), 4,11 (t, 2H), of 3.84 (s, 3H), 3.25 to 3,71 (m, 4H), 2,30-2,82 (m, 4H), 1,82-of 2.30 (m, 4H).

MC (m/z): 307 (M+), 292, 246, 171, 155, 125, 99 (100%).

In a similar way were polyethoxyethanol;

3-[2-(4-Benzylpiperazine)-1-yl]-ethoxy-4-methoxyphenylpiperazine;

3-[2-{4-(4-Chlorobenzyl)-piperazine-1-yl}-ethoxy]-4 - methoxybenzylamine;

3-[2-{4-(4-forebesi)-piperazine-1-yl}-ethoxy]-4 - methoxybenzylamine;

3-[3-(4-Benzylpiperazine-1-yl)-propoxy]-4-methoxybenzylamine; and

3-[3-(4-Methylpiperazin-1-yl)-propoxy]-4-methoxybenzylamine.

Example of getting 3

4-Chloro-5-[3-{ 3-(4-formylpiperazine-1-yl)-propoxy} -4 - methoxybenzylamine]-3(2H)-pyridazinone (Compound No. 50)

< / BR>
A mixture containing 11,58 g of 3-[3-(4-formylpiperazine-yl)-propoxy] -4-methoxybenzylamine, 5.0 g of 4,5-sodium dichloro-3(2H)-pyridazinone, 4.6 g of triethylamine, 50 ml of n-propanol and 50 ml of water was heated under reflux with stirring for 14 hours. After removal of the solvent under reduced pressure, to the obtained residue were added an aqueous solution of potassium carbonate, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. After that, the solvent is kept off, and the obtained residue was purified by column chromatography on silica gel, resulting in a received 6,21 g identified above compound in the form of yellowish-white to-3,74 (m, 4H), 2,30-2,84 (m, 6N), 1,76-of 2.30 (m, 2H).

Example getting 4

4-Chloro-5-[3-{ 3-(4-ethylpiperazin-1-yl)-propoxy} -4-methoxybenzylamine -3(2H)-pyridazinone

< / BR>
A mixture containing 1.0 g of 4-chloro-5-[3-{3-(4-formylpiperazine-1-yl)- propoxy} -4-methoxybenzylamine]-3(2H)-pyridazinone, and 0.62 g of potassium hydroxide, 7 ml of ethanol and 7 ml of water was heated under reflux for 3.5 hours under stirring, and then to this mixture was added 0.32 g of potassium carbonate and 570 mg of ethylbromide. The resulting mixture was stirred for 4 hours at a temperature of 60oC. After removal of the solvent under reduced pressure, to the obtained residue was added water. This mixture was extracted with chloroform. The extract solution was washed with water and saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. The solvent is then drove away. The residue was purified by column chromatography on silica gel and was obtained 0.50 g identified above compound as a slightly brownish solid.

NMR: the 7.65 (s,1H), 6.89 in (s, 3H), 5,41 (collapsiblenav, 1H), 4,50 (d, 5H), 4,08 (t, 2H), a 3.87 (s, 3H), 1,73-3,10 (m, 14N), a 1.08 (t, 3H).

MS (m/z): 435(M+), 365, 343, 206, 127 (100%), 99.

In a similar way there was obtained the compound, namely 4): 515 (M+), 109(100%).

Comparative example 5

2-Ethyl-4-chloro-5-[3-{ 2-(4-(4-forebesi)-piperazine-1-yl, ethoxy)-4-methoxybenzylamine}-3(2H)-pyridazinone

< / BR>
A mixture containing 500 mg of 4-chloro-5-[3-{2-(4-(4-forebesi)- piperazine-1-yl)-ethoxy}- 4-methoxybenzylamine]-3(2H)-pyridazinone, 130 mg ethylbromide, 190 mg of potassium carbonate, and 10 ml of 2-butanone, was heated under reflux with stirring for 5 hours. The inorganic substance was filtered, and the solvent is then drove away under reduced pressure. To the residue was added water, and the mixture was extracted with chloroform. The extract solution was washed with water and saturated aqueous sodium chloride, then dried with anhydrous sodium sulfate. Then, the solvent drove away. The obtained residue was purified by chromatography on a column of silica gel (eluent: chloroform/ethanol=19/1), and received 429 mg identified above compound in the form of a colorless transparent viscous substance.

NMR: 7,47 (s,1H), 7,00-7,31 (m,4H), to 6.88 (s, 3H), 5,20 (t,1H), 4,46 (d, 2H), 4,14 (t, 2H), 4,12 (square, 2H), 3,85 (s, 3H), 3,47 (s, 2H), by 2.73 (t, 2H), 2.21 are 3,05 (m, 10H), of 1.32 (t, 3H).

MS (m/z): 574 (M+), 493, 273, 221, 192 (100%), 164, 111, 84.

Comparative example 13

1-Chloroacetyl-4-(2-chenailler)-piperazine
oC, and then within 10 minutes, one drop was added to the stirred solution of 330 mg of acetylchloride and 5 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred for 1 hour at a temperature of -60oC, and then added water. This mixture was stirred for 20 minutes at room temperature. The reaction solution was subjected to distillation under reduced pressure, and then was extracted with chloroform. The organic layer was washed with an aqueous solution of potassium carbonate and dried with anhydrous sodium sulfate. After removal of the solvent under reduced pressure received 750 mg identified above compound as an oily substance.

NMR: 7,32-to 8.20 (m, 6N), to 4.01 (s, 2H), 3,20-3,90 (m, 6N), 2,30-to 2.74 (m, 4H).

MS (m/z): 143 (M+-160).

In a similar way there were obtained the following compounds:

1-Chloroacetyl-4-(4-Chlorobenzyl)-piperazine;

MS (m/z): 286 (M+), 125 (100%).

1-Chloroacetyl-4-[1-(4-forebesi)-2-methylbenzimidazolyl)-piperazine;

NMR: 6,66-7,40 (m, 8H), 5,44 (s, 2H), 3,95 (s, 2H), 3,74 (s, 2H), 3.04 from-of 3.60 (m, 4H), 2,24-of 2.66 (m, 4H).

1-Chloroacetyl-4-benzylpiperazine;

MC (m/z): 252(M+), 91 (100%).

1-Chloroacetyl-4-benzylpiperidine;

MS (m/z): 251 (M+), 91 (100%), and

1-Chloroacid what measures 14

N-t-Butyloxycarbonyl-3-[4-(2-chinaimmigration)-1-yl] carbonyloxy-4-methoxybenzylamine

< / BR>
A mixture containing 660 mg t-butyloxycarbonyl-3-hydroxy - 4-methoxybenzylamine, 10 ml of dimethylformamide, 510 mg of potassium carbonate and 750 mg of 1-chloroacetyl-4-(2-chenailler)-piperazine was heated overnight at a temperature of 80oC, stirring the while. Any insoluble matter was filtered, and then the reaction solution was subjected to distillation under reduced pressure and extracted with chloroform. The extract solution was washed with an aqueous solution of potassium carbonate, and then was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol, 19:1), resulting in a received 1.2 g identified above compound as an oily substance.

NMR: 7,32-8,03 (m, 6N), 6,63-6,93 (m, 3H), 5,15-of 5.50 (m, 1H), with 4.64 (s, 2H), 4.16 the (d, 2H), 3,38-3,93 (m, N), 2,30-by 2.73 (m, 4H), USD 1.43 (s, N).

MS (m/z ): 520 (M+), 144 (100%).

In a similar way there were obtained the following compounds:

N-t-Butyloxycarbonyl-3-[4-(4-Chlorobenzyl)-piperazine-1-yl]- carbonyloxy-4-methoxybenzylamine;

MS (m/z): 503 (M+), 125 (100%).

N-t-Butyloxycarbonyl-3-[4-{1-(4-forebesi)-2 - methylbenzimidazole}-piperazine-1-yl]-carb is 3,26 - the 3.65 (m, 4H), 3.27 to to 2.65 (m, 4H)

N-t-Butyloxycarbonyl-3-(4-benzylpiperidine-1-yl)- carbonyloxy-4-methoxybenzylamine;

MS (m/z): 468 (M+), 91 (100).

N-t-Butyloxycarbonyl-3-(4-t-butyloxycarbonyl-1-yl)-carbonyloxy-4-methoxybenzylamine.

MS (m/z): 585 (M+), 150 (100%).

Comparative example 15

3-[4-(2-Chenailler)-piperazine-1-yl]-carbonyloxy-4 - methoxybenzylamine

< / BR>
A mixture containing 1.3 g of t-butyloxycarbonyl-3-[4-(2-chenailler) -piperazine-1-yl]-carbonyloxy-4-methoxybenzylamine, 14 ml of chloroform and 2.8 g triperoxonane acid, was stirred for one day at room temperature. To this reaction solution were added 50 ml of chloroform and 50 ml of 0.5 N. hydrochloric acid, and the resulting mixture was subjected to back extraction process. The aqueous layer was brought to pH = 12 by adding an aqueous solution of sodium hydroxide, and then was extracted with chloroform. The organic layer was washed with an aqueous solution of potassium carbonate and dried with anhydrous sodium sulfate. After removal of the solvent under reduced pressure received 850 mg identified above compound as an oily substance.

NMR: 7,39-to 8.20 (m, 6N), 6,72-7,0 (m, 3H), 4,7 (s, 2H), 3,40-4,00 (m, 11N), 2, the following connections:

3-[4-(4-Chlorobenzyl)-piperazine-1-yl] -carbonyloxy - 4-methoxybenzylamine;

MC (m/z): 403 (M+), 125 (100%).

3-[3-{4-(4-forebesi)-piperazine-1-yl}-2,2-DIMETHYLPROPANE)- 4-methoxybenzylamine;

MS (m/z): 429 (M+), 109 (100%).

3-(4-Benzylpiperazine-1-yl)-carbonyloxy-4-methoxybenzylamine;

MS (m/z): 368 (M+), 91 (100%).

3-[4-{ 1-(4-Forebesi)-2-benzimidazolinyl} -piperazine-1-yl] -carbonyloxy-4-methoxybenzylamine.

MC (m/z): 517 (M+), 109 (100%).

An example of obtaining 6

4-Chloro-5-[3-{ 4-(2-chenailler)-piperazine-1-yl} - carbonyloxy-4-methoxybenzylamine]-6-ethoxy-3(2H)-pyridazinone

< / BR>
A mixture containing 2.4 g of 3-[4-(2-chenailler)-piperazine-1-yl] -carbonyloxy-4-methoxybenzylamine, 1 g of 4,5-sodium dichloro-6-ethoxy-3(2H)-pyridazinone, 580 mg of triethylamine, 10 ml of propanol and 10 ml of water was heated under reflux with stirring overnight. After removal of the solvent under reduced pressure the residue was extracted with chloroform. The organic layer was washed with an aqueous solution of potassium carbonate, and then dried with anhydrous sodium sulfate. After that, the solvent drove away. The obtained residue was purified by column chromatography on silica gel (eluent, e is received 1.5 g identified above compound in the form of white crystals.

NMR: 7,40-8, 28(m, 6N), 6,72-7,05 (m, 3H), 4,62-of 5.40 (m, 5H), 3,48-4,50 (m, 11N), 2,32-2,70 (m, 4H), to 1.31 (t, 3H).

MS (m/z): 592 (M+), 143 (100%).

Comparative example 16

1-Formyl-4-(4-aminobenzyl)-piperazine

< / BR>
A mixture containing 9 g of 1-formyl-4-(4-nitrobenzyl)-piperazine, 180 ml of methanol and 14.6 g of uranyl of Nickel chloride, cooled in an ice bath, was slowly added 4.6 g of sodium borohydride. The resulting mixture was stirred for 30 minutes at a temperature of 0oC and then for 30 minutes at room temperature. The reaction solution is kept under reduced pressure, and the resulting residue was dissolved by adding 200 ml of 10% hydrochloric acid and then brought to pH=10 by addition of 28% aqueous ammonia solution. The resulting mixture was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, then dried with anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was led from diethyl ether and was obtained 8.0 g identified above compound in the form of white crystals.

NMR: of 7.82 (s, 1H), 6,97 (d, 2H), 6,47 (d, 2H), 3,01-3,91 (m, 8H), 2,11-2,48 (m,4H).

MC (m/z): 263 (M+), 218 (100%).

Comparative example 17

1-Formyl-4-is and 50 ml of toluene and 4.8 g of di-t-BUTYLCARBAMATE, was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol, 9: 1), and then were led out of diethyl ether, resulting in the received 5,1 g identified above compound in the form of white crystals.

NMR: 7,87(s, 1H), 6,97-7,42 (m, 5H), 3,15-the 3.65 (m, 6N), 2,15-to 2.57 (m, 4H), 1,45 (s, N).

MS (m/z): 319 (M+), 106(100%).

Comparative example 18

1-(4-t-Butyloxycarbonyl)-piperazine

< / BR>
4 g of 1-Formyl-4-(t-butyloxycarbonyl)-piperazine was dissolved in 50 ml of methanol and to this solution was added a solution consisting of 1.5 g of sodium hydroxide dissolved in 10 ml of water. The resulting mixture was heated for 5 hours at a temperature of 60oC. the Reaction solution was concentrated under reduced pressure, and then was extracted with chloroform. The organic layer was washed with an aqueous solution of potassium carbonate and dried with anhydrous sodium sulfate. After that, the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel (eluent: chloroindole above compound in the form of white crystals.

NMR: of 7.0 to 7.7 (m, 5H), to 3.38 (s, 2H), 2,60-of 3.12 (m, 4H), 1,90 - 2,60 (m, 5H), 1,50 (s, N).

MC (m/z): 291 (M+), 206, 106 (100%).

Example of getting 7

4-Chloro-5-[3-(4-(4-aminobenzyl)-piperazine-1-yl) -carbonyloxy-4-methoxybenzylamine]-6-isopropoxy-3(2H)-pyridazinone

< / BR>
A mixture containing 1.6 g of 3-[4-(4-aminobenzyl) piperazine-1-yl] -carbonyloxy-4-methoxybenzylamine, 770 mg of 4,5-sodium dichloro-6-isopropoxy-3(2H)-pyridazinone, 460 mg of triethylamine and 20 ml of methanol was heated under reflux with stirring for 2 days. After removal of the solvent under reduced pressure the residue was extracted with chloroform. The organic layer was washed with an aqueous solution of potassium carbonate, and then dried with anhydrous sodium sulfate. After that, the solvent drove away. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/methanol=9:1 --->chloroform/methanol=15:1), and then were led out of diethyl ether, resulting in the received 1.6 g identified above compound in the form of white crystals.

NMR: 6,55-to 7.15 (m, 7H), 4,45-5,33 (m, 6N), 3,13-3,88 (m, 11N), 2,13-of 2.58 (m, 4H), 1.28 (in d, 6N).

MS (m/z): 465 (M+-106), 430, 106 (100%).

Example obtain 8

4-Chloro-5-[3{ 4-(4-formylmethyl)-piperazine-1-PII)piperazine-1-yl]- carbonyloxy-4-methoxybenzylamine-6-isopropoxy-3(2H)-pyridazinone was dissolved in 3 ml of performace. Then the solution was stirred at room temperature overnight. The reaction solution was subjected to distillation under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: chloroform/methanol, 9:1), and then were led out of diethyl ether, resulting in the received 830 mg identified above compound in the form of white crystals.

NMR: 11,75 (Shir. S., 1H), 8,2 cent to 8.85 (m, 2H), 6.75 in to 7.62 (m, 7H), 4,58-and 5.30 (m, 6N), of 3.77 (s, 3H), 3,20 of 3.75 (m, 6N), 2,05-2,60 (m, 4H), 1.27mm (d, 6N).

MS (m/z): 464 (M+-134), 137 (100%).

Example of getting 9

4-Chloro-5-[3-{ 4-(4-N-acetylaminobenzoic)-piperazine-1-yl} - carbonyloxy-4-methoxybenzylamine]-6-isopropoxy-3(2H)-pyridazinone

< / BR>
400 mg of 4-chloro-5-[3-(4-aminobenzyl)-piperazine-1-yl]- carbonyloxy-4-methoxybenzylamine-6-isopropoxy-3(2H)-pyridazinone was dissolved in 400 ml of pyridine and to this solution was added 220 mg of acetic anhydride. The resulting mixture was stirred for 2 hours at room temperature. After removal of the solvent under reduced pressure, the residue was extracted with chloroform. The organic layer was washed with an aqueous solution of potassium carbonate, and then dried with anhydrous sodium sulfate. After that, the solvent from the (eluent: chloroform/methanol=9:1), and then were led out of diethyl ether, resulting in the received 340 mg identified above compound in the form of white crystals.

NMR: 11,84 (Shir. s, 1H), 8,24 (Shir. S., 1H), 6,63-7,52 (m, 8H), to 4.52-and 5.30 (m, 6N), 3,30-to 3.92 (m, N), a 2.0 2,62 (m, 7H), 1,25 (d, 6N).

MS (m/z): 613 (M++N), 466.

Example 10

4-Bromo-5-[3-{2-(4-(4-Chlorobenzyl)-piperazine-1-yl)-ethoxy} -4-methoxybenzylamine]-3(2H)-pyridazinone hydrochloride (Compound # 7)

< / BR>
To a stirred solution consisting of 440 mg of 4-bromo-5-[3-{2-(4-Chlorobenzyl)piperazine-1-yl)ethoxy} -4 - methoxybenzylamine]-3(2H)-pyridazinone and 5 ml of chloroform, was added a solution of methanol in 10% hydrochloric acid up until the pH does not become equal to 2-3, and the mixture was stirred for 2 hours at room temperature. To the reaction solution was added diethyl ether for crystallization, and received 465 mg identified above compound in the form of white crystals having a melting point 176-183oC.

MS (m/z: 562 (M+-2HCl), 482, 238, 223 (100%), 203, 125, 91.

Example of getting 11

4-Bromo-5-3-{ 2-(4-(4-Chlorobenzyl)-piperazine-1-yl)ethoxy} - 4-methoxybenzylamine]-3(2H)-pyridazinone fumarate (compound No. 8)

< / BR>
A mixture containing 163 mg of 4-bromo-5-[3-{2-(4-(4-forma, was stirred at room temperature for 3 hours. To the reaction solution was added diethyl ether for crystallization, resulting in a received 120 mg identified above compound in the form of white crystals having so pl. 178-185oC.

MC (m/z: 562 (M+-(CHCO2H)2), 482, 237, 223, 125 (100%), 91.

Example 12

4-Bromo-5-[3-{ 2-(4-(4-Chlorobenzyl)-piperazine-1-yl)ethoxy] -4-methoxybenzylamine}-3(2H)-pyridazinone sulfate (compound No. 9)

< / BR>
A mixture containing 700 mg of 4-bromo-5-[3-{2-(4- (4-Chlorobenzyl)- piperazine-1-yl)-ethoxy}-4-methoxybenzylamine]-3(2H)-pyridazinone, 5 ml methanol, 5 ml of chloroform, and 140 mg of sulfuric acid was stirred for three hours at room temperature. The reaction solution is kept under reduced pressure. The obtained residue was led from isopropyl ether/diethyl ether, and received 800 mg identified above compound in the form of white crystals having so pl. 158-162oC.

MS (m/z): 482 (M+-Br-H2SO4), 238, 223 (100%), 125.

The compound obtained in the above examples was obtained, presented in table. II. The structure of these compounds, the numbers listed in this table, opisaniya composition (pill)

The compound N 39 10 grams

Lactose 20 g

Starch - 4 grams

The starch to a paste - 1 g

Magnesium stearate 0.1 g

Calcixerollic - 7 g

Just was 42.1 g

The above components were mixed in the usual way, and this mixture was molded in a covered sugar tablets, each containing 50 mg of active ingredient.

Example 2 obtaining the composition (capsules)

The compound N 43 10 grams

Lactose 20 g

Microcrystalline cellulose 10 grams

Magnesium stearate 1 g

Only 41 grams

The above components were mixed in the usual way, and the resulting mixture was filled gelatin capsules, each of which contained 50 mg of the active ingredient.

Example 3 obtaining the composition (soft capsules)

The compound N 7 to 10 grams

Corn oil - 35 grams

Only 45 grams

The above components were mixed and molded in the usual way to obtain soft capsules.

Example 4 obtaining the composition (ointment)

The compound N 25 - 1.0 g

Olive oil - 20 g

White petrolatum - 79 g

100 g

The above components were mixed in the usual way and got 1% ointment.

Example 5 obtaining the composition (aerosol with whom retitration and 1-CHLOROPENTAFLUOROETHANE - 73,25%

The components of the above composition (A) was mixed. The resulting mixture solution was loaded into a container fitted with a valve and propellant (In) injectively through the nozzle with valve to manometrical pressure of about 2,46-of 2.81 mg/cm2, resulting in the received aerosol suspension.

Examples test

I. Bronchodilator action

1. In. vitro analysis

Drug:

A sample of the test drug was dissolved in 100% dimethyl sulfoxide (DMSO, Wako. Junguaku) and kept for further use. Leukotriene D4(LTD4, Ultrafine) and isoproterenol (Isoproterenol, Sigma) was diluted with distilled water. Indomethacin (Indo Sigma) was dissolved in 100% ethanol (Et-OH, Komune Called). Aminophyllin (AP,Sigma) and histamine dihydrochloride (His. Wako Junyaku) was dissolved in distilled water. Final concentration of DMSO and OH Et in the bath was not more than 0.25% (vol./about), and not more than 0.1% (vol./vol.), respectively.

Method 1:1

Guinea pig (300-450 g) were killed by exsanguination and took the trachea. After removal of fat and connective tissues of the trachea was cut and divided into 2-3 spiral strips, each of which had a width of about 2 mm and contained tissue 4 smooth the new solution Tirade, aerated with 95% O2+ 5 % CO2at 37oC, after which it was applied load 1, muscle Relaxation were recorded on a chart recorder (Yokogawa Hokushin Electric, type 3066) using isotonic transducer (Nihon Kohden, TD-112S).

Specified modified mortar Tirade had the following composition (mm):

NaCl 137; KCl 2,5; CaCl21,8; MoCl21,0; NaHCO320; NaH2PO40,32; Glucose 11.

Then the sample was left for 50-60 minutes and was subjected to reduction using dihydrochloride of histamine (100 μm). After establishing the reaction at a constant level, the samples were washed and left for 20-30 minutes. Then added indomethacin (5 μm) and after incubation for 30 minutes, the samples were subjected to reduction by adding LTD4(30 nm). After stabilization of the reaction was completely added, the sample of the tested drugs. And finally, to achieve the maximum relaxation response was added to the AR(1 mm). The result was expressed as percent relaxation in relation to AR-mediated relaxation, which was taken as 100%; and then, measured the concentration at which achieved a 50% relaxation (EC50microns). As a reference medicinal product used Atodo 1-1. The sample was kept in for 60-90 minutes, and then subjected to relaxation by adding 1 μm of isoproterenol. Then the sample was washed, and this operation is repeated at intervals of 30-40 minutes until such time as the relaxation response has not reached a stable level. Then for relaxation of the whole sample was added to the tested drug. And finally, to achieve maximum relaxation response was added to 1 mm AR. The result was expressed as percent relaxation in relation to AR-mediated relaxation, which was taken as 100%; and, in addition, it was determined the concentration at which achieved a 50% relaxation (EC50microns). The final concentration of DMSO in the bath brought to 0.2. /vol.%. As a reference medicinal product used AR. The results are presented in table. III-2.

In vivo-tests

Effect on anaphylactic bronchostenosis mediated endogenous release of MPC-A (slow reacting substance (A) in passively sensitized Guinea pigs

1-2 days before the beginning of the experiment, male Guinea pigs (350-450 g) was passively senzibilizirani by intravenous (i.v.) injection 0,125 ml rabbit serum against EA (EA=egg albumin) (Capple Labora using a modified method of Konzett u Rossler (Arch. Exp. Path.Pharmak., 195, 71, 1940). Sensitized Guinea pigs were anestesiologi by intraperitoneal injection of urethane (1.5 g/kg). The right jugular vein was Coulibaly for all the agents, and the trachea was Coulibaly to register full pulmonary resistance. Guinea pigs were performed artificial lung ventilation using a small respirator for animals (Shinato, Model SN-480-7) installed on the stroke volume of the heart of 4.5 ml and a respiratory rate of 50 breaths per minute Changes in pulmonary resistance was measured using a pressure transducer (Nihon Kohden, Model TR-T) connected to the T-tube tracheotomies cannula. A percentage of the maximum bronchostenosis received by clamping the windpipe. Then after the described surgical preparation, animals pre-treated with indomethacin (2 mg/kg, 10 min), pyrilamine (2 mg/kg 6 min), and propranolol (0.1 mg/kg, 5 min) and then held antigenic stimulation EA (0.2 mg/kg). All test compounds were administered orally 2 hours prior to the introduction of provocative tests EA. Inhibition (%) bronchostenosis was determined by the following formula: Inhibition (%) = 1,0 - % maximum bronchostenosis test/ % maximum bronchostenosis in terms of control 100. Maximum CLASS="ptx2">

In table. III-3 shows % inhibition at the dose of the test compound, component 30 mg/kg

II. Antiallergic action

Test link using3-N-pyrilamine (test for binding to the receptor histamine H1)

This test was carried out according to the method of Chang and others (J. Neurochem 32, 1653 (1979)).

Tritium-labeled pyrilamine was added to a suspension of bovine cerebellum and 50 mm phosphate buffer solution (pH 7.5), after which the mixture was left for 30 minutes at 25oC. Then the mixture was rapidly filtered with suction through a filter paper of glass fiber, and on this filter paper was determined by the radioactivity. The degree of inhibition with respect to H1the receptor at a concentration of test compound (10 μm, was determined by the following equation:

The degree of inhibition (%) =

{1-(Amount of binding in the presence of a medicinal product - the amount of nonspecific binding)/(total binding - the amount of nonspecific binding)} 100, where total value binding is a3H-pyrilamine-binding radioactivity in the absence of the test compound, and the amount of nonspecific binding represents seabl. IV.

III. Action, inhibiting platelet aggregation

The effect of inhibition of platelet aggregation in rabbits

Blood from the abdominal artery of male Japanese white rabbits (weight: 1.8 to 2.5 kg) was collected in a syringe containing 1/10 volume of 3.8% sodium citrate. Thus obtained blood was centrifuged at 200 x g for 7 minutes at room temperature, and received platelet-rich plasma (PRP). In addition, the residue was subjected to centrifugation at 2000 x g for 10 minutes and got depleted platelet plasma (PPP). The measurements were carried out by diluting plasma, platelet rich plasma, depleted platelets, up to 300,000/mm3. PRP and PPP were placed in the cuvette and the limits of measurement of the transmittance was brought to 0% in the case of PRP, and to 100% in the case of PPP. After that the test drug dissolved in 100 % dimethyl sulfoxide (DMSO) was added to PRP (final concentration of DMSO was 0,25%). After incubation for 2 minutes at 37oC and at 900 rpm, was added agent that stimulates platelet aggregation, and recorded curve aggregation. The effect of the test drugs directed against platelet aggregation was expressed as the oxygen is kulinowski aggregation, namely ADP was used at a minimum concentration (5 µm and 10 µm), which causes the maximum aggregation. Measurement of platelet aggregation was performed using a tracking device NBS HEMA TPACER 601. The results are presented in table. V.

Industrial application

As evidenced by the above results, the compounds of the present invention have excellent bronchodilator activity, antiallergic activity, and activity, inhibiting platelet aggregation. Compounds of the present invention have a strong pharmacological effect even when administered orally. Therefore, these compounds can be used as prophylactic and therapeutic drugs for the treatment of allergic conditions of the immediate type, such as bronchial asthma, allergic rhinitis, hives, and hay fever; various inflammatory diseases, such as rheumatoid arthritis, arthritis of the spine; ischemic heart diseases such as angina, and myocardial infarction; and various thrombotic diseases.

1. Derivative 3(2H)-pyridazinone formula I

< / BR>
where R1represents a hydrogen atom or a C1-4
Y1represents a hydrogen atom, a halogen atom, a nitro-group or1-4-alkoxygroup;

Y2represents a C1-4-alkoxygroup;

But a1-5-alkylenes chain which may be substituted by a hydroxyl group;

Represents a carbonyl group or a methylene chain which may be substituted WITH1-4is an alkyl group;

a) R4represents a hydrogen atom, and R5represents-Z-Ar, where Z represents a C1-5-alkylenes chain, and Ar is pyridyl, or R4and R5taken with the adjacent nitrogen atom, form a 4-substituted pieperazinove ring formula

< / BR>
where R6represents a C1-4is an alkyl group, this alkyl group may be substituted by phenyl group which may be substituted by Y3where Y3is a halogen atom, amino group, N-formylamino or1-4-alquilervillapeniscola; pyridium; chinaillon or a group of the formula

< / BR>
where R9is1-4is an alkyl group, or benzyl group which may be substituted by a halogen atom, or R4and R5together with the adjacent nitrogen atom obrou group, which may be substituted by phenyl group,

or their pharmaceutically acceptable additive salt of the acid.

2. Derivative 3(2H)-pyridazinone under item 1, where R4and R5taken together with the adjacent nitrogen atom, form a 4-substituted pieperazinove ring formula

< / BR>
where R14represents a

< / BR>
where Y4is a hydrogen atom, halogen atom, amino group, N-formylamino or1-4-alkoxycarbonylmethyl, or

< / BR>
or

< / BR>
or

< / BR>
where R15represents a benzyl group which may be substituted by a halogen atom,

or their pharmaceutically acceptable additive salt of the acid.

3. Pharmaceutical composition having anti-allergic and/or antithrombotic activity, including an active ingredient and a pharmaceutically acceptable excipient or solvent, characterized in that it contains as active ingredient an effective amount of a derivative of 3(2H)-pyridazinone or its pharmaceutically acceptable salt, as defined under item 1.

Priority p. 1 and p. 3,

where R1, R2and R3have the meanings given in paragraph 1, Y1is is made WITH a1-5-alkylenes chain, represents a carbonyl group or a methylene chain, and R4and R5are shown for a) or b) when R4and R5taken together with the adjacent nitrogen atom, form a specified 4-substituted pieperazinove ring, R6is1-4alkyl group which may be substituted by phenyl group which may be substituted by Y3where Y3is a halogen atom; or pyridium or their pharmaceutically acceptable additive salts of acid - 29.06.93.

where R1, R2, R3X, Y1and Y2have the meanings given in paragraph 1, And is a1-5alkylenes chain which may be substituted by a hydroxyl group, A represents a carbonyl group or a methylene chain which may be substituted WITH1-4alkyl group, and R4and R5are shown for a) or b) when R4and R5taken together with the adjacent nitrogen atom, form a specified 4-substituted pieperazinove ring, R6is1-4alkyl group, this alkyl group may be substituted by phenyl group which may be substituted by Y3where Y3is at the sludge or a group of the formula

< / BR>
where R9is1-4alkyl group or a benzyl group which may be substituted by a halogen atom, or R4and R5together with the adjacent nitrogen atom form the above 4-substituted piperidine ring, or its pharmaceutically acceptable salt additive acid - 26.05.94.

 

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